Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drugeluting stents. N Engl J Med 2014;371: DOI: /NEJMoa

2 This supplement contains the following items: 1. Original protocol*, final protocol, summary of changes. 2. Original statistical analysis plan, final statistical analysis plan, summary of changes *Version 4.0 is the original protocol under which patients were first enrolled.

3 The DAPT Study A prospective, multi-center, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy (DAPT) in subjects undergoing percutaneous coronary intervention (PCI) with either drug-eluting stent (DES) or bare metal stent (BMS) placement for the treatment of coronary artery lesions. A POST MARKETING STUDY STUDY IDE # G Clinical Study Protocol CONFIDENTIAL June 29, 2009 Version 4.0 STUDY SPONSOR: Harvard Clinical Research Institute (HCRI) 930 Commonwealth Avenue, 3rd Floor Boston, MA USA Prepared by HCRI This protocol contains confidential information for use by the site principal investigators and their designated representatives participating in this clinical investigation. It should be held confidential and maintained in a secure location. It should not be copied or made available for review by any unauthorized person or firm.

4 DAPT Study Protocol APPROVAL SIGNATURES HCRI Signatures Name Signature Title/Department Date Chief Scientific Officer, Laura Mauri, MD, MSc Harvard Clinical Research Institute (HCRI) 6/29/2009 Joseph Massaro, PhD Senior Consulting Biostatistician, Harvard Clinical Research Institute (HCRI) 6/29/2009 June 29, 2009 Page 2 of 108 Version 4.0

5 DOCUMENT HISTORY Revision Author Date Changes Reason for Changes reviewed/revised Version 1.0 M. Claffey September 05, 2008 New Document N/A Version 1.1 M. Claffey October 4, 2008 Design modifications FDA and Manufacturer suggested changes from pre-ide meeting held September 9, Version 1.2 M. Claffey October 10, 2008 Design modifications Version 1.3 M. Claffey October 15, 2008 Minor language clarifications Version 2.0 M. Claffey February 18, 2009 Multiple; primarily relating to discrepancies and clarifications as well as inclusion of additional statistical analyses Version 3.0 M. Claffey May 8, 2009 Minor edits and Modifications per comments received by FDA as well as through other meeting/ conversations. Version 4.0 M. Claffey June 29, 2009 Minor edits and Modifications per comments received by FDA as well as through other meeting/ conversations. Manufacturer suggested changes from meeting held October 6, Recommended changes in advance of IDE submission. As per FDA requested modifications outlined, in part, in the November 2008 Conditional Approval letter. Modifications per comments received by FDA in the March 2009 Conditional Approval letter and other discussions Modifications per comments received by FDA in the June 2009 Conditional Approval letter and other discussions June 29, 2009 Page 3 of 108 Version 4.0

6 DAPT Study - Protocol Signature Page Site s name: Investigator s Responsibility Prior to enrolling subjects in the DAPT Study, the site Principal Investigator must obtain written approval from his/her Institutional Review Board (IRB) or Ethics Committee (EC). This approval must be in the site Principal Investigator s name and a copy sent to the HCRI, among other essential documents, along with the IRB/EC approved Informed Consent and the signed Clinical Trial Agreement. Additionally, the site Principal Investigator must sign the declaration below: I have read this protocol and agree to adhere to the requirements. I will provide copies of this protocol and all pertinent information to all site personnel involved in this study. I will discuss this material with them and ensure they are fully informed regarding the study products and the conduct of the study. Principal Investigator s Signature Date: Principal Investigator s Printed Name Site Name Site # June 29, 2009 Page 4 of 108 Version 4.0

7 Protocol Summary Title A prospective, multi-center, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy (DAPT) in subjects undergoing percutaneous coronary intervention (PCI) with either drug-eluting stent (DES) or bare metal stent (BMS) placement for the treatment of coronary artery lesions. The DAPT Study Study Number IDE # G Sponsor Harvard Clinical Research Institute (HCRI) 930 Commonwealth Avenue, 3rd Floor Boston, MA 02215, USA Chief Scientific Officer: Laura Mauri, MD, MSc Executive Director, Clinical Investigations: Donald Cutlip, MD In collaboration with: Abbott Vascular Boston Scientific Corporation Bristol-Myers Squibb/Sanofi-Aventis Cordis Corporation Eli Lilly/Daiichi Sankyo Medtronic Vascular, Inc. Study Drugs FDA-approved thienopyridines Clopidogrel Prasugrel (pending FDA approval) Study Devices FDA-approved DES (range of stent diameters 2.25 mm mm as approved and available). CYPHER Endeavor TAXUS (Express or Liberté) XIENCE/PROMUS FDA-approved BMS (range of stent diameters 2.25 mm mm as available). June 29, 2009 Page 5 of 108 Version 4.0

8 Primary Hypotheses There are two primary hypotheses to be tested in this study. Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with DAPT for an additional 18 months (total 30 months) will have increased survival free from death, myocardial infarction or stroke compared with subjects treated with only 12 total months of DAPT over the month post-stenting period. Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with DAPT for an additional 18 months (total 30 months) will have increased survival free from ARC definite/probable stent thrombosis (ST) compared with subjects treated with only 12 total months of DAPT over the month post-stenting period. The study will be considered a success for 30m DAPT arm in DES subjects if at least one of these two primary hypotheses is statistically proven using the Hochberg approach at an overall familywise error (FWE) rate of 0.05 (i.e., if each hypothesis is proven at the two-sided 0.05 level of significance, the study is considered a success for 30m DAPT arm in DES subjects; otherwise, if one objective is proven at the two-sided level of significance, then the study is considered a success for 30m DAPT arm in DES subjects). The primary safety hypothesis for this study is: Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with DAPT for an additional 18 months (total 30 months) will have major bleeding rates non-inferior to the rates of subjects treated with only 12 total months of DAPT over the month post-stenting period. Secondary Hypotheses The main secondary study hypotheses are: DAPT subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, will have a rate of death, myocardial infarction or stroke that is non-inferior compared with the rate of propensity score matched subjects treated with bare-metal stents over the month post-stenting period. DAPT subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, will have a rate of ARC definite/probable stent thrombosis (ST) that is non-inferior compared with the rate of propensity score matched subjects treated with bare-metal stents over the month post-stenting period. Study Design Subjects may be enrolled into the study either before or after the index procedure, PCI with stent placement. Enrollment of qualified subjects can occur up to 24 hours after index procedure. June 29, 2009 Page 6 of 108 Version 4.0

9 All enrolled subjects will be treated with either a drug eluting stent(s) (DES) or a bare metal stent(s) (BMS) (per their respective Instructions for Use) and assigned to 12 months of open label thienopyridine treatment in addition to aspirin. Study Design (Continued) Thienopyridine treatment dose will be according to the standard of practice for the selected medication. Aspirin treatment will be mg for the first 6 months after the procedure and mg subsequently, to be continued indefinitely. Subjects who are treated with 12 months of DAPT post index procedure and who are event free (from all death, myocardial infarction, stroke, repeat coronary revascularization, stent thrombosis, and major bleeding severe or moderate by GUSTO classification) during that time will be considered 12 Month Clear. Staged PCI is allowed (same stent type as index); repeat PCI and peri-procedural myocardial infarction occurring with the index procedure or repeat procedure within the first 6 weeks will not be considered exclusionary events for the definition of 12 Month Clear. All subjects treated with DES or BMS who are considered 12 Month Clear are eligible for randomization to either placebo (12 m DAPT arm) or an additional 18 months of thienopyridine treatment (30 m DAPT arm). Both arms will continue aspirin therapy. Randomization for subjects will be performed at 12 months post procedure in eligible subjects and will be stratified according to DES/BMS, hospital site, subject complexity and thienopyridine drug type. Eligible subjects will be randomized 1:1 to receive placebo or thienopyridine treatment for an additional 18 months. Subjects will be followed for an additional 3 months of observational follow-up at the end of the 18 month randomized treatment phase. Study Population Study subjects with ischemic heart disease due to stenotic lesions in either native coronary arteries or coronary artery bypass grafts undergoing PCI with stent placement and no contraindications to prolonged DAPT are eligible to be enrolled in this study. Subjects may have multi-vessel treatment. For the purposes of stratification, subjects are considered complex if they have either acute coronary syndrome (ACS), renal insufficiency or failure, ejection fraction <30%, greater than two vessels stented, in-stent restenosis of a DES, prior brachytherapy, or anatomically complex lesion treatment at the time of the procedure. ACS is defined as ischemic symptoms occurring at rest and lasting 10 minutes or more and occurring within 72 hours before index procedure and either ST-segment deviation of 1 mm or more or elevated levels of a cardiac biomarker of necrosis (CK- MB or troponin T or I greater than the upper limit of normal (ULN). If CK-MB or troponin is not available, total CK >2 times ULN). Subjects with STEMI can be enrolled at any time, and will be classified as ACS and therefore complex, within 14 days after onset of symptoms. Renal insufficiency is defined by Creatinine 2.0 mg/dl and renal failure is defined as being dialysis dependent. The lesion is to be considered anatomically complex if it involves: Unprotected left main >2 lesions per vessel June 29, 2009 Page 7 of 108 Version 4.0

10 Lesion length 30 mm Bifurcation lesion with sidebranch 2.5 mm Vein bypass graft (segment or anastomosis) Thrombus-containing lesion Subjects that do not meet the criteria for complex will be considered non-complex for the purposes of stratification of randomization and analysis. Study Population (Continued) Subjects who receive both DES and BMS during the index procedure will not be eligible for enrollment. The minimum percentage of subjects treated with each type of DES (CYPHER, Endeavor, TAXUS (Express or Liberté), and XIENCE/PROMUS) will be 15% as determined by placement of at least one DES during the index procedure. For each DES stent type a minimum of 20% of subjects are expected to be treated with a given thienopyridine drug. The number of subjects treated with each brand of study drug (clopidogrel or prasugrel pending approval) will be capped at 60%, as determined at the time of randomization. The proportion of subjects with at least one DES type and with each thienopyridine type (in total and per stent type) will be tallied during the enrollment period as well at the time of randomization to determine whether the minimum or maximum parameters described above will be met. These caps and minimums will be monitored by a study enrollment monitoring committee. Number of Centers and Subjects 20,645 subjects will be enrolled at up to 219 US and ex-us clinical study sites. Approximately 60% of sites will be in the U.S. and Canada. Enrollment in the study will be limited to 1,000 subjects at any single site. 15,245 subjects will receive PCI with DES and 5,400 will receive PCI with BMS. DES subjects enrolled in separate manufacturer-run PMS and/or COA studies will be included as part of the DES-treated analysis population. Only studies not randomizing to stent type and that are pre-specified and listed to the FDA will be eligible to contribute data. Subjects will be contributed in two ways. Either all of the subjects data will be contributed after 33 months of follow-up from their index procedure as a part of the various post-marketing studies and/or condition of approval studies or relevant baseline data and eligibility data to 12 months will be contributed and subjects will be dually enrolled at 12 months post-procedure for the purposes of randomization and completion of follow-up according to the DAPT protocol. The maximum proportion of patient data that will be transferred as cleaned data from completely separate studies meeting the above requirements will be 50% of analyzed drug-eluting stent subject data (approximately 6098 subjects). The maximum number of subjects who will be enrolled and randomized in the DAPT study at 12 months after initially entering a separate manufacturer-run PMS and/or COA study will be The total numbers of contributed patients, and their poolability with patients who are enrolled and randomized in the DAPT study will be assessed at regular intervals by an independent monitoring committee in order to confirm adequate enrollment of patients from the DAPT study. Trial Endpoints Co-Primary Endpoints: Incidence of composite of all death, myocardial infarction (MI) and stroke June 29, 2009 Page 8 of 108 Version 4.0

11 (defined as MACCE) months post-stent. Incidence of ARC definite or probable stent thrombosis (ST) months poststent. Primary Safety Endpoint: Major bleeding (GUSTO classification, severe and moderate bleeding combined) months post-stent. Statistical Considerations Statistical Considerations (Continued) Survival free of MACCE during the month post-procedure period will be compared between subjects randomized to the 30m DAPT DES treatment arm versus those randomized to the 12m DAPT DES arm using the stratified log-rank test (baseline strata will consist of the hospital site, subject complexity and thienopyridine drug type strata used in randomization). The analysis will be performed on all randomized DES subjects according to the principle of intention to treat. Primary Time period Population Hypothesis test Endpoint MACCE 12-33m DES Randomized - ITT Superiority (12-30m on randomized treatment) 30m vs. 12 m Survival free from stent thrombosis (ST) will be compared between the 30m DAPT DES arm and the 12m DAPT DES arm using the stratified log-rank test, adjusted for the same factors as the MACCE analysis. This analysis will be performed on all randomized DES subjects according to the principle of intention to treat. Primary Time period Population Hypothesis test Endpoint ST 12-33m DES Randomized - ITT Superiority (12-30m on randomized treatment) 30m vs. 12 m Assuming that the time to each endpoint follows an exponential distribution, with i. Incidence of MACCE =2.9% and incidence of ST=0.5% for 12m-DAPT annually for the 21 months following randomization during which randomized treatment is taken (i.e., for m following randomization). ii. Incidence of MACCE =2.175% and incidence of ST=0.225% for 30m- DAPT annually for the first 18 months following randomization during which randomized treatment is taken (12-30 month post-procedure period); iii. After randomized treatment stops at 30 months post-randomization, 30m- DAPT incidence rate increases to that of 12m-DAPT. The hazard ratio (30m DAPT to 12m DAPT) under these assumptions is 0.75 for MACCE and 0.45 for ST across the 12m 30m period and 1.0 for both endpoints across the 30-33m period. Further, if a. Randomization is 1:1 into the 12m and 30m arms (randomization occurs at 12m post-procedure time point); b. Annual lost to follow-up rate of 3% after randomization; June 29, 2009 Page 9 of 108 Version 4.0

12 c. Familywise (FWE) error rate is controlled at the 0.05 level using the Hochberg approach (reject both null hypotheses if both are significant at the 0.05 level; otherwise, if one null hypothesis is significant at the level, then that null hypothesis is rejected); then 12,196 DES subjects randomized at 12 months post-procedure will yield at least 80% power that the study has statistically met its objective under the above assumptions of treatment effect in both outcomes (power ranges from approximately 80% to 90% depending on correlation of outcomes). Thus, the number to be enrolled at time of stent implantation is approximately 12,196/.8 or 15,245 assuming 20% of enrolled subjects will not be 12 Month Clear". The study will be considered a success for 30m DAPT arm in DES subjects if at least one of these two primary hypotheses is statistically proven using the Hochberg approach at an overall familywise error (FWE) rate of If the null hypothesis is not rejected, the 95% confidence intervals of the difference between DAPT duration treatment groups will be calculated. Powered Secondary Analyses Statistical Considerations (Continued) With respect to the main secondary analysis of MACCE compared between subjects treated with DES and subjects treated with BMS, the null (H o ) and alternative (H a ) hypotheses are: H o : A C + H a : A < C + where A is the true MACCE rate for the DES group and C is the true MACCE rate for the control arm (BMS subjects) over the months post-index procedure period, and is the non-inferiority margin. With a sample size of 12,196 DES and 4,320 BMS subjects and a non-inferiority test at an = (1-sided) significance, the power is 84% to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with MACCE in the DES arm compared to the BMS arm, when the MACCE rate of the control arm across the entire month post-procedure period is 4.5%, a non-inferiority margin of 1.09%, 3% annual loss to follow-up and 1:1 randomization to DAPT in each group. Power Analysis and Sample Size (PASS) was used to compute the power. Rejection of the null hypothesis will signify that the DES arm is non-inferior to the BMS arm with respect to MACCE between 12 and 33 months post-index procedure. With respect to the main secondary analysis of stent thrombosis compared between subjects treated with DES and subjects treated with BMS, the null (H o ) and alternative (H a ) hypotheses are: H o : A C + H a : A < C + where A is the true ST rate for the DES group and C is the true ST rate for the control arm (BMS subjects) over the months post-index procedure period, and June 29, 2009 Page 10 of 108 Version 4.0

13 is the non-inferiority margin. With a sample size of 12,196 DES and 4,320 BMS subjects and a non-inferiority test at an = (1-sided) significance, the power is 80% to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with ST in the DES arm compared to the BMS arm, when the ST rate of the control arm is 0.67% across the month post-procedure period, a non-inferiority margin of 0.39%, 3% annual loss to follow-up and 1:1 randomization to DAPT in each group. Power Analysis and Sample Size (PASS) was used to compute the power. Rejection of the null hypothesis will signify that the DES arm is non-inferior to the BMS arm with respect to ST between 12 and 33 months post-index procedure. With respect to the primary safety endpoint major bleeding compared between DES subjects in the 30 m DAPT group and DES subjects in the 12 m DAPT group, the null (H o ) and alternative (H a ) hypotheses are: H o : A C + H a : A < C + Statistical Considerations (Continued) where A is the true major bleed rate for the 30 m DAPT group and C is the true major bleed rate for the control arm (12 m DAPT) over the months post-index procedure period, and is the non-inferiority margin. With a sample size of 12,196 randomized subjects and a non-inferiority test at an = (1-sided) significance, the power is 82% power to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with major bleed in the 30 m DAPT arm compared to 12 m DAPT arm, when the major bleed rate of the 30 m DAPT group between 12 and 30 months post index procedure is 2.22% and that of the 12 m DAPT group is 2.22% over the same time period, a non-inferiority margin of 0.8%, 3% loss to follow-up and 1:1 randomization. Power Analysis and Sample Size (PASS) was used to compute the power, assuming the Farrington-Manning test. Rejection of the null hypothesis will signify that the 30 m DAPT arm is non-inferior to the control arm (12 m DAPT) with respect to major bleed rate between 12 and 33 months post-index procedure. The statistical analysis plan summarizes the additional endpoints and hypothesis tests that will be performed for this study. Follow-up Assessments Day 0 / procedure (clinical) 6 mo (± 14 days) (telephone) 1 yr (minus 30 days) (clinical) 15 mo (± 30 days) (telephone) 24 mo (± 30 days) (telephone) 30 mo (± 30 days) (clinical) 33 mo (± 30 days) (telephone) June 29, 2009 Page 11 of 108 Version 4.0

14 Estimated Study Timelines Data Collection Clinical Event Committee Projected Study Timelines Principal Study Investigator: Estimated date of EC/IRB approval(s): July 15, 2009 Estimated date of the beginning of the subject accrual: September 4, 2009 Estimated proportion of subject enrolled during specific time: Anticipated Enrollment at 3 months: 303 subjects Anticipated Enrollment at 9 months: 10,531 subjects Anticipated Enrollment at 12 months: 15,331 subjects Anticipated Enrollment at 17 months: 20,645 subjects Estimated study completion date: October 2013 (33 mo follow-up completion) Estimated date for the final report submission: January 2014 Data will be collected via electronic case report forms from the index procedure through end of follow-up. Baseline demographic and procedural information will be captured as well as medication compliance, major events and SAEs. All endpoint events occurring after the first 12 months for subjects will be adjudicated by an independent Clinical Events Committee (CEC). The study duration is expected to be 4 years. 17 months of subject enrollment 33 months of study follow-up Laura Mauri, MD, MSc Division of Cardiovascular Medicine, Department of Medicine Brigham and Women s Hospital Co-Principal Investigator: 75 Francis Street Boston, MA Dean Kereiakes, MD, FACC Carl and Edyth Lindner Center for Research and Education Christ Hospital Heart and Vascular Center 2123 Auburn Ave Ste 424 Executive Operations Committee: Data Monitoring Committee Study Monitoring: Cincinnati, OH TBD TBD Within the United States: Harvard Clinical Research Institute (HCRI) 930 Commonwealth Avenue, 3rd Floor Boston, MA 02215, USA Associate Director, Site Management: Ann Marie Mercando, RN, MHA Telephone: , Fax: , June 29, 2009 Page 12 of 108 Version 4.0

15 Outside the United States: Quintiles Quintiles GmbH, Hugenottenallee 167 D Neu-Isenburg Germany Project Manager: Barbara Puettner Telephone: , Fax: , Study Management, Data Management, Data Analysis and CEC Coordination: Harvard Clinical Research Institute (HCRI) 930 Commonwealth Avenue, 3rd Floor Boston, MA 02215, USA Chief Scientific Officer: Laura Mauri, MD, MSc Executive Director, Clinical Investigations: Donald Cutlip, MD Senior Consulting Biostatistician: Joseph Massaro, PhD Senior Director of Biostatistics, Data Management and Trial Design: Theodora Cohen, PhD Global Project Manager: Suzanne Morin Telephone: , Fax: , Safety Processing: Within the United States: Harvard Clinical Research Institute (HCRI) 930 Commonwealth Avenue, 3rd Floor Boston, MA 02215, USA Senior Medical Director, Medical Affairs: Theresa Palabrica, MD Telephone: , Fax: , Outside the United States: Quintiles Post Office Box Research Triangle Park, North Carolina 27709, USA Project Contact: Brian Williams Telephone: (919) , Fax: (919) June 29, 2009 Page 13 of 108 Version 4.0

16 Regulatory Advisor: CardioMed Device Consultants, LLC 1327 Bluegrass Way Gambrills, MD President: H. Semih Oktay, PhD Telephone: , Fax: , clinicaltrials.gov database The DAPT Study will be registered in the clinicaltrials.gov database, and any required additional state or country specific databases. June 29, 2009 Page 14 of 108 Version 4.0

17 Table of Contents DOCUMENT HISTORY... 3 DAPT STUDY - PROTOCOL SIGNATURE PAGE... 4 PROTOCOL SUMMARY BACKGROUND Introduction Study Device Descriptions Device Description Medtronic Endeavor Stent Device Description Cordis CYPHER Stent Device Description Boston Scientific TAXUS Express Stent Device Description Boston Scientific TAXUS Liberté Stent Device Description Abbott XIENCE/Boston Scientific PROMUS Stent Device Description FDA-approved BMS Study Drug Descriptions Drug Description Clopidogrel Drug Description Prasugrel Study Rationale Selection of Doses Duration of the Investigation Compliance Statement...22 STUDY DESIGN AND POPULATION Study Design Subject Populations Number of Centers and Subjects PMS/COA (Post Market Surveillance / Condition of Approval ) Subjects Study Flow Diagram Determination of Subject Eligibility Enrollment Inclusion Criteria Enrollment Exclusion Criteria Randomization Inclusion Criterion at 12 months Randomization Exclusion Criteria at 12 months Subject Complexity Definitions Early Withdrawal and Discontinuation TRIAL TREATMENTS Treatment Assignment Drug Supplies and Administration Preparation and Dispensing Drug Storage and Drug Accountability Compliance Procedures for Interruption of Therapy Concomitant Medication(s) Medication(s) Not Permitted Before and/or During the Trial...36 STUDY OBJECTIVES Co-Primary Endpoints Primary Safety Endpoint Secondary Endpoints and Analyses...37 PROCEDURES AND ASSESSMENTS Pre-Procedure Stenting Procedure...39 June 29, 2009 Page 15 of 108 Version 4.0

18 5.3 Enrollment Clinical and Laboratory Procedures Angiography Follow-up Assessments Schedule of Events Description of Randomization and Blinding Procedures STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN Study Populations Definitions Analysis Populations Primary Hypotheses Co-Primary Endpoints Sample Size Considerations Primary Analyses Secondary Analyses of the Primary Endpoints Primary Safety Endpoint Powered Secondary Endpoints BMS vs. DES Comparisons Additional Endpoint Analyses Analysis of rebound effect Sensitivity Analysis of Non-compliance with Randomized Treatment (12 to 30 Months) Additional Subset Analysis Additional Analyses Missing Data Handling Multiple Center Effect Statistical Methods BENEFITS AND RISKS ASSOCIATED WITH STUDY DRUG/DEVICES Risks Possible Benefits...67 SAFETY AND ADVERSE EVENT REPORTING Serious Adverse Events Causality of Serious Adverse Event to Study Product(s) Intensity of Serious Adverse Event Unanticipated Adverse Device Effects (Device UADE) Life-Threatening Adverse Drug Experience (LTADE) Unexpected Adverse Drug Experience (Drug UADE) Reporting Requirements Device Failures and Malfunctions DEFINITIONS DATA SUBMISSION REQUIREMENTS Required Data Data Collection Data Collection and Tracking Endpoint Reporting Investigator Records Sponsor Records STUDY RESPONSIBILITIES AND QUALITY ASSURANCE Investigator Responsibility for Study Conduct Study Data Reporting and Processing Training Confidentiality and Protection of Study Files Source Documentation Requirements...94 June 29, 2009 Page 16 of 108 Version 4.0

19 11.4 Procedures for Database Management Protocol Deviations Data Transmittal and Record Retention Monitoring Procedures Study Suspension or Study Early Termination STUDY COMMITTEES Executive Operations Committee Steering Committee Data Safety Monitoring Board (DSMB) Clinical Events Committee (CEC) Study Enrollment Monitoring Committee Publication Policies ETHICAL AND REGULATORY CONSIDERATIONS Role of the Study Sponsor General Duties Subject Confidentiality Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Supplemental Applications Maintaining Records Submitting Reports Site Record Retention Policy Informed Consent REFERENCES June 29, 2009 Page 17 of 108 Version 4.0

20 1 Background 1.1 Introduction Despite the dramatic early efficacy of drug-eluting stents (DES) in reducing restenosis compared with bare metal stents (BMS) 1, 2, there is concern that DES might lead to higher rates of stent thrombosis - particularly beyond the first year after implantation 3. Stent thrombosis is a devastating outcome usually associated with ST segment elevation myocardial infarction and high mortality 4-7. The incremental risk of late stent thrombosis in DES vs. BMS is not known with certainty; randomized trials to date have been limited in their power to detect rare and late events 8, and observational studies have been limited by selection and ascertainment bias 9. Even large metaanalyses of broader randomized trial data have yet to resolve this uncertainty and suggest that DES might be associated with a 2-4 fold increased risk of very late thrombotic events 10. There is evidence to suggest that the risk of late and very late stent thrombosis may be modified by long term dual antiplatelet therapy. Clopidogrel in addition to aspirin for 12 months has been shown to be of benefit in the setting of acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI) These studies were largely performed using bare metal stents. The reduction in late myocardial infarction (MI) or death rate was largely driven by benefits in MI risk reduction at 30 days. Moreover, stent thrombosis rates were not reported in these studies. Nevertheless, these studies prompted the guidelines to recommend 12 months of antiplatelet therapy for patients with ACS. In an observational study using landmark analysis of a subset of 4666 patients treated with BMS or DES who were event-free at 6 or 12 months and followed for 2 years, extended use of clopidogrel (both >6 and 12 months; self-reported) in patients receiving DES was associated with a reduced risk of death and composite of death or MI, however, there was no such benefit in those who received BMS 15. The results from the PREMIER registry suggest that premature discontinuation of thienopyridine therapy is not uncommon with 13.6% of 500 MI patients who received DES having stopped before 30 days 16. In this study, premature cessation of thienopyridine was associated with significant increase in mortality at 1 year. More recent studies have examined the effect of prasugrel, a new thienopyridine inhibitor, after stent placement in the setting of ACS 17, 18. For DES, premature cessation of antiplatelet therapy (< 3 months for sirolimus-eluting stent; < 6 months for paclitaxel-eluting stent) is suggested to be the most significant factor in the development of late and very late stent thrombosis and an increased risk of death and MI 5, 6, 9, 15, 16, 19. In light of the current data with probable benefit of combined clopidogrel and aspirin therapy over an extended period, a recent advisory committee commissioned by the American Heart Association has recommended the continuation of dual antiplatelet therapy (and deferring any elective surgical procedure) for at least 1 year following the stenting procedure with DES, in the absence of contraindications 20. However, the extent to which dual antiplatelet therapy confers benefit against ST is not known with certainty. The strongest evidence to maintain dual antiplatelet therapy for one year comes from large randomized trials of BMS in acute coronary syndrome 11, 12 but no randomized data exist to evaluate extension of dual antiplatelet therapy beyond 6 months in non- ACS patients receiving stents or ACS patients, post-stent, beyond 1 year. Late stent thromboses have been noted with both BMS and DES in the presence of dual antiplatelet therapy 8, and events June 29, 2009 Page 18 of 108 Version 4.0

21 continue to accrue beyond 2 years 8. Other than early discontinuation of therapy, other predictors of late ST have been described: low left ventricular ejection fraction, renal insufficiency, and complex coronary anatomy 5. Extending dual antiplatelet therapy beyond one year is not without risk, with increased rates of bleeding noted in recent major trials 12, 13, 18, 21. The incremental risk of bleeding needs to be weighed against the risk of late ST in an individual patient until definitive randomized trials can determine the optimal duration of therapy. It is also possible that the impact of extended dual antiplatelet therapy, as seen in large trials of patients with acute coronary syndromes, is predominantly mediated by prevention of myocardial infarction outside the stent territory, as the absolute risk of progression of other atherosclerotic disease following treatment is greater than the risk of stent thrombosis. Given the lack of randomized data, there is considerable uncertainty in the medical community about the optimal duration of dual-antiplatelet therapy following PCI. It is unclear as to whether the duration of dual antiplatelet therapy in patients receiving DES should be 3-6 months (as per the pivotal DES RCT), 12 months (as per the ACC/AHA guidelines), or longer in patients without contraindication. It is also unclear whether the presumed benefit of extended dual antiplatelet therapy is specific to DES or whether non-acs patients treated with BMS (e.g. stable angina) may also benefit from extended dual antiplatelet therapy. 1.2 Study Device Descriptions FDA-approved stents: DES and BMS Device Description Medtronic Endeavor Stent Device description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for the Endeavor Zotarolimus Eluting Coronary Stent System or next generation model (herein known as the Endeavor stent) can be found in the Instructions for Use, which are provided with the product Device Description Cordis CYPHER Stent Device description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for the CYPHER Sirolimus-eluting Coronary Stent System or next generation model (herein known as the CYPHER stent) can be found in the Instructions for Use, which are provided with the product Device Description Boston Scientific TAXUS Express Stent Device description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for the TAXUS Express 2 Paclitaxel-Eluting Coronary Stent System or next generation model (herein known as the TAXUS Express stent) can be found in the Instructions for Use, which are provided with the product. June 29, 2009 Page 19 of 108 Version 4.0

22 1.2.4 Device Description Boston Scientific TAXUS Liberté Stent Device description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for the TAXUS Liberté Paclitaxel-Eluting Coronary Stent System or next generation model (herein known as the TAXUS Liberté stent) can be found in the Instructions for Use, which are provided with the product Device Description Abbott XIENCE/Boston Scientific PROMUS Stent Device description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for the XIENCE V Everolimus Eluting Coronary Stent System or PROMUS Everolimus-Eluting Coronary Stent System or next generation model (herein known as the XIENCE stent) can be found in the Instructions for Use, which are provided with the product Device Description FDA-approved BMS (range of stent diameters matching the range of stent diameters of all FDA-approved DES above, 2.25 mm mm). Detailed device descriptions and other information for the various FDA-approved bare metal stents can be found in the Instructions for Use, which are provided with the individual products. 1.3 Study Drug Descriptions FDA-approved thienopyridines Drug Description Clopidogrel Drug description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for clopidogrel bisulfate (herein known as clopidogrel) can be found in the Package Insert, which are provided with the product Drug Description Prasugrel (pending FDA approval) Drug description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for prasugrel can be found in the Package Insert, which are provided with the product. June 29, 2009 Page 20 of 108 Version 4.0

23 Enrollment Begins 12 months 16 months 28 months 36 months 49 months 1.4 Study Rationale The aim of this study is to conduct a multicenter, international, randomized trial to help the global medical community to better understand the optimal duration of dual antiplatelet therapy in subjects without contraindications following stenting procedure with DES. Current data suggest a probable benefit of combined thienopyridine and aspirin therapy over an extended period (at least 1 year) post DES implantation either by prevention of ST or by prevention of major adverse cerebral and cardiovascular events (MACCE) or both. It is uncertain whether the presumed benefit of extended dual antiplatelet therapy is specific to DES or if subjects treated with BMS may also benefit from extended dual antiplatelet therapy. The DAPT study has been developed to identify the optimal duration of dual antiplatelet therapy in subjects who undergo stenting procedures. 1.5 Selection of Doses Thienopyridine treatment dose will be according to the appropriate Package Insert for the selected medication. Aspirin treatment will be mg for the first 6 months after the procedure and mg subsequently, to be continued indefinitely. 1.6 Duration of the Investigation This study is expected to last approximately 50 months from the first subject being enrolled. Subject enrollment in the study will take place over approximately 17 months beginning in Q After an initial course of open label DAPT use, subjects who are 12 Month Clear will be randomized at 12 months and followed for an additional 21 months (18 months of randomized treatment plus 3 months of extended observation). Figure 1. DAPT Randomized Study Timeline Start Up First Subject Enrolled Last Subject Enrolled Treatment and Follow-up Period First 12 m DAPT Subject Randomized Last 12 m DAPT Subject Randomized June 29, 2009 Page 21 of 108 Version 4.0

24 1.7 Compliance Statement This trial is designed and planned to comply with the protocol, ICH E-6 Good Clinical Practices (GCP), the Declaration of Helsinki and the applicable local regulatory requirements. June 29, 2009 Page 22 of 108 Version 4.0

25 2 Study Design and Population 2.1 Study Design This study is designed as a prospective, multi-center, randomized, double-blind trial. Study enrollment will consist of subjects who in the opinion of the investigators are candidates for extended dual antiplatelet therapy (DAPT), treatment with either drug eluting stent(s) (DES) or a bare metal stent(s) (BMS), provide consent to participate in the study, and who receive at least one stent and dual antiplatelet therapy. Subjects with ischemic heart disease due to stenotic lesions in either native coronary arteries or coronary artery bypass grafts undergoing PCI with stent placement and no contraindications to prolonged DAPT are eligible to be enrolled in this study. Subjects may have multi-vessel treatment. Subjects may be enrolled into the study either before or after the index procedure of percutaneous coronary intervention (PCI) with stent placement. Enrollment of qualified subjects can occur up to 24 hours after index procedure. For the purposes of stratification, subjects are considered complex if they have either acute coronary syndrome (ACS), renal insufficiency or failure, ejection fraction <30%, greater than two vessels stented, in-stent restenosis of a DES, prior brachytherapy, or anatomically complex lesion treatment at the time of the procedure. ACS is defined as ischemic symptoms occurring at rest and lasting 10 minutes or more and occurring within 72 hours before index procedure and either ST-segment deviation of 1 mm or more or elevated levels of a cardiac biomarker of necrosis (CK-MB or troponin T or I greater than the upper limit of normal (ULN). If CK-MB or troponin is not available, total CK >2 times ULN). Subjects with STEMI can be enrolled at any time, and will be classified as ACS and therefore complex, within 14 days after onset of symptoms. Renal insufficiency is defined by Creatinine 2.0 mg/dl and renal failure is defined as being dialysis dependent. The lesion is to be considered anatomically complex if it involves: Unprotected left main >2 lesions per vessel Lesion length 30 mm Bifurcation lesion with sidebranch 2.5 mm Vein bypass graft (segment or anastomosis) Thrombus-containing lesion Subjects that do not meet the criteria for complex will be considered non-complex for the purposes of stratification of randomization and analysis. All enrolled subjects will be treated with either a drug eluting stent(s) (DES) or a bare metal stent(s) (BMS) (per their respective Instructions for Use) and assigned to 12 months of open label thienopyridine treatment in addition to aspirin. Thienopyridine treatment dose will be according to the standard of practice for the selected medication. Aspirin treatment will be mg for the first 6 months after the procedure and mg subsequently, to be continued indefinitely. June 29, 2009 Page 23 of 108 Version 4.0

26 Subjects who are treated with 12 months of DAPT post index procedure and who are event free (from all death, myocardial infarction, stroke, repeat coronary revascularization, stent thrombosis, and major bleeding severe or moderate by GUSTO classification) during that time will be considered 12 Month Clear. Staged PCI is allowed (same stent type as index); repeat PCI and peri-procedural myocardial infarction occurring with the index procedure or repeat procedure within the first 6 weeks will not be considered exclusionary events for the definition of 12 Month Clear. All enrolled subjects who are 12 Month Not Clear will be followed only until they are determined to be not clear. This may be at any time prior to 12 months post-procedure that they experience an event or are deemed non compliant to DAPT. All subjects treated with DES or BMS who are considered 12 Month Clear are eligible for randomization to either placebo (12 m DAPT arm) or an additional 18 months of thienopyridine treatment (30 m DAPT arm). Both arms will continue aspirin therapy. Randomization for subjects will be performed at 12 months post procedure in eligible subjects and will be stratified according to DES/BMS, hospital site, subject complexity and thienopyridine drug type. Eligible subjects will be randomized 1:1 to receive placebo or thienopyridine treatment for an additional 18 months. Subjects will be followed for an additional 3 months of observational followup at the end of the 18 month randomized treatment phase. 2.2 Subject Populations All Enrolled Subjects All subjects enrolled in the study. 12 Month Clear This population consists of subjects enrolled in the study who are free from death, MI, stroke, repeat coronary revascularization, major bleeding severe or moderate by GUSTO classification, and ST 12 months after stent implantation and who are compliant with 12 months of DAPT following stent implantation. 12 Month Not Clear This population consists of those subjects enrolled in the study who do not meet the requirements of 12 Month Clear. During the open label portion of this study (time 0-12m), a subject is considered compliant with the thienopyridine therapy for the purposes of eligibility if they take between 80% and 120% of the prescribed drug in a given period without an interruption of therapy longer than 14 days. This information will be ascertained via data collected at the subject interviews at 6 and 12 months postprocedure. Compliance at both time points is required to be considered clear. The primary analysis population used to test the study hypotheses will be complex and noncomplex subjects with DES randomized to either 12 or 30 months of DAPT. June 29, 2009 Page 24 of 108 Version 4.0

27 2.3 Number of Centers and Subjects 20,645 subjects will be enrolled at up to 219 US and ex-us clinical study sites. Approximately 60% of sites will be in the U.S. and Canada. Enrollment in the study will be limited to 1,000 subjects at any single site. 15,245 subjects will receive PCI with DES and 5,400 will receive PCI with BMS. Given the observational nature of the study, it is a possibility that some sites will exclusively use only one of the study thienopyridines or a limited selection of DES type. Subjects who receive both DES and BMS during the index procedure will not be eligible for enrollment. The minimum percentage of subjects treated with each type of DES (CYPHER, Endeavor, TAXUS Express or Liberté, and XIENCE/PROMUS) will be 15% as determined by placement of at least one DES during the index procedure. For each DES stent type a minimum of 20% of subjects are expected to be treated with a given thienopyridine drug. The number of subjects treated with each brand of study drug (clopidogrel or prasugrel) will be capped at 60%, as determined at the time of randomization. The proportion of subjects with at least one DES type and with each thienopyridine type (in total and per stent type) will be tallied during the enrollment period as well at the time of randomization to determine whether the minimum or maximum parameters described above will be met. These caps and minimums will be monitored by a study enrollment monitoring committee (Section 12.5) PMS/COA (Post Market Surveillance / Condition of Approval ) Subjects There are significant challenges to enrolling into the dual antiplatelet therapy (DAPT) study or into any randomized study of drug-eluting stents in the current clinical trials environment. In order to complete this study in a timeframe that would allow relevant information on patient care to inform current practice, and in response to a true clinical concern regarding the optimal duration of DAPT therapy, we anticipate that patient level data will be obtained from pre-specified non-randomized (to stent) studies whose primary objective is to assess FDAapproved stents (e.g. post market surveillance or condition of approval studies). This will decrease the total number of patients that would need to be enrolled in the DAPT study at the time of their index procedure. 1. DES subjects enrolled in separate manufacturer-run PMS and/or COA studies will be included as part of the DES-treated analysis population. Only studies not randomizing to stent type and that are pre-specified and listed to the FDA will be eligible to contribute data. In this protocol, it is assumed that uniform treatment and data collection processes will be performed within the original study protocol with relevant data transfer to HCRI for analysis. Such study data may be contributed either 1) at completion of follow-up within these external studies, in which case subjects would not be enrolled in the DAPT study, but data would be contributed after 33 months of follow-up, or 2) relevant baseline data and eligibility data to 12 months could be contributed and subjects could be enrolled June 29, 2009 Page 25 of 108 Version 4.0

28 under the DAPT protocol from 12 month for the purposes of randomization and completion of follow-up. Required data would be transferred to HCRI as clean SAS datasets to be merged with the DAPT database for statistical analysis. The following requirements have to be met by a study that is intended to provide patient level data for DAPT: 1. The determination of eligibility for enrollment and randomization is the same as in the DAPT study. 2. Data definitions are the same. 3. The same data are collected at the same time points. 4. Adjudication (or readjudication) of all endpoint events according to a central DAPT clinical events committee. 5. Contributed data are from consecutive patients meeting the specified requirements. The maximum proportion of patient data that will be transferred as cleaned data from completely separate studies meeting the above requirements will be 50% of analyzed drugeluting stent subject data (approximately 6098 subjects). The maximum number of subjects who will be enrolled and randomized in the DAPT study at 12 months after initially entering a separate manufacturer-run PMS and/or COA study will be The total numbers of contributed patients, and their poolability with patients who are enrolled and randomized in the DAPT study will be assessed at regular intervals by a study enrollment monitoring committee in order to confirm adequate enrollment of patients from the DAPT study. Data will be obtained from these studies at regular intervals so that clinical events adjudication under DAPT will occur throughout the duration of the study. The study will accept up to 6098 DES patients from four manufacturer companies contributed after completion of 33 months of follow-up from their index procedure as a part of the various post-marketing studies and/or condition of approval studies. The study will also accept DES patients from the manufacturer companies where relevant baseline and eligibility data to 12 months from the post-marketing study will be collected and then the subjects will be transferred at 12 months post-procedure to the DAPT study for the purposes of randomization and completion of follow-up per the DAPT protocol. A total of up to 2439 DES patients will be accepted via this approach. June 29, 2009 Page 26 of 108 Version 4.0

29 2.4 Study Flow Diagram Figure 2. DAPT Study Flow Chart Index Procedure - Enrollment Randomization (All Eligible Subjects) 0 mo 6 mo 12 mo 15 mo End of Treatment 30 mo End of Follow Up 33 mo 3% LTF annually 12 m DAPT arm obs DES n = 15,245 BMS n = 5,400 20% ineligible R Open label DAPT DES n=12,196 BMS n=4,320 PCI 3% LTF annually 30 m DAPT arm obs R = Randomization. Randomization will only occur for those eligible subjects who are 12 Month Clear. 12 Month Not Clear subjects will be followed only to the time when they are determined to not be clear. LTF = Lost to follow-up. 2.5 Determination of Subject Eligibility All subjects presenting to the cardiac catheterization laboratory for possible interventional treatment are potential candidates. The following eligibility criteria are designed to select subjects for whom protocol treatment is considered appropriate. All relevant medical and non-medical conditions should be taken into consideration when deciding whether this protocol is suitable for a particular subject. Whenever the investigator is prepared to treat the subject in his/her best interest with a drug eluting stent or a bare metal stent and DAPT in accordance with the applicable guidelines on percutaneous coronary interventions the subject should be considered for inclusion in this study. The study specific inclusion and exclusion criteria are: 2.6 Enrollment Inclusion Criteria Subject must meet all of the following criteria to be eligible for treatment in the study: 1. Subject is > 18 years of age. 2. Subjects undergoing percutaneous intervention with stent deployment (or has w/in 24 hours). June 29, 2009 Page 27 of 108 Version 4.0

30 3. Subjects without known contraindication to dual antiplatelet therapy for at least 30 months after enrollment and stent implantation. 4. The subject has consented to participate and has authorized the collection and release of his medical information by signing the Patient Informed Consent Form. The informed consent will be valid for the duration of the trial or until the subject withdraws. 2.7 Enrollment Exclusion Criteria Subjects will be excluded from the study if any of the following criteria are met: 1. Index procedure stent placement with stent diameter <2.25 mm or >4.0 mm. 2. Pregnant women. 3. Planned surgery necessitating discontinuation of antiplatelet therapy within the 30 months following enrollment. 4. Current medical condition with a life expectancy of less than 3 years. 5. Concurrent enrollment in another device or drug study whose protocol specifically excludes concurrent enrollment or that involves blinded placement of a DES or BMS other than those included as DAPT study devices. The subject may only be enrolled in the DAPT Study once. 6. Subjects on warfarin or similar anticoagulant therapy. 7. Subjects with hypersensitivity or allergies to one of the drugs or components indicated in the Instructions for Use for the device implanted. 8. Subjects unable to give informed consent. 9. Subject treated with both DES and BMS during the index procedure. 2.8 Randomization Inclusion Criterion at 12 months Subject must meet the following criterion to be eligible for randomization in the study: 1. Subject is 12 Month Clear. 2.9 Randomization Exclusion Criteria at 12 months Subjects will be excluded from randomization if any of the following criteria are met: 1. Pregnant women. 2. Subject switched thienopyridine type within 6 months prior to randomization. NOTE: thienopyridine switching during the open label portion of this study is discouraged. 3. Percutaneous coronary intervention or cardiac surgery between 6 weeks post index procedure and randomization. 4. Planned surgery necessitating discontinuation of antiplatelet therapy within the 21 months following randomization. 5. Current medical condition with a life expectancy of less than 3 years. 6. Subjects on warfarin or similar anticoagulant therapy. June 29, 2009 Page 28 of 108 Version 4.0

31 2.10 Subject Complexity Definitions Subjects will be classified as complex or non-complex for the purpose of stratification of randomization and analysis. Subjects who are considered to be at a higher risk of late MACCE or ST are considered complex according to the following definitions. Complex Subjects: Subject will be classified as complex if they meet any of the following criteria: 1. >2 vessels stented 2. In-stent restenosis of a drug-eluting stent 3. Subject treated with prior brachytherapy 4. Treatment lesion is anatomically complex, as defined by: Unprotected left main >2 lesions per vessel Lesion length 30 mm Bifurcation lesion with sidebranch 2.5 mm Vein bypass graft (segment or anastomosis) Thrombus-containing lesion Or the following clinical co-morbidities: 1. ACS presentation at the time of the index procedure (see definition in Section 9) 2. Renal insufficiency (Creatinine 2.0 mg/dl) or failure (dialysis dependent) 3. Ejection fraction <30% Subjects that do not meet the criteria for complex will be considered non-complex Early Withdrawal and Discontinuation Subjects may withdraw consent to participate in the study at any time and for any reason. A missed follow-up will be documented by the investigator and reported in the ecrf. The stopping of data collection for subjects in the study will occur in the following cases: Withdrawal of consent by subject Subject lost-to-follow-up (as defined in the note in Section 5.4) Subject death Study prematurely discontinued June 29, 2009 Page 29 of 108 Version 4.0

32 3 Trial Treatments All subjects enrolled will receive dual antiplatelet therapy (DAPT) (12 or 30 months) and have a DES or a BMS placed. After 12 months of open label DAPT use, subjects who are 12 Month Clear are eligible for randomization. Subjects will be randomized 1:1 to one of two treatment groups. Subject randomization will be stratified based on the thienopyridine treatment they were taking at the time of randomization. The treatment groups are: 1) Continue thienopyridine treatment for an additional 18 months along with continued aspirin use (30 m DAPT Arm) 2) Placebo treatment for an additional 18 months along with continued aspirin use (12 m DAPT Arm) Subjects can be prescribed one (of potentially two) FDA-approved thienopyridine(s) at the time of enrollment into the study. Details on both (clopidogrel and prasugrel) can be found in their respective package inserts (PI). In order to minimize bleeding risk, aspirin treatment is recommended to be the lowest acceptable dose per physician s discretion ( mg for the first 6 months after the procedure and mg indefinitely thereafter) Treatment Assignment This is a double-blind, randomized, multi-center, international study comparing 12 and 30 months of DAPT treatment in subjects undergoing PCI with stent placement. After index procedure, all subjects will take a daily dose of open label active drug (clopidogrel or prasugrel, pending FDA approval) through 12 months post index procedure and then, if eligible and randomized, they will receive the same drug that they were taking at the time of randomization or corresponding placebo in a blinded fashion for daily administration through 30 months. Eligible subjects will be randomized to 18 months of active treatment or placebo 12 months after index procedure (Section 2.2). In order to randomize an eligible subject, study personnel will access an on-line IVRS system to obtain the randomization information for the subject. Randomized subjects will receive either active drug or placebo identical in appearance to the active drug. The treating physician, personnel at investigative sites, sponsor s clinical team, and Clinical Events Committee (CEC) will remain blinded to the treatment assigned. Randomization will be stratified by site, stent type, subject complexity at baseline and thienopyridine drug. Following randomization, subjects will be assigned blinded study medication (thienopyridine or placebo). All subjects will be recommended to take aspirin at the dose directed by the investigator. Subjects who are randomized to receive blinded active drug, will receive the same thienopyridine (clopidogrel or prasugrel, pending FDA approval) that they were taking at the time of randomization. All subjects should also receive a daily dose of aspirin mg administered concomitantly with study drug. June 29, 2009 Page 30 of 108 Version 4.0

33 Study personnel will dispense the double blind study medication after randomization according to a sequence number assigned by the IVRS system. Subsequent study medication will be distributed to subjects in the United States by mail every three months. OUS sites will utilize drug distribution methodologies that adhere to local regulations. Patients will adhere to a drug return process in accordance with local regulations. Subjects randomized to receive 12 months of thienopyridine will receive a daily dose of placebo for 18 months and continue with aspirin therapy. Use of open label thienopyridine will be at the discretion of the treating physician after month 33. Subjects randomized to receive 30 months of thienopyridine will receive a daily dose of active drug for 30 months and continue with aspirin therapy. Use of open label thienopyridine will be at the discretion of the treating physician after month 33. A subject s compliance with study medication will be collected along with information on medication interruption and reason for interruption through 30 months of follow-up. No antiplatelet medication (other than aspirin) should be administered between 30 and 33 months of the study ( rebound period ). After month 33, use of open label thienopyridine will be at the discretion of the treating physician. 3.2 Drug Supplies and Administration Upon meeting all entrance criteria for the study and signing the informed consent form, the subject will be given a prescription by the Investigator (Principal or Sub) for the selected thienopyridine for the open label portion of this trial (first 12 months). The Investigator or study staff will review the proper dosing of the thienopyridine and will instruct the subjects to take the indicated daily dosage at the same time each day prior to the subject leaving the hospital. DES subjects must fill their prescriptions via commercially available supplies during the open label portion of the trial. The study will provide BMS subjects open label drug for months 2-12 of the open label portion of the study. If randomized, a subject will be given a three month supply of the blinded study drug (active drug or placebo) at the 12 month visit. The Investigator or study staff will review the proper dosing of the assigned blinded study medication with the subject prior to the subject leaving the office. Clinical supplies for the randomized portion of this trial will be provided every three months to active study participants. The subject will be dispensed the blinded treatment that they were randomized to receive as per the protocol. Patients will adhere to a drug return process in accordance with local regulations. The subject will not receive additional drug supplies once they withdraw from the study or the study treatment period ends. Study Medication Regimen Open Label portion clopidogrel + aspirin OR prasugrel + aspirin June 29, 2009 Page 31 of 108 Version 4.0

34 Randomized portion 30 m DAPT Arm clopidogrel + aspirin OR prasugrel + aspirin 12 m DAPT Arm placebo for clopidogrel + aspirin OR placebo for prasugrel + aspirin Formulation and Packaging Open label clopidogrel and prasugrel will be commercially supplied. The active drug and matching placebo will be identical in packaging as well as appearance. Study Drug Chemical name: methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-acetate sulfate (1:1) Generic name: clopidogrel bisulfate Trade name: Plavix Dosage form: tablet Strength: 75 mg Manufacturer: Bristol-Myers Squibb/Sanofi-Aventis Description: TBD Placebo to match clopidogrel Dosage form: tablet Manufacturer: Bristol-Myers Squibb/Sanofi-Aventis Description: TBD, same as above Study Drug Chemical name: TBD Generic name: prasugrel Trade name: Effient Dosage form: tablet Strength: TBD June 29, 2009 Page 32 of 108 Version 4.0

35 Manufacturer: Eli Lilly/Daiichi Sankyo Description: TBD Placebo to match prasugrel Dosage form: tablet Manufacturer: Eli Lilly/Daiichi Sankyo Description: TBD, same as above 3.3 Preparation and Dispensing DES subjects must fill their prescriptions via commercially available supplies during the open label portion of the trial. BMS subjects are responsible for procuring study drug for the first 30 days of the open label portion of the study. The study will provide BMS subjects open label drug for months 2-12 of the open label portion of the study. After the subject is randomized, the assigned blinded study drug (active drug or placebo) will be distributed to the subject free of charge in a controlled manner as outlined in this protocol. Drug will be distributed to subjects by mail every three months in the US. OUS sites will utilize drug distribution methodologies that adhere to local regulations. The pharmaceutical manufacturer will provide the study medication to a depot for distribution to study investigators. The site investigator or designee must ensure that deliveries of study drugs from the manufacturers/representatives are correctly received by a responsible party, that all receipts are entered/recorded as received in the IVRS system, and that the products are stored in a secure area under recommended storage conditions. It is the responsibility of the site investigator or designee to ensure that the integrity of packaged study products not be jeopardized prior to dispensing. Each individual subject packet must be dispensed as provided by the manufacturer or designee with no further repackaging or labeling done at the site. The investigator, study staff, or vendor will administer/dispense the study medication only to subjects included in this study following the procedures set out in this study protocol. All dispensing will be documented in the ecrfs and study drug record. The investigator is responsible for assuring the retrieval of all study supplies from subjects. Returned materials will be used to assess subject compliance to the drug therapy after randomization for the blinded treatment portion of the study. 3.4 Drug Storage and Drug Accountability All full, partially full and empty drug supply containers must be returned to the HCRI-designated subcontracting vendor for assessment. The vendor must maintain accurate and adequate records including dates of receipt and return of drug shipments, and lot number and quantities received/returned from/to the distributor, as well as, dates and amounts dispensed to and returned by the study subjects. All drug supplies must be stored in accordance with the manufacturers instructions. Until dispensed to the subjects, the study medication will be stored in a securely locked area, only accessible to authorized personnel. June 29, 2009 Page 33 of 108 Version 4.0

36 3.5 Compliance There are two methods of assessing drug compliance in this DAPT study; one for the open label portion of the trial and one for subjects randomized. The compliance or adherence to thienopyridine use during the open label portion of the trial will be ascertained from the subject interview at the 6 and 12 month contacts. This information will be used to screen out not clear subjects prior to randomization. At each contact, the subject will be asked to estimate the percentage compliance for the previous 6 months. They will also be asked about any significant interruptions in the prescribed treatment in the past 6 months. Subjects will also be asked specifically about their compliance over the previous two weeks for further monitoring of drug compliance. After subject randomization and when the distribution of drug is controlled by the trial protocol, the procedure for assessing drug compliance will be by examining the amount of medication used and returned by the subject on a quarterly basis through month 30. Subjects will be required to return previously dispensed study drug supplies with the receipt of each new shipment. The number of unused doses will be recorded on the ecrf or drug accountability form. The total number of doses taken will be divided by the number of doses required for continuous treatment during the three month period. Compliance will be assessed separately for each 3 month period. Subject compliance with the study medication will be calculated for each pill packet using the following formula: Compliance = number of supplied doses of medication taken by subject number of doses of medication required for continuous treatment during period The numerator of the above formula will be obtained from counting the returned pill packets and remaining pills. The acceptable percentage of compliance will be 80% to 120%. Compliance will be checked following each distribution of the medication (quarterly following subject randomization). Any subject found to be taking <80% or >120% of the prescribed study drug will be considered non-compliant. Once randomized, subjects should not be discontinued from study drug for noncompliance; however, the investigator or designee will determine factors that result in poor compliance with the study drug and will take steps to improve compliance. In addition, at each contact after randomization, the subject will be asked via a subject interview about any significant interruptions (as defined in Section 3.6) in the prescribed treatment since their last contact as well as confirmation of their compliance over the previous two weeks for further monitoring of drug compliance. Information captured during this interview will be details regarding therapy interruption (Y/N), reason for interruption, date interruption commenced, date interruption concluded, and events experienced before, during or after interruption. Data will also be collected regarding the number and frequency of doses missed during the two weeks preceding the interview. Data regarding the subject s use of the study drug (type of drug, start date, stop date, any interruptions with reason, discontinuation with reason, and any subsequent receipt of open label drug after randomization including name, dose, dates, etc.) will be captured on the ecrf as necessary. June 29, 2009 Page 34 of 108 Version 4.0

37 3.6 Procedures for Interruption of Therapy An interruption of therapy is defined as a period of time when the subject is not taking the prescribed therapy. A significant interruption of therapy is defined as when a subject is not taking the prescribed therapy for longer than 14 consecutive days. The procedure for determining any significant interruptions of therapy will be the acquisition of data resulting from subject interviews at the protocol-established contacts. Assessments may take place in person or via a phone conversation. As outlined above, information captured during this interview will be details regarding any significant therapy interruption, including reason and dates of the interruption. Significant interruptions of therapy during the first 12 months (open label) of the study will preclude the subject from participating in the randomized part of the trial. In the event that a subject temporarily discontinues drug therapy (for fewer than 14 days) not directly resulting from physician guidance, it is recommended that the subject consult with their physician and attempt to resume their prescribed therapy. This occurrence (including reason for temporarily discontinuing therapy as well as date of stopping and resuming therapy) should be documented on the ecrf, if possible. In case of severe allergy or intolerance to study drug, study participation for that subject will be discontinued and the subject will be managed at the discretion of the treating physician. If this occurs after the subject is randomized, then these subjects will continue to be followed for the duration of the study. Subjects who experience myocardial infarction (MI), stroke, PCI with stent placement, have cardiac surgery, stent thrombosis, and/or bleeding complication ( severe or moderate by GUSTO classification) prior to the 12-month randomization will not continue to participate in the study and may either continue or discontinue open label thienopyridine at the discretion of the treating physician. Staged PCI is allowed (same stent type as index); repeat PCI and peri-procedural myocardial infarction occurring with the index procedure or repeat procedure within the first 6 weeks will not be considered exclusionary events for the definition of 12 Month Clear. Subjects who experience MI, stroke, PCI with stent placement, have cardiac surgery, or stent thrombosis after randomization will discontinue study drug, receive open label thienopyridine at the discretion of the treating physician or in accordance with the manufacturer s labeling, and will be followed for the duration of the study. The change from study drug to open label thienopyridine, and the reason, should be documented by the investigator on the ecrf. At the discretion of the investigator, subjects who experience bleeding that is non-life threatening should be encouraged to reduce the aspirin dose to the minimal acceptable level and continue study drug, or to resume study drug after the minimum required interruption. Should a subject require the use of open label thienopyridine beyond the original indication during the treatment phase of this study (e.g. recurrent PCI), the subject and their physician should discontinue the subjects randomized treatment, switch to open label use, and record the date and reason for doing so on the ecrf. These subjects will continue to be followed for the duration of the study. Subjects who experience an event that is not a MACCE and that does not require suspension of DAPT are discouraged from discontinuing their treatment. June 29, 2009 Page 35 of 108 Version 4.0

38 3.7 Concomitant Medication(s) Any medication the subject takes other than the study drugs specified in the protocol is considered concomitant medication. All anticoagulant and antiplatelet concomitant medications must be recorded in the subject s medical record and on the ecrfs. In addition to APT, beta-blockers, statins, ACEI s, ARB s, NSAIDs, COX-2, PPIs and warfarin will be captured on the ecrf. The information related to the concomitant medications will be recorded starting 24 hours prior to the index procedure through the 33 month follow up visit. 3.8 Medication(s) Not Permitted Before and/or During the Trial Subjects who are using warfarin or similar anticoagulant therapy are not eligible for enrollment in this study. Subjects who develop an indication for warfarin use after randomization may be prescribed warfarin, will convert to open label thienopyridine or discontinue therapy at the discretion of the investigator, and continue to be followed in the study. June 29, 2009 Page 36 of 108 Version 4.0

39 4 Study Objectives The objectives of this study are to evaluate the composite of all death, myocardial infarction (MI) and stroke (MACCE) and the survival free from ARC definite or probable stent thrombosis (ST) in subjects treated with drug eluting stents (DES) and extended dual antiplatelet therapy. All of the primary analyses will be performed on the primary analysis population (randomized DES subjects followed through 33 months post-procedure, including the 3 month rebound observational period). The primary study hypotheses are: Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have increased survival free from death, myocardial infarction or stroke compared with subjects treated with only 12 total months of dual antiplatelet therapy over the month post-stenting period. Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have increased survival free from ARC definite/probable stent thrombosis (ST) compared with subjects treated with only 12 total months of dual antiplatelet therapy over the month post-stenting period. 4.1 Co-Primary Endpoints This study has two co-primary endpoints that will be assessed. They are: composite of all death, myocardial infarction (MI) and stroke (defined as MACCE) - 12 through 33 months ARC definite or probable stent thrombosis (ST) - 12 through 33 months 4.2 Primary Safety Endpoint The primary safety hypothesis for this study is: Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have non-inferior major bleeding rates compared to the rates of subjects treated with only 12 total months of dual antiplatelet therapy over the month post-stenting period.. The primary safety endpoint assessed for this study is: Major bleeding (GUSTO classification, severe and moderate bleeding combined) - 12 through 33 months 4.3 Secondary Endpoints and Analyses The main secondary study hypotheses are: June 29, 2009 Page 37 of 108 Version 4.0

40 DAPT subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, will have a rate of death, myocardial infarction or stroke that is non-inferior compared with the rate of propensity score matched subjects treated with bare-metal stents over the month post-stenting period. DAPT subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, will have a rate of ARC definite/probable stent thrombosis (ST) that is noninferior compared with the rate of propensity score matched subjects treated with bare-metal stents over the month post-stenting period. The main secondary endpoints to be assessed are: BMS Randomized subjects versus DES Randomized subjects, propensity score adjusted for baseline characteristics and duration of DAPT assigned MACCE - 12 through 33 months ST - 12 through 33 months DES Randomized subjects ITT population MACCE - 12 through 30 months ST - 12 through 30 months Major Bleed - 12 through 30 months DES Randomized subjects On Treatment population MACCE - 12 through 30 months and 12 through 33 months ST - 12 through 30 months and 12 through 33 months Major Bleed - 12 through 30 months and 12 through 33 months BMS Randomized subjects ITT population MACCE - 12 through 30 months and 12 through 33 months ST - 12 through 30 months and 12 through 33 months Major Bleed - 12 through 30 months and 12 through 33 months BMS Randomized subjects On Treatment population MACCE - 12 through 30 months and 12 through 33 months ST - 12 through 30 months and 12 through 33 months Major Bleed - 12 through 30 months and 12 through 33 months Incidence of MACCE at 12 months post-procedure as well as the incidence of death, MI, stroke, major bleeding and stent thrombosis will be reported and compared for DES vs. BMS. Death, cardiac death, MI, and stroke for each treatment arm will be compared using descriptive statistics for the overall, 12 Month Clear, 12 Month Not Clear, and BMS vs. DES populations. June 29, 2009 Page 38 of 108 Version 4.0

41 5 Procedures and Assessments 5.1 Pre-Procedure Signed written informed consent must be obtained for all subjects who are potential study candidates. Informed consent may be collected prior to the subject undergoing the index procedure or within 24 hours of the procedure for subjects who otherwise meet the study inclusion criteria. Additionally, the following evaluations must be completed for all subjects unless otherwise specified: Lesion Characteristics Eligibility Criteria Current Cardiac Status Demographics Cardiac Risk Factors Antiplatelet Therapy Antiplatelet therapy is mandatory for this trial. Recommended dosing options are as follows: Aspirin: 75 mg daily for 3 days prior to the procedure, or a peri-procedural loading dose of mg. Aspirin treatment will be mg for the first 6 months after the procedure and mg subsequently, to be continued indefinitely. Clopidogrel: A peri-procedural loading dose between mg. A maintenance dose of 75 mg daily of clopidogrel or as indicated by the treating physician should be continued for the duration of the treatment period. OR Prasugrel: A peri-procedural loading dose of 60 mg. A maintenance dose of 10 mg daily of prasugrel or as indicated by the treating physician should be continued for the duration of the treatment period. A lower dose may be considered pending product labeling. 5.2 Stenting Procedure Subject preparation and the treatment of the lesion(s) will be in accordance with standard hospital policy for the care of interventional cardiology subjects. The stenting procedure should be performed according to hospital standards. Use of all other co-medication (other than the antiplatelet therapy above) is at the investigators discretion and will therefore be done according to hospital routine. Site Investigators are requested to carefully document the stent implantation procedure angiography for possible later use by the Clinical Event Committee for event adjudication. Angiograms should be retrievable during the duration of the study. 5.3 Enrollment Enrollment will occur after confirming that the signed informed consent has been obtained and the subject has met all of the inclusion and none of the exclusion criteria. Subjects can be enrolled up to 24 hours post procedure. June 29, 2009 Page 39 of 108 Version 4.0

42 All reportable events occurring after enrollment must be documented in the ecrf. 5.4 Clinical and Laboratory Procedures Before the procedure, and preferably within 72 hours of the procedure, a creatine kinase (CK) enzyme, creatine kinase myocardial-band (CK-MB) isoenzyme test and/or troponin will be obtained for all subjects presenting with ACS. If possible, CK, CK-MB and/or troponin values should be collected for all subjects at least once post-index procedure (12-24 hours after the index procedure, or before discharge if hospitalized <12 hours). 5.5 Angiography Visual estimation of lesion characteristics in relation to the index procedure will be performed by the operator and recorded on the ecrf. There is no mandatory angiographic follow-up in the protocol. Investigators are advised to perform angiograms only on a clinically driven basis, i.e. in case of symptoms or demonstrable ischemia. Angiography is not mandated by protocol. Baseline and event angiograms will be collected that are related to a study primary or main secondary endpoint, including but not limited to death, (suspected) myocardial infarction or stent thrombosis. 5.6 Follow-up Assessments The general requirements for follow-up in the study of this trial include: 1. Enrolled subjects will be followed until they are either determined to be not clear (prior to 12 months post-procedure) or for 33 months if randomized. 2. The subject must return to the same investigational site where the procedure was performed for the follow-up clinical visits. 3. Brief clinical assessments must be performed at the clinical visits. 4. Endpoint data or information relating to endpoints (e.g. PCI, MI, stroke, CABG). 5. Contact information for referring physicians, general practitioners, cardiologists and family members should be collected to facilitate continued ability to contact a trial subject. Follow-up Schedule Day 0 (clinical) 6 mo (± 14 days) (telephone) 1 yr (minus 30 days) (clinical) 15 mo (± 30 days) (telephone) 24 mo (± 30 days) (telephone) 30 mo (± 30 days) (clinical) 33 mo (± 30 days) (telephone) The following information will be collected at each follow-up. 1. All serious adverse events (SAEs) since the previous follow-up June 29, 2009 Page 40 of 108 Version 4.0

43 2. All relevant concomitant medications since the previous follow-up 3. Information related to DAPT compliance 4. Any coronary treatment that occurred (e.g. interventional or surgical revascularization) since the previous follow-up This study does not require any specific test or procedure that falls outside a standard stenting procedure as routinely done in the hospital. The subject should be carefully interviewed regarding hospitalizations, myocardial infarctions, coronary angiographies/ interventions as well as compliance regarding thienopyridine and aspirin intake since the previous follow-up. MACCE and other events should be recorded in the ecrf within 10 working days after the investigator becomes aware of the event. The maximum follow-up period for each individual subject is 33 months. Note: Execution of the follow-up schedule is essential to enable an analysis of the results in a scientifically sound and meaningful way. If, for whatever reason, the subject follow-up cannot be scheduled within the time window or occurred outside the time window, it is still essential to document the subject data at a date as close as possible to the calculated follow-up date. Every effort should be made to maintain a subject s follow-up compliance. Contacting the subject s general practitioner or referring cardiologist should be considered in case the subject cannot be reached in order to obtain information about the subject s health status and documented in the subject s file. Several attempts over a period of time should have been made to contact the subject, family or referring physician before documenting a subject lost to follow up. Sites will be required to make three phone calls to a subject followed by a registered letter for each follow-up contact. Death registry databases should be consulted by the sites where these databases are available and accessible to treating physicians. June 29, 2009 Page 41 of 108 Version 4.0

44 5.7 Schedule of Events Baseline Procedure Followup 6 months (phone) Randomization 12 months 3 (clinic) Follow-up 15 (phone), 24 (phone), 30 (clinic) and 33 months (phone) Eligibility criteria X - - X - Demographics X Cardiac risk factors X Current cardiac status X - X X X Lesion characteristics X X Patient informed consent X Enrollment - X Procedure data - X Relevant concomitant X X X X X medications Antiplatelet compliance X X X MACCE / bleeding - X X X X complications Event related: - Cardiac biomarkers As Needed - ECG As Needed - Angiogram As Needed - Antiplatelet medication As Needed 1) If a myocardial infarction has occurred after the randomization of subjects, CK, CK-MB and/or troponin values should be recorded on the ecrf for adjudication purposes by a Clinical Event Committee (CEC). NOTE: If a hospital has the capacity to check only one type of biomarker, we recommend checking troponin I or troponin T instead of CK or CK-MB. If a revascularization procedure is performed after the randomization of subjects, CK, CK-MB and/or troponin values if performed (at least once hours after the procedure, or before discharge if hospitalized <12 hours) should be recorded on the ecrf. 2) Printouts of ECG will be collected for death or any suspected myocardial infarction or suspected stent thrombosis that occurs after the randomization of subjects for adjudication purposes by a Clinical Event Committee (CEC). 3) Randomization is for eligible 12 Month Clear subjects. 5.8 Description of Randomization and Blinding Procedures A computer-generated randomization schedule will be used to assign subjects to treatments. Randomization for subjects will be performed in a 1:1 manner at 12 months post procedure in eligible subjects and will be stratified according to DES/BMS, hospital site, subject complexity and thienopyridine drug type. A double blinding (investigator and subject) method will be used. The study drugs and their respective matching placebos will be similar in size, color, smell, taste and appearance. In case of emergency, the site PI may break the study blind as deemed medically necessary. When possible, this should be discussed with the HCRI prior to unblinding. The blind should only be June 29, 2009 Page 42 of 108 Version 4.0

45 broken for emergencies (determined at the discretion of the site PI), and only for the subject in question, or when required by regulatory authorities. In the event of such a circumstance, unblinding may be accomplished by accessing the IVRS contact telephone number as listed in the IVRS/Study Drug Dispensing Instructions. The site Investigator will notify HCRI as soon as possible, and whenever possible, prior to unblinding themselves or any subject. The date, time, and reason the blind was broken must be recorded in the source documents and on the appropriate ecrf. June 29, 2009 Page 43 of 108 Version 4.0

46 6 Statistical Considerations and Analysis Plan A statistical analysis plan will be prepared and finalized prior to the unblinding of the study or the database lock. This document will provide further details regarding the definition of analysis variables and analysis methodology to address all study objectives. 6.1 Study Populations Definitions The following populations are defined for DES and for BMS subjects separately and for all subjects combined. All Enrolled Subjects All subjects enrolled in the study. 12 Month Clear This population consists of subjects enrolled in the study who are free from death, MI, stroke, repeat coronary revascularization, major bleeding - severe or moderate by GUSTO classification, and ST 12 months after stent implantation and who are compliant with 12 months of DAPT following stent implantation. 12 Month Not Clear This population consists of those subjects enrolled in the study who do not meet the requirements of 12 Month Clear. During the open label portion of this study (time 0-12m post-index procedure), a subject is considered compliant with the thienopyridine therapy for the purposes of eligibility if they take between 80% and 120% of the prescribed drug in the 0-6 month and 6-12 month periods without an interruption of therapy longer than 14 days. This information will be ascertained via data collected at the subject interviews at 6 and 12 months post-procedure. Compliance at both time points is required to be considered clear. After randomization, a subject is considered On Treatment with the randomized therapy if they take between 80% and 120% of the randomized drug in a given period (assessed via quarterly examination of medication used) and do not have an interruption of therapy longer than 14 days (assessed via subject interview). As detailed in Section 3.5, the total number of doses taken will be divided by the number of doses required for continuous treatment during the three month period. Between 80% and 120% compliance at all six three-month intervals (12-30 months) is required to be considered On Treatment ; however, all randomized subjects regardless of compliance will be included in the primary analyses of primary and secondary endpoints, according to the principle of intent-to-treat. 6.2 Analysis Populations The DES Randomized - ITT sample includes all DES subjects randomized to either 12 months of DAPT or 30 months of DAPT. Randomization will occur at the 12 month post-stent implantation time point. Subjects randomized to the 12 m DAPT arm will receive placebo for 18 months following randomization; subjects randomized to the 30 m DAPT arm will receive additional DAPT for 18 months following randomization. All subjects will receive aspirin while on randomized treatment. All follow-up data will be included in the ITT statistical analyses regardless June 29, 2009 Page 44 of 108 Version 4.0

47 of compliance with the assigned treatment. Subjects will be analyzed for the primary endpoints according to the treatment to which they were randomized. The DES Randomized - On Treatment sample will be the subset of the DES Randomized ITT subjects who were On Treatment as defined above for all six three-month (12-30 months) time intervals. The BMS Randomized - ITT sample includes all BMS subjects randomized to either 12 months of DAPT or 30 months of DAPT. Randomization will occur at the 12 month post-stent implantation time point. Subjects randomized to the 12 m DAPT arm will receive placebo for 18 months following randomization; subjects randomized to the 30 m DAPT arm will receive additional DAPT for 18 months following randomization. All subjects will receive aspirin while on randomized treatment. All follow-up data will be included in the ITT statistical analyses regardless of compliance with the assigned treatment. Subjects will be analyzed for the primary endpoints according to the treatment to which they were randomized. The BMS Randomized - On Treatment sample will be the subset of the BMS Randomized ITT subjects who were On Treatment as defined above for all six three-month time (12-30 months) intervals. The BMS Randomized subjects versus DES Randomized subjects, propensity score adjusted sample will include all BMS Randomized ITT subjects who meet the criteria for 12 Month Clear and 12 Month Clear DES subjects from the DES Randomized ITT sample. Propensity score adjustment during analyses comparing BMS vs. DAPT will occur on clinically relevant baseline demographic and disease characteristics and duration of randomized treatment. 6.3 Primary Hypotheses The primary objective of the study is to compare 12 months of DAPT with 30 months of DAPT between 12 and 33 months post index procedure on the clinical and thrombosis endpoints for DES subjects (subjects will be on randomized treatment for months and off randomized treatment for months). Specifically, the primary hypotheses are: Clinical: In subjects treated with DES free from MI, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 m after PCI, DAPT for an additional 18 m (total 30 months) will increase survival free from death, MI or stroke compared with only 12 total months of DAPT over the month post-index procedure period. Stent Thrombosis: In subjects treated with DES free from MI, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 m after PCI, DAPT for an additional 18 m (total 30 months) will increase survival free from ARC definite/probable stent thrombosis (ST) compared with only 12 total months of DAPT over the month post-index procedure period. The study will be considered a success for 30m DAPT if at least one of these two hypotheses is statistically proven using the Hochberg approach on the DES Randomized ITT sample at an overall familywise error (FWE) rate of 0.05 (i.e., if each objective is proven at the two-sided 0.05 level of significance, the study is considered a success for 30m DAPT; otherwise, if one hypothesis is proven at the two-sided level of significance, then the study is considered a success for 30m DAPT). June 29, 2009 Page 45 of 108 Version 4.0

48 6.4 Co-Primary Endpoints There are two potential mechanisms of benefit of 30m of DAPT: a device oriented benefit manifesting as a reduction in ST; and a patient oriented benefit manifesting as reduction in disease progression/non-target lesion events. It is possible that an important treatment difference for the clinical endpoint may not be mediated by ST prevention, or a true treatment difference in ST may not be detected as a difference in the clinical endpoint. For this reason, two co-primary endpoints are specified. Specifically, the co-primary endpoints are Clinical: Incidence of the composite endpoint of death, MI or stroke within the month period following stent implantation (MACCE endpoint). Stent Thrombosis: Incidence of ARC definite/probable stent thrombosis (ST) within the month period following stent implantation (ST endpoint). The study will be considered a success for 30m DAPT if 30m DAPT is shown to yield a significantly lower rate (longer time-to-event) than 12m DAPT for at least one of these two endpoints using the Hochberg approach on the DES Randomized ITT sample at an overall FWE rate of 0.05 (i.e., if 30m DAPT has a significantly lower rate (longer time-to-event) than 12m DAPT on both endpoints using a two-sided 0.05 level of significance for each endpoint, the study is considered a success for 30m DAPT; otherwise, if 30m DAPT has a significantly lower endpoint rate (longer time-to-event) than 12m DAPT on one endpoint using a two-sided level of significance, then the study is considered a success for 30m DAPT) Sample Size Considerations The following is an estimate of DES sample size for the DAPT Study to compare the 12m DAPT regimen to 30m DAPT regimen under the following assumptions: a. Two primary outcomes: i. Time to MACCE between months post-procedure; hypotheses are H o : 12m-DAPT = 30m-DAPT H A : 12m-DAPT 30m,-DAPT where is the hazard rate of MACCE over the month period. ii. Time to ST between months post-procedure; hypotheses are H o : 12m-DAPT = 30m-DAPT H A : 12m-DAPT 30m-DAPT where is the hazard rate of ST over the month period. Time to each endpoint follows an exponential distribution, with June 29, 2009 Page 46 of 108 Version 4.0

49 i. Incidence of MACCE =2.9% and incidence of ST=0.5% for 12m-DAPT annually for the 21 months following randomization (12-33 month post-procedure period). 1, 2, 3. ii. Incidence of MACCE =2.175% and incidence of ST=0.225% for 30m-DAPT annually for the first 18 months following randomization (12-30 month postprocedure period); iii. After treatment stops at 30 months post-randomization, 30m-DAPT incidence rate increases to that of 12m-DAPT. The hazard ratio (30m DAPT to 12m DAPT) under these assumptions is 0.75 for MACCE and 0.45 for ST across the 12m 30m period and 1.0 for both endpoints across the 30-33m period. b. Randomization is 1:1 into the 12m and 30m arms (randomization occurs at 12m postprocedure time point). c. Annual lost to follow-up rate of 3% after randomization. d. Familywise (FWE) error rate is controlled at the 0.05 level using the Hochberg approach (reject both null hypotheses if both are significant at the 0.05 level; otherwise, if one null hypothesis is significant at the level, then that null hypothesis is rejected). For each endpoint separately, 12,196 DES subjects randomized at 12 months post-procedure yields 80% power to reject the null hypothesis for that endpoint under the above assumptions at a two-sided 0.05 level of significance. Mathematically, it can then be shown that 12,196 DES subjects randomized at 12 months post-procedure will yield at least 80% power that the study has statistically met its objective under the assumption of a treatment effect in both outcomes using the Hochberg approach to declare the study a success for these two endpoints (power ranges from approximately >80% to >90% depending on correlation of outcomes). Thus, the number to be enrolled at time of stent implantation is approximately 12,196/.8 or 15,245. This has also been shown via computer simulations. Note that in order to justify the validity of DAPT power and sample size calculations across the range of possible MACCE and ST estimates, a series of computer simulations were run to determine how much power would be retained if various event rates were realized. Under the worst case (i.e., lowest) assumptions of a 2.3% annual MACCE rate and 0.4% annual ST rate for the 12m DAPT group, there is still 80% power under Hochberg (still assuming hazard ratios of 0.75 for MACCE and 0.45 for ST) "regardless" of the correlation. 1 Mauri L, Hsieh WH, Massaro JM, Ho KK, D'Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med. 2007;356(10): Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20): Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Juni P, Sianos G, Hellige G, van Domburg RT, Hess OM, Boersma E, Meier B, Windecker S, Serruys PW. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 2007;369(9562): June 29, 2009 Page 47 of 108 Version 4.0

50 For the correlation, we simulated two extreme cases: (a) complete independence between the two endpoints, which is the most "liberal" (i.e., yields the best power); and (b) anyone who had an ST also had MACCE (but of course, not the reverse given that MACCE occurs at a higher rate than ST). Approach (b) is more conservative than (a), but still yields at least 80% power under Hochberg. For the protocol-assumed rates of 2.9% annual MACCE rate and 0.5% annual ST rate for 12m DAPT, Hochberg yields at least 80% power. This is true for both the most conservative assumption (perfectly correlated endpoints) and a more realistic conservative assumption (option (b) from above). Under the protocol assumed rates, the power is about 85% under assumption (b) above. Rejection of the combined null hypothesis will indicate that treatment with DAPT to 30 months post-pci is superior to treatment with DAPT to 12 months with respect to MACCE, ST, or both. If the study is not considered a success according to these criteria, the 95% confidence intervals of the difference between DAPT duration treatment groups will be calculated. The assumed MACCE rate is based on published rates of cardiac death, MI and stroke 4, 5, and adjusted to reflect that deaths from all causes are included in the primary endpoint rather than cardiac deaths only. These rates are 2.4% - 3.4%, with a median of 2.9% (12 to 30 months post- PCI) and the assumed ST rate is based on published data 6, 7, Primary Analyses The primary analyses will compare both the survival free of MACCE and ST between DES subjects randomized to the 30m DAPT arm versus those randomized to the 12m DAPT arm using the stratified log-rank test (where the strata are the randomization strata; specifically hospital site, subject complexity and thienopyridine drug type). These analyses will be performed on the randomized DES 12 Month Clear population according to the principle of intention to treat (the DES Randomized - ITT sample defined above). The FWE will be controlled at the two-sided 0.05 level of significance as discussed above using the Hochberg approach. The study will be considered a success for 30m DAPT if 30m DAPT is shown to yield a significantly lower rate than 12m DAPT for at least one of the two primary endpoints using the Hochberg approach on the DES Randomized ITT sample at an overall FWE rate of 0.05 (i.e., if 30m DAPT has a 4 Stone GW, Moses JW, Ellis SG, Schofer J, Dawkins KD, Morice MC, Colombo A, Schampaert E, Grube E, Kirtane AJ, Cutlip DE, Fahy M, Pocock SJ, Mehran R, Leon MB. Safety and efficacy of sirolimus- and paclitaxeleluting coronary stents. N Engl J Med. 2007;356(10): Steinhubl SR, Berger PB, Mann JT, 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19): Mauri L, Hsieh WH, Massaro JM, Ho KK, D'Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med. 2007;356(10): Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20): Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Juni P, Sianos G, Hellige G, van Domburg RT, Hess OM, Boersma E, Meier B, Windecker S, Serruys PW. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 2007;369(9562): June 29, 2009 Page 48 of 108 Version 4.0

51 significantly lower rate than 12m DAPT on both endpoints using a two-sided 0.05 level of significance for each endpoint, the study is considered a success for 30m DAPT; otherwise, if 30m DAPT has a significantly lower endpoint rate than 12m DAPT on one endpoint using a twosided level of significance, then the study is considered a success for 30m DAPT). Kaplan-Meier estimates of MACCE and ST will be presented for each treatment arm, as will a two-sided 95% confidence interval of the treatment difference in Kaplan-Meier rates (30 m DAPT minus 12 m DAPT). All subjects will be included regardless of time to follow-up. The Lakatos method 9 for calculating asymptotic mean and variance of the log-rank statistic will be used for comparison of the survival curves. Subjects not achieving the co-primary endpoints months post-procedure will be censored in the analysis at the time of withdrawal from the study or 33-months post-procedure, whichever is earlier. The log-rank statistic is given by L d 1i X i i 1 n1 i n2i d i 1 n n 1i 1i n n n 2i 2 2i where d is the number of (primary endpoint) events; i is the ith event; X i is the treatment group indicator for the ith event (0 = experimental, 1= control); n 1i is the number at risk in the experimental group just before the ith event, and n 2i is the number at risk in the control group just before the ith event. Details of the Lakatos calculation of the asymptotic mean and variance of the log-rank statistic can be found in Section 6.11 (Statistical Methods) Secondary Analyses of the Primary Endpoints The difference between survival curves will also be analyzed by Cox Proportional Hazard regression adjusting for demographic characteristics, randomization strata, and known risk factors. The validity of the proportional hazards assumption will be assessed prior to carrying out the analysis. All above analyses on the primary endpoints will be performed on each of the DES Randomized ITT, DES Randomized - On Treatment (OT), BMS Randomized ITT, and BMS Randomized - OT analysis sets. 6.5 Primary Safety Endpoint Major Bleeding The null hypothesis is that subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 9 Lakatos, Edward Sample Sizes Based on the Log-Rank Statistic in Complex Clinical Trials, Biometrics, Volume 44, March, pages June 29, 2009 Page 49 of 108 Version 4.0

52 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have major bleeding rates between 12 and 33 months post-index procedure that exceed that of the control arm (subjects treated with only 12 months of DAPT) by at least a pre-specified margin of (delta) > 0. The alternative hypothesis is that subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization. stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have major bleeding rates between 12 and 33 months post-index procedure that are no more than that of the control arm, or exceed that of the control arm but by less than. Rejection of the null hypothesis will signify that the 30 m DAPT arm is non-inferior to the control arm (12 m DAPT) with respect to major bleed rate between 12 and 33 months post-index procedure. Specifically, the null (H o ) and alternative (H a ) hypotheses are: H o : A C + H a : A < C + where A is the true major bleed rate for the 30 m DAPT group and C is the true major bleed rate for the control arm over the month post-index procedure period. With a sample size of 12,196 randomized subjects and a non-inferiority test at an = (1- sided) significance, the power is 82% to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with major bleed in the 30 m DAPT arm compared to 12 m DAPT arm, when the major bleed rate of the 30 m DAPT group between 12 and 33 months post index procedure is 2.22% and that of the 12 m DAPT group is 2.22% over the same time period, a non-inferiority margin of 0.8% 10 3% loss to follow-up and 1:1 randomization. Power Analysis and Sample Size (PASS) was used to compute the power, assuming the Farrington-Manning test 11. This analysis will be carried out both for the DES Randomized ITT and DES Randomized OT analysis sets. With the exception of the month post-index procedure period, any bleeding event occurring 14 days after randomized treatment has stopped will not be counted as a major bleeding event for the respective group. As a secondary analysis, the above major bleeding analysis will be repeated for each of the BMS Randomized ITT and BMS Randomized OT analysis sets. As an additional secondary analysis, the above major bleeding analysis will be repeated for the DES Randomized ITT and 10 Derived from data based on Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Hamm CW, Hankey GJ, Johnston SC, Mak K-H, Mas J-L, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Fabry-Ribaudo L, Hu T, Topol EJ, Fox KAA. Patients With Prior Myocardial Infarction, Stroke, or Symptomatic Peripheral Arterial Disease in the CHARISMA Trial. Journal of the American College of Cardiology. 2007;49(19): Farrington CP, Manning G. Test Statistics and Sample Size Formulae for Comparative Binomial Trials with Null Hypothesis of Non-zero Risk Difference or Non-unity Relative Risk. Statistics in Medicine. 1990; 9: June 29, 2009 Page 50 of 108 Version 4.0

53 BMS Randomized ITT combined analysis sets, and for the DES Randomized OT and BMS Randomized OT combined analysis sets. Prior to combining DES and BMS patients, an assessment of stent-type-by-randomized treatment interaction (where stent-type is defined as DES and BMS) on major bleeding will be assessed using logistic regression at the 0.10 level of significance. If not significant, or if significant and only quantitative in nature, the pooling of DES-BMS patients will be carried out; otherwise, the DES-BMS combined analyses will not be performed. Note that the non-inferiority assessment for the DES+BMS combined analysis sets will be done from the above-mentioned risk difference approach (with an absolute margin of 0.8%) and from a relative risk approach. For the relative risk approach, the null and alternative hypotheses are H o : A / C λ H a : A / C < λ where A is the true major bleed rate for the 30 m DAPT group, C is the true major bleed rate for the control arm over the month post-index procedure period, and λ is the relative noninferiority margin of 1.36 (1.36 corresponds to an absolute margin of 0.8% when the assumed bleeding rates are 2.2% in each of 30m DAPT and 12m DAPT). With a sample size of 16,516 (= 12,196 DES + 4,320 BMS) randomized subjects and a noninferiority test at an = (1-sided) significance, the power is 82% power to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with major bleed in the 30 m DAPT arm compared to 12 m DAPT arm, when the major bleed rate of the 30 m DAPT group between 12 and 33 months post index procedure is 2.22% and that of the 12 m DAPT group is 2.22% over the same time period, a relative noninferiority margin of 1.36 is used, 3% annual loss to follow-up and 1:1 randomization. Power Analysis and Sample Size (PASS) was used to compute the power, assuming the Farrington- Manning test Powered Secondary Endpoints BMS vs. DES Comparisons MACCE The null hypothesis is that DAPT subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, will have MACCE rates between 12 and 33 months post-index procedure that exceed that of the control arm (subjects treated BMS) by at least a prespecified margin of (delta) > 0. The alternative hypothesis is that DAPT subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization. stroke, stent thrombosis, or 12 Farrington CP, Manning G. Test Statistics and Sample Size Formulae for Comparative Binomial Trials with Null Hypothesis of Non-zero Risk Difference or Non-unity Relative Risk. Statistics in Medicine. 1990; 9: June 29, 2009 Page 51 of 108 Version 4.0

54 bleeding in the first 12 months after stenting and DAPT, will have MACCE rates between 12 and 33 months post-index procedure that are no more than that of the control arm, or exceed that of the control arm but by less than. Rejection of the null hypothesis will signify that the DES arm is non-inferior to the BMS arm with respect to MACCE between 12 and 33 months post-index procedure. Specifically, the null (H o ) and alternative (H a ) hypotheses are: H o : A C + H a : A < C + where A is the true MACCE rate for the DES group and C is the true MACCE rate for the control arm. With a sample size of 12,196 DES and 4,320 BMS subjects and a non-inferiority test at an = (1-sided) significance, the power is 84% to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with MACCE in the DES arm compared to the BMS arm, when the MACCE rate of the control arm is 4.5% over the month period, a non-inferiority margin of 1.09%, 3% annual loss to follow-up and 1:1 randomization to DAPT in each group. Power Analysis and Sample Size (PASS) was used to compute the power. The anticipated MACCE rate of 4.5% over the month period is calculated as follows: As discussed in the primary endpoint power analyses above, the annual MACCE rate is assumed to be 2.9% for the 12m-DAPT group and 2.175% for the 30m-DAPT group for the month post-procedure period; the average of these two annual rates is %; thus, the month post-procedure MACCE rate is anticipated to be 1.5*2.5375% = %. Over the 3 month month period, where it is anticipated the annual 30m-DAPT group MACCE rate = annual 12m-DAPT group MACCE rate = 2.9%, the event rate is expected to be 2.9%/4 = 0.725%. Thus the total anticipated rate across the month post-procedure period is *( ) = or 4.5%. Stent Thrombosis The null hypothesis is that DAPT subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, will have ST rates between 12 and 33 months postindex procedure that exceed that of the control arm (subjects treated BMS) by at least a prespecified margin of (delta) > 0. The alternative hypothesis is that DAPT subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization. stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, will have ST rates between 12 and 33 months post-index procedure that are no more than that of the control arm, or exceed that of the control arm but by less than > 0. Rejection of the null hypothesis will signify that the DES arm is non-inferior to the BMS arm with respect to ST between 12 and 33 months post-index procedure. Specifically, the null (H o ) and alternative (H a ) hypotheses are: June 29, 2009 Page 52 of 108 Version 4.0

55 H o : A C + H a : A < C + where A is the true ST rate for the DES group and C is the true ST rate for the control arm. With a sample size of 12,196 DES and 4,320 BMS subjects and a non-inferiority test at an = (1-sided) significance, the power is 80% to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with ST in the DES arm compared to the BMS arm, when the ST rate of the control arm is 0.67% over the month period, a non-inferiority margin of 0.39%, 3% annual loss to follow-up and 1:1 randomization to DAPT in each group. Power Analysis and Sample Size (PASS) was used to compute the power. The anticipated ST rate of 0..67% over the month period is calculated as follows: As discussed in the primary endpoint power analyses above, the annual ST rate is assumed to be 0.5% for the 12m-DAPT group and 0.225% for the 30m-DAPT group for the month post-procedure period; the average of these two annual rates is %; thus, the month post-procedure ST rate is anticipated to be 1.5*0.3625% = %. Over the 3 month month period, where it is anticipated the annual 30m-DAPT group ST rate = annual 12m-DAPT group ST rate = 0.5%, the event rate is expected to be 0.5%/4 = 0.125%. Thus the total anticipated rate across the month post-procedure period is *( ) = or 0.67%. Justification of deltas: The absolute and relative deltas for MACCE are 1.09% and 25% respectively. The absolute delta and relative deltas for ST are 0.39% and 58% respectively. The threshold at which a BMS strategy is superior to DES by decision analysis considering the balance of restenosis vs. thrombosis occurs at a net VLST BMS - DES risk = 0.42% 23 Given that subjects receiving each type of stent (DES vs. BMS) are not randomized to the type of stent and thus may not have similar baseline characteristics, the treatment group comparison on each endpoint will be carried out as follows: For each individual a propensity score (or i.e., predicted probability between 0 and 1) for group (DES, BMS) membership will be calculated using logistic regression, with group as the outcome and baseline variables including DAPT treatment, group assignment, stent size, patient and procedure characteristics as the independent variables (the set of baseline variables to be used will be fully specified in the statistical analysis plan). Subjects will then be categorized into quintiles based on this propensity score. The two treatments will be compared on the endpoint rate using a log-rank test for non-inferiority stratified across the propensity quintiles at a twosided 0.05 level of significance. In addition, Kaplan-Meier estimates of the endpoint rate will be presented for each treatment group within each propensity score quintile in order to assess comparability of treatments within groups of subjects with similar values of baseline characteristics. June 29, 2009 Page 53 of 108 Version 4.0

56 6.7 Additional Endpoint Analyses Table 1 summarizes the additional endpoints, analysis populations and hypothesis tests that are prespecified in this analysis plan. In addition, time on DAPT will be treated as a time-dependent covariate to determine if the pattern of DAPT usage affected the outcome. The primary safety objective of non-inferiority of Major Bleed rate (assessing non-inferiority of 30 m DAPT to 12 m DAPT over the month post-index procedure period) will be tested at a onesided significance level of For the remaining analyses presented in the table below, treatment difference will be estimated using a two-sided 95% confidence interval; no formal statistical hypothesis testing will be carried out, hence nor will any treatment comparison p-values be generated. Table 1. Additional Analyses Endpoint Time period Sample (s) Hypothesis test MACCE DES Randomized - ITT, OT BMS Randomized ITT, OT Superiority 30m vs. 12 m ST DES Randomized - ITT, OT BMS Randomized ITT, OT Superiority 30m vs. 12m Major Bleed DES Randomized - ITT, OT BMS Randomized ITT, OT DES Randomized ITT and BMS Non-inferiority 30m vs. 12m Randomized ITT combined DES Randomized OT and BMS Randomized OT combined MACCE DES Randomized - ITT, OT BMS Randomized ITT, OT Superiority 30m vs. 12 m ST DES Randomized - ITT, OT BMS Randomized ITT, OT Superiority 30m vs. 12m MACCE BMS Randomized versus DES Randomized, propensity score adjusted Equivalence DES vs. BMS ST BMS Randomized versus DES Randomized, propensity score adjusted Equivalence DES vs. BMS Analysis of rebound effect After discontinuation of dual antiplatelet therapy it is possible that a rebound phenomenon will occur where the hazard of either MACCE or ST is increased during the period immediately after discontinuation. The following analyses will be performed to estimate the magnitude of this June 29, 2009 Page 54 of 108 Version 4.0

57 possible phenomenon. The analysis will focus on the DES subjects from the randomized part of the study; however, the analysis will also be performed separately for the BMS subjects. Subjects will be followed for 3-months following the end of assigned treatment (or i.e., for a maximum of 33 months post procedure). Estimating the rebound effect The percentage of subjects who experience MACCE in the 3 months following discontinuation of randomized treatment (regardless of when the treatment is discontinued) and the corresponding exact 95% confidence interval will be calculated by group. In addition, the percentage of subjects who experience MACCE during randomized therapy will be calculated and normalized to correspond to a 3 months treatment period within each treatment group. The difference between the percentages will be reported. If a rebound effect is present the percentage of subjects with events in the 3 months following interruption of DAPT therapy will be higher than the percentage of subjects experiencing the events during DAPT treatment. This analysis will be performed separately for DES and BMS patients; it will be performed for all randomized subjects and for randomized subjects with the full randomized treatment 18 months following randomization. The above analyses will be repeated for the percentage of subjects who experience ST. In addition, the relationship between the percentage of subjects experiencing the events during rebound period and the length of DAPT treatment will be assessed. Graphical display of survival curves from 12 to 33 months comparing treatment arms for MACCE and ST will be presented Sensitivity Analysis of Non-compliance with Randomized Treatment (12 to 30 Months) The effect of compliance to the randomized treatment on the co-primary endpoints and the safety endpoint will be assessed via the secondary analyses performed on the ITT sample. For example, for subjects randomized to 30m DAPT, we will assess differences on endpoints for subjects who were less than 80% compliant versus subjects who were at least 80% compliant over 18 months post-randomization (12-30 month post-index procedure period) and 21 months post-randomization (12-33 post-index procedure period). In addition, for subjects randomized to 30 months of DAPT compliance will be determined for each 3 months treatment period both as a binary variable (yes/no) and a continuous variable (%compliance). For subjects randomized to 12 months of DAPT compliance will be set to yes for the binary variable and to 100% for the continuous variable. Data for subjects who are discontinued from their randomized treatment will be excluded post-discontinuation for this analysis. The incidence of MACCE, ST and major bleed in each 3-months time period will be compared between treatment groups using repeated measures models (general mixed model) with compliance as a factor in the model (for the binary variable) and separately as a covariate (for compliance expressed as a %) over the 18 and 21 month post-randomization periods Additional Subset Analysis June 29, 2009 Page 55 of 108 Version 4.0

58 All primary and secondary endpoints will be compared between treatments using descriptive techniques within a-priori identified subsets, such as subjects who were on and off Coumadin during the randomized portion of the study. Two-sided 95% confidence intervals for the differences between treatments will be presented within each subset; No p-values comparing treatments will be generated for subset analyses. 6.8 Additional Analyses Death, Cardiac Death, MI, stroke, and repeat revascularization for each treatment arm will be compared using descriptive statistics and two-sided 95% confidence intervals for the difference between treatment event rates for the main, 12 Month Clear, 12 Month Not Clear, and BMS vs. DES. In addition, the effect of the switching of thienopyrodine within the first 6 months post-index procedure on the primary outcomes will be examined in an exploratory fashion. No p-values comparing treatments will be generated for these additional analyses. 6.9 Missing Data Handling The co-primary endpoint analyses will be based on the intent-to-treat (ITT) population. Sensitivity analysis using simple and multiple imputation methods and tipping analyses will be performed to evaluate the impact of the missing values on study conclusions. All other analyses will be based on available data with missing data excluded. Any unused or spurious data will be noted as appropriate in the final report Multiple Center Effect The randomization for this trial is stratified by study site to ensure the sample sizes for the two treatment arms are balanced in the desired ratio within each site. Data are to be pooled across all study sites for all analyses. The possibility of a center effect will be examined for the co-primary endpoints. The Breslow-Day statistic will be used to test for a common odds ratio across the different levels of the center. Cox proportional hazards will also be used to assess the significance of a treatment-by-center interaction; the Cox model will include effects for treatment, center, the treatment-by-center interaction, and the baseline strata. Data from smaller trial sites may be combined by geographic region or another common factor for these analyses. If there is evidence of inconsistency in treatment effect at a 0.15 significance level that is qualitative in nature, treatment differences will be inspected within each center separately and outlier or influential sites will be identified; in addition subject demographics, baseline clinical and angiographic characteristics will be examined to assess if such factors contribute to the cause of the significant qualitative treatment-by-center interaction. PMS/COA (Post Market Surveillance / Condition of Approval ) Subjects Non DAPT sources of DES data for the primary analysis will include: 1. Patients who enter another study (e.g. post market surveillance single arm studies, or nonrandomized (to stent) trials of currently approved DES) and have data collected between 0 and 12 months in their original study. At 12 months, if the subject is eligible for June 29, 2009 Page 56 of 108 Version 4.0

59 randomization based on the DAPT criteria, they are enrolled and randomized in the DAPT study. All further data collection is according to the DAPT study protocol 2. Patients who enter another study (e.g. post market surveillance) that is designed to collect the same information as the DAPT study. These subjects data are transferred to HCRI as clean SAS datasets to be merged with the DAPT database for statistical analysis The following requirements have to be met by a study that is intended to provide patient level data for DAPT: 1. The determination of eligibility for enrollment and randomization is the same as in the DAPT study. 2. Data definitions are the same. 3. The same data are collected at the same time points. 4. Adjudication (or readjudication) of all endpoint events according to a central DAPT clinical events committee. 5. Contributed data are from consecutive patients meeting the specified requirements. The maximum proportion of patient data that will be transferred as cleaned data (data source type 2 above) from completely separate studies meeting the above requirements will be 50% of analyzed drug-eluting stent subject data (approximately 6098 subjects). The maximum number of patients that will be transferred via method type 1 described above will be The total numbers of contributed patients, and their poolability with patients who are enrolled and randomized in the DAPT study will be assessed at regular intervals by an independent monitoring committee in order to confirm adequate enrollment of patients from the DAPT study. Data will be obtained from these studies at regular intervals so that clinical events adjudication under DAPT will occur throughout the duration of the study. The validity of the overall study results is supported by stratification of randomization and analysis by enrollment source. In order to ensure the generalizability of the overall study, minimum and maximum parameters will be placed on certain patient and treatment characteristics for the DES analysis cohort (DAPT and non-dapt sources combined): e.g. at least 15% of subjects have been treated with a given DES stent type and a maximum of 60% with a given thienopyridine type. In addition, an important issue is to assess if the treatment effect is constant across the patients followed in the DAPT study and the patients not followed by DAPT but whose data are transferred for inclusion in the DAPT analysis. An assessment of treatment-by-enrollment-source interaction on each outcome will be assessed using Cox-proportional hazards regression, where treatment is 12 month DAPT vs. 30 month DAPT, and cohort is followed-by-dapt vs. notfollowed-by-dapt (data source type 2). Included in the Cox model will be the main effects of treatment, cohort, and clinically relevant covariates, and the treatment-by-cohort interaction effect. The treatment-by-cohort interaction effect will be assessed at the 0.15 level of significance. If non-significant, or if significant and only quantitative in nature, (i.e., only the magnitude of the treatment effect, and not the direction of the effect, differs across cohorts), then pooling of data across the two patient cohorts is supported; otherwise, if qualitative in nature, analyses of treatment difference by cohort and by relevant patient subgroup (complex vs. non complex, masked stent type, masked drug type) and by study will be carried out to help determine potential cause(s) of the interaction. June 29, 2009 Page 57 of 108 Version 4.0

60 The clinically relevant covariates to be used in the above model are age (years); sex; ethnicity; race; histories of each of diabetes, hypertension, stroke, transient ischemic attack, congestive heart failure, peripheral arterial disease, percutaneous coronary revascularization, coronary artery bypass graft surgery, atrial fibrillation, and myocardial infarction; current smoking status; lesion length (mm); reference vessel diameter (mm); minimum lumen diameter (mm); lesion class; lesion type; TIMI grade flow; presence of thrombus; pre-procedure % stenosis. In addition to using multivariate-adjusted interaction modeling to assess the appropriateness of pooling across the two cohorts, the following analysis will be performed for each primary endpoint: for each individual a propensity score for cohort ( followed by DAPT vs. not followed by DAPT ) membership will be calculated using logistic regression, with cohort as the outcome and randomized treatment and the above-mentioned clinically relevant baseline variables as the independent variables. Patients will then be categorized into quintiles based on this propensity score. A stratified log-rank test, where propensity quintiles are the strata, will be carried out to assess the significance of the cohort difference on the endpoint adjusted for the propensity score. A similar analysis (excluding the propensity score analysis) will be carried out to assess treatment-by-trial effect, where trial is the classification variable indicating the clinical trial from which the patient s data came. Note that in this analysis, randomized patients followed within the DAPT study will be considered DAPT patients, regardless of the clinical trial in which they were originally enrolled Statistical Methods Lakatos Log-Rank Test Details: The following is reprinted from Power and Sample Size (PASS) Help System, PASS version 8.05, page 715-4, by Dr. Jerry L. Hintze; Kaysville, Utah Copyright June 29, 2009 Page 58 of 108 Version 4.0

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64 Other Statistical Analysis Methods: Baseline demographic, clinical, angiographic, procedural and device data, and treatment results will be summarized using descriptive summary statistics. Data collected in the trial will be summarized overall and by treatment arms. For continuous variables (e.g., age, percent diameter stenosis, and lesion length), results within treatment arm will be summarized with the numbers of observations, means, standard deviations, minimums, and maximums, and 95% confidence intervals for the means. For treatment comparisons, the difference between the two treatment arms will be summarized with the difference of the two means and 95% confidence interval for the difference of the means. These calculations will be done under the assumption that the data for the two arms are independent and approximately normal in distribution. If not otherwise specified, the confidence interval for the difference of two means is calculated assuming unequal variance between the two groups. If asymptotic assumptions fail, then nonparametric summary statistics (medians, 25th and 75th percentiles) may be displayed as an alternative. In addition, more appropriate non-parametric tests will be considered if the assumptions for the parametric tests are violated. For the comparison of two independent samples, if the data are not normally distributed, Wilcoxon rank sum test will be performed instead of the parametric t-test. Formulas for calculation of the confidence intervals for the continuous variables are given below: June 29, 2009 Page 62 of 108 Version 4.0

65 1. 100(1- α)% Confidence Interval For A Single Mean x t 2 s n where: x sample mean s sample standard deviation n sample size t 2 the alpha/2 t - statisticfor n 1degrees of freedom (1-α)% Confidence Interval For The Difference of Two Means Under The Assumption Of Equal Variances Between The Two Groups 1 2 x 1 x2 t s p 2 n1 n2 where: x s s n t 1 2 p sample mean for group 1 ( n 1 sample standard deviation for group 1 1 1) s1 ( n2 1) s n n samplesizefor group the alpha/2 t - statisticfor n n 1 2 x s n sample mean for group 2 sample standard deviation for group 2 sample size for group 2 2 degrees of freedom (1-α)% Confidence Interval For The Difference of Two Means Under The Assumption of Unequal Variances Between The Two Groups x x t SED The degrees of freedom (df) for the approximate t statistic is determined by Satterthwaite s formula: June 29, 2009 Page 63 of 108 Version 4.0

66 df 2 w1 w2 2 2 w n w2 n 1 where: 2 1 s w1 n s w2 n 2 x x 1 2 sample mean for group 1 sample mean for group 2 s s 1 2 sample standard deviation for group 1 sample standard deviation for group 2 n n 1 2 samplesize for group 1 sample size for group 2 SED 2 1 s n s n 2 For categorical variables such as MACCE, ST, etc., results within each arm will be summarized with subject counts, percentages, and exact 95% Clopper-Pearson confidence intervals. The differences between the two treatment arms will be summarized with the difference in percents and the asymptotic 95% confidence interval for the difference of two percentages. Formulas for calculation of the confidence intervals for the categorical variables are given below. Please note that in using these formulas, it is assumed that the data are independent and binomially distributed. For the confidence interval for the difference of two proportions, it is also assumed that the two samples are independent, the samples sizes for the two groups are large ( 20 per group), in that the event and non-event counts for both groups are at least 5, and the distribution is asymptotically normal. If this is not the case, the Farrington-Manning approach 11 will be used to calculate the confidence interval of the difference in two proportions (1-α)% Exact Clopper-Pearson Confidence Interval For A Single Proportion June 29, 2009 Page 64 of 108 Version 4.0

67 Lower Confidence Limit x ( n x 1) F Upper Confidence where: n sample size x number of "events" F ( df1, df2) 1 2 ( x 1) F 1 2 Limit n x ( x 1) F x (2( n x 1),2x) 1 2 (2( x 1),2( n x)) 1 2 (2( x 1),2( n x)) the(1- alpha/2) F- statisticfor degrees of freedom df1 and df (1-α)% Asymptotic Confidence Interval For The Difference Of Two Proportions pˆ pˆ Z pˆ ˆ 1q Lower Confidence Limit = 1 2 n1 n2 pˆ pˆ Z 2 pˆ ˆ 1q 1 pˆ qˆ Upper Confidence Limit = 1 2 n 2 1 n2 where: pˆ qˆ 2 2 pˆ qˆ Z 2 sample proportionfor group 1 1 pˆ 1 n samplesizefor group 1 the(1- alpha/2) Z -statistic pˆ qˆ n sample proportionfor group 2 1 pˆ 2 sample size for group 2 The denominators used in the calculations of categorical variables will be determined as follows for the intent-to-treat population: Subjects who had follow-up information and/or occurrence of an event will be included in the denominator. In another words, subjects who are truly lost to follow-up will be excluded from the denominator. Truly lost to follow up is defined as subjects who are lost to follow up through 33 months without any MACCE. For stent thrombosis, truly lost to follow up is defined as subjects who are lost to follow up through 33 months without any occurrence of stent thrombosis. The same definitions will be used for bleeding complications. June 29, 2009 Page 65 of 108 Version 4.0

68 Survival analysis techniques will be used to analyze the time-to-event variables. Survival curves will be constructed using Kaplan-Meier estimates. Log-rank test results will also be computed for comparison of survival distributions. For the comparison data, summary tables for safety and efficacy endpoints will include event rates (Kaplan-Meier estimates of event rates will be given for event-free variables), relative risk (i.e., the ratio of rates), confidence interval for the relative risk (CI: exp(ln(rr) ± 1.96 * SE), where SE = sqrt((1-p 1 )/n 11 + (1-p 2 )/n 21 )), the difference in means/rates, the confidence interval for difference in means/rates (using previously-described formulas), and a p-value. June 29, 2009 Page 66 of 108 Version 4.0

69 7 Benefits and Risks Associated with Study Drug/Devices 7.1 Risks For more detailed information on the risks of stent implantation, including a complete list of warnings, precautions and potential adverse events, please refer to the Instructions for Use for each stent provided with the product. Similarly, please refer to the Package Inserts of the study drugs for a descriptive listing of known risks associated with the drugs. 7.2 Possible Benefits Anticipated clinical benefits Trial subjects implanted with an approved stent will receive the same medical treatment as if they were not participating in this clinical study except for DAPT duration. Participation contributes to define the optimum duration of thienopyridine use in subjects treated with stents according to the physician s preference, and without the interference of a per protocol angiographic evaluation. It is possible that treatment with longer than 12m of DAPT will be associated with reduction in death, myocardial infarction, stroke, or stent thrombosis (see Section 1.1). Balance of anticipated clinical benefits against the risk Only subjects with no contraindication to >12 months of DAPT will be randomized. Those subjects who develop a contraindication to continuation of DAPT after randomization will be treated according to their physician s preference (see Section 3.6). It is possible that treatment with longer than 12m of DAPT will be associated a higher risk of bleeding, which may be balanced or outweighed by clinical benefits listed above. June 29, 2009 Page 67 of 108 Version 4.0

70 8 Safety and Adverse Event Reporting 8.1 Serious Adverse Events The investigator is to record all serious adverse events observed and spontaneously reported by the trial subject on the SAE ecrf. In addition, each trial subject will be questioned about serious adverse events. A serious adverse event is any untoward medical occurrence that: Results in death Is life-threatening (immediate risk of death) Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Results in congenital anomaly/birth defect Other important medical event (see below) Medical and scientific judgment should be exercised in determining whether an event is an important medical event. An important medical event may not be immediately life threatening and/or result in death or hospitalization. However, if it is determined that the event may jeopardize the subject and/or may require intervention to prevent one of the other outcomes listed in the definition above, the important medical event should be reported as serious. 8.2 Causality of Serious Adverse Event to Study Product(s) The investigator s assessment of causality must be provided for all serious adverse events. An investigator s causality assessment is the determination of whether there exists a reasonable possibility that the study product caused or contributed to the serious adverse event. Causality determination for an SAE will be made for devices and drugs separately. The investigator is to classify the relatedness of the SAE to the use of the Study Products in one of the following: Definitely Related Probably Related Possibly Related Unlikely Not Related 8.3 Intensity of Serious Adverse Event Mild- Awareness of a sign or symptom that does not interfere with the subject's usual activity or is transient, resolved without treatment and with no sequelae. Moderate- Interferes with the subject's usual activity and/or requires symptomatic treatment. Severe- Symptom(s) causing severe discomfort and significant impact of the subject s usual activity and requires treatment. June 29, 2009 Page 68 of 108 Version 4.0

71 8.4 Unanticipated Adverse Device Effects (Device UADE) A SAE that has been determined to be device or procedure-related should be further classified as anticipated or unanticipated. An unanticipated adverse device effect is defined as any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the product IFU or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects. These are expected to be rare events. 8.5 Life-Threatening Adverse Drug Experience (LTADE) Any adverse drug experience that places the patient or subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred. This does not include a reaction that, had it occurred in a more severe form, might have caused death. 8.6 Unexpected Adverse Drug Experience (Drug UADE) Any adverse drug experience, the specificity or severity of which is not consistent with the current product insert, investigator brochure; or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. "Unexpected," as used in this definition, refers to an adverse drug experience that has not been previously observed (e.g., included in the investigator brochure or product insert) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product. 8.7 Reporting Requirements All serious adverse events (SAEs) will be recorded on the SAE ecrf page(s) using concise medical terminology. Causality classification and whether or not the SAE was anticipated will also be collected. If a serious adverse device or drug event occurs, HCRI is to be notified within 24 hours of awareness of the event by the investigator. Specifically, the investigator must complete all applicable SAE ecrf page(s) for all SAEs that occur from the subject s enrollment through study completion. In addition, if the serious adverse event is fatal or life-threatening, notification to HCRI must be made immediately, irrespective of the extent of available adverse event information. This timeframe also applies to additional new information (follow-up) on previously forwarded serious adverse event reports. For all serious adverse events, the investigator is required to pursue and provide information to HCRI in accordance with the specified reporting timeframes. In addition, an investigator may be requested by HCRI to obtain specific additional follow-up information in an expedited fashion. In general, this will include a description of the serious adverse event in sufficient detail to allow for a complete medical assessment of the case and independent determination of possible causality. Information on other possible causes of the event, such as concomitant medications and illnesses must be provided. In the case of a subject death, a copy of the death records, death certificate and an autopsy report (if performed) must be sent to HCRI or its designated representative as soon as possible. In the case of a subject death, the investigator is encouraged to request an autopsy. June 29, 2009 Page 69 of 108 Version 4.0

72 Each serious adverse event is to be assessed and classified as indicated above. If a serious adverse event is determined as being a UADE (device or drug), the investigator will notify HCRI as soon as possible providing a brief description of the event within 24 hours of the event. The investigational site will report the UADE (device or drug) to their IRB/EC within 10 working days of the UADE. HCRI will query the site to obtain additional information as required. SAEs recorded by the investigator will be forwarded to and analyzed by the DSMB and all endpoint events recorded by the investigator post- randomization will be forwarded to and analyzed by the CEC. Site investigator attribution of relatedness will not affect distribution or analysis of any SAE. Table 2. Site SAE Reporting Requirements Type of event Prepared by Investigator For Time of Notification Anticipated Drug/Device SAEs HCRI, via ecrf SAE page(s) Within 24 hours of knowledge of event All fatal events HCRI, via ecrf SAE page(s) Within 24 hours of knowledge of event Unanticipated Adverse Device Effects HCRI, via ecrf SAE page(s) Within 24 hours of knowledge of event Unanticipated Adverse Drug Experiences HCRI, via ecrf SAE page(s) Within 24 hours of knowledge of event HCRI will provide safety services including MedDRA coding and review of SAEs and coding of concomitant medications using WHODrug. HCRI will maintain a safety database and collect, process, and follow all SAEs to resolution that occur during the period spanning from the subject s enrollment through randomization or until a MACCE endpoint event occurs that prevents the subject from participating in the randomization process. That initial MACCE event will be entered in the ClinTrace TM database, followed to resolution, and processed for inclusion in the DSMB safety reports without CEC adjudication. This MACCE event would exclude the subject from achieving 12 Month Clear status resulting in the subject s discontinuation from the trial without further SAE collection. It is estimated that 20% of patients will fail to achieve 12 Month Clear status. After the 12 Month Clear subject s randomization, all SAEs excluding MACCE events will be processed and reported as outlined in Table 3. The serious MACCE events will be adjudicated by the CEC, and reviewed by the DSMB but will not be processed or reported by the HCRI Safety Group. All events and drug and device UADEs will be reported to FDA within the notification timeframes outlined below in Table 4. The annual IDE report and 6 month progress reports will contain a tabular listing of SAEs and a summary of all reported fatal events and drug and device related UADEs. June 29, 2009 Page 70 of 108 Version 4.0

73 Table 3. HCRI Format of SAE Reporting to Regulatory Authorities Type of SAE Pre-Randomization Post Randomization Related Unrelated Expected Unexpected MACCE non MACCE MACCE (plus bleeding events) non MACCE IDE Safety/6 month progress reports IDE Safety/6 month progress/dsmb reports Expedited + IDE Safety/6 month progress reports IDE Safety/6 month progress/dsmb reports IDE Safety/6 month progress reports IDE Safety/6 month progress reports + CEC (MACCE plus bleeding events) CEC & DSMB Expedited + IDE Safety/6 month progress reports CEC & DSMB IDE Safety/6 month progress reports Table 4. HCRI Regulatory Reporting Requirements Type of event Prepared by HCRI For Time of Notification Anticipated Drug and Device SAEs FDA / competent authorities Annually in the IDE Safety Report and 6 month progress reports Unanticipated Adverse Device Events FDA / competent authorities Within 10 working days of knowledge of event Unanticipated Adverse Drug Effects FDA competent authorities Within 15 calendar days of knowledge of event Unexpected Drug Associated Fatal or Life Threatening Event FDA / competent authorities Within 15 calendar days of knowledge of event (initial FDA notification via phone/fax within 7 calendar days) Device Related SAE (PMS/PAS subjects with MDR tag)* Manufacturer FDA / competent authorities Within 5 days of knowledge of event Annually in the IDE Safety Report and 6 month progress reports * For subjects who originated in device manufacturer sponsored PMS/PAS studies who have data collected and analyzed in this study, SAE collection will occur as described above. These subjects will be identified by their MDR number and the event details will be forward to the manufacturer for tracking in the PMS/PAS. The IDE annual report will include the SAE information for these subjects and also provide a reference to their MDR number. 8.8 Device Failures and Malfunctions A device malfunction is defined as the failure of the device to meet its performance specifications or otherwise perform as intended. A device failure is defined as the device is used in accordance with the IFU, but does not perform according to IFU and negatively impacts the treatment. June 29, 2009 Page 71 of 108 Version 4.0

74 If there are device failures or malfunctions to be reported, these will be handled by the investigational sites directly and reported to the HCRI via the ecrf. HCRI will then provide this information to the manufacturer as outlined below. Table 5. Site Reporting Requirements for Device Failure/Malfunction Type of event Prepared by Investigator For Time of Notification Device Failure/Malfunction HCRI, via ecrf Within 5 working days of knowledge of event Table 6. HCRI Regulatory Reporting Requirements Type of event Prepared by HCRI For Time of Notification Device Failure/Malfunction Manufacturer Within 5 days of knowledge of event June 29, 2009 Page 72 of 108 Version 4.0

75 9 Definitions Abrupt Closure Acute Coronary Syndrome (ACS) Adverse Effect Adverse Event (AE) Anticipated Adverse Event Abrupt Closure. Defined as the occurrence of new (during the index procedure) severely reduced flow (TIMI grade 0-1) within the target vessel that persisted and required rescue by stenting or other treatment, or resulted in myocardial infarction or death. Abrupt closure requires proven association with a mechanical dissection of the treatment site or instrumented vessel, coronary thrombus, or severe spasm. Abrupt closure does not connote no reflow (due to microvascular flow limitation), in which the epicardial artery is patent but had reduced flow. Abrupt closure also does not connote transient closure with reduced flow in which the index treatment application does reverse the closure. Subabrupt Closure. Defined as abrupt closure that occurred after the index procedure is completed (and the subject left the catheterization laboratory) and before the 30-day follow-up evaluation. Threatened Abrupt Closure. Defined as a grade B dissection and 50% diameter stenosis or any dissection of grade C or higher. ACS is defined as ischemic symptoms occurring at rest and lasting 10 minutes or more and occurring within 72 hours before index procedure and either ST-segment deviation of 1 mm or more or elevated levels of a cardiac biomarker of necrosis (CK-MB or troponin T or I greater than the upper limit of normal. If CK-MB or troponin is not available, total CK >2 times upper limit of normal). Subjects with STEMI can be enrolled at any time, and will be classified as ACS and therefore complex, within 14 days after onset of symptoms. An adverse event which was or may have been caused by a device or drug. An adverse event is any undesirable medical occurrence in a clinical study subject, whether it is considered to be related to the drug, the device or neither, that includes a clinical sign, symptom, or condition and/or an observation of a near incident. Any undesirable experience (sign, symptom, illness, abnormal laboratory value, or other medical event) occurring to a subject, whether or not considered related to the investigational product(s) or drug regimen prescribed as part of the clinical protocol, predefined in the clinical protocol and/or IFU, that is identified or worsens during a clinical study. June 29, 2009 Page 73 of 108 Version 4.0

76 Bleeding classification (Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)) Major Bleeding endpoint will be defined by the GUSTO classification of Severe or Moderate as defined below: Severe or lifethreatening Moderate Mild Either intracranial hemorrhage or bleeding that causes hemodynamic compromise and requires intervention Bleeding that requires blood transfusion but does not result in hemodynamic compromise Bleeding that does not meet criteria for either severe or moderate bleeding Bleeding events that are medically important, but that do not meet the severe/moderate levels (e.g. require laboratory testing, evaluation by a physician, ER visit, or cessation of either study medication or other antithrombotic therapies) will be collected. Braunwald Classification of Unstable Angina Severity: Class 1: New onset of severe or accelerated angina. Subjects with new onset (<2 months in duration) exertional angina pectoris that is severe or frequent (>3 episodes/day) or subjects with chronic stable angina who develop accelerated angina (that is, angina distinctly more frequent, severe, longer in duration, or precipitated by distinctly less exertion than previously) but who have not experienced pain at rest during the preceding 2 months. Class 2: Angina at rest, subacute. Subjects with one or more episodes of angina at rest during the preceding month but not within the preceding 48 hours. Class 3: Angina at rest, acute. Subjects with one or more episodes of angina at rest within the preceding 48 hours. Clinical circumstances in which unstable angina occurs: Class A: Secondary unstable angina. Subjects in whom unstable angina develops secondary to a clearly identified condition extrinsic to the coronary vascular bed that has intensified myocardial ischemia. Such conditions reduce myocardial oxygen supply or increase myocardial oxygen demand and include anaemia, fever, infection, hypotension, uncontrolled hypertension, tachyarhythmia, unusual emotional stress, thyrotoxicosis, and hypoxemia secondary to respiratory failure. Class B: Primary unstable angina. Subjects who develop unstable angina pectoris in the absence of an extracardiac condition that have intensified ischemia, as in class A. Class C: Postinfarction unstable angina. Subjects who develop unstable angina within the first 2 weeks after a documented acute myocardial infarction. CABG Coronary Artery Bypass Graft June 29, 2009 Page 74 of 108 Version 4.0

77 Canadian Cardiovascular Society Classification (CCSC) of Angina Class I Class II Class III Class IV Ordinary physical activity does not cause angina, such as walking and climbing stairs. Angina with strenuous or rapid or prolonged exertion at work or recreation. Slight limitation of ordinary activity. Angina upon walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, or in cold, or in wind, or under emotional stress, or only during the first hours after awakening. Angina if walking more than two blocks on the level and climbing more than one flight of ordinary stairs at a normal pace and in normal conditions. Marked limitations of ordinary physical activity. Walking one to two blocks on the level and climbing one flight of stairs in normal conditions and at a normal pace. Inability to carry on any physical activity without discomfort. Angina syndrome may be present at rest. Cerebrovascular Accident (CVA) or Stroke Cerebrovascular accident is defined as the occurrence of cerebral infarction (ischemic stroke) or intracerebral hemorrhage and subarachnoid hemorrhage (hemorrhagic stroke). Stroke is defined as sudden onset of vertigo, numbness, dysphasia, weakness, visual field defects, dysarthria or other focal neurological deficits due to vascular lesions of the brain such as hemorrhage, embolism, thrombosis, or rupturing aneurysm that either: 1. persists more than 24 hours or results in death in less than 24 hours, or 2. persists <24 hours duration if the following treatments were used: a. pharmacologic, i.e. thrombolytic drug administration, or b. non-pharmacologic, i.e. neurointerventional procedure (e.g. intracranial angioplasty) 3. persists <24 hours but has neuro-radiological (MRI or CT) diagnostic changes suggestive of acute tissue injury. Death (ARC Definition) 24 All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established. Specifically, any unexpected death even in subjects with coexisting potentially fatal non-cardiac disease (e.g. cancer, infection) should be classified as cardiac. Cardiac death Any death due to immediate cardiac cause (e.g. MI, low-output failure, fatal arrhythmia). Unwitnessed death and death of unknown cause will be classified as cardiac death. This includes all procedure related deaths including those related to concomitant treatment. Vascular death Death due to cerebrovascular disease, pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular cause. Non-cardiovascular death Any death not covered by the above definitions, including death due to infection, sepsis, pulmonary causes, accident, suicide or trauma. June 29, 2009 Page 75 of 108 Version 4.0

78 Drug Related Adverse Event A drug related adverse event is defined as any adverse event for which a causal relationship between the drug and the event is possibly, probably, or definitely related as determined by the Investigator and confirmed via adverse event medical review. Dissection Classification (NHLBI National Heart, Lung, and Blood Institute) Type A Type B Type C Type D Type E Type F Small radiolucent area within the lumen of the vessel disappearing with the passage of the contrast material. Appearance of contrast medium parallel to the lumen of the vessel disappearing within a few cardiac cycles. Dissection protruding outside the lumen of the vessel persisting after passage of the contrast material. Spiral shaped filling defect with or without delayed runoff of the contrast material in the antegrade flow. Persistent luminal filling defect with delayed run-off of the contrast material in the distal lumen. Filling defect accompanied by total coronary occlusion. Emergent Bypass Surgery Intracoronary Thrombus Emergent Bypass Surgery is defined as coronary bypass surgery performed on an urgent or emergent basis for severe vessel dissection or closure, or treatment failure resulting in new ischemia. Intracoronary Thrombus is defined as the presence of a filling defect within the lumen, surrounded by contrast material seen in multiple projections in the absence of calcium within the filling defect, or the persistence of contrast material within the lumen or a visible embolization of intraluminal material downstream. Lesion Classification (American College of Cardiology/ American Heart Association Class) Type A Type B Type C Minimally complex, discrete (length <10 mm), concentric, readily accessible, non-angulated segment (<45 ), smooth contour, little or no calcification, less than totally occlusive, not ostial in location, no major side branch involvement, and an absence of thrombus. Moderately complex, tubular (length 10 to 20 mm), eccentric, moderate tortuosity of proximal segment, moderately angulated segment (>45, <90 ), irregular contour, moderate or heavy calcification, total occlusions <3 months old, ostial in location, bifurcation lesions requiring double guidewires, and some thrombus present. Type B1: One type B characteristic Type B2: Two or more type B characteristics Severely complex, diffuse (length >2 cm), excessive tortuosity of proximal segment, extremely angulated segments >90, total occlusions >3 months old and/or bridging collaterals, inability to protect major side branches, and degenerated vein grafts with friable lesions. June 29, 2009 Page 76 of 108 Version 4.0

79 Life-Threatening Adverse Drug Experience Major Adverse Cardiac and Cerebral Events (MACCE) Major Bleeding Myocardial Infarction (MI) (ARC Definition) 24 Any adverse drug experience that places the patient or subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death. MACCE is defined as all death, myocardial infarction and stroke. A severe or moderate bleeding complication (based on GUSTO classification). Classification Biomarker Criteria Additional Criteria Peri-procedural PCI (within 48h after PCI) or Peri-Procedural CABG (within 72h after CABG) Spontaneous (>48h following PCI, >72h following CABG) Silent Troponin >3 times URL or CKMB > 3 times URL Troponin >5 times URL or CKMB >5 times URL Troponin >URL or CKMB >URL No biomarker data available Baseline value <URL Baseline value <URL AND Any of the following: New pathologic Q waves or LBBB New native or graft vessel occlusion Imaging evidence of loss of viable myocardium Baseline value <URL AND Any of the following: symptoms of ischemia, ECG changes indicative of new ischemia (new ST-T changes or new LBBB), development of pathological Q waves, or imaging evidence of a new loss of viable myocardium or a new regional wall motion abnormality New pathologic Q waves or LBBB June 29, 2009 Page 77 of 108 Version 4.0

80 Myocardial Infarction (MI) (ARC Definition) 24 (Continued) Classification Biomarker Criteria Additional Criteria Sudden Death Reinfarction (base definition) (Infarction extension) Death before biomarkers obtained or before expected to be elevated Stable or decreasing values on 2 samples AND 20% increase 3-6 hours after second sample Symptoms suggestive of ischemia AND Any of the following: New ST elevation or LBBB Documented thrombus by angiography or autopsy If biomarkers increasing or peak not reached then insufficient data to diagnose recurrent myocardial infarction. Adapted from Global Task Force [Universal Definition of Myocardial Infarction (Thygesen et al.)] 25 Baseline biomarker value required before study procedure and presumes a typical rise and fall Pathologic Q waves may be defined according to the Global Task Force, Minnesota code, or Novacode URL = upper reference limit, defined as 99 th percentile of normal reference range LBBB = left bundle branch block ST = stent thrombosis PCI = percutaneous coronary intervention CABG = coronary artery bypass graft Perforation Percutaneous Coronary Intervention (PCI) Procedure Success Perforations will be classified as follows: Angiographic perforation: perforation detected by the clinical site or the core laboratory at any point during the procedure. Clinical perforation: perforation requiring additional treatment (including efforts to seal the perforation or pericardial drainage), or resulting in significant pericardial effusion, abrupt closure, myocardial infarction, or death. Pericardial hemorrhage/tamponade: perforation resulting in cardiac tamponade. Refers to all interventional cardiology methods for treatment of coronary artery disease. Attainment of <30% residual stenosis of the target lesion and no inhospital MACCE. June 29, 2009 Page 78 of 108 Version 4.0

81 Serious Adverse Event (SAE) A serious adverse event is any untoward medical occurrence that: Results in death Is life-threatening (immediate risk of death) Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Results in congenital anomaly/birth defect Other important medical event Stent Thrombosis (ARC Definition) 24 Stent Thrombosis should be reported as a cumulative value over time and at the various individual time points as specified below. Time 0 is defined as the time point after the guiding catheter has been removed and the subject has left the cardiac Cathlab. Timing: Acute stent thrombosis(1): 0 24 hours post stent implantation Subacute stent thrombosis(1): > 24 hours 30 days post stent implantation Late stent thrombosis(2): >30 days 1 year post stent implantation Very late stent thrombosis(2): >1 year post stent implantation (1) acute or subacute can also be replaced by the term early stent thrombosis. Early stent thrombosis (0 30 days) will be used in the remainder of this document. (2) including primary as well as secondary late stent thrombosis; secondary late stent thrombosis is a stent thrombosis after a target segment revascularization. June 29, 2009 Page 79 of 108 Version 4.0

82 Stent Thrombosis (ARC Definition) (Continued) Definite stent thrombosis We recognize three categories of evidence in defining stent thrombosis. Definite stent thrombosis is considered to have occurred by either angiographic or pathologic confirmation. Angiographic confirmation of stent thrombosis Thrombolysis In Myocardial Infarction (TIMI) flow is: A. TIMI flow grade 0 with occlusion originating in the stent or in the segment 5mm proximal or distal to the stent region in the presence of a thrombus(*). B. TIMI flow grade 1, 2, or 3 originating in the stent or in the segment 5mm proximal or distal to the stent region in the presence of a thrombus(*). AND at least one of the following criteria has been fulfilled within a 48 hour time window: 1. new acute onset of ischemic symptoms at rest (typical chest pain with duration >20 minutes) 2. new ischemic ECG changes suggestive of acute ischemia 3. typical rise and fall in cardiac biomarkers (refer to definition nonprocedural related MI). Comment: the incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not considered a confirmed stent thrombosis (silent occlusion). (*) Intracoronary thrombus [Ellis et al., Mabin et al., Capone et al.] (ref. 5,6,7) Non-occlusive thrombus: Intracoronary thrombus is defined as a (spheric, ovoid or irregular) noncalcified filling defect or lucency surrounded by contrast material (on three sides or within a coronary stenosis) seen in multiple projections, or persistence of contrast material within the lumen, or a visible embolization of intraluminal material downstream. Occlusive thrombus: A TIMI 0 or TIMI 1 intra-stent or proximal to a stent up to the most adjacent proximal side branch or main branch (if originating from the side branch). June 29, 2009 Page 80 of 108 Version 4.0

83 Stent Thrombosis (ARC Definition) (Continued) Probable stent thrombosis Possible stent thrombosis Stroke Study Deviation Pathologic confirmation of stent thrombosis Evidence of recent thrombus within the stent determined at autopsy or via examination of tissue retrieved following thrombectomy. Probable stent thrombosis Clinical definition of probable stent thrombosis is considered to have occurred after intracoronary stenting in the following cases: 1) Any unexplained death within the first 30 days. 2) Irrespective of the time after the index procedure any myocardial infarction (MI), which is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause. Possible stent thrombosis Clinical definition of possible stent thrombosis is considered to have occurred with any unexplained death from 30 days following intracoronary stenting until end of trial follow-up. See Cerebrovascular Accident (CVA) or Stroke above. An incident where the Investigator or site personnel did not conduct the study according to the clinical protocol or the Investigator agreement. Major deviation: Any deviation from subject inclusion and exclusion criteria or subject informed consent procedures. Minor deviation: Deviation from a clinical protocol requirement such as incomplete/inadequate subject testing procedures, non-compliance with medication regimens, follow-ups performed outside specified time windows, etc. Target Lesion Revascularization (TLR) (ARC Definition) 24 Target Vessel Revascularization (TVR) (ARC Definition) 24 Non Target Lesion Revascularization (Non TLR) (ARC Definition) 24 TLR is defined as any repeat percutaneous intervention of the target lesion or bypass surgery of the target vessel performed for restenosis or other complication of the target lesion. The target lesion is defined as the treated segment starting 5 mm proximal to the stent and ending 5 mm distal to the stent. TVR is defined as any repeat percutaneous intervention or surgical bypass of any segment of the target vessel. The target vessel is defined as the entire major coronary vessel proximal and distal to the target lesion including upstream and downstream branches and the target lesion itself. Any revascularization in a lesion other than the target lesion is considered a non-tlr. June 29, 2009 Page 81 of 108 Version 4.0

84 Non Target Vessel Revascularization (Non TVR) (ARC Definition) 24 Any revascularization in a vessel other than the target vessel is considered a non-tvr. Thrombolysis in Myocardial Infarction (TIMI) classification TIMI 0 TIMI 1 TIMI 2 TIMI 3 - No perfusion - Penetration with minimal perfusion. Contrast fails to opacify the entire bed distal to the stenosis for the duration of the cine run. - Partial perfusion. Contrast opacifies the entire coronary bed distal to the stenosis. However, the rate of entry and/or clearance is slower in the coronary bed distal to the obstruction than in comparable areas not perfused by the dilated vessel. - Complete perfusion. Filling and clearance of contrast equally rapid in the coronary bed distal to stenosis as in other coronary beds. Unanticipated Adverse Device Effect (Device UADE) Unexpected Adverse Drug Experience (Drug UADE) Vascular Complications An unanticipated adverse device effect (device UADE) is defined as any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of patients. Any adverse drug experience, the specificity or severity of which is not consistent with the current product insert, investigator brochure; or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. "Unexpected," as used in this definition, refers to an adverse drug experience that has not been previously observed (e.g., included in the investigator brochure or product insert) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product. Vascular complications may include the following: 1. Pseudoaneurysm 2. Arteriovenous fistula (AVF) 3. Peripheral ischemia/nerve injury 4. Vascular event requiring transfusion or surgical repair June 29, 2009 Page 82 of 108 Version 4.0

85 Acronyms and/or Abbreviations Acronym/ Abbreviation Term % DS Percent diameter stenosis % VO Percent volume obstruction g Microgram ABR Angiographic binary restenosis ACC American College of Cardiology ACT Activated clotting time ACS Acute Coronary Syndrome AE Adverse event AHA American Heart Association ALP Alkaline phosphatase ALT Alanine aminotransferase ARC Academic Research Consortium AST Aspartate aminotransferase atm Atmospheric pressure AVF Arteriovenous fistula BID Twice Daily BMS Bare Metal Stent BUN Blood urea nitrogen CABG Coronary artery bypass graft CBC Complete blood count CCSC Canadian Cardiovascular Society Classification CEC Clinical Events Committee CFR Code of Federal Regulations CFR Coronary flow reserve CHF Coronary Heart Failure CK Creatine kinase CK-MB Creatine kinase myocardial-band isoenzyme cm Centimeter COA Condition of Approval study CPK Creatine Phosphokinase ecrf Electronic case report form CRO Contract Research Organization CVA Cerebrovascular accident DCA Directional coronary atherectomy DES Drug Eluting Stent DFU Directions for Use dl Deciliter DS Diameter stenosis DSMB Data Safety Monitoring Board ECG Electrocardiogram EC Ethics Committee ecrf Electronic Case Report Form FFR Fractional flow reserve FIM First-in-man FPG Fasting plasma glucose GCP Good Clinical Practice June 29, 2009 Page 83 of 108 Version 4.0

86 Acronym/ Abbreviation GGT GI gm GP HCRI HCT HDL HGB HHS HIPAA ICH IDE IFU in IRB ITT IVRS IVUS L/l LA LAD LCX LDL LIMA LV LVEF MACCE MACE MEC MedDRA mg MI MLA MLD mm mmol mrna mtor NHLBI NSTEMI NTG OGTT PC PCI PG Plt PMS PRN Term Gamma glutamyl transferase Gastrointestinal Gram Glycoprotein Harvard Clinical Research Institute Hematocrit High density lipoprotein Hemoglobin Health and Human Services (Department of) Health Insurance Portability and Accountability Act International Conference on Harmonization Investigational Device Exemption Instructions for Use Inch Institutional Review Board Intent-to-treat Interactive Voice Response System Intravascular ultrasound Liter Liposomal Alendronate Left anterior descending coronary artery Left circumflex coronary artery Low density lipoprotein Left internal mammary artery Lumen volume Left ventricular ejection fraction Major Adverse Cardiac and Cerebral Event Major Adverse Cardiac Event Medical Ethics Committee Medical Dictionary for Regulatory Activities, ICH Standardization of Terminology Milligram Myocardial infarction Minimal lumen area Minimum luminal/lumen diameter Millimeter Millimole Messenger ribonucleic acid Mammalian target of rapamycin National Heart, Lung, and Blood Institute [Dissection Grade Classification] Non-ST segment Elevation Myocardial Infarction Nitroglycerin Oral glucose tolerance test Phosphorylcholine Percutaneous coronary intervention Post-load glucose Platelet Post Marketing Surveillance study As Required June 29, 2009 Page 84 of 108 Version 4.0

87 Acronym/ Abbreviation PTCA PVD QD QCA RBC RCA RCT RIMA RVD SAE SD SGOT SGPT ST STEMI SV TIA TIMI TLR TPD TSR TVF TVR UADR ULN US USFDA VO WBC WHO Term Percutaneous transluminal coronary angioplasty Peripheral Vascular Disease Once Daily Quantitative coronary angiography Red blood cell Right coronary artery Randomized Controlled Trial Right internal mammary artery Reference vessel diameter Serious adverse event Standard deviation Serum glutamic oxaloacetic transaminase Serum glutamic pyruvic transaminase Stent Thrombosis ST segment Elevation Myocardial Infarction Stent volume Transient ischemic attack Thrombolysis in myocardial infarction Target lesion(s) revascularization Trademark Therapeutic Products Directorate Target site revascularization Target vessel failure Target vessel revascularization Unexpected Adverse Drug Reaction Upper Limit of Normal United States United States Food and Drug Administration Volume obstruction White blood cell World Health Organization June 29, 2009 Page 85 of 108 Version 4.0

88 10 Data Submission Requirements Required Data All required data for this trial will be collected via electronic case report forms (ecrf) and securely transferred by a 21 CFR Part 11 compliant electronic data capture (EDC) system. All data points are required in the ecrf unless otherwise noted on the form. The completed ecrfs are the sole property of HCRI and should not be made available in any form to third parties, except for authorized representatives of HCRI or appropriate regulatory authorities, without written permission from HCRI Data Collection Electronic Case Report Form Development, Modification and Maintenance The final set of ecrfs will be designed to accommodate the specific features of the trial design. Modification of ecrfs will only be made if deemed necessary by HCRI. Components of the ecrf: 1. Enrollment confirmation and subject eligibility. 2. Baseline subject demographic and clinical data. 3. Procedure data (including procedural complications). 4. Hospital discharge data (including post-procedural complications, ischemic or vascular complications, in-hospital major events, and pertinent laboratory tests). 5. Serious Adverse Events. 6. Information relating to antiplatelet compliance 7. Clinical event follow-up data related to study endpoints (includes incidence and timing of any ischemic or major clinical event from hospital discharge to study completion, such as death, stroke, bleeding complication, MI, and stent thrombosis). Description of data variables to be collected The ecrf will have separate pages to capture data on MACCE and surgical procedures, and separate pages to collect concomitant medication information. The concomitant medication page will be limited to capture data on relevant antiplatelet medication and those identified in Section 3.7. Table 7. Data variables and documents to be collected The list is not all-inclusive; please refer to ecrf for further details. Time Baseline Variable Age Gender Race and Ethnicity Inclusion/Exclusion Exceptions Current Cardiac status June 29, 2009 Page 86 of 108 Version 4.0

89 Time Variable Cardiac History Cardiac Risk factors Lab values Lesion characteristics Vessel Lesion location Lesion type Degree of tortuosity Degree of calcification Thrombus present TIMI flow Pre-procedure angiography (complete visual estimate in ecrf): Procedure Post procedure final result Hospital Discharge Follow-up (6, 12, 15, 24, 30, and 33 months) In case a death occurred Reference Vessel Diameter (RVD) in mm Pre-procedure Minimum Lumen Diameter (MLD) in mm Lesion length in mm Date of Procedure Number of stents used Study Stent details Antiplatelet medication Concomitant medication Procedural complications Diameter Stenosis (%) Date of discharge Any new MACCE event since the procedure Current Cardiac status Antiplatelet Medication Concomitant medication Date of follow-up Type of follow-up (telephone) MACCE events ST events Major Bleeds Change in Antiplatelet Medication Concomitant medication In case of death, please provide, if available a copy of: hospital discharge letter death certificate / autopsy report multiple ECGs related to event all available lab results all angiograms (procedure and event related) June 29, 2009 Page 87 of 108 Version 4.0

90 Time In case an MI occurred In case a Stent Thrombosis occurred In case of Major Bleeding complications In case of Stroke In case of PCI Variable cath lab report / technical worksheet In case of an MI, please provide, if available a copy of: hospital discharge letter multiple ECGs related to event all available lab results all angiograms (procedure and event related) cath lab report / technical worksheet In case of a (suspected) stent thrombosis, please provide, if available a copy of: hospital discharge letter multiple ECGs related to event all lab results all angiograms (procedure and event related) cath lab report / technical worksheet In case of a bleeding complication, please provide, if available a copy of: hospital discharge letter relevant lab results (HGB, HCT) Neurological Event ecrf should be completed MRI or CT-scan if available (data shipped to HCRI for inclusion in source documentation packet) For any surgical or percutaneous TL or non-tl intervention, the revascularization form should be completed. Angiograms should be collected for all TLR and TVR after 12 months Data Collection and Tracking It is the investigator's responsibility to ensure completion and to review and approve all ecrfs. A pre-determined subset of ecrfs will be signed by the principal investigator or authorized staff member. These signatures serve to attest that the information contained on the ecrfs is true. At all times, the investigator has final personal responsibility for the accuracy and authenticity of all clinical and laboratory data entered on the ecrfs. Subject source documents are the physician's subject records maintained at the trial site. In most cases, the source documents will be the hospital's or the physician's chart. In cases where the source documents are the hospital or the physician's chart, the information collected on the ecrfs must match those charts. Research coordinators at each clinical site will perform primary data collection from source document (e.g., hospital chart, office record) reviews. Data will be entered by the site personnel into ecrfs on the internet-based EDC system. This will ensure data are forwarded to HCRI in an expedited fashion. HCRI will provide selected clinical monitoring, including review of EDC data. Please see Table 8 below for ecrf submission details. June 29, 2009 Page 88 of 108 Version 4.0

91 In the initial phase of the protocol, periodic teleconference calls between HCRI/designated CRO and each clinical site may be performed to resolve any problems concerning the protocol and data collection. Periodic recruitment status reports generated by the EDC system will identify variations in recruitment frequency among sites. If any action is taken by an IRB/EC with respect to the study, the information must be forwarded to HCRI. Time Windows for Expected Completion of Electronic Case Report Forms/Reports The ecrf data submission detailed in the following table should be completed as follows: Table 8. Responsibilities for Submitting ecrfs Type of ecrf Prepared by Investigator For Time of Notification Subject Enrollment ecrf HCRI Within 24 hours of enrollment Baseline ecrfs HCRI Within 48 hours of enrollment Hospital Discharge Form HCRI Within 48 hours of ecrf Clinical Follow-up ecrfs HCRI discharge Within 48 hours of subject contact Unanticipated Serious Adverse Event ecrf HCRI, IRB/EC Within 24 hours of knowledge of event Major Event ecrfs HCRI Within 48 hours of event occurrence Study Exit ecrf HCRI Within 48 hours of subject exit Other data and reports detailed in the following table should be submitted (by fax, mail, or overnight courier, if necessary) to HCRI as follows: June 29, 2009 Page 89 of 108 Version 4.0

92 Table 9. Responsibilities for Submitting Reports and Other Data Type of Notification/Report Informed consent not obtained from subject Subject death during the investigation Unexpected Adverse Drug/Device Effect/Reaction (drug or device UADE, UADR) Withdrawal of IRB/EC approval Annual reports Deviation from the Investigational Plan (Emergency) Prepared by Investigator For Notify HCRI and IRB/EC Notify HCRI and IRB/EC Notify HCRI and IRB/EC Notify HCRI Submit to HCRI and IRB/EC, FDA Notify HCRI and IRB/EC, FDA Time of Notification Within 5 working days of index procedure Within 1 working day of knowledge of event Within 24 hours of knowledge of event Within 5 working days of withdrawal Annually Within 5 working days of deviation Final report IRB/EC, FDA Within 3 months of study completion or termination Endpoint Reporting Data related to Major Adverse Cerebral and Cardiac Events (MACCE), which are expected Serious Adverse Events, will be recorded in the ecrf within 10 working days after the investigator becomes aware of the event. In accordance with the primary objectives of this study, adverse event collection is mainly focused on the collection of Major Adverse Cerebral and Cardiac Events as this is a widely accepted clinical parameter at assessing the impact of PCI with stent placement. All FDA-approved stents and drugs used in the study have had extensive data collected related to product safety and efficacy. This study will collect data related to the primary clinical endpoint (MACCE) as well as stent thrombosis and major bleeding, irrespective of whether it is related to a MACCE. June 29, 2009 Page 90 of 108 Version 4.0

93 Table 10. Endpoint Reporting Requirements Major Adverse Cerebral and Cardiac Events (MACCE) Investigator submit to: HCRI by ecrf Stent Thrombosis Investigator submit to: HCRI by ecrf Major Bleeding Investigator submit to: HCRI by ecrf Death Investigator submit to: HCRI by ecrf Within 10 working days after the investigator first learns of the event. Within 10 working days after the investigator first learns of the event. Within 10 working days after the investigator first learns of the event. Within 24 hours after the investigator first learns of the event Investigator Records The investigator is responsible for the preparation and retention of the records cited below. All of the records below, with the exception of subject s hospital file, should be kept in the Investigator Site File (i.e., regulatory binder provided to the investigator) or appropriate Subject Study Binder. Subject s medical record Protocol and, if applicable, any amendment Instructions For Use/Package Inserts Blank IRB/EC approved Informed Consent Signed and dated informed consent for each subject Signed and dated Clinical Trial Agreement IRB/EC approval documentation for protocol, amendments and informed consent Indemnification agreement, if applicable Enrollment confirmation for each subject Curriculum Vitae, principal investigator and sub-investigators Safety reports and the progress reports to the IRB/EC, if required Any other records that IRBs\ECs or other local regulatory agencies require to be maintained Sponsor Records HCRI and/or the designated CRO will maintain the following records: All study documents and correspondence which pertains to the study Protocol and, if applicable, any amendments List of participating institutions Names/contact addresses of monitors Statistical analyses and underlying supporting data June 29, 2009 Page 91 of 108 Version 4.0

94 Enrollment procedure Final report of the clinical investigation Signed and dated Clinical Trial Agreements Copies of all IRB/EC approval documentation Instructions for Use/Package Inserts IRB/EC approved informed consent Indemnification agreement, if applicable Any other records that FDA requires to be maintained Depending on final HCRI and/or its designee CRO responsibilities, certain Sponsor records may be filed at the CRO during the course of the study. June 29, 2009 Page 92 of 108 Version 4.0

95 11 Study Responsibilities and Quality Assurance 11.1 Investigator Responsibility for Study Conduct The post-market release study will be conducted according to the Declaration of Helsinki, ISO 14155, 21 CFR 822 and applicable local regulations. The adverse event collection will be focused on clinical events specific to drug eluting stents and bleeding complications. The participating investigator is responsible for adhering to this protocol, the Declaration of Helsinki, ISO 14155, 21 CFR 822, the agreement and the regulatory requirements. It is the responsibility of each study-site Principal Investigator to provide the current study protocol to all sub-investigators and other staff responsible for study conduct, as well as provide for the training of all sub-investigators or other staff involved in the conduct of this research. Study-site Principal Investigators will acknowledge that the use of electronic signatures within the EDC system are the legally binding equivalent of traditional handwritten signatures and that they will be accountable and responsible for actions initiated under their electronic signatures. Upon completion of the trial, the Principal Investigator will submit a final written report to HCRI, and the reviewing IRB or EC. The report should be submitted to HCRI within three (3) months of completion or termination of the study. Investigator / Site selection For this study, the following investigator/site selection criteria are applicable: Center must have sufficient patient population Investigator should have adequate dedicated staff that has time to manage the study Center must be willing to comply with the protocol and data requirements Center has preferably demonstrated experience with conducting clinical (device and drug) trials that comply with applicable regulatory standards Center has an Internet connection with sufficient speed of data transfer Stents are available from hospital stock Center willing to participate in study with follow-up of subjects for 33 months All investigators will be appropriately qualified practitioners legally entitled to practice, and experienced in the diagnosis and treatment of subjects requiring a percutaneous coronary intervention (PCI) procedure with a Drug Eluting or Bare Metal Stent. The following documentation (at a minimum) must be in place before site initiation both at the participating site and at HCRI (or the designated CRO) before subject enrollment begins: IRB/EC approval Signed Site Clinical Trial Agreement 11.2 Study Data Reporting and Processing HCRI will develop a study specific Electronic Data Capture (EDC) system that will capture all data as defined in the study protocol. This system will be hosted on a central, secure server provided and managed to good clinical practice (GCP) levels of security. Data entered into the system will be transmitted to the server utilizing Secure Sockets Layer (SSL) technology and 128-bit June 29, 2009 Page 93 of 108 Version 4.0

96 encryption. HCRI Data Management will review and clean the data on an ongoing basis for accuracy and consistency and send queries to sites as needed. Standard reports will be available on the EDC system to track such items as data entry compliance and current enrollment Training The training of appropriate clinical site personnel will be the responsibility of HCRI and/or its designees prior to or at the initiation. The Investigator is responsible for ensuring that his/her staff conduct the study according to the protocol. To ensure compliance with the protocol requirements, HCRI and/or designee will present a formal training session to study site personnel that will include review of all aspects of the study to include protocol and ecrf review, review of regulatory requirements, specific study procedures, informed consent process, and drug and device accountability. HCRI will provide training on the EDC system at a formalized, pre-study training session(s) (e.g. via webcast) and throughout the study as necessary. Additional assistance with ecrf data entry questions may be provided via the site monitor Confidentiality and Protection of Study Files The EDC system requires a unique combination of Username and Password for access to the study data. Access rights are governed by the role of that individual user, and only those tasks or data that are authorized will be allowed by the system. This includes Investigators, Site Personnel, Monitors, and HCRI personnel. Access to the system will not be granted to any individual until it can be demonstrated that the individual has the knowledge, skill and education to perform their expected tasks and has been positively identified in compliance with 21 CFR, Part 11. At HCRI, access rights are assigned to appropriate personnel to insure confidentiality and protection of the cleaning and analysis databases. HCRI will assign user access rights to subject data only to the appropriate qualified study personnel Source Documentation Requirements Regulations require that Investigators maintain information in the study subject s medical records which corroborate data collected on the electronic case report forms (ecrf). In order to comply with these regulatory requirements, the Investigator will maintain and make available as required by HCRI or Quintiles monitors (or qualified contract monitor) and/or its regulatory inspectors the following information that includes but is not limited to: 1. Signed Informed Consent documents. 2. Medical history/physical condition of the study subject before involvement in the study sufficient to verify protocol entry criteria. 3. Dated and signed notes in the subject s medical record on the day of entry into the study that identify: the subject s date of entry into the study, the clinical site, subject number assigned and a statement that informed consent was obtained and a signed copy given to the subject.. June 29, 2009 Page 94 of 108 Version 4.0

97 4. Dated and signed notes for each study subject contact with reference to the ecrfs for further information, if appropriate (for specific results of procedures and exams). 5. Description of device implantation procedure (material used, drugs administered during the procedure, date, time duration, angiographic, US and clinical findings, etc.). 6. Notations for example; clinically significant or not clinically significant on abnormal lab results and their resolution. 7. Dated printouts or reports of any special assessments, i.e., ECGs, laboratory tests. 8. Serious adverse event reporting and follow-up of the serious adverse events (minimally event description, severity, onset date, duration, relation to study device/drug, outcome and treatment for serious adverse event). 9. Source documents relative to suspected endpoint events. 10. Progress notes regarding concomitant medications taken during the study (including start and stop dates). 11. Study subject s condition upon completion of or withdrawal from the study Procedures for Database Management Data collected on each subject will be recorded on a web-based electronic Case Report Form (ecrf). A paper version of the ecrfs may be printed at the sites to use as a working copy. Instructions for proper completion of the ecrf and how the web-based system is used will be provided to the clinical site. The investigator or an authorized member of the investigational team must sign all completed ecrfs, by using an electronic signature (the electronic signatures will be provided by HCRI at the start of the study). The clinical study team at HCRI (or designated CRO) is responsible for assuring that the investigator has completed the ecrfs correctly. Data will be checked for consistency and completeness on a regular basis, both manually as well as by using computer software capabilities of the clinical database. Electronic Data Clarification Forms will be used to document the recovery of incomplete, inconsistent, or missing data Protocol Deviations A protocol deviation is defined as any instance during the conduct of the study where the clinical investigator or other site personnel changed or failed to adhere to the study design or procedures specified by the protocol approved by the US Food and Drug Administration (FDA) or the equivalent applicable Competent Authority in other countries, and the Investigational Review Board/Ethics Committee that oversees the Investigative Site. Examples of protocol deviations may include: a) enrollment of a study subject who does not meet all of the inclusion/exclusion criteria specified in the protocol; b) failure to obtain a key safety procedure or lab test; or c) enrollment of a patient during a lapse in IRB approval of the study. Each Investigator shall conduct this clinical study in accordance with this clinical protocol, FDA regulations, Good Clinical Practices, and any conditions of approval imposed by their IRB/EC. Failure to comply with and/or inability to meet FDA regulations may jeopardize further participation of the Investigator or Investigative Center in this and future clinical studies. June 29, 2009 Page 95 of 108 Version 4.0

98 All relevant protocol deviations are submitted, reviewed and assessed for their impact on subject safety by HCRI. Each Investigative Center will receive notifications of its deviations at least annually. Investigators are required to notify HCRI/Quintiles clinical study management before initiating any deviations from the protocol, except where necessary to protect the life or physical well being of a subject in an emergency. Notification shall be documented in writing and maintained in clinical study management and investigator files. Prior notification is generally not expected in situations where unforeseen circumstances are beyond the Investigator s control, (e.g., subject did not respond to scheduled follow-up, blood sample lost by laboratory, etc.), however, the event is still considered a deviation. Specific deviations shall be reported to HCRI regardless of whether medically justifiable, preapproved by HCRI, or taken to protect the subject in an emergency. Subject specific deviations will be reported through the EDC system. Reported protocol deviations will be classified into 4 categories are as follows: 1. Issues related to subject informed consent or confidentiality 2. Deviations from protocol inclusion and exclusion criteria 3. Deviations associated with medication compliance 4. Deviations associated with follow-up compliance (including deviations from protocol specified evaluations as well as subjects missing their scheduled visits) Major Deviations are defined as any unapproved change in the study procedures or study design that are within the Investigator s control that may adversely affect the participant s rights, safety or well-being, or the accuracy and reliability of the study data. Minor Deviations are defined as any unapproved change in the study procedures that are within the Investigator s control that do not have an impact on the participant s rights, safety or well-being, or the accuracy and reliability of the study data. Investigators will also adhere to procedures for reporting protocol deviations to their IRB/EC in accordance with their specific IRB/EC reporting policies and procedures. Regulations require that Investigators maintain accurate, complete and current records, including documents showing the dates of and reasons for each deviation from the protocol. Any major deviations that will be reported to the IRB/EC should also be recorded on the ecrf for collection and review by HCRI Data Transmittal and Record Retention Required data will be recorded on the appropriate ecrf at the time of or as soon as possible after the subject contact or the availability of test results. Any supporting documents must be faxed to HCRI or designee and/or retrieved from the Investigator according to the outlined time windows. Sponsor records and reports will be stored at HCRI during the course of the study. Site specific records may be stored at HCRI and/or the monitoring CRO during the course of the study. After the closure of the study, all records and reports will be archived by HCRI permanently. June 29, 2009 Page 96 of 108 Version 4.0

99 The investigator must be willing to give access to study monitors, auditors, EC/IRB members and FDA inspectors, and have appropriate facilities to retain relevant study documents. Investigators records will be retained for at least two years after the formal discontinuation of clinical development of the device, and according to the local IRB/EC requirements Monitoring Procedures Site Initiation Prior to subject enrollment, a study initiation will be conducted to ensure the following: IRB/EC approval has been obtained and documented prior to subject screening, the Investigators and study personnel are appropriately trained and clearly understand the study, the Investigators and study personnel accept the obligations incurred in undertaking this clinical investigation. Documentation of the training of key site personnel will be completed prior to or during the site initiation. Periodic Monitoring visits In order to ensure a high degree of data quality, selected clinical sites will be monitored with an onsite visit and through remote monitoring in accordance with the Monitoring Plan. These on- site visits will be conducted to monitor the following on selected subjects: compliance with the protocol and adherence to the data collection procedures, to assess the accuracy and completeness of submitted clinical data, to verify that records and documents are being properly maintained for the duration of the study. The monitor will perform source data verification by reviewing original subject documents. Monitoring will consist of 100% of source document data on all reported endpoint events and predefined non-event critical fields on an approximate 10% subject sampling. Pre-defined critical fields will be monitored for all sampled subjects including, but not limited to, those related to informed consent, inclusion/exclusion criteria, medical history, and post randomization study visits. Additional monitoring, including a larger subject sampling, will be conducted at any site if deemed necessary. Frequency of the monitoring will be based on subject enrollment, compliance and any suspected inconsistency in data that requires investigation. Monitoring processes and procedures are outlined in the Monitoring Plan. Study Close Out Upon completion of the clinical study (when all subjects have completed the follow-ups, all data has been entered into the EDC system and cleaned, all queries resolved, and final electronic signatures have been obtained a closeout will be conducted to ensure regulatory compliance with regard to record retention, proper disposition of the study drug and accountability, and most importantly that the site is audit ready Study Suspension or Study Early Termination If a center is terminated or suspended, no additional enrollments will be allowed at the center. Possible reasons for clinical investigator or center termination or suspension include but are not limited to: Non compliance to obtain patient informed consent Non compliance with adhering to the inclusion/exclusion criteria Failure to follow subjects per scheduled follow-ups Failure to submit data in a timely manner IRB/EC approval expiration June 29, 2009 Page 97 of 108 Version 4.0

100 IRB/EC suspension of the center If the study is terminated prematurely or suspended: HCRI will promptly inform the clinical investigators of the termination or suspension and the reasons, and inform the U.S. FDA. The IRBs/ECs will also be promptly informed and provided with the reasons(s) for termination or suspension by HCRI or by the clinical investigator. The investigator will promptly inform the subjects and the personal physician of the subjects, assure appropriate therapy and follow-up for the subjects. In case of early termination the investigator agreement will be terminated. If the investigator (or IRB/EC) terminates or suspends the investigation without prior agreement of HCRI: The investigator will promptly inform HCRI and the IRB/EC, and provide a detailed written explanation of the termination or suspension. The investigator will inform the institution. The investigator will promptly inform the subjects and the personal physician of the subjects, and assure appropriate therapy and follow-up for the subjects. HCRI will inform the regulatory authority. In case of early termination the investigator agreement will be terminated. Subject follow-up in case of study early termination In case of early termination, the subjects need to be followed until at least 30-days after the index procedure. June 29, 2009 Page 98 of 108 Version 4.0

101 12 Study Committees 12.1 Executive Operations Committee The Executive Operations Committee will be responsible for the day-to-day administrative management of the trial. This committee will meet periodically by teleconference to monitor subject enrollment, clinical site progress, and protocol compliance. This committee will be responsible for reviewing the final results, determining the methods of presentation and publication, and selection of secondary projects and publications by members of the Steering Committee. Committee Members: Laura Mauri, M.D., Principal Investigator Dean Keriakes, M.D., Co-Principal Investigator Mitch Krucoff, M.D. Donald Cutlip, M.D. Sharon-Lise Normand, PhD Theodora Cohen, PhD Suzanne Morin 12.2 Steering Committee The Steering Committee consists of members of the Executive Operations Committee and others outlined below. The Steering Committee participates in HCRI requested meetings to review study progress and conduct and to provide feedback to Executive Operations Committee on an ad hoc basis. Committee Members: TBD 12.3 Data Safety Monitoring Board (DSMB) The Data Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC) is composed of at least five members (physicians from the fields of cardiology and interventional cardiology and at least one biostatistician), who are not directly involved in the conduct of the trial. The DSMB will review the study (including reported SAEs) on a periodic basis to be defined at their first meeting. Based on the safety data, the DSMB may recommend that the Executive Operations Committee modify or stop the trial. All final decisions, however, regarding trial modifications, rest with the Executive Operations Committee. No formal statistical rule for stopping the trial will be defined in this trial and no formal interim analysis is planned. The DSMB will remain blinded to the treatment assignment (duration of DAPT) and masked to study drug (as well as study device) in their review and analysis of all endpoint events and SAEs. If the DSMB requests reports that unblind or unmask the above study data, HCRI will notify the FDA of such requests. June 29, 2009 Page 99 of 108 Version 4.0

102 12.4 Clinical Events Committee (CEC) The Clinical Events Committee (CEC) is made up of interventional and non-interventional cardiologists and other clinical experts as required who are not participants in the DAPT Study. The CEC is charged with the adjudication of pre-specified clinical endpoint events. Adjudication of events for qualification into the randomized subject population is not a requirement under this protocol. At the onset of the trial, the CEC will establish specific criteria used for the categorization of clinical endpoint events, explicit rules outlining the minimum amount of data required for adjudication of each event, and the algorithm followed in order to classify a study endpoint related clinical event. All members of the CEC will remain blinded to the treatment assignment (duration of DAPT) and masked to study drug (as well as study device) in their review and adjudication of all endpoint events. The CEC will meet regularly to review and adjudicate clinical endpoint events for which the required minimum data are available. The procedures by which the CEC will operate will be documented in a separate manual. All endpoint events, including all deaths, occurring after the first 12 months for the randomized subjects will be adjudicated by the CEC. Angiographic assessment of suspected stent thrombosis is critical for CEC adjudication. Since an angiographic core laboratory is not planned for this study, appropriate expertise of the CEC membership will be utilized to provide this assessment. The determination of stent thrombosis will be based on the location of the occlusion and presence of thrombus as assessed by the CEC, composed of at least 2 interventional cardiologists. The CEC will be blinded to duration of antiplatelet therapy, and masked to drug and stent type, and investigator. In order to allow the independent assessment of the angiograms, the CEC interventional cardiologists will review the angiograms in the absence of clinical data first, before reviewing the event with the totality of the evidence with the entire committee. An attempt will be made to resolve all disagreements with consensus; however, in case of a tie, an additional interventional cardiologist will be asked to assess the angiogram and event. Independent and blinded assessment of the electrocardiogram will also be performed by board certified cardiologists who serve as members of the CEC. The electrocardiogram will be interpreted as whether ST elevation or ST depression suggestive of myocardial infarction is present and if the evolution of the electrocardiograms indicate evidence of Q wave myocardial infarction. The readers will also use electrocardiographic evidence to code the event as likely related to the target vessel territory or non-target vessel territory. The electrocardiogram will be interpreted by the CEC for all suspected myocardial infarctions that are referred to CEC for adjudication. The ECG will be interpreted first in the absence of clinical data and then utilized to provide a final adjudication based on the totality of clinical data. Adjudications for myocardial infarction and probable stent thrombosis will depend on the electrocardiographic interpretation. In the absence of an ECG core laboratory, the CEC members will use criteria based on the Minnesota code for ECG interpretation: June 29, 2009 Page 100 of 108 Version 4.0

103 1. Q wave myocardial infarction will be diagnosed when newly present Q waves that measure at least 40 msec width and 1 mm depth are identified in 2 or more contiguous ECG leads. 2. ST elevation will be defined as at least 1 mm of ST segment elevation in 2 or more contiguous limb leads or at least 2 mm elevations in 2 or more precordial leads V1- V4. The relationship to study drug of each major bleeding event will be determined by the CEC while the trial is ongoing (after randomization). If, prior to the occurrence of the event, study drug was discontinued for more than 14 days, the event will not be counted as associated with the drug (this analysis will be performed independently of the CEC adjudication of the event itself). The CEC will not differentiate between the comparative groups with this 14 day cut off Study Enrollment Monitoring Committee The Study Enrollment Monitoring Committee will be responsible for managing the enrollment goals including the caps and minimums to specific populations for the DAPT study. This committee will meet frequently by teleconference to monitor subject enrollment and their proportions with respect to the study limitations set forth in the protocol. The membership of this committee will be persons both familiar with and not affiliated with the conduct of the DAPT Study. In an effort to ensure the generalizability of the overall study, minimum and maximum parameters have been placed on certain patient and treatment characteristics for the DES analysis cohort (DAPT and non-dapt sources combined): e.g. at least 15% of subjects have been treated with a given DES stent type and a maximum of 60% with a give thienopyridine type. Section shows what the exact populations restrictions are for the DAPT study. This committee will also directly monitor the proportion of subjects with complex vs. non-complex classification as well as the balance of those subjects who present with ACS according to troponin, CK-MB, and STEMI throughout the study. Based on the enrollment data from the DAPT study as well as from the contributing PMS/COA studies, the Study Enrollment Monitoring Committee may recommend that the Executive Operations Committee close enrollment to certain groups of subjects (e.g. DES of a certain type). This committee is also charged with monitoring the characteristics of subjects who are randomized. Committee Members: TBD 12.6 Publication Policies Subject confidentiality and disclosure of data All records and other information about subjects participating in this study will be treated as confidential. HCRI and/or its designee CROs/AROs will collect data and monitor study records. Auditors, IRB/EC members, CEC/DSMB or the U.S. FDA may also have access to the study June 29, 2009 Page 101 of 108 Version 4.0

104 records. Participating subjects will not be identified by name in any published reports about this study. Publication policy The results of this study will be made public and are intended to be presented and published. The study will be registered in the clinicaltrials.gov database. HCRI will form a publication committee. The committee will develop a final publication plan. The scientific validity and timing of publications will be evaluated in order to maximize the benefits derived from the publication of the clinical data of the study. In general, publications utilizing data will be managed as described below. Publication Committee The Publication Committee will be defined during the course of the study and after enrollment is completed. Committee membership will include representatives of the Executive Committee and HCRI. The goal of the Committee is to ensure that the study results are published. The Publication Committee is responsible for reviewing proposals for publication, overseeing the development of manuscripts/abstracts, plus identifying and appointing the manuscript/abstract author(s)/writer(s). The Committee reviews not only main publications, but also ancillary publications. If necessary, specified authorship criteria may be applied for ancillary publications. The Committee may decide that no publications/abstracts will be prepared prior to the end of the study, and also not on individual center data. Authorship Selection Authors will be selected on the basis of the following: A significant contribution to the design of the clinical study A significant contribution to subject enrollment in the clinical study High quality of data as determined by the clinical study requirements Demonstration of a high level of interest in the outcome of the study, and the ability to write, review, edit, and present the publication A demonstration of a good publication history A willingness to contribute to the publication All investigators not listed as co-authors will be acknowledged as investigators and will be individually listed according to the guidelines of the applicable scientific journal. All publications and presentations of data from the DAPT Study should use the phrase following the listed authors for the DAPT Study investigators. Review and Communication Guidelines Investigators will receive communication regarding the authorship selection, the publication coauthors and to which scientific platform the publication will be submitted. Prior to submission of a publication (abstracts and manuscripts), the Publication Committee and all co-authors will review and authorize the publication (contents and platform). June 29, 2009 Page 102 of 108 Version 4.0

105 13 Ethical and Regulatory Considerations 13.1 Role of the Study Sponsor As the study sponsor of this clinical study, HCRI has the overall responsibility for the conduct of the study, including assurance that the study meets and is conducted within the regulatory requirements specified by each reviewing regulatory authority. In this study, HCRI will have certain direct responsibilities and will delegate other responsibilities to other designees. HCRI will ensure adherence to the sponsor general duties, selection of Investigators, monitoring, supplemental applications, maintaining records, and submitting reports General Duties HCRI s general duties (which may be assisted by designees) include submitting the application to appropriate regulatory authorities and obtaining overall regulatory approval. HCRI is responsible for ensuring informed consent is obtained, proper clinical site monitoring is performed, providing quality data that satisfies regulations and informing study Investigators of unanticipated adverse drug and device effects events and deviations from the protocol, as appropriate. As the designated data coordinating center, HCRI will prepare written reports and a final report as directed by the protocol and will coordinate data collection and transfer with other vendors Subject Confidentiality Subject confidentiality will be maintained throughout the clinical study in a way that assures that data can always be tracked back to the source data. For this purpose, a unique subject identification code (Site number, subject number and initials) will be used that allows identification of all data reported for each subject. Data relating to the study might be made available to third parties (for example in case of an audit performed by regulatory authorities) provided the data are treated confidential and that the subject s privacy is guaranteed Institutional Review Board (IRB)/Independent Ethics Committee (IEC) It is the responsibility of the investigator to obtain approval of the trial protocol, protocol amendments, informed consent forms, and other relevant documents, e.g., advertisements, if applicable, from the IRB/IEC. All correspondence with the IRB/IEC should be retained in the Investigator File. After obtaining IRB approval, the investigator will submit the approval letter indicating the approved version of the protocol, Patient Informed Consent, and any other reviewed documentation to HCRI and/or its designee for review. The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is where the change is necessary to eliminate apparent immediate hazards to the subjects. In that event, the investigator must notify the IRB/IEC and HCRI in writing within 5 working days after the implementation. June 29, 2009 Page 103 of 108 Version 4.0

106 13.5 Supplemental Applications If required, HCRI and/or designees will submit changes in the protocol to the appropriate regulatory authorities and Investigators to obtain IRB/EC approval to implement the changes Maintaining Records HCRI and/or its designees will maintain copies to include all trial related correspondence, regulatory documents, data, shipment of drug accountability logs, adverse device effects and other records related to the clinical trial. HCRI and/or its designees will maintain records related to the signed Investigator Agreements Submitting Reports HCRI will submit the reports required by each reviewing regulatory authority. This includes unanticipated adverse drug and device effects, withdrawal of IRB/EC or regulatory approval, current Investigators list, annual progress reports, recall information and final reports. Sites will notify HCRI within 24 hours of the time the Investigator becomes aware of any unanticipated adverse drug or device effects or withdrawal of IRB/EC approval. HCRI will also assist in the preparation of annual progress reports and a final report for the DAPT Study. HCRI will provide 6 month progress reports to FDA that include items such as the following: number of subjects enrolled, number of sites enrolled/active, anticipated conclusion of enrollment, and a summary of UAEs reported to report date. In the Clinical Study Report (CSR), HCRI will submit a listing of all subjects who died as well as all discontinuations (including discontinuations due to serious as well as other discontinuations). Included will be the start and end dates of drug treatment as well as start and end dates of the adverse events and whether or not the events were resolved, resolving, or ongoing. Electronic case report forms (ecrfs) for all patients who died and for all discontinuations will be made available to FDA if requested. Narratives will not have to be submitted with the CSR. Narratives for patients experiencing endpoint events or SAEs will be made available to FDA if requested. The CSR will also include a listing of "Investigator Reported Events" that were also adjudicated as events by the CEC as well as a listing of "Investigator Reported Events" that were reviewed by the CEC but not thought to be events. The unmasking of drug brand will only be added to the CSR submitted to FDA after blinded and masked adjudication by the CEC and review by DSMB has been completed Site Record Retention Policy All clinical sites will maintain study records until HCRI notifies them and the reviewing regulatory authorities that research is completed or terminated under the clinical investigation in compliance with national law. Record retention dates will be provided to study sites by HCRI or its designee Informed Consent All subjects must provide written Informed Consent in accordance with the local clinical site s IRB/EC. A copy of the consent form from each site must be forwarded to HCRI or Quintiles for review and approval prior to submission to the site IRB/EC. Each site must provide HCRI with a copy of the study site s IRB/EC approval letter and the approved informed consent document. A signed Informed Consent must be obtained from each subject or his/her relative/guardian prior to commencing screening/baseline evaluations. Any revisions to the approved Informed Consent must be reviewed and approved by HCRI or its designee before submission to the IRB/EC. June 29, 2009 Page 104 of 108 Version 4.0

107 The process for obtaining informed consent shall be as follows: Avoid any coercion or undue influence of subjects to participate Not waive or appear to waive subject s legal rights Use language that is non-technical and understandable to the subject or his/her legal representative Provide ample time for the subject to consider participation Include dated signatures of the subject or the subject s legal representative (or impartial witness according to IRB/EC requirements) and the investigator Show and document how informed consent will be obtained and recorded in circumstances in which the subject is unable to give it An IRB/EC approved informed consent will be given to each subject for review and signing. The approved informed consent form will include an explanation of the study, duration, expected benefits and risks or inconveniences, explanation of alternatives, medical record access and subject anonymity, if data is used for publications or submission for reimbursement support. The site Principal Investigator may delegate the responsibility to obtain informed consent to one or more of the staff members. This will be documented in the delegation of authority log filed at the site. A sample template of the patient informed consent form will be available for the IDE submission. The signed consent forms will be retained by the investigator and made available (for review only) to study monitors, auditors or inspectors on request. A copy of the signed and dated informed consent form will be provided to each study subject. In the event that the subject is unable to provide written informed consent, verbal consent from the subject or written assent from a legally acceptable representative will be accepted to facilitate enrolment. The legal representative may provide written consent on behalf of the subject only after having been fully informed about the study. Where a subject is providing verbal consent, an impartial witness must be present during the entire informed consent discussion. Once consent has been given, the witness must sign and personally date the consent form, to confirm that the information contained within the informed consent and any further information provided by the investigator, was explained to and apparently understood by the subject and that consent was freely given. Where a subject has initially verbally consented or a subject s legally acceptable representative has assented on behalf of the subject, written consent should be sought from the subject as soon as, in the investigator s opinion, the subject is capable of understanding the process and capable of signing the consent form, or as required by their IRB/EC. June 29, 2009 Page 105 of 108 Version 4.0

108 14 References 1. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O'Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349(14): Stone GW, Ellis SG, Cox DA, Hermiller J, O'Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med. 2004;350(3): Pfisterer M, Brunner-La Rocca HP, Buser PT, Rickenbacher P, Hunziker P, Mueller C, Jeger R, Bader F, Osswald S, Kaiser C. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol. 2006;48(12): Cutlip DE, Baim DS, Ho KK, Popma JJ, Lansky AJ, Cohen DJ, Carrozza JP, Jr., Chauhan MS, Rodriguez O, Kuntz RE. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation. 2001;103(15): Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293(17): Kuchulakanti PK, Chu WW, Torguson R, Ohlmann P, Rha SW, Clavijo LC, Kim SW, Bui A, Gevorkian N, Xue Z, Smith K, Fournadjieva J, Suddath WO, Satler LF, Pichard AD, Kent KM, Waksman R. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation. 2006;113(8): Ong AT, Hoye A, Aoki J, van Mieghem CA, Rodriguez Granillo GA, Sonnenschein K, Regar E, McFadden EP, Sianos G, van der Giessen WJ, de Jaegere PP, de Feyter P, van Domburg RT, Serruys PW. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation. J Am Coll Cardiol. 2005;45(6): Mauri L, Hsieh W-h, Massaro JM, Ho KKL, D'Agostino R, Cutlip DE. Stent Thrombosis in Randomized Clinical Trials of Drug-Eluting Stents. N Engl J Med. 2007;356(10): Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Juni P, Sianos G, Hellige G, van Domburg RT, Hess OM, Boersma E, Meier B, Windecker S, Serruys PW. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 2007;369(9562): Stettler C, Wandel S, Allemann S, Kastrati A, Morice MC, Schomig A, Pfisterer ME, Stone GW, Leon MB, de Lezo JS, Goy J-J, Park S-J, Sabate M, Suttorp MJ, Kelbaek H, Spaulding C, Menichelli M, Vermeersch P, Dirksen MT, Cervinka P, Petronio AS, Nordmann AJ, Diem P, Meier B, Zwahlen M, Reichenbach S, Trelle S, Windecker S, Juni P. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. The Lancet. 2007;370(9591): Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358(9281): June 29, 2009 Page 106 of 108 Version 4.0

109 12. Steinhubl SR, Berger PB, Mann JT, 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19): Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7): Budaj A, Yusuf S, Mehta SR, Fox KA, Tognoni G, Zhao F, Chrolavicius S, Hunt D, Keltai M, Franzosi MG. Benefit of clopidogrel in patients with acute coronary syndromes without STsegment elevation in various risk groups. Circulation. 2002;106(13): Eisenstein EL, Anstrom KJ, Kong DF, Shaw LK, Tuttle RH, Mark DB, Kramer JM, Harrington RA, Matchar DB, Kandzari DE, Peterson ED, Schulman KA, Califf RM. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297(2): Spertus JA, Kettelkamp R, Vance C, Decker C, Jones PG, Rumsfeld JS, Messenger JC, Khanal S, Peterson ED, Bach RG, Krumholz HM, Cohen DJ. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation. 2006;113(24): Wiviott SD, Braunwald E, McCabe CH, Horvath I, Keltai M, Herrman JP, Van de Werf F, Downey WE, Scirica BM, Murphy SA, Antman EM. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet. 2008;371(9621): Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20): Ong AT, McFadden EP, Regar E, de Jaegere PP, van Domburg RT, Serruys PW. Late angiographic stent thrombosis (LAST) events with drug-eluting stents. Journal of the American College of Cardiology. 2005;45(12): Grines CL, Bonow RO, Casey DE, Jr., Gardner TJ, Lockhart PB, Moliterno DJ, O'Gara P, Whitlow P. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Journal of the American College of Cardiology. 2007;49(6): Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry- Ribaudo L, Booth J, Topol EJ. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16): Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin Dose for the Prevention of Cardiovascular Disease: A Systematic Review. JAMA. 2007;297(18): Garg P, Cohen DJ, Gaziano T, Mauri L. Balancing the Risks of Restenosis and Stent Thrombosis in Bare-Metal Versus Drug-Eluting Stents: Results of a Decision Analytic Model. Journal of the American College of Cardiology. 2008;51(19): Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es G-A, Gabriel Steg P, Morel M- a, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW, on behalf of the Academic Research C. Clinical End Points in Coronary Stent Trials: A Case for Standardized Definitions. Circulation. 2007;115(17): Thygesen K, Alpert JS, White HD, on behalf of the Joint ESCAAHAWHFTFftRoMI, Task Force Members: Chairpersons: Kristian Thygesen JSAHDW, Biomarker Group: Allan S. Jaffe June 29, 2009 Page 107 of 108 Version 4.0

110 CFSAMGHAKLKNJR, Ecg Group: Bernard Chaitman C-oPMCMDHHPP, Imaging Group: Richard Underwood CJJBGABRBEEVDW, Intervention Group: Jean-Pierre Bassand C- owwctbfpgsbfudow, Clinical Investigation Group: Paul W. Armstrong CEMAKAFCWHEMOMLS, Global Perspective Group: Philip A. Poole-Wilson CEPGJ-LL- SPPSMJ-RZ, Implementation Group: Lars C. Wallentin Coordinator FF-AKMFANPSGPMTL- MV-P, Esc Committee For Practice G, Alec Vahanian CAJCRDCVDKDGFCF-BIHSDK, Document R, Joao Morais RCSBRHDMUSMLMAM-RSSGNLWBG. Universal Definition of Myocardial Infarction. Circulation. 2007;116(22): June 29, 2009 Page 108 of 108 Version 4.0

111 The DAPT Study A prospective, multi-center, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy (DAPT) in subjects undergoing percutaneous coronary intervention (PCI) with either drug-eluting stent (DES) or bare metal stent (BMS) placement for the treatment of coronary artery lesions. STUDY SPONSOR: Harvard Clinical Research Institute (HCRI) 930 Commonwealth Avenue, 3rd Floor Boston, MA USA Prepared by HCRI A POST MARKETING STUDY STUDY IDE # G Clinical Study Protocol CONFIDENTIAL This protocol contains confidential information for use by the site principal investigators and their designated representatives participating in this clinical investigation. It should be held confidential and maintained in a secure location. It should not be copied or made available for review by any unauthorized person or firm.

112 DAPT Study Protocol APPROVAL SIGNATURES HCRI Signatures Name Signature Title/Department Date Chief Scientific Officer, Laura Mauri, MD, MSc Harvard Clinical Research Institute (HCRI) 02/14/2011 Senior Consulting Biostatistician, Joseph Massaro, PhD Harvard Clinical Research Institute (HCRI) 02/14/2011 Page 2 of 118

113 DOCUMENT HISTORY Revision Author Date reviewed/revised Changes Reason for Changes Version 1.0 M. Claffey September 05, 2008 New Document N/A Version 1.1 M. Claffey October 4, 2008 Design FDA and Manufacturer modifications suggested changes from pre-ide meeting held September 9, Version 1.2 M. Claffey October 10, 2008 Design modifications Version 1.3 M. Claffey October 15, 2008 Minor language clarifications Version 2.0 M. Claffey February 18, 2009 Multiple; primarily relating to discrepancies and clarifications as well as inclusion of additional statistical analyses Version 3.0 M. Claffey May 8, 2009 Minor edits and Modifications per comments received by FDA as well as through other meeting/ conversations. Version 4.0 M. Claffey June 29, 2009 Minor edits and Modifications per comments received by FDA as well as through other meeting/ conversations. Version 5.0 M. Claffey July 24, 2009 Modification of MI definition. Content edits related to formal (additional) thienopyridine approval Manufacturer suggested changes from meeting held October 6, Recommended changes in advance of IDE submission. As per FDA requested modifications outlined, in part, in the November 2008 Conditional Approval letter. Modifications per comments received by FDA in the March 2009 Conditional Approval letter and other discussions Modifications per comments received by FDA in the June 2009 Conditional Approval letter and other discussions Modifications per received by FDA on July 19, 2009 as well as modifications based on US FDA approval of Effient (prasugrel) Page 3 of 118

114 Revision Author Date reviewed/revised Changes Version 6.0 M. Claffey October 23, 2009 Minor edits and modifications reflecting operational updates since the last version Version 7.0 M. Claffey December 07, 2009 Minor edits and Modifications per comments received by FDA as well as those reflecting operational updates since the last version Version 8.0 M. Claffey May 14, 2010 Minor edits and modifications reflecting operational updates since the last version Version 9.0 M. Claffey October 15, 2010 Modification of secondary BMS analysis, patient followup, periprocedural MI endpoint assessment, minor edits and modifications reflecting operational updates since the last version L. Hesse Modification of the 12 month visit window; widening the window from 1 year minus 30 days to 1 year +/- 30 days. Reason for Changes Updates for operational process refinements as well as inclusion of an ancillary study Modifications per comments received by FDA in the November 2009 Conditional Approval letter and other discussions Updates for operational process refinements Modifications per revised BMS enrollment expectations and updates for operational process refinements Modifications per comments received from FDA. Page 4 of 118

115 DAPT Study - Protocol Signature Page Site s name: Investigator s Responsibility Prior to enrolling subjects in the DAPT Study, the site Principal Investigator must obtain written approval from his/her Institutional Review Board (IRB) or Ethics Committee (EC). This approval must be in the site Principal Investigator s name and a copy sent to the HCRI, among other essential documents, along with the IRB/EC approved Informed Consent and the signed Clinical Trial Agreement. Additionally, the site Principal Investigator must sign the declaration below: I have read this protocol and agree to adhere to the requirements. I will provide copies of this protocol and all pertinent information to all site personnel involved in this study. I will discuss this material with them and ensure they are fully informed regarding the study products and the conduct of the study. Principal Investigator s Signature Date: Principal Investigator s Printed Name Site Name Site # Page 5 of 118

116 Protocol Summary Title A prospective, multi-center, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy (DAPT) in subjects undergoing percutaneous coronary intervention (PCI) with either drug-eluting stent (DES) or bare metal stent (BMS) placement for the treatment of coronary artery lesions. The DAPT Study Study Number IDE # G Sponsor Harvard Clinical Research Institute (HCRI) 930 Commonwealth Avenue, 3rd Floor Boston, MA 02215, USA Chief Scientific Officer: Laura Mauri, MD, MSc Executive Director, Clinical Investigations: Donald Cutlip, MD In collaboration with: Abbott Vascular Boston Scientific Corporation Bristol-Myers Squibb/Sanofi-Aventis Cordis Corporation Eli Lilly/Daiichi Sankyo Medtronic Vascular, Inc. Study Drugs FDA-approved thienopyridines Clopidogrel Prasugrel Study Devices FDA- and locally-approved DES (range of stent diameters 2.25 mm mm as approved and available). CYPHER Endeavor TAXUS (Express, Liberté or Element) XIENCE V/XIENCE PRIME/PROMUS These devices should only be used where they have been approved by the local regulatory agency. FDA-approved BMS (range of stent diameters 2.25 mm mm as available). Page 6 of 118

117 Primary Hypotheses There are two primary hypotheses to be tested in this study. Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with DAPT for an additional 18 months (total 30 months) will have increased survival free from death, myocardial infarction or stroke compared with subjects treated with only 12 total months of DAPT over the month post-stenting period. Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with DAPT for an additional 18 months (total 30 months) will have increased survival free from ARC definite/probable stent thrombosis (ST) compared with subjects treated with only 12 total months of DAPT over the month post-stenting period. The study will be considered a success for 30m DAPT arm in DES subjects if at least one of these two primary hypotheses is statistically proven using the Hochberg approach at an overall familywise error (FWE) rate of 0.05 (i.e., if each hypothesis is proven at the two-sided 0.05 level of significance, the study is considered a success for 30m DAPT arm in DES subjects; otherwise, if one objective is proven at the two-sided level of significance, then the study is considered a success for 30m DAPT arm in DES subjects). The primary safety hypothesis for this study is: Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with DAPT for an additional 18 months (total 30 months) will have major bleeding rates non-inferior to the rates of subjects treated with only 12 total months of DAPT over the month post-stenting period. Secondary Hypotheses The main secondary study hypotheses are: DAPT subjects treated with drug-eluting stents will have a rate of death, myocardial infarction or stroke that is non-inferior compared with the rate of propensity score matched subjects treated with bare-metal stents over the 0-33 month post-stenting period. DAPT subjects treated with drug-eluting stents will have a rate of ARC definite/probable stent thrombosis (ST) that is non-inferior compared with the rate of propensity score matched subjects treated with bare-metal stents over the 0-33 month post-stenting period. Study Design Subjects may be enrolled into the study either before or after the index procedure, PCI with stent placement. Enrollment of qualified subjects can occur up to 3 calendar days after index procedure. All enrolled subjects will be treated with either a drug eluting stent(s) (DES) or a bare metal stent(s) (BMS) (per their respective Instructions for Use) and assigned to 12 months of open label thienopyridine treatment in addition to aspirin. Page 7 of 118

118 Study Design (Continued) Operators will select the thienopyridine at their discretion. Thienopyridine treatment dose will be according to the standard of practice and prescribing information for the selected medication. Aspirin treatment will be mg for the first 6 months after the procedure and mg subsequently, to be continued indefinitely. Subjects who are treated with 12 months of DAPT post index procedure and who are event free (from all death, myocardial infarction, stroke, repeat coronary revascularization, stent thrombosis, and major bleeding severe or moderate by GUSTO classification) during that time will be considered 12 Month Clear. Subject are considered compliant with the thienopyridine therapy for the purposes of eligibility if they take between 80% and 120% of the prescribed drug in the 0-6 month and 6-12 month periods without an interruption of therapy longer than 14 days. Additional PCI(s) within 6 weeks of the index procedure do not disqualify a subject from randomization. Operators are strongly encouraged to use the same stent type at the second procedure (BMS or DES). Assignment to BMS or DES groups will be based on the stent received at the time of index without regard for prior or subsequent stenting. Repeat PCI, stent thrombosis, or MI within the first 6 weeks will not be considered exclusionary events for the definition of 12 Month Clear. Only major bleeding events, stroke, or CABG should be exclusionary events prior to 6 weeks from randomization. All subjects treated with DES or BMS who are considered 12 Month Clear are eligible for randomization to either placebo (12 m DAPT arm) or an additional 18 months of thienopyridine treatment (30 m DAPT arm). Both arms will continue aspirin therapy. Randomization for subjects will be performed at 12 months post procedure in eligible subjects and will be stratified according to DES/BMS, hospital site, subject complexity and thienopyridine drug type. Eligible subjects will be randomized 1:1 to receive placebo or thienopyridine treatment for an additional 18 months. Subjects will be followed for an additional 3 months of observational follow-up at the end of the 18 month randomized treatment phase. All enrolled subjects will be followed for the full 33 months regardless of whether they are randomized. Study Population Study subjects with ischemic heart disease due to stenotic lesions in either native coronary arteries or coronary artery bypass grafts undergoing PCI with stent placement and no contraindications to prolonged DAPT are eligible to be enrolled in this study. Subjects may have multi-vessel treatment. For the purposes of stratification, subjects are considered complex if they have either acute coronary syndrome (ACS), renal insufficiency or failure, ejection fraction <30%, greater than two vessels stented, in-stent restenosis of a DES treated with a stent at the time of the index procedure, prior brachytherapy, or anatomically complex lesion treated with a stent at the time of the index procedure. Subjects that do not meet the criteria for complex will be considered non-complex for the purposes of stratification of randomization and analysis. Subjects who receive both DES and BMS during the index procedure will not be eligible for enrollment. Page 8 of 118

119 Study Population (Continued) The minimum percentage of subjects treated with each type of DES (CYPHER, Endeavor, TAXUS (Express, Liberté, or Element), and XIENCE (V or PRIME)/PROMUS will be 15% as determined by placement of at least one DES during the index procedure. These devices should only be used where they have been approved by the local regulatory agency. For each DES stent type a target minimum of 20% of subjects are expected to be treated with a given thienopyridine drug. The target maximum percentage of subjects treated with each brand of study drug (clopidogrel and prasugrel) will be 60%, as determined at the time of randomization. The proportion of subjects with at least one DES type and with each thienopyridine type (in total and per stent type) will be tallied during the enrollment period as well at the time of randomization to determine whether the minimum or maximum parameters described above will be met. These caps and minimums will be monitored by a study enrollment monitoring committee. Number of Centers and Subjects Trial Endpoints Up to 20,645 subjects will be enrolled at up to 285 US and ex-us clinical study sites. Approximately 70% of sites will be in the US. Enrollment in the study will be limited to 1,000 subjects at any single site. Approximately 15,245 subjects will receive PCI with DES, assuming a 12 Month Not-Clear rate of 20% or less, and approximately 2300 subjects will receive PCI with BMS. DES subjects enrolled in separate manufacturer-run PMS and/or COA studies will be included as part of the DES-treated analysis population. Only studies not randomizing to stent type and that are pre-specified and listed to the FDA will be eligible to contribute data. Subjects will be contributed in two ways. Either all of the subjects data will be contributed after 33 months of follow-up from their index procedure as a part of the various post-marketing studies and/or condition of approval studies or relevant baseline data and eligibility data to 12 months will be contributed and subjects will be dually enrolled at 12 months post-procedure for the purposes of randomization and completion of follow-up according to the DAPT protocol. The maximum number of drug-eluting stent patients whose data that will be transferred as cleaned data from completely separate studies meeting the above requirements will be The maximum number of subjects who will be enrolled and randomized in the DAPT study at 12 months after initially entering a separate manufacturer-run PMS and/or COA study will be The total numbers of contributed patients, and their poolability with patients who are enrolled and randomized in the DAPT study will be assessed at regular intervals by an independent monitoring committee in order to confirm adequate enrollment of patients from the DAPT study. Co-Primary Endpoints: Incidence of composite of all death, myocardial infarction (MI) and stroke (defined as MACCE) months post-stent. Incidence of ARC definite or probable stent thrombosis (ST) months poststent. Primary Safety Endpoint: Major bleeding (GUSTO classification, severe and moderate bleeding combined) months post-stent. Page 9 of 118

120 Statistical Considerations Survival free of MACCE during the month post-procedure period will be compared between subjects randomized to the 30m DAPT DES treatment arm versus those randomized to the 12m DAPT DES arm using the stratified log-rank test (baseline strata will consist of the hospital site, subject complexity and thienopyridine drug type strata used in randomization). The analysis will be performed on all randomized DES subjects according to the principle of intention to treat. Primary Time period Population Hypothesis test Endpoint MACCE 12-33m DES Randomized - Superiority ITT (12-30m on randomized 30m vs. 12 m treatment) Survival free from stent thrombosis (ST) will be compared between the 30m DAPT DES arm and the 12m DAPT DES arm using the stratified log-rank test, adjusted for the same factors as the MACCE analysis. This analysis will be performed on all randomized DES subjects according to the principle of intention to treat. Primary Time period Population Hypothesis test Endpoint ST 12-33m DES Randomized - Superiority ITT (12-30m on randomized 30m vs. 12 m treatment) Assuming that the time to each endpoint follows an exponential distribution, with Incidence of MACCE =2.9% and incidence of ST=0.5% for 12m-DAPT annually for the 21 months following randomization during which randomized treatment is taken (i.e., for m following randomization). Incidence of MACCE =2.175% and incidence of ST=0.225% for 30m- DAPT annually for the first 18 months following randomization during which randomized treatment is taken (12-30 month post-procedure period); After randomized treatment stops at 30 months post-randomization, 30m- DAPT incidence rate increases to that of 12m-DAPT. The hazard ratio (30m DAPT to 12m DAPT) under these assumptions is 0.75 for MACCE and 0.45 for ST across the 12m 30m period and 1.0 for both endpoints across the 30-33m period. Further, if a. Randomization is 1:1 into the 12m and 30m arms (randomization occurs at 12m post-procedure time point); b. Annual lost to follow-up rate of 3% after randomization; c. Familywise (FWE) error rate is controlled at the 0.05 level using the Hochberg approach (reject both null hypotheses if both are significant at the 0.05 level; otherwise, if one null hypothesis is significant at the level, then that null hypothesis is rejected); then 12,196 DES subjects randomized at 12 months post-procedure will yield at least 80% power that the study has statistically met its objective under the above assumptions of treatment effect in both outcomes (power ranges from approximately 80% to 90% depending on correlation of outcomes). Thus, the number to be enrolled Page 10 of 118

121 Statistical Considerations (Continued) at time of stent implantation is approximately 12,196/.8 or 15,245 assuming 20% of enrolled subjects will not be 12 Month Clear". The study will be considered a success for 30m DAPT arm in DES subjects if at least one of these two primary hypotheses is statistically proven using the Hochberg approach at an overall familywise error (FWE) rate of If the null hypothesis is not rejected, the 95% confidence intervals of the difference between DAPT duration treatment groups will be calculated. Powered Secondary Analyses With respect to the main secondary analysis of MACCE compared between subjects treated with DES and subjects treated with BMS, the null (H o ) and alternative (H a ) hypotheses are: H o : A C + H a : A < C + where A is the true MACCE rate for the DES group and C is the true MACCE rate for the control arm (BMS subjects) over the 0-33 months post-index procedure period, and is the non-inferiority margin. This analysis will be performed primarily using all available BMS patients and a sample of DES that match BMS patients on clinically relevant baseline characteristics. MI events occurring < 72 hours after the index procedure will be excluded. With 2,300 enrolled BMS subjects and a non-inferiority test at an = (1-sided) significance, the power is at least 82% to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with MACCE in the DES arm compared to the BMS arm, when the MACCE rate of the control arm across the entire 0-33 month post-procedure period is 9.5%, a noninferiority margin of 2.28%, 10% of patients prematurely withdrawing in the first 12 months prior to randomization, 3% annual loss to follow-up thereafter, and a minimum matched DES:BMS ratio of 1:1 though the expected average matched DES:BMS ratio will be at least 2:1 (this ratio is anticipated to be achieved given the number of enrolled DES subjects available for matching is anticipated to be approximately 5-6 times greater than the number of available BMS subjects). Power Analysis and Sample Size (PASS) software was used to compute the power. Rejection of the null hypothesis will signify that the DES arm is non-inferior to the BMS arm with respect to MACCE between 0 and 33 months post-index procedure. With respect to the main secondary analysis of stent thrombosis compared between subjects treated with DES and subjects treated with BMS, the null (H o ) and alternative (H a ) hypotheses are: H o : A C + H a : A < C + where A is the true ST rate for the DES group and C is the true ST rate for the control arm (BMS subjects) over the 0-33 months post-index procedure period, and Page 11 of 118

122 Statistical Considerations (Continued) is the non-inferiority margin. This analysis will be performed primarily using all available BMS patients and a sample of available DES that match BMS patients on clinically relevant baseline characteristics. With 2,300 enrolled BMS subjects and a non-inferiority test at an = (1-sided) significance, the power is at least 81% to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with ST in the DES arm compared to the BMS arm, when the ST rate of the control arm is 1.67% across the 0-33 month post-procedure period, a non-inferiority margin of 0.97%, 10% of patients prematurely withdrawing in the first 12 months prior to randomization, 3% annual loss to follow-up thereafter, and a minimum matched DES:BMS ratio of 1:1 though the expected average matched DES:BMS ratio will be at least 2:1 (this ratio is anticipated to be achieved given the number of enrolled DES subjects available for matching is anticipated to be approximately 5-6 times greater than the number of available BMS subjects). Power Analysis and Sample Size (PASS) software was used to compute the power. Rejection of the null hypothesis will signify that the DES arm is non-inferior to the BMS arm with respect to ST between 0 and 33 months post-index procedure. With respect to the primary safety endpoint major bleeding compared between DES subjects in the 30 m DAPT group and DES subjects in the 12 m DAPT group, the null (H o ) and alternative (H a ) hypotheses are: H o : A C + H a : A < C + where A is the true major bleed rate for the 30 m DAPT group and C is the true major bleed rate for the control arm (12 m DAPT) over the months post-index procedure period, and is the non-inferiority margin. With a sample size of 12,196 randomized subjects and a non-inferiority test at an = (1-sided) significance, the power is 82% power to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with major bleed in the 30 m DAPT arm compared to 12 m DAPT arm, when the major bleed rate of the 30 m DAPT group between 12 and 30 months post index procedure is 2.22% and that of the 12 m DAPT group is 2.22% over the same time period, a non-inferiority margin of 0.8%, 3% loss to follow-up and 1:1 randomization. Power Analysis and Sample Size (PASS) was used to compute the power, assuming the Farrington-Manning test. Rejection of the null hypothesis will signify that the 30 m DAPT arm is non-inferior to the control arm (12 m DAPT) with respect to major bleed rate between 12 and 33 months post-index procedure. The statistical analysis plan summarizes the additional endpoints and hypothesis tests that will be performed for this study. Follow-up Assessments Day 0 / procedure (clinical) 6 mo (± 14 days) (telephone) Page 12 of 118

123 1 yr (± 30 days) (clinical) 15 mo (± 30 days) (telephone) 24 mo (± 30 days) (telephone) 30 mo (± 30 days) (clinical) 33 mo (± 30 days) (telephone) Estimated Study Timelines Data Collection Clinical Event Committee Projected Study Timelines Principal Study Investigator: Estimated date of EC/IRB approval(s): July 15, 2009 Estimated date of the beginning of the subject accrual: October 1, 2009 Estimated proportion of subject enrolled during specific time: Anticipated Enrollment at 3 months: 303 subjects Anticipated Enrollment at 9 months: 10,531 subjects Anticipated Enrollment at 12 months: 15,331 subjects Anticipated Enrollment at 18 months: Up to 20,645 subjects Estimated study completion date: December 2013 (33 mo follow-up completion) Estimated date for the final report submission: March 2014 Data will be collected via electronic case report forms from the index procedure through end of follow-up. Baseline demographic and procedural information will be captured as well as medication compliance, major events and SAEs. All endpoint events will be adjudicated by an independent Clinical Events Committee (CEC). The study duration is expected to be 4 years. 18 months of subject enrollment 33 months of study follow-up Laura Mauri, MD, MSc Division of Cardiovascular Medicine, Department of Medicine Brigham and Women s Hospital Co-Principal Investigator: 75 Francis Street Boston, MA Dean Kereiakes, MD, FACC Carl and Edyth Lindner Center for Research and Education Christ Hospital Heart and Vascular Center 2123 Auburn Ave Ste 424 Cincinnati, OH Executive Committee: o Laura Mauri, M.D., Principal Investigator o Dean Kereiakes, M.D., Co-Principal Investigator o Donald Cutlip, M.D. Page 13 of 118

124 o Sharon-Lise Normand, PhD o Ph. Gabriel Steg, M.D. o Theodora Cohen, PhD o Priscilla Driscoll Shempp Data Monitoring Committee Robert Bonow, M.D., Committee Chairperson Charles Davidson, M.D., James Neaton, PhD, William Wijns, M.D., PhD, Clyde Yancy, M.D., FACC, FAHA, MACP Study Monitoring: Within the United States: Harvard Clinical Research Institute (HCRI) 930 Commonwealth Avenue, 3rd Floor Boston, MA 02215, USA Associate Director, Site Management: Ann Marie Mercando, RN, MHA Telephone: , Fax: , annmarie.mercando@hcri.harvard.edu Europe: Quintiles Parc d'innovation Rue Jean-Dominique Cassini Illkirch FRANCE Senior Project Manager: Catherine Scherrer Telephone: Fax: Catherine.scherrer@quintiles.com Australia and New Zealand: Pacific Clinical Research Group (PCRG) Suite GO3, 1 Cassins Ave North Sydney, NSW 2060 Australia Project Manager: Stephanie Simpson-Plaumann Page 14 of 118

125 Telephone: Fax: Stephanie.simpson-plaumann@pcrg.com.au Study Management, Data Management, Data Analysis and CEC Coordination: Harvard Clinical Research Institute (HCRI) 930 Commonwealth Avenue, 3rd Floor Boston, MA 02215, USA Chief Scientific Officer: Laura Mauri, MD, MSc Executive Director, Clinical Investigations: Donald Cutlip, MD Senior Consulting Biostatistician: Joseph Massaro, PhD Senior Director of Biostatistics, Data Management and Trial Design: Theodora Cohen, PhD Director, Sponsored Trials: Priscilla Driscoll Shempp Telephone: , Fax: , pdriscollshempp@hcri.harvard.edu Safety Processing: Within the United States: Harvard Clinical Research Institute (HCRI) 930 Commonwealth Avenue, 3rd Floor Boston, MA 02215, USA Medical Director, Clinical Safety: James Cappola, MD Telephone: , Fax: , james.cappola@hcri.harvard.edu Europe: Quintiles East Point Business Park Dublin 3 IRELAND Safety Lead : Lisa Codd Telephone: Fax: Lisa.codd@quintiles.com Medical Director: Cheryl Key, MD Telephone: Cheryl.key@quintiles.com Australia and New Zealand: Page 15 of 118

126 Pacific Clinical Research Group (PCRG) Suite GO3, 1 Cassins Ave North Sydney, NSW 2060 Australia Safety & Regulatory Affairs Specialist: Aoifa Daly Telephone: +61-(0) Fax: +61-(0) aoifa.daly@pcrg.com.au Medical Monitors: Quintiles Contact: Richard Oh, MD Sr. Director, Medical and Scientific Services Telephone: +1 (919) , Fax: richard.oh@quintiles.com Europe: Quintiles Contact: Klara Der, MD Medical Director, Medical & Scientific Services, Cardio/Endo Therapeutic team Telephone: +36 (1) Klara.der@quintiles.com Australia and New Zealand: Pacific Clinical Research Group (PCRG) Contact: Ross Prpic, MD Chairman, Pacific Clinical Research Group Telephone: Fax: ross.prpic@pcrg.com.au Safety and Regulatory Consulting Advisors: CardioMed Device Consultants, LLC 1327 Bluegrass Way Gambrills, MD President: H. Semih Oktay, PhD Telephone: , Fax: , soktay@cardiomedllc.com Halloran Consulting Page 16 of 118

127 Safety and Regulatory Consulting Advisors (continued): 135 Beaver St, Suite 211 Waltham, MA 02452, USA Gregory Dombal Managing Partner Telephone: Europe: Quintiles Parc d'innovation Rue Jean-Dominique Cassini Illkirch FRANCE Senior Project Manager: Catherine Scherrer Telephone: Fax: Catherine.scherrer@quintiles.com Australia and New Zealand: Pacific Clinical Research Group (PCRG) Suite GO3, 1 Cassins Ave North Sydney, NSW 2060 Australia Project Manager: Stephanie Simpson-Plaumann Telephone: Fax: Stephanie.simpson-plaumann@pcrg.com.au IRT/IWT Services: Cenduit Chelsea Place 1007 Slater Road, Suite 301, Durham, NC 27703, USA Grant Dietrich, MHR Manager, Project Management, C.I.R.T. Telephone: Fax: grant.dietrich@cenduit.com Page 17 of 118

128 Drug Distribution and Drug Accountability Services: Fisher Clinical Services 7554 Schantz Road Allentown, PA USA Marsha Meron Project Manager Telephone: Mobile: clinicaltrials.gov database: The DAPT Study has been registered in the clinicaltrials.gov database. Identifier Number: NCT Page 18 of 118

129 Table of Contents DOCUMENT HISTORY... 3 DAPT STUDY - PROTOCOL SIGNATURE PAGE... 5 PROTOCOL SUMMARY BACKGROUND Introduction Study Device Descriptions Device Description Medtronic Endeavor Stent Device Description Cordis CYPHER Stent Device Description Boston Scientific TAXUS Express Stent Device Description Boston Scientific TAXUS Liberté Stent Device Description Boston Scientific TAXUS Element Stent Device Description Abbott XIENCE V/Boston Scientific PROMUS Stent Device Description Abbott XIENCE PRIME Device Description FDA-approved BMS Study Drug Descriptions Drug Description Clopidogrel Drug Description Prasugrel Study Rationale Selection of Doses Duration of the Investigation Compliance Statement...26 STUDY DESIGN AND POPULATION Study Design Subject Populations Number of Centers and Subjects PMS/COA (Post Market Surveillance / Condition of Approval ) Subjects Study Flow Diagram Determination of Subject Eligibility Enrollment Inclusion Criteria Enrollment Exclusion Criteria Randomization Inclusion Criterion at 12 months Randomization Exclusion Criteria at 12 months Subject Complexity Definitions Early Withdrawal and Discontinuation TRIAL TREATMENTS Treatment Assignment Drug Supplies and Administration Preparation and Dispensing Drug Storage and Drug Accountability Compliance Procedures for Interruption of Therapy Concomitant Medication(s) Medication(s) Not Permitted Before and/or During the Trial...41 STUDY OBJECTIVES Co-Primary Endpoints Primary Safety Endpoint Secondary Endpoints and Analyses...42 PROCEDURES AND ASSESSMENTS Page 19 of 118

130 6 5.1 Pre-Procedure Stenting Procedure Enrollment Clinical and Local Laboratory Procedures Central Laboratory Procedures after Enrollment Angiography Follow-up Assessments Schedule of Events Description of Randomization and Blinding Procedures Central Laboratory Procedures at Randomization...48 STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN Study Populations Definitions Analysis Populations Primary Hypotheses Co-Primary Endpoints Sample Size Considerations Primary Analyses Secondary Analyses of the Primary Endpoints Primary Safety Endpoint Powered Secondary Endpoints BMS vs. DES Comparisons Additional Endpoint Analyses Analysis of rebound effect Sensitivity Analysis of Non-compliance with Randomized Treatment (12 to 30 Months) Additional Subset Analysis Additional Analyses Missing Data Handling Multiple Center Effect Statistical Methods BENEFITS AND RISKS ASSOCIATED WITH STUDY DRUG/DEVICES Risks Possible Benefits SAFETY AND ADVERSE EVENT REPORTING Adverse Event Serious Adverse Events Causality of Serious Adverse Event to Study Product(s) Intensity of Serious Adverse Event Unanticipated Adverse Device Effects (Device UADE) Life-Threatening Adverse Drug Experience (LTADE) Unexpected Adverse Drug Experience (Drug UADE) Reporting Requirements Pregnancy Device Failures and Malfunctions DEFINITIONS DATA SUBMISSION REQUIREMENTS Required Data Data Collection Data Collection and Tracking Endpoint Reporting Investigator Records...98 Page 20 of 118

131 10.6. Sponsor Records STUDY RESPONSIBILITIES AND QUALITY ASSURANCE Investigator Responsibility for Study Conduct Study Data Reporting and Processing Training Confidentiality and Protection of Study Files Source Documentation Requirements Procedures for Database Management Protocol Deviations Data Transmittal and Record Retention Monitoring Procedures Study Suspension or Study Early Termination STUDY COMMITTEES Executive Committee Advisory Committee Data Monitoring Committee (DMC) Clinical Events Committee (CEC) Study Enrollment Monitoring Committee Publication Policies ETHICAL AND REGULATORY CONSIDERATIONS Role of the Study Sponsor General Duties Subject Confidentiality Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Supplemental Applications Maintaining Records Submitting Reports Site Record Retention Policy Informed Consent REFERENCES APPENDIX 1. ANCILLARY PLATELET FUNCTION & BIOMARKER SUB-STUDY SUMMARY... 1 APPENDIX 2. ANCILLARY GENETIC SUB-STUDY SUMMARY... 1 APPENDIX 3. CLOPIDOGREL PACKAGE INSERT... 1 APPENDIX 4A. PRASUGREL PACKAGE INSERT UNITED STATES... 1 APPENDIX 4B. PRASUGREL PACKAGE INSERT EUROPE... 1 Page 21 of 118

132 1 Background 1.1 Introduction Despite the dramatic early efficacy of drug-eluting stents (DES) in reducing restenosis compared with bare metal stents (BMS) 1, 2, there is concern that DES might lead to higher rates of stent thrombosis - particularly beyond the first year after implantation 3. Stent thrombosis is a devastating outcome usually associated with ST segment elevation myocardial infarction and high mortality 4-7. The incremental risk of late stent thrombosis in DES vs. BMS is not known with certainty; randomized trials to date have been limited in their power to detect rare and late events 8, and observational studies have been limited by selection and ascertainment bias 9. Even large metaanalyses of broader randomized trial data have yet to resolve this uncertainty and suggest that DES might be associated with a 2-4 fold increased risk of very late thrombotic events 10. There is evidence to suggest that the risk of late and very late stent thrombosis may be modified by long term dual antiplatelet therapy. Clopidogrel or prasugrel in addition to aspirin for 12 months has been shown to be of benefit in the setting of acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI) These studies were largely performed using bare metal stents. The reduction in late myocardial infarction (MI) or death rate was largely driven by benefits in MI risk reduction at 30 days. Moreover, stent thrombosis rates were not reported in these studies. Nevertheless, these studies prompted the guidelines to recommend 12 months of antiplatelet therapy for patients with ACS. In an observational study using landmark analysis of a subset of 4666 patients treated with BMS or DES who were event-free at 6 or 12 months and followed for 2 years, extended use of clopidogrel (both >6 and 12 months; self-reported) in patients receiving DES was associated with a reduced risk of death and composite of death or MI, however, there was no such benefit in those who received BMS 15. The results from the PREMIER registry suggest that premature discontinuation of thienopyridine therapy is not uncommon with 13.6% of 500 MI patients who received DES having stopped before 30 days 16. In this study, premature cessation of thienopyridine was associated with significant increase in mortality at 1 year. More recent studies have examined the effect of prasugrel, a new thienopyridine inhibitor, after stent placement in the setting of ACS 17, 18. For DES, premature cessation of antiplatelet therapy (< 3 months for sirolimus-eluting stent; < 6 months for paclitaxel-eluting stent) is suggested to be the most significant factor in the development of late and very late stent thrombosis and an increased risk of death and MI 5, 6, 9, 15, 16, 19. In light of the current data with probable benefit of combined clopidogrel and aspirin therapy over an extended period, a recent advisory committee commissioned by the American Heart Association has recommended the continuation of dual antiplatelet therapy (and deferring any elective surgical procedure) for at least 1 year following the stenting procedure with DES, in the absence of contraindications 20. However, the extent to which dual antiplatelet therapy confers benefit against ST is not known with certainty. The strongest evidence to maintain dual antiplatelet therapy for one year comes from large randomized trials of BMS in acute coronary syndrome 11, 12 but no randomized data exist to evaluate extension of dual antiplatelet therapy beyond 6 months in non- ACS patients receiving stents or ACS patients, post-stent, beyond 1 year. Late stent thromboses have been noted with both BMS and DES in the presence of dual antiplatelet therapy 8, and events continue to accrue beyond 2 years 8. Other than early discontinuation of therapy, other predictors of Page 22 of 118

133 late ST have been described: low left ventricular ejection fraction, renal insufficiency, and complex coronary anatomy 5. Extending dual antiplatelet therapy beyond one year is not without risk, with increased rates of bleeding noted in recent major trials 12, 13, 18, 21. The incremental risk of bleeding needs to be weighed against the risk of late ST in an individual patient until definitive randomized trials can determine the optimal duration of therapy. It is also possible that the impact of extended dual antiplatelet therapy, as seen in large trials of patients with acute coronary syndromes, is predominantly mediated by prevention of myocardial infarction outside the stent territory, as the absolute risk of progression of other atherosclerotic disease following treatment is greater than the risk of stent thrombosis. Given the lack of randomized data, there is considerable uncertainty in the medical community about the optimal duration of dual-antiplatelet therapy following PCI. It is unclear as to whether the duration of dual antiplatelet therapy in patients receiving DES should be 3-6 months (as per the pivotal DES RCT), 12 months (as per the ACC/AHA guidelines), or longer in patients without contraindication. It is also unclear whether the presumed benefit of extended dual antiplatelet therapy is specific to DES or whether non-acs patients treated with BMS (e.g. stable angina) may also benefit from extended dual antiplatelet therapy. 1.2 Study Device Descriptions Stents: FDA- and locally-approved DES and FDA-approved BMS These devices should only be used where they have been approved by the local regulatory agency Device Description Medtronic Endeavor Stent Device description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for the Endeavor Zotarolimus Eluting Coronary Stent System or next generation model (herein known as the Endeavor stent) can be found in the Instructions for Use, which are provided with the product Device Description Cordis CYPHER Stent Device description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for the CYPHER Sirolimus-eluting Coronary Stent System or next generation model (herein known as the CYPHER stent) can be found in the Instructions for Use, which are provided with the product Device Description Boston Scientific TAXUS Express Stent Device description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for the TAXUS Express 2 Paclitaxel-Eluting Coronary Stent Page 23 of 118

134 System or next generation model (herein known as the TAXUS Express stent) can be found in the Instructions for Use, which are provided with the product Device Description Boston Scientific TAXUS Liberté Stent Device description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for the TAXUS Liberté Paclitaxel-Eluting Coronary Stent System or next generation model (herein known as the TAXUS Liberté stent) can be found in the Instructions for Use, which are provided with the product Device Description Boston Scientific TAXUS Element Stent Device description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for the TAXUS Element Paclitaxel-Eluting Coronary Stent System or next generation model (herein known as the TAXUS Element stent) can be found in the Instructions for Use, which are provided with the product Device Description Abbott XIENCE V/Boston Scientific PROMUS Stent Device description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for the XIENCE V Everolimus Eluting Coronary Stent System or PROMUS Everolimus-Eluting Coronary Stent System or next generation model (herein known as the XIENCE stent) can be found in the Instructions for Use, which are provided with the product Device Description Abbott XIENCE PRIME Device description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for the XIENCE PRIME Everolimus Eluting Coronary Stent System or next generation model (herein known as the XIENCE PRIME stent) can be found in the Instructions for Use, which are provided with the product Device Description FDA-approved BMS (range of stent diameters matching the range of stent diameters of all FDA-approved DES above, 2.25 mm mm). Detailed device descriptions and other information for the various FDA-approved bare metal stents can be found in the Instructions for Use, which are provided with the individual products. Page 24 of 118

135 1.3 Study Drug Descriptions FDA-approved thienopyridines Drug Description Clopidogrel Drug description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for clopidogrel bisulfate (herein known as clopidogrel) can be found in the Package Insert, which are provided with the product Drug Description Prasugrel Drug description details, including information on intended use, clinical and pre-clinical testing, indications and contraindications, as well as a complete list of warning, precautions and potential adverse events, for prasugrel can be found in the Package Insert, which are provided with the product. 1.4 Study Rationale The aim of this study is to conduct a multicenter, international, randomized trial to help the global medical community to better understand the optimal duration of dual antiplatelet therapy in subjects without contraindications following stenting procedure with DES. Current data suggest a probable benefit of combined thienopyridine and aspirin therapy over an extended period (at least 1 year) post DES implantation either by prevention of ST or by prevention of major adverse cerebral and cardiovascular events (MACCE) or both. It is uncertain whether the presumed benefit of extended dual antiplatelet therapy is specific to DES or if subjects treated with BMS may also benefit from extended dual antiplatelet therapy. The DAPT study has been developed to identify the optimal duration of dual antiplatelet therapy in subjects who undergo stenting procedures. 1.5 Selection of Doses Thienopyridine treatment dose will be according to the appropriate Package Insert for the selected medication (see Appendix 3 and 4). Aspirin treatment will be mg for the first 6 months after the procedure and mg subsequently, to be continued indefinitely. 1.6 Duration of the Investigation This study is expected to last approximately 50 months from the first subject being enrolled. Subject enrollment in the study will take place over approximately 18 months beginning in Q Page 25 of 118

136 Enrollment Begins 12 months 18 months 24 months 29 months 33 months 36 months 48 months 50 months Figure 1. DAPT Randomized Study Timeline Start Up First Subject Enrolled Last Subject Enrolled Treatment and Follow-up Period First 12 m DAPT Subject Randomized Last 12 m DAPT Subject Randomized First Randomized DAPT Subject follow-up complete Last Randomized DAPT Subject follow-up complete 1.7 Compliance Statement This trial is designed and planned to comply with the protocol, ICH E-6 Good Clinical Practices (GCP), the Declaration of Helsinki and the applicable local regulatory requirements. Page 26 of 118

137 2 Study Design and Population 2.1 Study Design This study is designed as a prospective, multi-center, randomized, double-blind trial. Study enrollment will consist of subjects who in the opinion of the investigators are candidates for extended dual antiplatelet therapy (DAPT), treatment with either drug eluting stent(s) (DES) or a bare metal stent(s) (BMS), provide consent to participate in the study, and who receive at least one stent and dual antiplatelet therapy. Subjects with ischemic heart disease due to stenotic lesions in either native coronary arteries or coronary artery bypass grafts undergoing PCI with stent placement and no contraindications to prolonged DAPT are eligible to be enrolled in this study. Subjects may have multi-vessel treatment. Subjects may be enrolled into the study either before or after the index procedure of percutaneous coronary intervention (PCI) with stent placement. Enrollment of qualified subjects can occur up to 3 calendar days after index procedure. For the purposes of stratification, subjects are considered complex if they have either acute coronary syndrome (ACS), renal insufficiency or failure, ejection fraction <30%, greater than two vessels stented, in-stent restenosis of a DES treated with a stent at the time of the index procedure, prior brachytherapy, or anatomically complex lesion treated with a stent at the time of the index procedure. Subjects that do not meet the criteria for complex will be considered non-complex for the purposes of stratification of randomization and analysis. ACS is defined as ischemic symptoms occurring at rest and lasting 10 minutes or more and occurring within 72 hours before index procedure and either ST-segment deviation of 1 mm or more or elevated levels of a cardiac biomarker of necrosis (CK-MB or troponin T or I greater than the upper limit of normal (ULN). If CK-MB or troponin is not available, total CK >2 times ULN). Subjects with STEMI can be enrolled and will be classified as ACS and complex if the index procedure is performed within 14 days after onset of symptoms. Renal insufficiency is defined by Creatinine 2.0 mg/dl and renal failure is defined as being dialysis dependent. The lesion is to be considered anatomically complex if it involves: Unprotected left main >2 lesions per vessel Lesion length 30 mm Bifurcation lesion with sidebranch 2.5 mm Vein bypass graft (segment or anastomosis) Thrombus-containing lesion Subjects that do not meet the criteria for complex will be considered non-complex for the purposes of stratification of randomization and analysis. All enrolled subjects will be treated with either a drug eluting stent(s) (DES) or a bare metal stent(s) (BMS) (per their respective Instructions for Use) and assigned to 12 months of open label thienopyridine treatment in addition to aspirin. Operators will select the thienopyridine according to the package insert (See Appendix 3 and 4). Thienopyridine treatment dose will be according to Page 27 of 118

138 the standard of practice and prescribing information for the selected medication. Aspirin treatment will be mg for the first 6 months after the procedure and mg subsequently, to be continued indefinitely. Subjects who are treated with 12 months of DAPT post index procedure and who are event free (from all death, myocardial infarction, stroke, repeat coronary revascularization, stent thrombosis, and major bleeding severe or moderate by GUSTO classification) during that time will be considered 12 Month Clear. Additional PCI(s) within 6 weeks of the index procedure do not disqualify a subject from randomization. Operators are strongly encouraged to use the same stent type at the second procedure (BMS or DES). Assignment to BMS or DES groups will be based on the stent received at the time of index without regard for prior or subsequent stenting. Repeat PCI, stent thrombosis, or MI within the first 6 weeks will not be considered exclusionary events for the definition of 12 Month Clear. Only major bleeding events, stroke, or CABG should be exclusionary events prior to 6 weeks from randomization. All enrolled subjects will be followed for the full 33 months regardless of whether they are randomized. All subjects treated with DES or BMS who are considered 12 Month Clear are eligible for randomization to either placebo (12 m DAPT arm) or an additional 18 months of thienopyridine treatment (30 m DAPT arm). Both arms will continue aspirin therapy. Randomization for subjects will be performed at 12 months post procedure in eligible subjects and will be stratified according to DES/BMS, hospital site, subject complexity and thienopyridine drug type. Eligible subjects will be randomized 1:1 to receive placebo or thienopyridine treatment for an additional 18 months. Subjects will be followed for an additional 3 months of observational followup at the end of the 18 month randomized treatment phase. Subjects who are not 12 Month Clear and are not randomized will be followed for 33 months post-index procedure. After it is determined that the subject is not going to be randomized, dual antiplatelet therapy will be at the discretion of the treating physician and all dual antiplatelet medication will be collected on the ecrf. 2.2 Subject Populations All Enr ol l ed Subj ect s All subjects enrolled in the study. 12 M ont h Cl ear This population consists of subjects enrolled in the study who are free from death, MI, stroke, repeat coronary revascularization, major bleeding severe or moderate by GUSTO classification, and ST 12 months after stent implantation and who are compliant with 12 months of DAPT following stent implantation. A subject is considered compliant with the thienopyridine therapy for the purposes of eligibility if they take between 80% and 120% of the prescribed drug in the 0-6 month and 6-12 month periods without an interruption of therapy longer than 14 days. Page 28 of 118

139 12 M ont h Not Clea r This population consists of those subjects enrolled in the study who do not meet the requirements of 12 Month Clear. During the open label portion of this study (time 0-12m), a subject is considered compliant with the thienopyridine therapy for the purposes of eligibility if they take between 80% and 120% of the prescribed drug in a given period without an interruption of therapy longer than 14 days. This information will be ascertained via data collected at the subject interviews at 6 and 12 months postprocedure. Compliance at both time points is required to be considered clear. The primary analysis population used to test the study hypotheses will be complex and noncomplex subjects with DES randomized to either 12 or 30 months of DAPT. 2.3 Number of Centers and Subjects Up to 20,645 subjects will be enrolled at up to 285 US and ex-us clinical study sites. Approximately 70% of sites will be in the US. Enrollment in the study will be limited to 1,000 subjects at any single site. Approximately 15,245 subjects will receive PCI with DES, assuming a 12 Month Not-Clear rate of 20% or less, and approximately 2300 subjects will receive PCI with BMS. Given the observational nature of the study, it is a possibility that some sites will exclusively use only one of the study thienopyridines or a limited selection of DES type. Subjects who receive both DES and BMS during the index procedure will not be eligible for enrollment. The minimum percentage of subjects treated with each type of DES (CYPHER, Endeavor, TAXUS (Express, Liberté, or Element), and XIENCE (V or PRIME)/PROMUS will be 15% as determined by placement of at least one DES during the index procedure. These devices should only be used where they have been approved by the local regulatory agency. For each DES stent type a target minimum of 20% of subjects are expected to be treated with a given thienopyridine drug. The target maximum percentage of subjects treated with each brand of study drug (clopidogrel and prasugrel) will be 60%, as determined at the time of randomization. The proportion of subjects with at least one DES type and with each thienopyridine type (in total and per stent type) will be tallied during the enrollment period as well at the time of randomization to determine whether the minimum or maximum parameters described above will be met. These caps and minimums will be monitored by a study enrollment monitoring committee (Section 12.5) PMS/COA (Post Market Surveillance / Condition of Approval ) Subjects There are significant challenges to enrolling into the dual antiplatelet therapy (DAPT) study or into any randomized study of drug-eluting stents in the current clinical trials environment. In order to complete this study in a timeframe that would allow relevant information on patient care to inform current practice, and in response to a true clinical concern regarding the optimal duration of DAPT therapy, we anticipate that patient level data will be obtained from Page 29 of 118

140 pre-specified non-randomized (to stent) studies whose primary objective is to assess FDAapproved stents (e.g. post market surveillance or condition of approval studies). This will decrease the total number of patients that would need to be enrolled in the DAPT study at the time of their index procedure. 1. DES subjects enrolled in separate manufacturer-run PMS and/or COA studies will be included as part of the DES-treated analysis population. Only studies not randomizing to stent type and that are pre-specified and listed to the FDA will be eligible to contribute data. In this protocol, it is assumed that uniform treatment and data collection processes will be performed within the original study protocol with relevant data transfer to HCRI for analysis. Such study data may be contributed either 1) at completion of follow-up within these external studies, in which case subjects would not be enrolled in the DAPT study, but data would be contributed after 33 months of follow-up, or 2) relevant baseline data and eligibility data to 12 months could be contributed and subjects could be enrolled under the DAPT protocol from 12 month for the purposes of randomization and completion of follow-up. Required data would be transferred to HCRI as clean SAS datasets to be merged with the DAPT database for statistical analysis. The following requirements have to be met by a study that is intended to provide patient level data for DAPT: 1. The determination of eligibility for enrollment and randomization is the same as in the DAPT study. 2. Data definitions are the same. 3. The same data are collected at the same time points. 4. Adjudication (or readjudication) of all endpoint events according to a central DAPT clinical events committee. 5. Contributed data are from consecutive patients meeting the specified requirements. The maximum number of drug-eluting stent patients whose data that will be transferred as cleaned data from completely separate studies meeting the above requirements will be The maximum number of subjects who will be enrolled and randomized in the DAPT study at 12 months after initially entering a separate manufacturer-run PMS and/or COA study will be The total numbers of contributed patients, and their poolability with patients who are enrolled and randomized in the DAPT study will be assessed at regular intervals by a study enrollment monitoring committee in order to confirm adequate enrollment of patients from the DAPT study. Data will be obtained from these studies at regular intervals so that clinical events adjudication under DAPT will occur throughout the duration of the study. The study will accept up to 8500 DES patients from four manufacturer companies contributed after completion of 33 months of follow-up from their index procedure as a part of the various post-marketing studies and/or condition of approval studies. The study will also accept DES patients from the manufacturer companies where relevant baseline and eligibility data to 12 months from the post-marketing study will be collected and then the subjects will be transferred at 12 months post-procedure to the DAPT study for the Page 30 of 118

141 purposes of randomization and completion of follow-up per the DAPT protocol. A total of up to 2439 DES patients will be accepted via this approach. 2.4 Study Flow Diagram Figure 2. DAPT Study Flow Chart Index Procedure - Enrollment Randomization (All Eligible Subjects) End of Treatment End of Follow Up 0 mo 6 mo 12 mo 15 mo 30 mo 33 mo 3% LTF annually 12 m DAPT arm obs Up to DES n = 15,245 BMS n = 2,300 Open label DAPT 20% ineligible * R DES n=12,196 BMS n=1,840 PCI 3% LTF annually 30 m DAPT arm obs R = Randomization. Randomization will only occur for those eligible subjects who are 12 Month Clear. * Patients who are ineligible for randomization will be followed through 33 months. LTF = Lost to follow-up. Page 31 of 118

142 2.5 Determination of Subject Eligibility All subjects presenting to the cardiac catheterization laboratory for possible interventional treatment are potential candidates. The following eligibility criteria are designed to select subjects for whom protocol treatment is considered appropriate. All relevant medical and non-medical conditions should be taken into consideration when deciding whether this protocol is suitable for a particular subject. Whenever the investigator is prepared to treat the subject in his/her best interest with a drug eluting stent or a bare metal stent and DAPT in accordance with the applicable guidelines on percutaneous coronary interventions the subject should be considered for inclusion in this study. The study specific inclusion and exclusion criteria are: 2.6 Enrollment Inclusion Criteria Subject must meet all of the following criteria to be eligible for treatment in the study: 1. Subject is > 18 years of age. 2. Subjects undergoing percutaneous intervention with stent deployment (or has w/in 3 calendar days). 3. Subjects without known contraindication to dual antiplatelet therapy for at least 30 months after enrollment and stent implantation. 4. The subject has consented to participate and has authorized the collection and release of his medical information by signing the Patient Informed Consent Form. The informed consent will be valid for the duration of the trial or until the subject withdraws. 2.7 Enrollment Exclusion Criteria Subjects will be excluded from the study if any of the following criteria are met: 1. Index procedure stent placement with stent diameter <2.25 mm or >4.0 mm. 2. Pregnant women. 3. Planned surgery necessitating discontinuation of antiplatelet therapy (>14 days) within the 30 months following enrollment. 4. Current medical condition with a life expectancy of less than 3 years. 5. Concurrent enrollment in another device or drug study where the primary endpoint has not yet been reached or the device/drug might affect major endpoint outcomes in either open label or randomized phases of the DAPT study. The subject may only be enrolled in the DAPT Study once. 6. Subjects on long-term warfarin (or similar anticoagulant) therapy who are anticipated to still be on warfarin at the time of randomization. 7. Subjects with hypersensitivity or allergies to one of the drugs or components indicated in the Instructions for Use for the device implanted. 8. Subjects unable to give informed consent. 9. Subject treated with both DES and BMS during the index procedure. Page 32 of 118

143 2.8 Randomization Inclusion Criterion at 12 months Subject must meet the following criterion to be eligible for randomization in the study: 1. Subject is 12 Month Clear, defined as subjects who are treated with 12 months of DAPT post index procedure and who are event free (from all death, myocardial infarction, stroke, repeat coronary revascularization, stent thrombosis, and major bleeding severe or moderate by GUSTO classification) during that time. During the open label portion of this study (time 0-12m post-index procedure), a subject is considered compliant with the thienopyridine therapy for the purposes of eligibility if they take between 80% and 120% of the prescribed drug in the 0-6 month and 6-12 month periods without an interruption of therapy longer than 14 days. 2.9 Randomization Exclusion Criteria at 12 months Subjects will be excluded from randomization if any of the following criteria are met: 1. Pregnant women. 2. Subject switched thienopyridine type or dose within 6 months prior to randomization. NOTE: thienopyridine switching during the open label portion of this study is discouraged. 3. Percutaneous coronary intervention or cardiac surgery between 6 weeks post index procedure and randomization. 4. Planned surgery necessitating discontinuation of antiplatelet therapy (>14 days) within the 21 months following randomization. 5. Current medical condition with a life expectancy of less than 3 years. 6. Subjects on warfarin or similar anticoagulant therapy Subject Complexity Definitions Subjects will be classified as complex or non-complex for the purpose of stratification of randomization and analysis. Subjects who are considered to be at a higher risk of late MACCE or ST are considered complex according to the following definitions. Complex Subjects: Subject will be classified as complex if they meet any of the following criteria: 1. >2 vessels stented 2. In-stent restenosis of a drug-eluting stent 3. Subject treated with prior brachytherapy 4. Treatment lesion is anatomically complex, as defined by: Unprotected left main >2 lesions per vessel Lesion length 30 mm Bifurcation lesion with sidebranch 2.5 mm Page 33 of 118

144 Vein bypass graft (segment or anastomosis) Thrombus-containing lesion Or the following clinical co-morbidities: 1. ACS presentation at the time of the index procedure (see definition in Section 9) 2. Renal insufficiency (Creatinine 2.0 mg/dl) or failure (dialysis dependent) 3. Ejection fraction <30% Subjects that do not meet the criteria for complex will be considered non-complex Early Withdrawal and Discontinuation Subjects may withdraw consent to participate in the study at any time and for any reason. A missed follow-up will be documented by the investigator and reported in the ecrf. The stopping of data collection for subjects in the study will occur in the following cases: Withdrawal of consent by subject Subject lost-to-follow-up (as defined in the note in Section 5.7) Subject death Study prematurely discontinued Page 34 of 118

145 3 Trial Treatments All subjects enrolled will receive dual antiplatelet therapy (DAPT) (12 or 30 months) and have a DES or a BMS placed. After 12 months of open label DAPT use, subjects who are 12 Month Clear are eligible for randomization. Subjects will be randomized 1:1 to one of two treatment groups. Subject randomization will be stratified based on the thienopyridine treatment they were taking at the time of randomization. The treatment groups are: 1) Continue thienopyridine treatment for an additional 18 months along with continued aspirin use (30 m DAPT Arm) 2) Placebo treatment for an additional 18 months along with continued aspirin use (12 m DAPT Arm) Subjects can be prescribed one of two FDA-approved thienopyridine(s) at the time of enrollment into the study. Details on both (clopidogrel and prasugrel) can be found in their respective package inserts (PI). In order to minimize bleeding risk, aspirin treatment is recommended to be the lowest acceptable dose per physician s discretion ( mg for the first 6 months after the procedure and mg indefinitely thereafter) 22. Subjects who are not 12 Month Clear and are not randomized will be followed for 33 months postindex procedure. After it is determined that the subject is not going to be randomized, dual antiplatelet therapy will be at the discretion of the treating physician. 3.1 Treatment Assignment This is a double-blind, randomized, multi-center, international study comparing 12 and 30 months of DAPT treatment in subjects undergoing PCI with stent placement. After index procedure, all subjects will take a daily dose of open label active drug (clopidogrel or prasugrel) through 12 months post index procedure and then, if eligible and randomized, they will receive the same drug that they were taking at the time of randomization or corresponding placebo in a blinded fashion for daily administration through 30 months. 12 Month Clear Subjects: Eligible subjects will be randomized to 18 months of active treatment or placebo 12 months after index procedure (Section 2.2). In order to randomize an eligible subject, study personnel will access an on-line IVRS system to obtain the randomization information for the subject. Randomized subjects will receive either active drug or placebo identical in appearance to the active drug. The treating physician, personnel at investigative sites, sponsor s clinical team, and Clinical Events Committee (CEC) will remain blinded to the treatment assigned. Randomization will be stratified by site, stent type, subject complexity at baseline and thienopyridine drug. Following randomization, subjects will be assigned blinded study medication Page 35 of 118

146 (thienopyridine or placebo). All subjects will be recommended to take aspirin at the dose directed by the investigator. Subjects who are randomized to receive blinded active drug, will receive the same thienopyridine (clopidogrel or prasugrel) that they were taking at the time of randomization. All subjects should also receive a daily dose of aspirin mg administered concomitantly with study drug. Study personnel will dispense the double blind study medication after randomization according to a sequence number assigned by the IVRS system. Subsequent study medication will be distributed to subjects on a regular basis according to local regulations and capabilities. Patients will adhere to a drug return process in accordance with local regulations. Subjects randomized to receive 12 months of thienopyridine will receive a daily dose of placebo for 18 months and continue with aspirin therapy. Use of open label thienopyridine will be at the discretion of the treating physician after month 33. Subjects randomized to receive 30 months of thienopyridine will receive a daily dose of active drug for 30 months and continue with aspirin therapy. Use of open label thienopyridine will be at the discretion of the treating physician after month 33. A subject s compliance with study medication will be collected along with information on medication interruption and reason for interruption through 30 months of follow-up. No antiplatelet medication (other than aspirin) should be administered between 30 and 33 months of the study ( rebound period ). After month 33, use of open label thienopyridine will be at the discretion of the treating physician. 12 Month Not Clear Subjects: Dual antiplatelet therapy will be at the discretion of the treating physician for those subjects that are not eligible for randomization. Study personnel will indicate the subject s ineligible status through the on-line IVRS system. 3.2 Drug Supplies and Administration Upon meeting all entrance criteria for the study and signing the informed consent form, the subject will be given a prescription by the Investigator (Principal or Sub) for the selected thienopyridine for the open label portion of this trial (first 12 months). The Investigator or study staff will review the proper dosing of the thienopyridine and will instruct the subjects to take the indicated daily dosage at the same time each day prior to the subject leaving the hospital. If allowable by local regulation, DES subjects must fill their prescriptions via commercially available supplies during the open label portion of the trial. Open label drug will be provided to patients in countries where regulations require distribution of drug at any point during the first 12 months of the study until the time when it is determined that they are ineligible for randomization. The study will provide BMS subjects open label drug for months 2-12 of the open label portion of the study until the time when it is determined that they are ineligible for randomization. If the subject is randomized and enters the double blind portion of the trial, they will be given a three or six month supply of the blinded study drug (active drug or placebo), depending on local Page 36 of 118

147 regulation, at the 12 month visit. The Investigator or study staff will review the proper dosing of the assigned blinded study medication with the subject prior to the subject leaving the office. Clinical supplies for the randomized portion of this trial will be provided every three or six months to active study participants. The subject will be dispensed the blinded treatment that they were randomized to receive as per the protocol. Patients will adhere to a drug return process in accordance with local regulations. The subject will not receive additional drug supplies once they withdraw from the study or the study treatment period ends. Study Medication Regimen Open Label portion clopidogrel + aspirin OR prasugrel + aspirin Randomized portion 30 m DAPT Arm clopidogrel + aspirin OR prasugrel + aspirin 12 m DAPT Arm placebo for clopidogrel + aspirin OR placebo for prasugrel + aspirin Formulation and Packaging Open label clopidogrel and prasugrel will be commercially supplied. For the double blind portion of the trial, the active drug and matching placebo will be supplied by the manufacturer and provided by the sites and will be identical in packaging as well as appearance. The study drugs will be labeled in the local language according to the regulatory requirements in each country, as well as in accordance with ICH Good Clinical Practice. Study Drug Chemical name: methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-acetate sulfate (1:1) Generic name: clopidogrel bisulfate Trade name: Plavix Dosage form: tablet Strength: 75 mg Manufacturer: Bristol-Myers Squibb/Sanofi-Aventis Description: TBD Page 37 of 118

148 Placebo to match clopidogrel Dosage form: tablet Manufacturer: Bristol-Myers Squibb/Sanofi-Aventis Description: TBD, same as above Study Drug Chemical name: 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride Generic name: prasugrel Trade name: Effient Dosage form: tablet Strength: 5 mg and 10 mg Manufacturer: Eli Lilly/Daiichi Sankyo Description: TBD Placebo to match prasugrel Dosage form: tablet Manufacturer: Eli Lilly/Daiichi Sankyo Description: TBD, same as above 3.3 Preparation and Dispensing If allowable by local regulation, DES subjects must fill their prescriptions via commercially available supplies during the open label portion of the trial. Drug will be provided to DES patients in countries where local authorities mandate drug distribution at any point during the first 12 months of the study until the time when it is determined that they are ineligible for randomization. BMS subjects are responsible for procuring study drug for the first 30 days of the open label portion of the study. The study will provide BMS subjects open label drug for months 2-12 of the open label portion of the study until the time when it is determined that they are ineligible for randomization. After the subject is randomized and enters the double blind portion of the trial, the assigned blinded study drug (active drug or placebo) will be distributed to the subject free of charge in a controlled manner as outlined in this protocol. Drug will be distributed to subjects on a regular basis according to local regulations and capabilities. The pharmaceutical manufacturer will provide the study medication to a depot for distribution to study investigators. The site investigator or designee must ensure that deliveries of study drugs from the manufacturers/representatives are correctly received by a responsible party, that all receipts are entered/recorded as received in the IVRS system, and that the products are stored in a Page 38 of 118

149 secure area under recommended storage conditions. It is the responsibility of the site investigator or designee to ensure that the integrity of packaged study products not be jeopardized prior to dispensing. Each individual subject packet must be dispensed as provided by the manufacturer or designee with no further repackaging or labeling done at the site. The investigator, study staff, or vendor will administer/dispense the study medication only to subjects included in this study following the procedures set out in this study protocol. All dispensing will be documented in the ecrfs and study drug record. The investigator is responsible for assuring the retrieval of all study supplies from subjects. Returned materials will be used to assess subject compliance to the drug therapy after randomization for the blinded treatment portion of the study. 3.4 Drug Storage and Drug Accountability DES subjects in the first year and BMS subjects in the first 30 days will receive open label study drug from commercial sources. Storage conditions should be maintained as per the respective drug s package leaflet. In the double blind portion of the trial post randomization, all full, partially full and empty drug supply containers must be returned to the HCRI-designated subcontracting vendor for assessment. The vendor must maintain accurate and adequate records including dates of receipt and return of drug shipments, and lot number and quantities received/returned from/to the distributor, as well as, dates and amounts dispensed to and returned by the study subjects. The investigator also must maintain a drug dispensing log. All drug supplies must be stored in accordance with the manufacturers instructions. Until dispensed to the subjects, the study medication will be stored in a securely locked area, only accessible to authorized personnel. 3.5 Compliance There are two methods of assessing drug compliance in this DAPT study; one for the open label portion of the trial and one for subjects randomized. The compliance or adherence to thienopyridine use during the open label portion of the trial will be ascertained from the subject interview at the 6 and 12 month contacts. This information will be used to screen out not clear subjects prior to randomization. At each contact, the subject will be asked to estimate the percentage compliance for the previous 6 months. They will also be asked about any significant interruptions in the prescribed treatment in the past 6 months. Subjects will also be asked specifically about their compliance over the previous two weeks for further monitoring of drug compliance. After subject randomization and when the distribution of drug is controlled by the trial protocol, the procedure for assessing drug compliance will be by examining the amount of medication used and returned by the subject on a quarterly basis through month 30. Subjects will be required to return previously dispensed study drug supplies with the receipt of each new shipment. Sites will forward all unused drug supply to the designated drug distributer for accountability purposes. The total number of doses taken will be divided by the number of doses required for continuous treatment during the three month period. Compliance will be assessed separately for each 3 month period. Compliance will be calculated by the drug distributer and supplied to HCRI. Page 39 of 118

150 Subject compliance with the study medication will be calculated for each pill packet using the following formula: Compliance = number of supplied doses of medication taken by subject number of doses of medication required for continuous treatment during period The numerator of the above formula will be obtained from counting the returned pill packets and remaining pills. The acceptable percentage of compliance will be 80% to 120%. Compliance will be checked following each distribution of the medication (quarterly following subject randomization). Any subject found to be taking <80% or >120% of the prescribed study drug will be considered non-compliant. Once randomized, subjects should not be discontinued from study drug for noncompliance; however, the investigator or designee will determine factors that result in poor compliance with the study drug and will take steps to improve compliance. In addition, at each contact after randomization, the subject will be asked via a subject interview about any significant interruptions (as defined in Section 3.6) in the prescribed treatment since their last contact as well as confirmation of their compliance over the previous two weeks for further monitoring of drug compliance. Information captured during this interview will be details regarding therapy interruption (Y/N), reason for interruption, date interruption commenced, date interruption concluded, and events experienced before, during or after interruption. Data will also be collected regarding the number and frequency of doses missed during the two weeks preceding the interview. Data regarding the subject s use of the study drug (type of drug, start date, stop date, any interruptions with reason, discontinuation with reason, and any subsequent receipt of open label drug after randomization including name, dose, dates, etc.) will be captured on the ecrf as necessary. 3.6 Procedures for Interruption of Therapy An interruption of therapy is defined as a period of time when the subject is not taking the prescribed therapy. A significant interruption of therapy is defined as when a subject is not taking the prescribed therapy for longer than 14 consecutive days. The procedure for determining any significant interruptions of therapy will be the acquisition of data resulting from subject interviews at the protocol-established contacts. Assessments may take place in person or via a phone conversation. As outlined above, information captured during this interview will be details regarding any significant therapy interruption, including reason and dates of the interruption. Significant interruptions of therapy during the first 12 months (open label) of the study will preclude the subject from participating in the randomized part of the trial. In the event that a subject temporarily discontinues drug therapy (for fewer than 14 days) not directly resulting from physician guidance, it is recommended that the subject consult with their physician and attempt to resume their prescribed therapy. This occurrence (including reason for temporarily discontinuing therapy as well as date of stopping and resuming therapy) should be documented on the ecrf, if possible. In case of severe allergy or intolerance to study drug, study participation for that subject will be discontinued and the subject will be managed at the discretion of the treating physician. These subjects will continue to be followed for the duration of the study. Page 40 of 118

151 Subjects who experience myocardial infarction (MI), stroke, PCI with stent placement, have cardiac surgery, stent thrombosis, and/or bleeding complication ( severe or moderate by GUSTO classification) prior to the 12-month randomization may either continue or discontinue open label thienopyridine at the discretion of the treating physician. These subjects will continue to be followed for the duration of the study. Additional PCI(s) within 6 weeks of the index procedure do not disqualify a subject from randomization. Operators are strongly encouraged to use the same stent type at the second procedure (BMS or DES). Assignment to BMS or DES groups, and thereby determination of study drug dispensation, will be driven by assignment of stent type at the time of index without regard for prior or subsequent stenting. Repeat PCI, stent thrombosis, or MI within the first 6 weeks will not be considered exclusionary events for the definition of 12 Month Clear. Only major bleeding events, stroke, or CABG prior to 6 weeks post-index procedure should be exclusionary events from randomization. Subjects who experience MI, stroke, PCI with stent placement, have cardiac surgery, or stent thrombosis after randomization will discontinue study drug, receive open label thienopyridine at the discretion of the treating physician or in accordance with the manufacturer s labeling, and will be followed for the duration of the study. The change from study drug to open label thienopyridine, and the reason, should be documented by the investigator on the ecrf. At the discretion of the investigator, subjects who experience bleeding that is non-life threatening should be encouraged to reduce the aspirin dose to the minimal acceptable level and continue study drug, or to resume study drug after the minimum required interruption. Should a subject require the use of open label thienopyridine beyond the original indication during the treatment phase of this study (e.g. recurrent PCI), the subject and their physician should discontinue the subject s randomized treatment, switch to open label use, and record the date and reason for doing so on the ecrf. These subjects will continue to be followed for the duration of the study. Subjects who experience an event that is not a MACCE and that does not require suspension of DAPT are discouraged from discontinuing their treatment. 3.7 Concomitant Medication(s) Any medication the subject takes other than the study drugs specified in the protocol is considered concomitant medication. All anticoagulant and antiplatelet concomitant medications must be recorded in the subject s medical record and on the ecrfs. In addition to APT, beta-blockers, statins, ACEI s, ARB s, NSAIDs, COX-2, PPIs and warfarin will be captured on the ecrf. The information related to the concomitant medications will be recorded starting 24 hours prior to the index procedure through the 33 month follow up visit. 3.8 Medication(s) Not Permitted Before and/or During the Trial Subjects who are on long-term warfarin (or similar anticoagulant) therapy who are anticipated to still be on warfarin at the time of randomization are not eligible for enrollment in this study. Subjects who develop an indication for warfarin use after randomization may be prescribed warfarin, will convert to open label thienopyridine or discontinue therapy at the discretion of the investigator, and continue to be followed in the study. Page 41 of 118

152 4 Study Objectives The objectives of this study are to evaluate the composite of all death, myocardial infarction (MI) and stroke (MACCE) and the survival free from ARC definite or probable stent thrombosis (ST) in subjects treated with drug eluting stents (DES) and extended dual antiplatelet therapy. All of the primary analyses will be performed on the primary analysis population (randomized DES subjects followed through 33 months post-procedure, including the 3 month rebound observational period). The primary study hypotheses are: Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have increased survival free from death, myocardial infarction or stroke compared with subjects treated with only 12 total months of dual antiplatelet therapy over the month post-stenting period. Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have increased survival free from ARC definite/probable stent thrombosis (ST) compared with subjects treated with only 12 total months of dual antiplatelet therapy over the month post-stenting period. 4.1 Co-Primary Endpoints This study has two co-primary endpoints that will be assessed. They are: composite of all death, myocardial infarction (MI) and stroke (defined as MACCE) - 12 through 33 months ARC definite or probable stent thrombosis (ST) - 12 through 33 months 4.2 Primary Safety Endpoint The primary safety hypothesis for this study is: Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have non-inferior major bleeding rates compared to the rates of subjects treated with only 12 total months of dual antiplatelet therapy over the month post-stenting period. The primary safety endpoint assessed for this study is: Major bleeding (GUSTO classification, severe and moderate bleeding combined) - 12 through 33 months 4.3 Secondary Endpoints and Analyses The main secondary study hypotheses are: Page 42 of 118

153 DAPT subjects treated with drug-eluting stents will have a rate of death, myocardial infarction or stroke that is non-inferior compared with the rate of propensity score matched subjects treated with bare-metal stents over the 0-33 month post-stenting period. DAPT subjects treated with drug-eluting stents will have a rate of ARC definite/probable stent thrombosis (ST) that is non-inferior compared with the rate of propensity score matched subjects treated with bare-metal stents over the 0-33 month post-stenting period. The main secondary endpoints to be assessed are: BMS subjects versus DES subjects, propensity score matched for baseline characteristics and duration of DAPT assigned MACCE - 0 through 33 months ST - 0 through 33 months DES Randomized subjects ITT population MACCE - 12 through 30 months ST - 12 through 30 months Major Bleed - 12 through 30 months DES Randomized subjects On Treatment population MACCE - 12 through 30 months and 12 through 33 months ST - 12 through 30 months and 12 through 33 months Major Bleed - 12 through 30 months and 12 through 33 months BMS Randomized subjects ITT population MACCE - 12 through 30 months and 12 through 33 months ST - 12 through 30 months and 12 through 33 months Major Bleed - 12 through 30 months and 12 through 33 months BMS Randomized subjects On Treatment population MACCE - 12 through 30 months and 12 through 33 months ST - 12 through 30 months and 12 through 33 months Major Bleed - 12 through 30 months and 12 through 33 months Incidence of MACCE at 12 months post-procedure as well as the incidence of death, MI, stroke, major bleeding and stent thrombosis will be reported and compared for DES vs. BMS. Death, cardiac death, MI, and stroke for each treatment arm will be compared using descriptive statistics for the overall, 12 Month Clear, 12 Month Not Clear, and BMS vs. DES populations. Page 43 of 118

154 5 Procedures and Assessments 5.1 Pre-Procedure Signed written informed consent must be obtained for all subjects who are potential study candidates. Informed consent may be collected prior to the subject undergoing the index procedure or within 3 calendar days of the procedure for subjects who otherwise meet the study inclusion criteria. Additionally, the following evaluations must be completed for all subjects unless otherwise specified: Lesion Characteristics Eligibility Criteria Current Cardiac Status Demographics Cardiac Risk Factors Antiplatelet Therapy Antiplatelet therapy is mandatory for this trial. Recommended dosing options are as follows: Aspirin: 75 mg daily for 3 days prior to the procedure, or a peri-procedural loading dose of mg. Aspirin treatment will be mg for the first 6 months after the procedure and mg subsequently, to be continued indefinitely. Clopidogrel: A peri-procedural loading dose between mg. A maintenance dose of 75 mg daily of clopidogrel or as indicated by the treating physician should be continued for the duration of the treatment period. OR Prasugrel: A peri-procedural loading dose of 60 mg. A maintenance dose of 10 mg daily of prasugrel or as indicated by the treating physician should be continued for the duration of the treatment period. A daily maintenance dose of 5 mg may be considered under certain circumstances as noted in the product labeling. NOTE: The effectiveness and safety of the 5 mg dose have not been prospectively studied. 5.2 Stenting Procedure Subject preparation and the treatment of the lesion(s) will be in accordance with standard hospital policy for the care of interventional cardiology subjects. The stenting procedure should be performed according to hospital standards. Use of all other co-medication (other than the antiplatelet therapy above) is at the investigators discretion and will therefore be done according to hospital routine. Site Investigators are requested to carefully document the stent implantation procedure angiography for possible later use by the Clinical Event Committee for event adjudication. Angiograms should be retrievable during the duration of the study. Page 44 of 118

155 5.3 Enrollment Enrollment will occur after confirming that the signed informed consent has been obtained and the subject has met all of the inclusion and none of the exclusion criteria. Subjects can be enrolled up to 3 calendar days post procedure. All reportable events occurring after enrollment must be documented in the ecrf. 5.4 Clinical and Local Laboratory Procedures Before the procedure, and preferably within 72 hours of the procedure, a creatine kinase (CK) enzyme, creatine kinase myocardial-band (CK-MB) isoenzyme test and/or troponin will be obtained for all subjects presenting with ACS. If possible, CK, CK-MB and/or troponin values should be collected for all subjects at least once post-index procedure (12-24 hours after the index procedure, or before discharge if hospitalized <12 hours). If a myocardial infarction has occurred, CK, CK-MB and/or troponin values should be recorded on the ecrf for adjudication purposes by a Clinical Event Committee (CEC). NOTE: We recommend checking troponin I or troponin T to detect spontaneous MI. If a revascularization procedure is performed, CK, CK-MB values (if performed at least once hours after the procedure, or before discharge if hospitalized <12 hours) should be recorded on the ecrf. If CK and CK-MB is not available, troponin should be recorded. 5.5 Central Laboratory Procedures after Enrollment At least 6 hours after the loading dose of thienopyridine, blood samples will be obtained for platelet function testing, biomarkers, and DNA in select subjects (see Appendix 1 and 2). 5.6 Angiography Visual estimation of lesion characteristics in relation to the index procedure will be performed by the operator and recorded on the ecrf. There is no mandatory angiographic follow-up in the protocol. Investigators are advised to perform angiograms only on a clinically driven basis, i.e. in case of symptoms or demonstrable ischemia. Angiography is not mandated by protocol. Baseline and event angiograms will be collected that are related to a study primary or main secondary endpoint, including but not limited to death, (suspected) myocardial infarction or stent thrombosis. 5.7 Follow-up Assessments The general requirements for follow-up in the study of this trial include: 1. Enrolled subjects will be followed for 33 months. 2. The subject must return in person for the follow-up clinical visits. 3. Brief clinical assessments must be performed at the clinical visits. 4. Endpoint data or information relating to endpoints (e.g. PCI, MI, stroke, CABG). 5. Contact information for referring physicians, general practitioners, cardiologists and family members should be collected to facilitate continued ability to contact a trial subject. Follow-up Schedule Page 45 of 118

156 Day 0 (clinical) 6 mo (± 14 days) (telephone) 1 yr (± 30 days) (clinical) 15 mo (± 30 days) (telephone) 24 mo (± 30 days) (telephone) 30 mo (± 30 days) (clinical/telephone*) 33 mo (± 30 days) (telephone) *Telephone contact for 30 mo visit may be used only for subjects who were not randomized. The following information will be collected at each follow-up. 1. All serious adverse events (SAEs) since the previous follow-up 2. All relevant concomitant medications since the previous follow-up 3. Information related to DAPT usage (and DAPT compliance for 12 Month Clear subjects) 4. Any coronary treatment that occurred (e.g. interventional or surgical revascularization) since the previous follow-up This study does not require any specific test or procedure that falls outside a standard stenting procedure as routinely done in the hospital. The subject should be carefully interviewed regarding hospitalizations, myocardial infarctions, coronary angiographies/ interventions as well as compliance regarding thienopyridine and aspirin intake since the previous follow-up. MACCE and other events should be recorded in the ecrf within 10 working days after the investigator becomes aware of the event. The maximum follow-up period for each individual subject is 33 months. Subjects enrolled under a previous version of the protocol should be re-consented to allow subject follow-up for complete 33 months if the subject is not randomized. Re-consenting should occur per the site s ethics board requirements. Note: Execution of the follow-up schedule is essential to enable an analysis of the results in a scientifically sound and meaningful way. If, for whatever reason, the subject follow-up cannot be scheduled within the time window or occurred outside the time window, it is still essential to document the subject data at a date as close as possible to the calculated follow-up date. Every effort should be made to maintain a subject s follow-up compliance. Contacting the subject s general practitioner or referring cardiologist should be considered in case the subject cannot be reached in order to obtain information about the subject s health status and documented in the subject s file. Several attempts over a period of time should have been made to contact the subject, family or referring physician before documenting a subject lost to follow up. Sites will be required to make three phone calls to a subject followed by a registered letter for each follow-up contact. Death registry databases should be consulted by the sites where these databases are available and accessible to treating physicians. Page 46 of 118

157 5.8 Schedule of Events Baseline Procedure Followup 6 months (phone) Randomization 12 months 5 (clinic) Follow-up 15 (phone), 24 (phone), 30 (clinic/phone 6 ) and 33 months (phone) Eligibility criteria X - - X - Demographics X Cardiac risk factors X Current cardiac status X - X X X Lesion characteristics X X Patient informed consent X Enrollment - X Procedure data - X Cardiac biomarkers 1 X Central laboratory X 4 X Relevant concomitant X X X X X medications Antiplatelet compliance X X X MACCE / bleeding - X X X X complications Event related: - Cardiac biomarkers 2 - As As As As Needed Needed Needed Needed - ECG As Needed - Angiogram As Needed As Needed - Antiplatelet medication - As Needed As Needed As Needed 1) Cardiac biomarkers required for all ACS subjects. 2) If a myocardial infarction has occurred, CK, CK-MB and/or troponin values should be recorded on the ecrf for adjudication purposes by a Clinical Event Committee (CEC). NOTE: We recommend checking troponin I or troponin T to detect spontaneous MI. If a revascularization procedure is performed, CK, CK-MB values (if performed at least once hours after the procedure, or before discharge if hospitalized <12 hours) should be recorded on the ecrf. If CK and CK-MB is not available, troponin should be recorded. 3) Printouts of ECG will be collected for death or any suspected myocardial infarction or suspected stent thrombosis that occurs after the randomization of subjects for adjudication purposes by a Clinical Event Committee (CEC). 4) For ancillary study subjects only. Blood samples to be obtained at least 6 hours after the loading dose of thienopyridine; can be before or after the PCI. 5) Randomization is for eligible 12 Month Clear subjects. 6) Telephone contact for 30 mo visit may be used only for subjects who were not randomized. Page 47 of 118

158 5.9 Description of Randomization and Blinding Procedures A computer-generated randomization schedule will be used to assign subjects to treatments. Randomization for subjects will be performed in a 1:1 manner at 12 months post procedure in eligible subjects and will be stratified according to DES/BMS, hospital site, subject complexity and thienopyridine drug type. A double blinding (investigator and subject) method will be used. The study drugs and their respective matching placebos will be similar in size, color, smell, taste and appearance. In case of emergency, the site PI may break the study blind as deemed medically necessary. When possible, this should be discussed with the local HCRI medical monitor prior to unblinding. The blind should only be broken for emergencies (determined at the discretion of the site PI), and only for the subject in question, or when required by regulatory authorities. In the event of such a circumstance, unblinding may be accomplished by accessing the IVRS contact telephone number as listed in the IVRS/Study Drug Dispensing Instructions. The site Investigator will notify HCRI as soon as possible, and whenever possible, prior to unblinding themselves or any subject. The date, time, and reason the blind was broken must be recorded in the source documents and on the appropriate ecrf Central Laboratory Procedures at Randomization On the day of randomization, blood samples will be obtained for platelet function testing and biomarkers in select subjects (see Appendix 1). Page 48 of 118

159 6 Statistical Considerations and Analysis Plan A statistical analysis plan will be prepared and finalized prior to the unblinding of the study or the database lock. This document will provide further details regarding the definition of analysis variables and analysis methodology to address all study objectives. 6.1 Study Populations Definitions The following populations are defined for DES and for BMS subjects separately and for all subjects combined. All Enrolled Subjects All subjects enrolled in the study. 12 Month Clear This population consists of subjects enrolled in the study who are free from death, MI, stroke, repeat coronary revascularization, major bleeding - severe or moderate by GUSTO classification, and ST 12 months after stent implantation and who are compliant with 12 months of DAPT following stent implantation. Additional PCI(s) within 6 weeks of the index procedure do not disqualify a subject from randomization. Operators are strongly encouraged to use the same stent type at the second procedure (BMS or DES). The primary analysis will be for intention to treat by assignment to BMS or DES based on the stent received at the time of index without regard for prior or subsequent stenting. For the secondary sensitivity analysis, subjects who receive both types of stent (BMS and DES) during the index and subsequent PCI(s) will be considered DES subjects. Repeat PCI, stent thrombosis, or MI within the first 6 weeks will not be considered exclusionary events for the definition of 12 Month Clear. Only major bleeding events, stroke, or CABG should be exclusionary events prior to 6 weeks. 12 Month Not Clear This population consists of those subjects enrolled in the study who do not meet the requirements of 12 Month Clear. During the open label portion of this study (time 0-12m post-index procedure), a subject is considered compliant with the thienopyridine therapy for the purposes of eligibility if they take between 80% and 120% of the prescribed drug in the 0-6 month and 6-12 month periods without an interruption of therapy longer than 14 days. This information will be ascertained via data collected at the subject interviews at 6 and 12 months post-procedure. Compliance at both time points is required to be considered clear. After randomization, a subject is considered On Treatment with the randomized therapy if they take between 80% and 120% of the randomized drug in a given period (assessed via quarterly examination of medication used) and do not have an interruption of therapy longer than 14 days (assessed via subject interview). As detailed in Section 3.5, the total number of doses taken will be divided by the number of doses required for continuous treatment during the three month period. Between 80% and 120% compliance at all six three-month intervals (12-30 months) is required to be considered On Treatment ; however, all randomized subjects regardless of compliance will be included in the primary analyses of primary and secondary endpoints, according to the principle of intent-to-treat. Page 49 of 118

160 6.2 Analysis Populations The DES Randomized - ITT sample includes all DES subjects randomized to either 12 months of DAPT or 30 months of DAPT. Randomization will occur at the 12 month post-stent implantation time point. Subjects randomized to the 12 m DAPT arm will receive placebo for 18 months following randomization; subjects randomized to the 30 m DAPT arm will receive additional DAPT for 18 months following randomization. All subjects will receive aspirin while on randomized treatment. All follow-up data will be included in the ITT statistical analyses regardless of compliance with the assigned treatment. Subjects will be analyzed for the primary endpoints according to the treatment to which they were randomized. The DES Randomized - On Treatment (OT) sample will be the subset of the DES Randomized ITT subjects who were On Treatment as defined above for all six three-month (12-30 months) time intervals. The BMS Randomized - ITT sample includes all BMS subjects randomized to either 12 months of DAPT or 30 months of DAPT. Randomization will occur at the 12 month post-stent implantation time point. Subjects randomized to the 12 m DAPT arm will receive placebo for 18 months following randomization; subjects randomized to the 30 m DAPT arm will receive additional DAPT for 18 months following randomization. All subjects will receive aspirin while on randomized treatment. All follow-up data will be included in the ITT statistical analyses regardless of compliance with the assigned treatment. Subjects will be analyzed for the primary endpoints according to the treatment to which they were randomized. The BMS Randomized - On Treatment (OT) sample will be the subset of the BMS Randomized ITT subjects who were On Treatment as defined above for all six three-month time (12-30 months) intervals. The BMS subjects versus DES subjects, propensity score matched sample will include all BMS subjects and DES subjects who match the BMS subjects on clinically relevant baseline demographic and disease characteristics and duration of DAPT treatment. It is anticipated that the minimum matched DES:BMS ratio of 1:1 though the expected average matched DES:BMS ratio will be at least 2:1 (this ratio is anticipated to be achieved given the number of enrolled DES subjects available for matching is anticipated to be approximately 5-6 times greater than the number of available BMS subjects)overall matching ratio will be at least 2:1. This sample will be used to assess non-inferiority of DES to BMS with respect to MACCE and ST rates for the 0-33 month period as discussed below. The BMS subjects versus DES subjects, propensity score adjusted sample will include all enrolled BMS subjects and all enrolled DES subjects. Propensity score adjustment during analyses comparing BMS vs. DAPT will occur on clinically relevant baseline demographic and disease characteristics and duration of DAPT treatment. This sample will be used to assess non-inferiority of DES to BMS with respect to MACCE and ST rates for the 0-33 month period as discussed below, adjusting for propensity score. 6.3 Primary Hypotheses The primary objective of the study is to compare 12 months of DAPT with 30 months of DAPT between 12 and 33 months post index procedure on the clinical and thrombosis endpoints for DES Page 50 of 118

161 subjects (subjects will be on randomized treatment for months and off randomized treatment for months). Specifically, the primary hypotheses are: Clinical: In subjects treated with DES free from MI, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 m after PCI, DAPT for an additional 18 m (total 30 months) will increase survival free from death, MI or stroke compared with only 12 total months of DAPT over the month post-index procedure period. Stent Thrombosis: In subjects treated with DES free from MI, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 m after PCI, DAPT for an additional 18 m (total 30 months) will increase survival free from ARC definite/probable stent thrombosis (ST) compared with only 12 total months of DAPT over the month post-index procedure period. The study will be considered a success for 30m DAPT if at least one of these two hypotheses is statistically proven using the Hochberg approach on the DES Randomized ITT sample at an overall familywise error (FWE) rate of 0.05 (i.e., if each objective is proven at the two-sided 0.05 level of significance, the study is considered a success for 30m DAPT; otherwise, if one hypothesis is proven at the two-sided level of significance, then the study is considered a success for 30m DAPT). 6.4 Co-Primary Endpoints There are two potential mechanisms of benefit of 30m of DAPT: a device-oriented benefit manifesting as a reduction in ST; and a patient oriented benefit manifesting as reduction in disease progression/non-target lesion events. It is possible that an important treatment difference for the clinical endpoint may not be mediated by ST prevention, or a true treatment difference in ST may not be detected as a difference in the clinical endpoint. For this reason, two co-primary endpoints are specified. Specifically, the co-primary endpoints are Clinical: Incidence of the composite endpoint of death, MI or stroke within the month period following stent implantation (MACCE endpoint). Stent Thrombosis: Incidence of ARC definite/probable stent thrombosis (ST) within the month period following stent implantation (ST endpoint). The study will be considered a success for 30m DAPT if 30m DAPT is shown to yield a significantly lower rate (longer time-to-event) than 12m DAPT for at least one of these two endpoints using the Hochberg approach on the DES Randomized ITT sample at an overall FWE rate of 0.05 (i.e., if 30m DAPT has a significantly lower rate (longer time-to-event) than 12m DAPT on both endpoints using a two-sided 0.05 level of significance for each endpoint, the study is considered a success for 30m DAPT; otherwise, if 30m DAPT has a significantly lower endpoint rate (longer time-to-event) than 12m DAPT on one endpoint using a two-sided level of significance, then the study is considered a success for 30m DAPT). Page 51 of 118

162 Sample Size Considerations The following is an estimate of DES sample size for the DAPT Study to compare the 12m DAPT regimen to 30m DAPT regimen under the following assumptions: i. Two primary outcomes: i. Time to MACCE between months post-procedure; hypotheses are H o : 12m-DAPT = 30m-DAPT where H A : 12m-DAPT 30m,-DAPT is the hazard rate of MACCE over the month period. ii. Time to ST between months post-procedure; hypotheses are H o : 12m-DAPT = 30m-DAPT where H A : 12m-DAPT 30m-DAPT is the hazard rate of ST over the month period. Time to each endpoint follows an exponential distribution, with ii. Incidence of MACCE =2.9% and incidence of ST=0.5% for 12m-DAPT annually for the 21 months following randomization (12-33 month post-procedure period). 1, 2, 3. iii. Incidence of MACCE =2.175% and incidence of ST=0.225% for 30m-DAPT annually for the first 18 months following randomization (12-30 month postprocedure period); iv. After treatment stops at 30 months post-randomization, 30m-DAPT incidence rate increases to that of 12m-DAPT. The hazard ratio (30m DAPT to 12m DAPT) under these assumptions is 0.75 for MACCE and 0.45 for ST across the 12m 30m period and 1.0 for both endpoints across the 30-33m period. v. Randomization is 1:1 into the 12m and 30m arms (randomization occurs at 12m postprocedure time point). vi. Annual lost to follow-up rate of 3% after randomization. vii. Familywise (FWE) error rate is controlled at the 0.05 level using the Hochberg approach (reject both null hypotheses if both are significant at the 0.05 level; otherwise, if one null hypothesis is significant at the level, then that null hypothesis is rejected). 1 Mauri L, Hsieh WH, Massaro JM, Ho KK, D'Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med. 2007;356(10): Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20): Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Juni P, Sianos G, Hellige G, van Domburg RT, Hess OM, Boersma E, Meier B, Windecker S, Serruys PW. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 2007;369(9562): Page 52 of 118

163 For each endpoint separately, 12,196 DES subjects randomized at 12 months post-procedure yields 80% power to reject the null hypothesis for that endpoint under the above assumptions at a two-sided 0.05 level of significance. Mathematically, it can then be shown that 12,196 DES subjects randomized at 12 months post-procedure will yield at least 80% power that the study has statistically met its objective under the assumption of a treatment effect in both outcomes using the Hochberg approach to declare the study a success for these two endpoints (power ranges from approximately >80% to >90% depending on correlation of outcomes). Thus, the number to be enrolled at time of stent implantation is approximately 12,196/.8 or 15,245. This has also been shown via computer simulations. Note that in order to justify the validity of DAPT power and sample size calculations across the range of possible MACCE and ST estimates, a series of computer simulations were run to determine how much power would be retained if various event rates were realized. Under the worst case (i.e., lowest) assumptions of a 2.3% annual MACCE rate and 0.4% annual ST rate for the 12m DAPT group, there is still 80% power under Hochberg (still assuming hazard ratios of 0.75 for MACCE and 0.45 for ST) "regardless" of the correlation. For the correlation, we simulated two extreme cases: (a) complete independence between the two endpoints, which is the most "liberal" (i.e., yields the best power); and (b) anyone who had an ST also had MACCE (but not the reverse given that MACCE occurs at a higher rate than ST). Approach (b) is more conservative than (a), but still yields at least 80% power under Hochberg. For the protocol-assumed rates of 2.9% annual MACCE rate and 0.5% annual ST rate for 12m DAPT, Hochberg yields at least 80% power. This is true for both the most conservative assumption (perfectly correlated endpoints) and a more realistic conservative assumption (option (b) from above). Under the protocol assumed rates, the power is about 85% under assumption (b) above. Rejection of the combined null hypothesis will indicate that treatment with DAPT to 30 months post-pci is superior to treatment with DAPT to 12 months with respect to MACCE, ST, or both. If the study is not considered a success according to these criteria, the 95% confidence intervals of the difference between DAPT duration treatment groups will be calculated. The assumed MACCE rate is based on published rates of cardiac death, MI and stroke 4, 5, and adjusted to reflect that deaths from all causes are included in the primary endpoint rather than cardiac deaths only. These rates are 2.4% - 3.4%, with a median of 2.9% (12 to 30 months post- PCI) and the assumed ST rate is based on published data 6, 7, 8. 4 Stone GW, Moses JW, Ellis SG, Schofer J, Dawkins KD, Morice MC, Colombo A, Schampaert E, Grube E, Kirtane AJ, Cutlip DE, Fahy M, Pocock SJ, Mehran R, Leon MB. Safety and efficacy of sirolimus- and paclitaxeleluting coronary stents. N Engl J Med. 2007;356(10): Steinhubl SR, Berger PB, Mann JT, 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19): Mauri L, Hsieh WH, Massaro JM, Ho KK, D'Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med. 2007;356(10): Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in Page 53 of 118

164 Primary Analyses The primary analyses will compare both the survival free of MACCE and ST between DES subjects randomized to the 30m DAPT arm versus those randomized to the 12m DAPT arm using the stratified log-rank test (where the strata are the randomization strata; specifically hospital site, subject complexity and thienopyridine drug type). These analyses will be performed on the randomized DES 12 Month Clear population according to the principle of intention to treat (the DES Randomized - ITT sample defined above). The FWE will be controlled at the two-sided 0.05 level of significance as discussed above using the Hochberg approach. The study will be considered a success for 30m DAPT if 30m DAPT is shown to yield a significantly lower rate than 12m DAPT for at least one of the two primary endpoints using the Hochberg approach on the DES Randomized ITT sample at an overall FWE rate of 0.05 (i.e., if 30m DAPT has a significantly lower rate than 12m DAPT on both endpoints using a two-sided 0.05 level of significance for each endpoint, the study is considered a success for 30m DAPT; otherwise, if 30m DAPT has a significantly lower endpoint rate than 12m DAPT on one endpoint using a twosided level of significance, then the study is considered a success for 30m DAPT). Kaplan-Meier estimates of MACCE and ST will be presented for each treatment arm, as will a two-sided 95% confidence interval of the treatment difference in Kaplan-Meier rates (30 m DAPT minus 12 m DAPT). All subjects will be included regardless of time to follow-up. The Lakatos method 9 for calculating asymptotic mean and variance of the log-rank statistic will be used for comparison of the survival curves. Subjects not achieving the co-primary endpoints months post-procedure will be censored in the analysis at the time of withdrawal from the study or 33-months post-procedure, whichever is earlier. The log-rank statistic is given by d L d X i i 1 n 1i n 1i n 2i n 1i n 2i i 1 n 1i n 2i 2 where d is the number of (primary endpoint) events; i is the ith event; X i is the treatment group indicator for the ith event (0 = experimental, 1= control); n 1i is the number at risk in the experimental group just before the ith event, and n 2i is the number at risk in the control group just before the ith event. Details of the Lakatos calculation of the asymptotic mean and variance of the log-rank statistic can be found in Section 6.11 (Statistical Methods). patients with acute coronary syndromes. N Engl J Med. 2007;357(20): Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Juni P, Sianos G, Hellige G, van Domburg RT, Hess OM, Boersma E, Meier B, Windecker S, Serruys PW. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 2007;369(9562): Lakatos, Edward Sample Sizes Based on the Log-Rank Statistic in Complex Clinical Trials, Biometrics, Volume 44, March, pages Page 54 of 118

165 Secondary Analyses of the Primary Endpoints The difference between survival curves will also be analyzed by Cox Proportional Hazard regression adjusting for demographic characteristics, randomization strata, and known risk factors. The validity of the proportional hazards assumption will be assessed prior to carrying out the analysis. All above analyses on the primary endpoints will be performed on each of the DES Randomized ITT, DES Randomized - On Treatment (OT), BMS Randomized ITT, and BMS Randomized - OT analysis sets. 6.5 Primary Safety Endpoint Major Bleeding The null hypothesis is that subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have major bleeding rates between 12 and 33 months post-index procedure that exceed that of the control arm (subjects treated with only 12 months of DAPT) by at least a pre-specified margin of (delta) > 0. The alternative hypothesis is that subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization. stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have major bleeding rates between 12 and 33 months post-index procedure that are no more than that of the control arm, or exceed that of the control arm but by less than. Rejection of the null hypothesis will signify that the 30 m DAPT arm is non-inferior to the control arm (12 m DAPT) with respect to major bleed rate between 12 and 33 months post-index procedure. Specifically, the null (H o ) and alternative (H a ) hypotheses are: H o : A C + H a : A < C + where A is the true major bleed rate for the 30 m DAPT group and C is the true major bleed rate for the control arm over the month post-index procedure period. With a sample size of 12,196 randomized subjects and a non-inferiority test at an = (1- sided) significance, the power is 82% to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with major bleed in the 30 m DAPT arm compared to 12 m DAPT arm, when the major bleed rate of the 30 m DAPT group between 12 and 33 months post index procedure is 2.22% and that of the 12 m DAPT group is 2.22% over the same time period, a non-inferiority margin of 0.8% 10 3% loss to follow-up and 10 Derived from data based on Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Page 55 of 118

166 1:1 randomization. Power Analysis and Sample Size (PASS) was used to compute the power, assuming the Farrington-Manning test 11. This analysis will be carried out both for the DES Randomized ITT and DES Randomized OT analysis sets. With the exception of the month post-index procedure period, any bleeding event occurring 14 days after randomized treatment has stopped will not be counted as a major bleeding event for the respective group. As a secondary analysis, the above major bleeding analysis will be repeated for each of the BMS Randomized ITT and BMS Randomized OT analysis sets. As an additional secondary analysis, the above major bleeding analysis will be repeated for the DES Randomized ITT and BMS Randomized ITT combined analysis sets, and for the DES Randomized OT and BMS Randomized OT combined analysis sets. Prior to combining DES and BMS patients, an assessment of stent-type-by-randomized treatment interaction (where stent-type is defined as DES and BMS) on major bleeding will be assessed using logistic regression at the 0.10 level of significance. If not significant, or if significant and only quantitative in nature, the pooling of DES-BMS patients will be carried out; otherwise, the DES-BMS combined analyses will not be performed. Note that the non-inferiority assessment for the DES+BMS combined analysis sets will be done from the above-mentioned risk difference approach (with an absolute margin of 0.8%) and from a relative risk approach. For the relative risk approach, the null and alternative hypotheses are H o : A / C λ H a : A / C < λ where A is the true major bleed rate for the 30 m DAPT group, C is the true major bleed rate for the control arm over the month post-index procedure period, and λ is the relative noninferiority margin of 1.36 (1.36 corresponds to an absolute margin of 0.8% when the assumed bleeding rates are 2.2% in each of 30m DAPT and 12m DAPT). 6.6 Powered Secondary Endpoints BMS vs. DES Comparisons MACCE The null hypothesis is that DAPT subjects treated with drug-eluting stents will have MACCE rates between 0 and 33 months post-index procedure that exceed that of the control arm (subjects treated BMS) by at least a pre-specified margin of (delta) > 0. Cohen EA, Creager MA, Easton JD, Hamm CW, Hankey GJ, Johnston SC, Mak K-H, Mas J-L, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Fabry-Ribaudo L, Hu T, Topol EJ, Fox KAA. Patients With Prior Myocardial Infarction, Stroke, or Symptomatic Peripheral Arterial Disease in the CHARISMA Trial. Journal of the American College of Cardiology. 2007;49(19): Farrington CP, Manning G. Test Statistics and Sample Size Formulae for Comparative Binomial Trials with Null Hypothesis of Non-zero Risk Difference or Non-unity Relative Risk. Statistics in Medicine. 1990; 9: Page 56 of 118

167 The alternative hypothesis is that DAPT subjects treated with drug-eluting stents will have MACCE rates between 0 and 33 months post-index procedure that are no more than that of the control arm, or exceed that of the control arm but by less than. Rejection of the null hypothesis will signify that the DES arm is non-inferior to the BMS arm with respect to MACCE between 0 and 33 months post-index procedure. Specifically, the null (H o ) and alternative (H a ) hypotheses are: H o : A C + H a : A < C + where A is the true MACCE rate for the DES group and C is the true MACCE rate for the control arm. Assessment of the null hypothesis will be performed on the BMS subjects versus DES subjects, propensity score matched sample. MI events occurring < 72 hours after the index procedure will be excluded. With 2,300 enrolled BMS subjects, a non-inferiority test at an = (1-sided) significance has at least 82% power to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with MACCE in the DES arm compared to the BMS arm, when (a) assuming the true MACCE rate of the control arm is 9.5% over the 0-33 month period, (b) using a non-inferiority margin of 2.28%, (c) assuming 10% of patients prematurely withdraw in the first 12 months prior to randomization with 3% annual loss to follow-up thereafter, and (d) assuming a minimum matched DES:BMS ratio of 1:1 though the expected average matched DES:BMS ratio will be at least 2:1. Power Analysis and Sample Size (PASS) was used to compute the power. It is anticipated that up to 12,000 DES subjects will be available for the matching with the 2,300 BMS subjects. In other words, not all 15,245 enrolled DES subjects may be available for matching. For example, at least one PMS/COA study is not following DES subjects for the full 0-33 month post-index procedure period if the subjects are not 12 Month Clear or if they have an event in the randomized phase (hence to avoid bias in the results, all DES subjects from this PMS/COA study will be excluded from the matching process). Overall, the required DES:BMS matching ratio of 2:1 is anticipated to be achieved given the number of enrolled DES subjects available for matching is anticipated to be approximately 5-6 times greater than the 2,300 enrolled BMS subjects. The anticipated MACCE rate of 9.5% over the 0-33 month period is calculated as follows: As discussed in the primary endpoint power analyses above, the annual MACCE rate is assumed to be 2.9% for the 12m-DAPT group and 2.175% for the 30m-DAPT group for the month post-procedure period; the average of these two annual rates is %; thus, the month post-procedure MACCE rate is anticipated to be 1.5*2.5375% = %. Over the 3 month month period, where it is anticipated the annual 30m-DAPT group MACCE rate = annual 12m-DAPT group MACCE rate = 2.9%, the event rate is expected to be 2.9%/4 = 0.725%. Thus the total anticipated rate across the month post-procedure period is *( ) = or 4.5%. It is further anticipated the MACCE rate for DES and BMS patients in the 0-12 month post-index procedure/pre-randomization period will be approximately 5-5.5%%. Thus the 0-33 month MACCE rate is anticipated to be approximately 9.5%. Stent Thrombosis Page 57 of 118

168 The null hypothesis is that DAPT subjects treated with drug-eluting stents will have ST rates between 0 and 33 months post-index procedure that exceed that of the control arm (subjects treated BMS) by at least a pre-specified margin of (delta) > 0. The alternative hypothesis is that DAPT subjects treated with drug-eluting stents will have ST rates between 0 and 33 months post-index procedure that are no more than that of the control arm, or exceed that of the control arm but by less than > 0. Rejection of the null hypothesis will signify that the DES arm is non-inferior to the BMS arm with respect to ST between 0 and 33 months post-index procedure. Specifically, the null (H o ) and alternative (H a ) hypotheses are: H o : A C + H a : A < C + where A is the true ST rate for the DES group and C is the true ST rate for the control arm. Assessment of the null hypothesis will be performed on the BMS subjects versus DES subjects, propensity score matched sample. With 2,300 enrolled BMS subjects, a non-inferiority test at an = (1-sided) significance has at least 81% power to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with ST in the DES arm compared to the BMS arm, when (a) assuming the true ST rate of the control arm is 1.67% over the 0-33 month period, (b) using a non-inferiority margin of 0.97%, (c) assuming 10% of patients prematurely withdraw in the first 12 months prior to randomization with 3% annual loss to follow-up thereafter,,and (d) assuming the average matched DES:BMS ratio will be at least 1:1. Power Analysis and Sample Size (PASS) was used to compute the power. It is anticipated that up to 12,000 DES subjects will be available for the matching with the 2,300 enrolled BMS subjects. In other words, not all 15,245 enrolled DES subjects may be available for matching. For example, at least one PMS/COA study is not following DES subjects for the full 0-33 month post-index procedure period if the subjects are not 12-month clear or if they have an event in the randomized phase (hence to avoid bias in the results, all DES subjects from this PMS/COA study will be excluded from the matching process). Overall, the required DES:BMS matching ratio of 2:1 is anticipated to be achieved given the number of enrolled DES subjects available for matching is anticipated to be approximately 5-6 times greater than the 2,300 enrolled BMS subjects. The anticipated ST rate of 0.67% over the 0-33 month period is calculated as follows: As discussed in the primary endpoint power analyses above, the annual ST rate is assumed to be 0.5% for the 12m-DAPT group and 0.225% for the 30m-DAPT group for the month postprocedure period; the average of these two annual rates is %; thus, the month postprocedure ST rate is anticipated to be 1.5*0.3625% = %. Over the 3 month month period, where it is anticipated the annual 30m-DAPT group ST rate = annual 12m-DAPT group ST rate = 0.5%, the event rate is expected to be 0.5%/4 = 0.125%. Thus the total anticipated rate across the month post-procedure period is *( ) = or 0.67%. It is further anticipated the ST rate for all DES and BMS patients in the 0-12 month post-index procedure/pre-randomization period will be 1%. Thus the 0-33 month MACCE rate is anticipated to be approximately 1.67%. Justification of deltas: Page 58 of 118

169 Analysis The absolute and relative deltas for MACCE are 2.28% and 25% respectively. The absolute delta and relative deltas for ST are 0.97% and 58% respectively. The threshold at which a BMS strategy is superior to DES by decision analysis considering the balance of restenosis vs. thrombosis occurs at a net very late stent thrombosis BMS - DES risk that is of clinical significance. 23 The non-inferiority analysis will be carried out using the Farrington-Manning approach at a onesided level of significance. Given that subjects receiving each type of stent (DES vs. BMS) are not randomized to the type of stent and thus may not have similar baseline characteristics, the non-inferiority assessment on each endpoint will be carried out on the propensity- matched DES:BMS sample as mentioned above. Specifically, for each individual a propensity score (or i.e., predicted probability between 0 and 1) for group (DES, BMS) membership will be calculated using logistic regression, with group as the outcome and baseline variables including DAPT treatment, group assignment, stent dimension, patient and procedure characteristics as the independent variables (the set of baseline variables to be used will be fully specified in the statistical analysis plan). Matching of at least one DES patient to each BMS patient will be carried out using propensity matching with the Mahalanobis distance approach (D Agostino, 1998; Austin, 2008) Once a DES subject is matched to a BMS subject, the DES subject is no longer available for future matching. As a secondary non-inferiority analysis, all available DES (including unmatched DES subjects) and BMS subjects will be used in the non-inferiority analysis. Subjects will first be categorized into quintiles based on the calculated propensity score. Non-inferiority will then be carried out on the rate of each endpoint using a Mantel-Haenszel risk difference stratified across the propensity quintiles at a one-sided level of significance. In addition, endpoint rates will be presented for each treatment group within each propensity score quintile in order to assess comparability of treatments within groups of subjects with similar values of baseline characteristics. As a sensitivity analysis comparing DES subjects to BMS subjects in this secondary analysis will only include subjects who have exclusively received DES compared to those that have exclusively received BMS. Stent type used during any repeat or staged procedure within 6 weeks of the index procedure will be captured to assist in determining if a subject has received both stent types. Additionally, record of any prior PCI(s) performed within 1 year prior to the index PCI, including stent type used, will be collected for the purposes of determining whether mixed stent types are present. If mixed stent types are used in a subject, then they will be excluded from this analysis. 6.7 Additional Endpoint Analyses Table 1 summarizes the additional endpoints, analysis populations and hypothesis tests that are prespecified in this analysis plan. 12 D Agostino RB Jr. Tutorial in Biostatistics: propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Statistics in Medicine. 1998; 17: Austin PC. Assessing balance in measured baseline covariates when using many-to-one matching on the propensity score. Pharmacoepidemiology and Drug Safety. 2008; 17: Page 59 of 118

170 In addition, time on DAPT will be treated as a time-dependent covariate to determine if the pattern of DAPT usage affected the outcome. The primary safety objective of non-inferiority of Major Bleed rate (assessing non-inferiority of 30 m DAPT to 12 m DAPT over the month post-index procedure period) will be tested at a onesided significance level of For the remaining analyses presented in the table below, treatment difference will be estimated using a two-sided 95% confidence interval; no formal statistical hypothesis testing will be carried out, hence nor will any treatment comparison p-values be generated. Table 1. Additional Analyses Endpoint Time period Sample (s) Hypothesis test MACCE DES Randomized - ITT, OT Superiority BMS Randomized ITT, OT 30m vs. 12 m ST DES Randomized - ITT, OT Superiority BMS Randomized ITT, OT 30m vs. 12m Major Bleed DES Randomized - ITT, OT BMS Randomized ITT, OT DES Randomized ITT and BMS Randomized ITT combined DES Randomized OT and BMS Randomized OT combined Non-inferiority 30m vs. 12m MACCE DES Randomized - ITT, OT Superiority BMS Randomized ITT, OT 30m vs. 12 m ST DES Randomized - ITT, OT Superiority BMS Randomized ITT, OT 30m vs. 12m MACCE BMS Randomized versus DES Non-inferiority Randomized, propensity score adjusted DES vs. BMS ST BMS Randomized versus DES Non-inferiority Randomized, propensity score adjusted DES vs. BMS MACCE 0-33 BMS Randomized versus DES Non-inferiority Randomized, propensity score matched DES vs. BMS ST 0-33 BMS Randomized versus DES Non-inferiority Randomized, propensity score matched DES vs. BMS MACCE 0-33 BMS Randomized versus DES Non-inferiority Randomized, propensity score adjusted DES vs. BMS ST 0-33 BMS Randomized versus DES Non-inferiority Randomized, propensity score adjusted DES vs. BMS Page 60 of 118

171 Analysis of rebound effect After discontinuation of dual antiplatelet therapy it is possible that a rebound phenomenon will occur where the hazard of either MACCE or ST is increased during the period immediately after discontinuation. The following analyses will be performed to estimate the magnitude of this possible phenomenon. The analysis will focus on the DES subjects from the randomized part of the study; however, the analysis will also be performed separately for the BMS subjects. Subjects will be followed for 3-months following the end of assigned treatment (or i.e., for a maximum of 33 months post procedure). Estimating the rebound effect The percentage of subjects who experience MACCE in the 3 months following discontinuation of randomized treatment (regardless of when the treatment is discontinued) and the corresponding exact 95% confidence interval will be calculated by group. In addition, the percentage of subjects who experience MACCE during randomized therapy will be calculated and normalized to correspond to a 3 months treatment period within each treatment group. The difference between the percentages will be reported. If a rebound effect is present the percentage of subjects with events in the 3 months following interruption of DAPT therapy will be higher than the percentage of subjects experiencing the events during DAPT treatment. This analysis will be performed separately for DES and BMS patients; it will be performed for all randomized subjects and for randomized subjects with the full randomized treatment 18 months following randomization. The above analyses will be repeated for the percentage of subjects who experience ST. In addition, the relationship between the percentage of subjects experiencing the events during rebound period and the length of DAPT treatment will be assessed. Graphical display of survival curves from 12 to 33 months comparing treatment arms for MACCE and ST will be presented Sensitivity Analysis of Non-compliance with Randomized Treatment (12 to 30 Months) The effect of compliance to the randomized treatment on the co-primary endpoints and the safety endpoint will be assessed via the secondary analyses performed on the ITT sample. For example, for subjects randomized to 30m DAPT, we will assess differences on endpoints for subjects who were less than 80% compliant versus subjects who were at least 80% compliant over 18 months post-randomization (12-30 month post-index procedure period) and 21 months post-randomization (12-33 post-index procedure period). In addition, for subjects randomized to 30 months of DAPT compliance will be determined for each 3 months treatment period both as a binary variable (yes/no) and a continuous variable (%compliance). For subjects randomized to 12 months of DAPT compliance will be set to yes for the binary variable and to 100% for the continuous variable. Data for subjects who are discontinued from their randomized treatment will be excluded post-discontinuation for this analysis. The incidence of MACCE, ST and major bleed in each 3-months time period will be compared between treatment groups using repeated measures models (general mixed model) with Page 61 of 118

172 compliance as a factor in the model (for the binary variable) and separately as a covariate (for compliance expressed as a %) over the 18 and 21 month post-randomization periods Additional Subset Analysis All primary and secondary endpoints will be compared between treatments using descriptive techniques within a-priori identified subsets, such as subjects who were on and off Coumadin during the randomized portion of the study. Two-sided 95% confidence intervals for the differences between treatments will be presented within each subset; No p-values comparing treatments will be generated for subset analyses. 6.8 Additional Analyses Death, Cardiac Death, MI, stroke, and repeat revascularization for each treatment arm will be compared using descriptive statistics and two-sided 95% confidence intervals for the difference between treatment event rates for the main, 12 Month Clear, 12 Month Not Clear, and BMS vs. DES. In addition, the effect of the switching of thienopyrodine or thienopyridine dose within the first 6 months post-index procedure on the primary outcomes will be examined in an exploratory fashion. No p-values comparing treatments will be generated for these additional analyses. 6.9 Missing Data Handling The co-primary endpoint analyses will be based on the intent-to-treat (ITT) population. Sensitivity analysis using simple and multiple imputation methods and tipping analyses will be performed to evaluate the impact of the missing values on study conclusions. All other analyses will be based on available data with missing data excluded. Any unused or spurious data will be noted as appropriate in the final report Multiple Center Effect The randomization for this trial is stratified by study site to ensure the sample sizes for the two treatment arms are balanced in the desired ratio within each site. Data are to be pooled across all study sites for all analyses. The possibility of a center effect will be examined for the co-primary endpoints. The Breslow-Day statistic will be used to test for a common odds ratio across the different levels of the center. Cox proportional hazards will also be used to assess the significance of a treatment-by-center interaction; the Cox model will include effects for treatment, center, the treatment-by-center interaction, and the baseline strata. Data from smaller trial sites may be combined by geographic region or another common factor for these analyses. If there is evidence of inconsistency in treatment effect at a 0.15 significance level that is qualitative in nature, treatment differences will be inspected within each center separately and outlier or influential sites will be identified; in addition subject demographics, baseline clinical and angiographic characteristics will be examined to assess if such factors contribute to the cause of the significant qualitative treatment-by-center interaction. PMS/COA (Post Market Surveillance / Condition of Approval ) Subjects Page 62 of 118

173 Non DAPT sources of DES data for the primary analysis will include: 1. Patients who enter another study (e.g. post market surveillance single arm studies, or nonrandomized (to stent) trials of currently approved DES) and have data collected between 0 and 12 months in their original study. At 12 months, if the subject is eligible for randomization based on the DAPT criteria, they are enrolled and randomized in the DAPT study. All further data collection is according to the DAPT study protocol 2. Patients who enter another study (e.g. post market surveillance) that is designed to collect the same information as the DAPT study. These subjects data are transferred to HCRI as clean SAS datasets to be merged with the DAPT database for statistical analysis The following requirements have to be met by a study that is intended to provide patient level data for DAPT: 1. The determination of eligibility for enrollment and randomization is the same as in the DAPT study. 2. Data definitions are the same. 3. The same data are collected at the same time points. 4. Adjudication (or readjudication) of all endpoint events according to a central DAPT clinical events committee. 5. Contributed data are from consecutive patients meeting the specified requirements. The maximum number of drug-eluting stent patients whose data (data source type 2 above) that will be transferred as cleaned data from completely separate studies meeting the above requirements will be The maximum number of patients that will be transferred via method type 1 described above will be The total numbers of contributed patients, and their poolability with patients who are enrolled and randomized in the DAPT study will be assessed at regular intervals by an independent monitoring committee in order to confirm adequate enrollment of patients from the DAPT study. Data will be obtained from these studies at regular intervals so that clinical events adjudication under DAPT will occur throughout the duration of the study. The validity of the overall study results is supported by stratification of randomization and analysis by enrollment source. In order to ensure the generalizability of the overall study, minimum and maximum parameters will be placed on certain patient and treatment characteristics for the DES analysis cohort (DAPT and non-dapt sources combined): e.g. at least 15% of subjects have been treated with a given DES stent type and a target maximum of 60% with a given thienopyridine type. In addition, an important issue is to assess if the treatment effect is constant across the patients followed in the DAPT study and the patients not followed by DAPT but whose data are transferred for inclusion in the DAPT analysis. An assessment of treatment-by-enrollment-source interaction on each outcome will be assessed using Cox-proportional hazards regression, where treatment is 12 month DAPT vs. 30 month DAPT, and cohort is followed-by-dapt vs. notfollowed-by-dapt (data source type 2). Included in the Cox model will be the main effects of treatment, cohort, and clinically relevant covariates, and the treatment-by-cohort interaction effect. The treatment-by-cohort interaction effect will be assessed at the 0.15 level of significance. If non-significant, or if significant and only quantitative in nature, (i.e., only the magnitude of the treatment effect, and not the direction of the effect, differs across cohorts), then Page 63 of 118

174 pooling of data across the two patient cohorts is supported; otherwise, if qualitative in nature, analyses of treatment difference by cohort and by relevant patient subgroup (complex vs. non complex, masked stent type, masked drug type) and by study will be carried out to help determine potential cause(s) of the interaction. The clinically relevant covariates to be used in the above model are age (years); sex; ethnicity; race; histories of each of diabetes, hypertension, stroke, transient ischemic attack, congestive heart failure, peripheral arterial disease, percutaneous coronary revascularization, coronary artery bypass graft surgery, atrial fibrillation, and myocardial infarction; current smoking status; lesion length (mm); reference vessel diameter (mm); minimum lumen diameter (mm); lesion class; lesion type; TIMI grade flow; presence of thrombus; pre-procedure % stenosis. In addition to using multivariate-adjusted interaction modeling to assess the appropriateness of pooling across the two cohorts, the following analysis will be performed for each primary endpoint: for each individual a propensity score for cohort ( followed by DAPT vs. not followed by DAPT ) membership will be calculated using logistic regression, with cohort as the outcome and randomized treatment and the above-mentioned clinically relevant baseline variables as the independent variables. Patients will then be categorized into quintiles based on this propensity score. A stratified log-rank test, where propensity quintiles are the strata, will be carried out to assess the significance of the cohort difference on the endpoint adjusted for the propensity score. A similar analysis (excluding the propensity score analysis) will be carried out to assess treatment-by-trial effect, where trial is the classification variable indicating the clinical trial from which the patient s data came. Note that in this analysis, randomized patients followed within the DAPT study will be considered DAPT patients, regardless of the clinical trial in which they were originally enrolled Statistical Methods Lakatos Log-Rank Test Details: The following is reprinted from Power and Sample Size (PASS) Help System, PASS version 8.05, page 715-4, by Dr. Jerry L. Hintze; Kaysville, Utah Copyright Page 64 of 118

175 er-7 oapt '\l,..-/ S T U D Y The logrank statistic L is define-d as HARVARD CLIN I CAL RESEARCH I N STIT U TE wber e X 1 is an indicator for the control group, 111 is tbe number a t risk in t he experimental group just befor e the f'l event (dealih), and n,a is the nmnber at risk in the. control group just before the idt ent (death). Following Freedman (1982) a nd Lakaros (1982), the trial is partitioned ioio K equal intervals. The distribution of I is asymptotically nmmal with mean E and va riance V given by and f1:tt and hu 1 are tbe haz11rds of dying in tbe treatment and control groups respectively, jmt before the f death in ilie it.r 1 inrerval dt is the. nwnber of deaihs in t he Jtlr inte-rval 1\e,xt, assnme tha the i:nre.rvals are' short enough w tbat the paramete-rs ar e constant within an interval That is. so that Page 65 of 118

176 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE The \talue; of E and V then rec:wc:e to where and! Pt is the proportion. of the events (deaths) ihat occur in interval k. The intervals mentioned! above are comtruct ed to correspond! io a non-stationary Markov process, one for each group _ This rkov pro.cs is defined! as fol ows Su = T:..t-..t-1Su-1 where Su is a vector giving tbe occt1pancy pr-obabilities for e.ach of tb.e fom pos5ible sta tes of the pwcess: lo5.t, de-ad, active complier OJ active men-complier aud TU...t J is <:he iirarnsiriou marri.. constructed so that each element gives t be. probability of transferring from statejl to sw.rejl in the treatment group. A similar form.ubtion i.5 defined for the control group. Al each ite:ra ti.on Page 66 of 118

177 er-7 oapt '\l,..-/ S T U D Y A1t tbe beginning oftbe trial HARVARD CLIN I CAL RESEARCH I N STIT U TE st.o = [ :.]. s.o =l- : ] 0 1- ql 1.vbere q 1 is the control proportion oftbe total sample. The transition matrices may be different for each group, but this does not need to be so. Us elements a re as follows (tbe first row and colunm c-ontains labels which are not part of the acmal ma trix). Smtes Lost Event Complier Non -complier Lost 0 Ps-_. Pou. rt.t.-t = Event 0 1 P.ew:or:_. p..,,z.k Complie-r swn. Pdr<Jp-JJo.t Non - complier 0 0 P p.k 1-sum" wbere sum"' and.snm.. represem the sum ofille o:her elements of their colnnws. These values Iepres.eru param.eters of the popula tion such as -event rates, loss to follow-up rates, and recruitment rate:s. The parawe ers!/it,8", and d 11 are e.stimated from the occupancy pr-obabilities as follows EY-ents (dea rihs) Censored At Rik a t.t = (.sj.:-u +.su-u) au = (s2j:-u ) Hazard Page 67 of 118

178 Other Statistical Analysis Methods: Baseline demographic, clinical, angiographic, procedural and device data, and treatment results will be summarized using descriptive summary statistics. Data collected in the trial will be summarized overall and by treatment arms. For continuous variables (e.g., age, percent diameter stenosis, and lesion length), results within treatment arm will be summarized with the numbers of observations, means, standard deviations, minimums, and maximums, and 95% confidence intervals for the means. For treatment comparisons, the difference between the two treatment arms will be summarized with the difference of the two means and 95% confidence interval for the difference of the means. These calculations will be done under the assumption that the data for the two arms are independent and approximately normal in distribution. If not otherwise specified, the confidence interval for the difference of two means is calculated assuming unequal variance between the two groups. If asymptotic assumptions fail, then nonparametric summary statistics (medians, 25th and 75th percentiles) may be displayed as an alternative. In addition, more appropriate non-parametric tests will be considered if the assumptions for the parametric tests are violated. For the comparison of two independent samples, if the data are not normally distributed, Wilcoxon rank sum test will be performed instead of the parametric t-test. Formulas for calculation of the confidence intervals for the continuous variables are given below: Page 68 of 118

179 1. 100(1- α)% Confidence Interval For A Single Mean x t where: s 2 n x sample mean s sample standard deviation n sample size t the alpha/2 t - statistic for n 2 1 degrees of freedom (1-α)% Confidence Interval For The Difference of Two Means Under The Assumption Of Equal Variances Between The Two Groups x 1 x 2 t s p 2 n 1 n 2 where: x 1 samp le mean fo r g ro u p1 x 2 samp le mean fo r g ro u p2 s 2 (n 1 p s 1 n )s 1 (n 2 1)s 2 n 1 n 2 2 samp le stan d ard d ev iatio nfo r g ro u p1 samp le size fo r g ro u p1 t th e alp h a/2 t - statistic fo r n 1 n 2 2 s 2 n 2 samp le stan d ard d ev iatio nfo r g ro u p2 2 d eg rees of freed o m samp le size fo r g ro u p (1-α)% Confidence Interval For The Difference of Two Means Under The Assumption of Unequal Variances Between The Two Groups x 1 x 2 t SED 2 The degrees of freedom (df) for the approximate t statistic is determined by Satterthwaite s formula: Page 69 of 118

180 df w w w 1 n 1 1 w 2 n 2 1 where: w 1 w 2 2 s 1 n 1 2 s 2 n 2 x 1 sample mean for group 1 x 2 sample mean for group 2 s 1 s 2 sample standard deviation sample standard deviation for group 1 for group 2 n 1 sample size for group 1 n 2 sample size for group 2 s 2 2 SED 1 s 2 n1 n2 For categorical variables such as MACCE, ST, etc., results within each arm will be summarized with subject counts, percentages, and exact 95% Clopper-Pearson confidence intervals. The differences between the two treatment arms will be summarized with the difference in percents and the asymptotic 95% confidence interval for the difference of two percentages. Formulas for calculation of the confidence intervals for the categorical variables are given below. Please note that in using these formulas, it is assumed that the data are independent and binomially distributed. For the confidence interval for the difference of two proportions, it is also assumed that the two samples are independent, the samples sizes for the two groups are large ( 20 per group), in that the event and non-event counts for both groups are at least 5, and the distribution is asymptotically normal. If this is not the case, the Farrington-Manning approach 11 will be used to calculate the confidence interval of the difference in two proportions (1-α)% Exact Clopper-Pearson Confidence Interval For A Single Proportion Page 70 of 118

181 Lower Confidence Limit x (n x 1)F 1 x (2(n 2 x 1),2x) Upper ConfidenceLimit where: ( x 1)F 1 n x ( x 1)F 1 2 (2( x 2 (2( x 1),2(n 1),2(n x)) x)) n samplesize x numberof "events" F (df 1, df 2 ) 1 2 the (1- alpha/2)f - statisticfor degreesof freedomdf 1 and df (1-α)% Asymptotic Confidence Interval For The Difference Of Two Proportions Lower Confidence Limit = pˆ1 pˆ 2 Z pˆ1qˆ1 pˆ 2 qˆ 2 2 n 1 n 2 Upper Confidence Limit = where: pˆ pˆ 1 2 Z pˆ1qˆ1 n pˆ 2 qˆ2 n pˆ1 sample proportion for group 1 pˆ 2 sample proportion for group 2 qˆ1 1 pˆ1 qˆ2 1 pˆ 2 n 1 sample size for group 1 Z 2 the (1 - alpha/2) Z- statistic n 2 sample size for group 2 The denominators used in the calculations of categorical variables will be determined as follows for the intent-to-treat population: Subjects who had follow-up information and/or occurrence of an event will be included in the denominator. In another words, subjects who are truly lost to follow-up will be excluded from the denominator. Truly lost to follow up is defined as subjects who are lost to follow up through 33 months without any MACCE. For stent thrombosis, truly lost to follow up is defined as subjects who are lost to follow up through 33 months without any occurrence of stent thrombosis. The same definitions will be used for bleeding complications. Page 71 of 118

182 Survival analysis techniques will be used to analyze the time-to-event variables. Survival curves will be constructed using Kaplan-Meier estimates. Log-rank test results will also be computed for comparison of survival distributions. For the comparison data, summary tables for safety and efficacy endpoints will include event rates (Kaplan-Meier estimates of event rates will be given for event-free variables), relative risk (i.e., the ratio of rates), confidence interval for the relative risk (CI: exp(ln(rr) ± 1.96 * SE), where SE = sqrt((1-p 1 )/n 11 + (1-p 2 )/n 21 )), the difference in means/rates, the confidence interval for difference in means/rates (using previously-described formulas), and a p-value. Page 72 of 118

183 7 Benefits and Risks Associated with Study Drug/Devices 7.1 Risks For more detailed information on the risks of stent implantation, including a complete list of warnings, precautions and potential adverse events, please refer to the Instructions for Use for each stent provided with the product. Similarly, please refer to the Package Inserts of the study drugs for a descriptive listing of known risks associated with the drugs. 7.2 Possible Benefits Anticipated clinical benefits Trial subjects implanted with an approved stent will receive the same medical treatment as if they were not participating in this clinical study except for DAPT duration. Participation contributes to define the optimum duration of thienopyridine use in subjects treated with stents according to the physician s preference, and without the interference of a per protocol angiographic evaluation. It is possible that treatment with longer than 12m of DAPT will be associated with reduction in death, myocardial infarction, stroke, or stent thrombosis (see Section 1.1). Balance of anticipated clinical benefits against the risk Only subjects with no contraindication to >12 months of DAPT will be randomized. Those subjects who develop a contraindication to continuation of DAPT after randomization will be treated according to their physician s preference (see Section 3.6). It is possible that treatment with longer than 12m of DAPT will be associated a higher risk of bleeding, which may be balanced or outweighed by clinical benefits listed above. Page 73 of 118

184 8 Safety and Adverse Event Reporting 8.1 Adverse Event Any untoward medical occurrence in a subject administered a study product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study product, whether or not considered related to the study product. Adverse events that do not meet serious criteria should only be collected and reported by investigators if they result in study discontinuation (see Section 2.11). 8.2 Serious Adverse Events The investigator is to record all serious adverse events (SAE) (other than endpoint events) observed and spontaneously reported by the trial subject on the SAE ecrf form. Endpoint events should be recorded on the appropriate event-specific ecrf. In addition, each trial subject will be questioned about serious adverse events. SAEs should be collected from the time the subject signed the informed consent through study exit. A serious adverse event is any untoward medical occurrence that: Results in death Is life-threatening (immediate risk of death) Requires in-patient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Results in congenital anomaly/birth defect Cancer Drug Dependency/Abuse Other important medical event (see below) Medical and scientific judgment should be exercised in determining whether an event is an important medical event. An important medical event may not be immediately life threatening and/or result in death or hospitalization. However, if it is determined that the event may jeopardize the subject and/or may require intervention to prevent one of the other outcomes listed in the definition above, the important medical event should be reported as serious. Note that the inclusion of cancer and drug dependency/abuse in the above list is per request of the US FDA. 8.3 Causality of Serious Adverse Event to Study Product(s) The Sponsor s and investigator s assessment of causality must be provided for all serious adverse events. An investigator s causality assessment is the determination of whether there exists a reasonable possibility that the study product caused or contributed to the serious adverse event. Causality determination for an SAE will be made for devices and drugs separately. The investigator is to classify the relatedness of the SAE to the use of the Study Products in one of the following: Page 74 of 118

185 Definitely Related Probably Related Possibly Related Unlikely Not Related 8.4 Intensity of Serious Adverse Event Mild- Awareness of a sign or symptom that does not interfere with the subject's usual activity or is transient, resolved without treatment and with no sequelae. Moderate- Interferes with the subject's usual activity and/or requires symptomatic treatment. Severe- Symptom(s) causing severe discomfort and significant impact of the subject s usual activity and requires treatment. 8.5 Unanticipated Adverse Device Effects (Device UADE) A SAE that has been determined to be device or procedure-related should be further classified as anticipated or unanticipated. An unanticipated adverse device effect is defined as any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the product IFU or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects. These are expected to be rare events. 8.6 Life-Threatening Adverse Drug Experience (LTADE) Any adverse drug experience that places the patient or subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred. This does not include a reaction that, had it occurred in a more severe form, might have caused death. 8.7 Unexpected Adverse Drug Experience (Drug UADE) Any adverse drug experience, the specificity or severity of which is not consistent with the current product insert, investigator brochure; or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. "Unexpected," as used in this definition, refers to an adverse drug experience that has not been previously observed (e.g., included in the investigator brochure or product insert) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product. 8.8 Reporting Requirements All SAEs (other than endpoint events) will be recorded on the SAE ecrf page(s) using concise medical terminology. Endpoint events should be recorded on the appropriate event-specific ecrf. Causality will be collected and assessed independently by an HCRI (or designee) physician for regulatory reporting purposes. If a serious adverse device or drug event occurs, HCRI is to be notified within 24 hours of awareness of the event by the investigator, irrespective of the extent of available adverse event information. Specifically, the investigator must complete the ecrf SAE form for all SAEs that occur from the time the subject signed informed consent through study exit. This timeframe also Page 75 of 118

186 applies to additional new information (follow-up) on previously forwarded serious adverse event reports. For all serious adverse events, the investigator is required to pursue and provide information to HCRI in accordance with the specified reporting timeframes. In addition, an investigator may be requested by HCRI to obtain specific additional follow-up information in an expedited fashion. In general, this will include a description of the serious adverse event in sufficient detail to allow for a complete medical assessment of the case and independent determination of possible causality. Information on other possible causes of the event, such as concomitant medications and illnesses must be provided. In the case of a subject death, a copy of the death records, death certificate and an autopsy report (if performed) must be sent to HCRI or its designated representative as soon as possible. In the case of a subject death, the investigator is encouraged to request an autopsy. Each serious adverse event is to be assessed and classified as indicated above. If a serious adverse event is identified by the investigator, the investigator will notify HCRI as soon as possible providing a brief description of the event within 24 hours of the event onset. The investigational site will report their site UADE (device or drug) to their IRB/EC within the required time frame of the UADE. HCRI will query the site to obtain additional information as required. SAEs and endpoint events will be forwarded to the DMC and CEC respectively by HCRI. SAEs will then be analyzed by the DMC and all endpoint events recorded by the investigator will then be analyzed by the CEC. Site investigator attribution of relatedness will not affect reporting, distribution or analysis of any SAE. Table 2 below lists the established reporting requirements and notification timelines for all SAEs. Table 2. Site SAE Reporting Requirements Type of event Prepared by Investigator For Time of Notification Anticipated Drug/Device SAEs HCRI, via ecrf SAE page(s) Within 24 hours of knowledge of event All Life Threatening or Fatal events HCRI, via ecrf SAE page(s) Within 24 hours of knowledge of event Unanticipated Adverse Device Effects HCRI, via ecrf SAE page(s) Within 24 hours of knowledge of event Unanticipated Adverse Drug Experiences HCRI, via ecrf SAE page(s) Within 24 hours of knowledge of event HCRI will provide safety services including MedDRA coding and review of SAEs and coding of concomitant medications using WHODrug. HCRI will maintain a safety database and collect, process, and follow all applicable SAEs to resolution that occur during the period spanning from the time the subject signs informed consent through study exit. MACCE, ST or major bleeding events that occur after the informed consent is signed will not be considered SAEs and therefore an SAE form will not be required and the event will not be entered in the ClinTrace TM database, followed to resolution, and processed for inclusion in the DMC safety reports. Operators are strongly encouraged to use the same stent type at the second procedure (BMS or DES). The primary analysis and drug dispensing will be for intention to treat by assignment to BMS or DES based on the stent received at the time of index without regard for prior or subsequent stenting. All SAEs excluding MACCE, ST or major bleeding events will be processed and reported as outlined Page 76 of 118

187 in Table 3. The serious MACCE, ST or major bleeding events will be adjudicated by the CEC, and reviewed by the DMC but will not be processed or reported by the HCRI Safety Group. All events and drug and device UADEs will be reported to FDA within the notification timeframes outlined below in Table 4 and to Competent Authorities outside the US (as outlined in Table 4) or in accordance with local reporting requirements. The annual IDE report and 6 month progress reports will contain a tabular listing of all SAEs. Table 3. HCRI Format of SAE Reporting to Regulatory Authorities Type of SAE Related Unrelated Expected/Anticipated Unexpected/Unanticipated MACCE, ST or major bleeding MACCE, ST, or major bleeding non MACCE, ST, or major bleeding non MACCE, ST or major bleeding Reporting IDE Safety/6 month progress reports + CEC (MACCE, ST, or major bleeding)/dmc Reports CEC & DMC Expedited* + IDE Safety/6 month progress reports/dmc Reports CEC & DMC IDE Safety/6 month progress reports/dmc Reports * Expedited SAE reporting determination will be based upon independent HCRI (or designee) physician review and documented in the expedited SAE report. The investigator s assessment also will be included as part of the expedited SAE report. Page 77 of 118

188 Table 4. HCRI Regulatory Reporting Requirements Type of event Anticipated Drug and Device SAEs Unanticipated Adverse Device Events Unanticipated Adverse Drug Effects Unexpected Drug Associated Fatal or Life Threatening Event Device Related SAE (PMS/PAS subjects with MDR tag)** Prepared by HCRI/Quintiles For FDA / competent authorities FDA / competent authorities FDA competent authorities FDA / competent authorities DES Manufacturer FDA / competent authorities Time of Notification US Annually in the IDE Safety Report and 6 month progress reports Within 10 working days of knowledge of event and Annually in the IDE Safety Report and 6 month progress reports* Within 15 calendar days of knowledge of event and Annually in the IDE Safety Report and 6 month progress reports* Within 15 calendar days of knowledge of event and Annually in the IDE Safety Report and 6 month progress reports* Within 5 days of knowledge of event Annually in the IDE Safety Report and 6 month progress reports Time of Notification - EU As per local reporting requirements As per local reporting requirements * Within 15 calendar days of knowledge of event and/or As per local reporting requirements * No later than 7 calendar days after first knowledge by the sponsor that a case qualifies, followed by as complete a report as possible within 8 additional calendar days if necessary and/or as per local reporting requirements * N/A N/A Time of Notification - ANZ Periodic Safety Update Reports Up to 15 calendar days of knowledge of event and Annually in the IDE Safety Report and 6 month progress reports* Within 15 calendar days of knowledge of event and Annually in the IDE Safety Report and 6 month progress reports* No later than 7 calendar days after first knowledge by the sponsor that a case qualifies, followed by as complete a report as possible within 8 additional calendar days and Annually in the IDE Safety Report and 6 month progress reports* N/A N/A * Expedited SAE reporting determination will be based upon independent HCRI (or designee) physician review and documented in the expedited SAE report. The investigator s assessment also will be included as part of the expedited SAE report. ** For subjects who originated in device manufacturer sponsored PMS/PAS studies who have data collected and analyzed in this study, SAE collection will occur as described above. These subjects will be identified by their MDR number and the event details will be forward to the manufacturer for tracking in the PMS/PAS. The IDE annual report will include the SAE information for these subjects and also provide a reference to their MDR number. Page 78 of 118

189 8.9 Pregnancy HCRI or designee must be notified of any subject who becomes pregnant while participating in the clinical study. Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to determine their outcome. If the outcome of a pregnancy is an SAE e.g. if the baby has a congenital anomaly, then SAE reporting procedures will be followed. This information is important for both drug safety and public health concerns. It is the responsibility of the Investigator, or designee, to report any pregnancy in a subject, which occurs during the study Device Failures and Malfunctions A device malfunction is defined as the failure of the device to meet its performance specifications or otherwise perform as intended. A device failure is defined as the device is used in accordance with the IFU, but does not perform according to IFU and negatively impacts the treatment. If there are device failures or malfunctions to be reported, these will be handled by the investigational sites directly and reported to the HCRI via the ecrf. HCRI will then provide this information to the manufacturer as outlined below. Table 5. Site Reporting Requirements for Device Failure/Malfunction Type of event Prepared by Investigator For Time of Notification Device Failure/Malfunction HCRI, via ecrf Within 5 working days of knowledge of event Table 6. HCRI Regulatory Reporting Requirements Type of event Prepared by HCRI For Time of Notification Device Failure/Malfunction Manufacturer Within 5 days of knowledge of event Page 79 of 118

190 9 Definitions Abrupt Closure Acute Coronary Syndrome (ACS) Adverse Effect Adverse Event (AE) Anticipated Adverse Event Abrupt Closure. Defined as the occurrence of new (during the index procedure) severely reduced flow (TIMI grade 0-1) within the target vessel that persisted and required rescue by stenting or other treatment, or resulted in myocardial infarction or death. Abrupt closure requires proven association with a mechanical dissection of the treatment site or instrumented vessel, coronary thrombus, or severe spasm. Abrupt closure does not connote no reflow (due to microvascular flow limitation), in which the epicardial artery is patent but had reduced flow. Abrupt closure also does not connote transient closure with reduced flow in which the index treatment application does reverse the closure. Subabrupt Closure. Defined as abrupt closure that occurred after the index procedure is completed (and the subject left the catheterization laboratory) and before the 30-day follow-up evaluation. Threatened Abrupt Closure. Defined as a grade B dissection and 50% diameter stenosis or any dissection of grade C or higher. ACS is defined as ischemic symptoms occurring at rest and lasting 10 minutes or more and occurring within 72 hours before index procedure and either ST-segment deviation of 1 mm or more or elevated levels of a cardiac biomarker of necrosis (CK-MB or troponin T or I greater than the upper limit of normal. If CK-MB or troponin is not available, total CK >2 times upper limit of normal). Subjects with STEMI can be enrolled and will be classified as ACS and complex if the index procedure is performed within 14 days after onset of symptoms. An adverse event which was or may have been caused by a device or drug. An adverse event is any undesirable medical occurrence in a clinical study subject, whether it is considered to be related to the drug, the device or neither, that includes a clinical sign, symptom, or condition and/or an observation of a near incident. Any undesirable experience (sign, symptom, illness, abnormal laboratory value, or other medical event) occurring to a subject, whether or not considered related to the investigational product(s) or drug regimen prescribed as part of the clinical protocol, predefined in the clinical protocol and/or IFU, that is identified or worsens during a clinical study. Page 80 of 118

191 Bleeding classification (Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)) Major Bleeding endpoint will be defined by the GUSTO classification of Severe or Moderate as defined below: Severe or lifethreatening Moderate Mild Either intracranial hemorrhage or bleeding that causes hemodynamic compromise and requires intervention Bleeding that requires blood transfusion but does not result in hemodynamic compromise Bleeding that does not meet criteria for either severe or moderate bleeding Bleeding events that are medically important, but that do not meet the severe/moderate levels (e.g. require laboratory testing, evaluation by a physician, ER visit, or cessation of either study medication or other antithrombotic therapies) will be collected. Braunwald Classification of Unstable Angina Severity: Class 1: New onset of severe or accelerated angina. Subjects with new onset (<2 months in duration) exertional angina pectoris that is severe or frequent (>3 episodes/day) or subjects with chronic stable angina who develop accelerated angina (that is, angina distinctly more frequent, severe, longer in duration, or precipitated by distinctly less exertion than previously) but who have not experienced pain at rest during the preceding 2 months. Class 2: Angina at rest, subacute. Subjects with one or more episodes of angina at rest during the preceding month but not within the preceding 48 hours. Class 3: Angina at rest, acute. Subjects with one or more episodes of angina at rest within the preceding 48 hours. Clinical circumstances in which unstable angina occurs: Class A: Secondary unstable angina. Subjects in whom unstable angina develops secondary to a clearly identified condition extrinsic to the coronary vascular bed that has intensified myocardial ischemia. Such conditions reduce myocardial oxygen supply or increase myocardial oxygen demand and include anaemia, fever, infection, hypotension, uncontrolled hypertension, tachyarhythmia, unusual emotional stress, thyrotoxicosis, and hypoxemia secondary to respiratory failure. Class B: Primary unstable angina. Subjects who develop unstable angina pectoris in the absence of an extracardiac condition that have intensified ischemia, as in class A. Class C: Postinfarction unstable angina. Subjects who develop unstable angina within the first 2 weeks after a documented acute myocardial infarction. CABG Coronary Artery Bypass Graft Page 81 of 118

192 Canadian Cardiovascular Society Classification (CCSC) of Angina Class I Class II Class III Class IV Ordinary physical activity does not cause angina, such as walking and climbing stairs. Angina with strenuous or rapid or prolonged exertion at work or recreation. Slight limitation of ordinary activity. Angina upon walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, or in cold, or in wind, or under emotional stress, or only during the first hours after awakening. Angina if walking more than two blocks on the level and climbing more than one flight of ordinary stairs at a normal pace and in normal conditions. Marked limitations of ordinary physical activity. Walking one to two blocks on the level and climbing one flight of stairs in normal conditions and at a normal pace. Inability to carry on any physical activity without discomfort. Angina syndrome may be present at rest. Cerebrovascular Accident (CVA) or Stroke Cerebrovascular accident is defined as the occurrence of cerebral infarction (ischemic stroke) or intracerebral hemorrhage and subarachnoid hemorrhage (hemorrhagic stroke). Stroke is defined as sudden onset of vertigo, numbness, dysphasia, weakness, visual field defects, dysarthria or other focal neurological deficits due to vascular lesions of the brain such as hemorrhage, embolism, thrombosis, or rupturing aneurysm that either: 1. persists more than 24 hours or results in death in less than 24 hours, or 2. persists <24 hours duration if the following treatments were used: a. pharmacologic, i.e. thrombolytic drug administration, or b. non-pharmacologic, i.e. neurointerventional procedure (e.g. intracranial angioplasty) 3. persists <24 hours but has neuro-radiological (MRI or CT) diagnostic changes suggestive of acute tissue injury. Death (ARC Definition) 24 All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established. Specifically, any unexpected death even in subjects with coexisting potentially fatal non-cardiac disease (e.g. cancer, infection) should be classified as cardiac. Cardiac death Any death due to immediate cardiac cause (e.g. MI, low-output failure, fatal arrhythmia). Unwitnessed death and death of unknown cause will be classified as cardiac death. This includes all procedure related deaths including those related to concomitant treatment. Vascular death Death due to cerebrovascular disease, pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular cause. Non-cardiovascular death Any death not covered by the above definitions, including death due to infection, sepsis, pulmonary causes, accident, suicide or trauma. Page 82 of 118

193 Drug Related Adverse Event A drug related adverse event is defined as any adverse event for which a causal relationship between the drug and the event is possibly, probably, or definitely related as determined by the Investigator and confirmed via adverse event medical review. Dissection Classification (NHLBI National Heart, Lung, and Blood Institute) Type A Type B Type C Type D Type E Type F Small radiolucent area within the lumen of the vessel disappearing with the passage of the contrast material. Appearance of contrast medium parallel to the lumen of the vessel disappearing within a few cardiac cycles. Dissection protruding outside the lumen of the vessel persisting after passage of the contrast material. Spiral shaped filling defect with or without delayed runoff of the contrast material in the antegrade flow. Persistent luminal filling defect with delayed run-off of the contrast material in the distal lumen. Filling defect accompanied by total coronary occlusion. Emergent Bypass Surgery Intracoronary Thrombus Emergent Bypass Surgery is defined as coronary bypass surgery performed on an urgent or emergent basis for severe vessel dissection or closure, or treatment failure resulting in new ischemia. Intracoronary Thrombus is defined as the presence of a filling defect within the lumen, surrounded by contrast material seen in multiple projections in the absence of calcium within the filling defect, or the persistence of contrast material within the lumen or a visible embolization of intraluminal material downstream. Lesion Classification (American College of Cardiology/ American Heart Association Class) Type A Type B Type C Minimally complex, discrete (length <10 mm), concentric, readily accessible, non-angulated segment (<45 ), smooth contour, little or no calcification, less than totally occlusive, not ostial in location, no major side branch involvement, and an absence of thrombus. Moderately complex, tubular (length 10 to 20 mm), eccentric, moderate tortuosity of proximal segment, moderately angulated segment (>45, <90 ), irregular contour, moderate or heavy calcification, total occlusions <3 months old, ostial in location, bifurcation lesions requiring double guidewires, and some thrombus present. Type B1: One type B characteristic Type B2: Two or more type B characteristics Severely complex, diffuse (length >2 cm), excessive tortuosity of proximal segment, extremely angulated segments >90, total occlusions >3 months old and/or bridging collaterals, inability to protect major side branches, and degenerated vein grafts with friable lesions. Page 83 of 118

194 Life-Threatening Adverse Drug Experience Major Adverse Cardiac and Cerebral Events (MACCE) Major Bleeding Myocardial Infarction (MI) (ARC Definition) 24 Any adverse drug experience that places the patient or subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death. MACCE is defined as all death, myocardial infarction and stroke. A severe or moderate bleeding complication (based on GUSTO classification). Classification Biomarker Criteria Additional Criteria Peri-procedural PCI (within 48h after PCI) 1 or Peri-Procedural CABG (within 72h after CABG) Spontaneous (>48h following PCI, >72h following CABG) Silent Troponin >3 times URL or CKMB > 3 times URL Troponin >5 times URL or CKMB >5 times URL Troponin >URL or CKMB >URL No biomarker data available Baseline value <URL Baseline value <URL AND Any of the following: New pathologic Q waves or LBBB New native or graft vessel occlusion Imaging evidence of loss of viable myocardium Baseline value <URL AND Any of the following: symptoms of ischemia, ECG changes indicative of new ischemia (new ST-T changes or new LBBB), development of pathological Q waves, or imaging evidence of a new loss of viable myocardium or a new regional wall motion abnormality New pathologic Q waves or LBBB Page 84 of 118

195 Myocardial Infarction (MI) (ARC Definition) 24 (Continued) Classification Biomarker Criteria Additional Criteria Sudden Death Reinfarction, spontaneous and peri-procedural (base definition) (Infarction extension) Death before biomarkers obtained or before expected to be elevated Stable or decreasing values on 2 samples >6 hours apart AND 20% increase 3-6 hours after second sample Symptoms suggestive of ischemia AND Any of the following: New ST elevation or LBBB Documented thrombus by angiography or autopsy If biomarkers are not stable (increasing or peak not reached), then insufficient data to diagnose recurrent myocardial infarction. Adapted from Global Task Force [Universal Definition of Myocardial Infarction (Thygesen et al.)] 25 1 The assessment of CK-MB is preferred over the assessment of troponin for the diagnosis of peri-procedural MI, if possible. Baseline biomarker value required before study procedure and presumes a typical rise and fall Pathologic Q waves may be defined according to the Global Task Force, Minnesota code, or Novacode URL = upper reference limit, defined as 99 th percentile of normal reference range LBBB = left bundle branch block ST = stent thrombosis PCI = percutaneous coronary intervention CABG = coronary artery bypass graft Perforation Percutaneous Coronary Intervention (PCI) Procedure Success Perforations will be classified as follows: Angiographic perforation: perforation detected by the clinical site or the core laboratory at any point during the procedure. Clinical perforation: perforation requiring additional treatment (including efforts to seal the perforation or pericardial drainage), or resulting in significant pericardial effusion, abrupt closure, myocardial infarction, or death. Pericardial hemorrhage/tamponade: perforation resulting in cardiac tamponade. Refers to all interventional cardiology methods for treatment of coronary artery disease. Attainment of <30% residual stenosis of the target lesion and no in-hospital MACCE. Page 85 of 118

196 Serious Adverse Event (SAE) A serious adverse event is any untoward medical occurrence that: Results in death Is life-threatening (immediate risk of death) Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Results in congenital anomaly/birth defect Cancer Drug Dependency/Abuse Other important medical event Note that the inclusion of cancer and drug dependency/abuse in the above list is per request of the US FDA. Stent Thrombosis (ARC Definition) 24 Stent Thrombosis should be reported as a cumulative value over time and at the various individual time points as specified below. Time 0 is defined as the time point after the guiding catheter has been removed and the subject has left the cardiac Cathlab. Timing: Acute stent thrombosis(1): 0 24 hours post stent implantation Subacute stent thrombosis(1): > 24 hours 30 days post stent implantation Late stent thrombosis(2): >30 days 1 year post stent implantation Very late stent thrombosis(2): >1 year post stent implantation (1) acute or subacute can also be replaced by the term early stent thrombosis. Early stent thrombosis (0 30 days) will be used in the remainder of this document. (2) including primary as well as secondary late stent thrombosis; secondary late stent thrombosis is a stent thrombosis after a target segment revascularization. Page 86 of 118

197 Stent Thrombosis (ARC Definition) (Continued) Definite stent thrombosis We recognize three categories of evidence in defining stent thrombosis. Definite stent thrombosis is considered to have occurred by either angiographic or pathologic confirmation. Angiographic confirmation of stent thrombosis Thrombolysis In Myocardial Infarction (TIMI) flow is: A. TIMI flow grade 0 with occlusion originating in the stent or in the segment 5mm proximal or distal to the stent region in the presence of a thrombus(*). B. TIMI flow grade 1, 2, or 3 originating in the stent or in the segment 5mm proximal or distal to the stent region in the presence of a thrombus(*). AND at least one of the following criteria has been fulfilled within a 48 hour time window: 1. new acute onset of ischemic symptoms at rest (typical chest pain with duration >20 minutes) 2. new ischemic ECG changes suggestive of acute ischemia 3. typical rise and fall in cardiac biomarkers (refer to definition nonprocedural related MI). Comment: the incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not considered a confirmed stent thrombosis (silent occlusion). (*) Intracoronary thrombus [Ellis et al., Mabin et al., Capone et al.] (ref. 5,6,7) Non-occlusive thrombus: Intracoronary thrombus is defined as a (spheric, ovoid or irregular) noncalcified filling defect or lucency surrounded by contrast material (on three sides or within a coronary stenosis) seen in multiple projections, or persistence of contrast material within the lumen, or a visible embolization of intraluminal material downstream. Occlusive thrombus: A TIMI 0 or TIMI 1 intra-stent or proximal to a stent up to the most adjacent proximal side branch or main branch (if originating from the side branch). Page 87 of 118

198 Stent Thrombosis (ARC Definition) (Continued) Probable stent thrombosis Possible stent thrombosis Stroke Study Deviation Pathologic confirmation of stent thrombosis Evidence of recent thrombus within the stent determined at autopsy or via examination of tissue retrieved following thrombectomy. Probable stent thrombosis Clinical definition of probable stent thrombosis is considered to have occurred after intracoronary stenting in the following cases: 1) Any unexplained death within the first 30 days. 2) Irrespective of the time after the index procedure any myocardial infarction (MI), which is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause. Possible stent thrombosis Clinical definition of possible stent thrombosis is considered to have occurred with any unexplained death from 30 days following intracoronary stenting until end of trial follow-up. See Cerebrovascular Accident (CVA) or Stroke above. An incident where the Investigator or site personnel did not conduct the study according to the clinical protocol or the Investigator agreement. Major deviation: Any deviation from subject inclusion and exclusion criteria or subject informed consent procedures. Minor deviation: Deviation from a clinical protocol requirement such as incomplete/inadequate subject testing procedures, non-compliance with study thienopyridine medication regimens, follow-ups performed outside specified time windows, etc. Target Lesion Revascularization (TLR) (ARC Definition) 24 Target Vessel Revascularization (TVR) (ARC Definition) 24 Non Target Lesion Revascularization (Non TLR) (ARC Definition) 24 TLR is defined as any repeat percutaneous intervention of the target lesion or bypass surgery of the target vessel performed for restenosis or other complication of the target lesion. The target lesion is defined as the treated segment starting 5 mm proximal to the stent and ending 5 mm distal to the stent. TVR is defined as any repeat percutaneous intervention or surgical bypass of any segment of the target vessel. The target vessel is defined as the entire major coronary vessel proximal and distal to the target lesion including upstream and downstream branches and the target lesion itself. Any revascularization in a lesion other than the target lesion is considered a non-tlr. Page 88 of 118

199 Non Target Vessel Revascularization (Non TVR) (ARC Definition) 24 Any revascularization in a vessel other than the target vessel is considered a non-tvr. Thrombolysis in Myocardial Infarction (TIMI) classification TIMI 0 TIMI 1 TIMI 2 TIMI 3 -No perfusion -Penetration with minimal perfusion. Contrast fails to opacify the entire bed distal to the stenosis for the duration of the cine run. -Partial perfusion. Contrast opacifies the entire coronary bed distal to the stenosis. However, the rate of entry and/or clearance is slower in the coronary bed distal to the obstruction than in comparable areas not perfused by the dilated vessel. -Complete perfusion. Filling and clearance of contrast equally rapid in the coronary bed distal to stenosis as in other coronary beds. Unanticipated Adverse Device Effect (Device UADE) Unexpected Adverse Drug Experience (Drug UADE) Vascular Complications An unanticipated adverse device effect (device UADE) is defined as any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of patients. Any adverse drug experience, the specificity or severity of which is not consistent with the current product insert, investigator brochure; or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. "Unexpected," as used in this definition, refers to an adverse drug experience that has not been previously observed (e.g., included in the investigator brochure or product insert) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product. Vascular complications may include the following: 1. Pseudoaneurysm 2. Arteriovenous fistula (AVF) 3. Peripheral ischemia/nerve injury 4. Vascular event requiring transfusion or surgical repair Page 89 of 118

200 Acronyms and/or Abbreviations Acronym/ Abbreviation Term % DS Percent diameter stenosis % VO Percent volume obstruction g Microgram ABR Angiographic binary restenosis ACC American College of Cardiology ACT Activated clotting time ACS Acute Coronary Syndrome AE Adverse event AHA American Heart Association ALP Alkaline phosphatase ALT Alanine aminotransferase ARC Academic Research Consortium AST Aspartate aminotransferase atm Atmospheric pressure AVF Arteriovenous fistula BID Twice Daily BMS Bare Metal Stent BUN Blood urea nitrogen CABG Coronary artery bypass graft CBC Complete blood count CCSC Canadian Cardiovascular Society Classification CEC Clinical Events Committee CFR Code of Federal Regulations CFR Coronary flow reserve CHF Coronary Heart Failure CK Creatine kinase CK-MB Creatine kinase myocardial-band isoenzyme cm Centimeter COA Condition of Approval study CPK Creatine Phosphokinase ecrf Electronic case report form CRO Contract Research Organization CVA Cerebrovascular accident DCA Directional coronary atherectomy DES Drug Eluting Stent DFU Directions for Use DMC Data Monitoring Committee dl Deciliter DS Diameter stenosis ECG Electrocardiogram EC Ethics Committee ecrf Electronic Case Report Form FFR Fractional flow reserve FIM First-in-man FPG Fasting plasma glucose Page 90 of 118

201 Acronym/ Abbreviation GCP GGT GI gm GP HCRI HCT HDL HGB HHS HIPAA ICH IDE IFU in IRB ITT IVRS IVUS L/l LA LAD LCX LDL LIMA LV LVEF MACCE MACE MEC MedDRA mg MI MLA MLD mm mmol mrna mtor NHLBI NSTEMI NTG OGTT PC PCI PG Plt PMS Term Good Clinical Practice Gamma glutamyl transferase Gastrointestinal Gram Glycoprotein Harvard Clinical Research Institute Hematocrit High density lipoprotein Hemoglobin Health and Human Services (Department of) Health Insurance Portability and Accountability Act International Conference on Harmonization Investigational Device Exemption Instructions for Use Inch Institutional Review Board Intent-to-treat Interactive Voice Response System Intravascular ultrasound Liter Liposomal Alendronate Left anterior descending coronary artery Left circumflex coronary artery Low density lipoprotein Left internal mammary artery Lumen volume Left ventricular ejection fraction Major Adverse Cardiac and Cerebral Event Major Adverse Cardiac Event Medical Ethics Committee Medical Dictionary for Regulatory Activities, ICH Standardization of Terminology Milligram Myocardial infarction Minimal lumen area Minimum luminal/lumen diameter Millimeter Millimole Messenger ribonucleic acid Mammalian target of rapamycin National Heart, Lung, and Blood Institute [Dissection Grade Classification] Non-ST segment Elevation Myocardial Infarction Nitroglycerin Oral glucose tolerance test Phosphorylcholine Percutaneous coronary intervention Post-load glucose Platelet Post Marketing Surveillance study Page 91 of 118

202 Acronym/ Abbreviation PRN PTCA PVD QD QCA RBC RCA RCT RIMA RVD SAE SD SGOT SGPT ST STEMI SV TIA TIMI TLR TPD TSR TVF TVR UADR ULN US USFDA VO WBC WHO Term As Required Percutaneous transluminal coronary angioplasty Peripheral Vascular Disease Once Daily Quantitative coronary angiography Red blood cell Right coronary artery Randomized Controlled Trial Right internal mammary artery Reference vessel diameter Serious adverse event Standard deviation Serum glutamic oxaloacetic transaminase Serum glutamic pyruvic transaminase Stent Thrombosis ST segment Elevation Myocardial Infarction Stent volume Transient ischemic attack Thrombolysis in myocardial infarction Target lesion(s) revascularization Trademark Therapeutic Products Directorate Target site revascularization Target vessel failure Target vessel revascularization Unexpected Adverse Drug Reaction Upper Limit of Normal United States United States Food and Drug Administration Volume obstruction White blood cell World Health Organization Page 92 of 118

203 10 Data Submission Requirements Required Data All required data for this trial will be collected via electronic case report forms (ecrf) and securely transferred by a 21 CFR Part 11 compliant electronic data capture (EDC) system. All data points are required in the ecrf unless otherwise noted on the form. The completed ecrfs are the sole property of HCRI and should not be made available in any form to third parties, except for authorized representatives of HCRI or appropriate regulatory authorities, without written permission from HCRI Data Collection Electronic Case Report Form Development, Modification and Maintenance The final set of ecrfs will be designed to accommodate the specific features of the trial design. Modification of ecrfs will only be made if deemed necessary by HCRI. Components of the ecrf: 1. Enrollment confirmation and subject eligibility. 2. Baseline subject demographic and clinical data. 3. Procedure data (including procedural complications). 4. Sub-study biomarker data. 5. Hospital discharge data (including post-procedural complications, ischemic or vascular complications, in-hospital major events, and pertinent laboratory tests). 6. Serious Adverse Events. 7. Information relating to antiplatelet compliance 8. Clinical event follow-up data related to study endpoints (includes incidence and timing of any ischemic or major clinical event from hospital discharge to study completion, such as death, stroke, bleeding complication, MI, and stent thrombosis). Description of data variables to be collected The ecrf will have separate pages to capture data on MACCE and surgical procedures, and separate pages to collect concomitant medication information. The concomitant medication page will be limited to capture data on relevant antiplatelet medication and those identified in Section 3.7. Table 7. Data variables and documents to be collected The list is not all-inclusive; please refer to ecrf for further details. Time Baseline Variable Age Gender Race and Ethnicity Page 93 of 118

204 Time Variable Inclusion/Exclusion Exceptions Current Cardiac status Cardiac History Cardiac Risk factors Lab values Lesion characteristics Vessel Lesion location Lesion type Degree of tortuosity Degree of calcification Thrombus present TIMI flow Pre-procedure angiography (complete visual estimate in ecrf): Procedure Post procedure final result Ancillary Study Hospital Discharge Follow-up (6, 12, 15, 24, 30, and 33 months) In case a death occurred Reference Vessel Diameter (RVD) in mm Pre-procedure Minimum Lumen Diameter (MLD) in mm Lesion length in mm Date of Procedure Number of stents used Study Stent details Antiplatelet medication Concomitant medication Procedural complications Diameter Stenosis (%) Consent Kit/Sample information Shipping information Date of discharge Any new MACCE event since the procedure Current Cardiac status Antiplatelet Medication Concomitant medication Date of follow-up Type of follow-up (telephone) MACCE events ST events Major Bleeds Change in Antiplatelet Medication Concomitant medication In case of death, please provide, if available a copy of: Page 94 of 118

205 Time In case an MI occurred In case a Stent Thrombosis occurred In case of Major Bleeding complications In case of Stroke In case of PCI Variable hospital discharge letter death certificate / autopsy report multiple ECGs related to event all available lab results all angiograms (procedure and event related) cath lab report / technical worksheet In case of an MI, please provide, if available a copy of: hospital discharge letter multiple ECGs related to event all available lab results all angiograms (procedure and event related) cath lab report / technical worksheet In case of a (suspected) stent thrombosis, please provide, if available a copy of: hospital discharge letter multiple ECGs related to event all lab results all angiograms (procedure and event related) cath lab report / technical worksheet In case of a bleeding complication, please provide, if available a copy of: hospital discharge letter relevant lab results (HGB, HCT) Neurological Event ecrf should be completed MRI or CT-scan if available (data shipped to HCRI for inclusion in source documentation packet) For any surgical or percutaneous TL or non-tl intervention, the revascularization form should be completed. Angiograms should be collected for all TLR and TVR after 12 months Data Collection and Tracking It is the investigator's responsibility to ensure completion and to review and approve all ecrfs. A pre-determined subset of ecrfs will be signed by the principal investigator or authorized staff member. These signatures serve to attest that the information contained on the ecrfs is true. At all times, the investigator has final personal responsibility for the accuracy and authenticity of all clinical and laboratory data entered on the ecrfs. Subject source documents are the physician's subject records maintained at the trial site. In most cases, the source documents will be the hospital's or the physician's chart. In cases where the source documents are the hospital or the physician's chart, investigators must ensure that the information collected on the ecrfs match those charts. Research coordinators at each clinical site will perform primary data collection from Page 95 of 118

206 source document (e.g., hospital chart, office record) reviews. Data will be entered by the site personnel into ecrfs on the internet-based EDC system. This will ensure data are forwarded to HCRI in an expedited fashion. HCRI will provide selected clinical monitoring, including review of EDC data. Please see Table 8 below for ecrf submission details. In the initial phase of the protocol, periodic teleconference calls between HCRI/designated CRO and each clinical site may be performed to resolve any problems concerning the protocol and data collection. Periodic recruitment status reports generated by the EDC system will identify variations in recruitment frequency among sites. If any action is taken by an IRB/EC with respect to the study, the information must be forwarded to HCRI. Time Windows for Expected Completion of Electronic Case Report Forms/Reports The ecrf data submission detailed in the following table should be completed as follows: Table 8. Responsibilities for Submitting ecrfs Type of ecrf Prepared by Investigator For Time of Notification Subject Enrollment ecrf HCRI Within 24 hours of enrollment Baseline ecrfs HCRI Within 48 hours of enrollment Hospital Discharge Form HCRI Within 48 hours of ecrf Clinical Follow-up ecrfs HCRI discharge Within 48 hours of subject contact Unanticipated Serious Adverse Event ecrf HCRI, IRB/EC Within 24 hours of knowledge of event Major Event ecrfs HCRI Within 48 hours of event occurrence Study Exit ecrf HCRI Within 48 hours of subject exit Other data and reports detailed in the following table should be submitted (by fax, mail, or overnight courier, if necessary) to HCRI as follows: Page 96 of 118

207 Table 9. Responsibilities for Submitting Reports and Other Data Type of Notification/Report Informed consent not obtained from subject Subject death during the investigation Unexpected Adverse Drug/Device Effect/Reaction (drug or device UADE, UADR) Withdrawal of IRB/EC approval Annual reports Deviation from the Investigational Plan (Emergency) Prepared by Investigator For Notify HCRI and IRB/EC Notify HCRI and IRB/EC Notify HCRI and IRB/EC Notify HCRI Submit to HCRI and IRB/EC, FDA Notify HCRI and IRB/EC, FDA Time of Notification Within 5 working days of index procedure Within 1 working day of knowledge of event Within 24 hours of knowledge of event Within 5 working days of withdrawal Annually Within 5 working days of deviation Final report IRB/EC, FDA Within 3 months of study completion or termination Endpoint Reporting Data related to Major Adverse Cerebral and Cardiac Events (MACCE), which are expected Serious Adverse Events, will be recorded in the ecrf within 10 working days after the investigator becomes aware of the event. In accordance with the primary objectives of this study, adverse event collection is mainly focused on the collection of Major Adverse Cerebral and Cardiac Events as this is a widely accepted clinical parameter at assessing the impact of PCI with stent placement. All FDA-approved stents and drugs used in the study have had extensive data collected related to product safety and efficacy. This study will collect data related to the primary clinical endpoint (MACCE) as well as stent thrombosis and major bleeding, irrespective of whether it is related to a MACCE. Page 97 of 118

208 Table 10. Endpoint Reporting Requirements Major Adverse Cerebral and Cardiac Events (MACCE, including MI and Stroke) Investigator submit to: HCRI by ecrf Stent Thrombosis Investigator submit to: HCRI by ecrf Major Bleeding Investigator submit to: HCRI by ecrf Death Investigator submit to: HCRI by ecrf Within 10 working days after the investigator first learns of the event. Within 10 working days after the investigator first learns of the event. Within 10 working days after the investigator first learns of the event. Within 24 hours after the investigator first learns of the event Investigator Records The investigator is responsible for the preparation and retention of the records cited below. All of the records below, with the exception of subject s hospital file, should be kept in the Investigator Site File (i.e., regulatory binder provided to the investigator) or appropriate Subject Study Binder. Subject s medical record Protocol and, if applicable, any amendment Instructions For Use/Package Inserts Blank IRB/EC approved Informed Consent Signed and dated informed consent for each subject Signed and dated Clinical Trial Agreement IRB/EC approval documentation for protocol, amendments and informed consent Indemnification agreement, if applicable Enrollment confirmation for each subject Curriculum Vitae, principal investigator and sub-investigators Safety reports and the progress reports to the IRB/EC, if required Any other records that IRBs\ECs or other local regulatory agencies require to be maintained Sponsor Records HCRI and/or the designated CRO will maintain the following records: All study documents and correspondence which pertains to the study Protocol and, if applicable, any amendments List of participating institutions Names/contact addresses of monitors Page 98 of 118

209 Statistical analyses and underlying supporting data Enrollment procedure Final report of the clinical investigation Signed and dated Clinical Trial Agreements Copies of all IRB/EC approval documentation Instructions for Use/Package Inserts IRB/EC approved informed consent Indemnification agreement, if applicable Any other records that FDA or local regulatory authority requires to be maintained Depending on final HCRI and/or its designee CRO responsibilities, certain Sponsor records may be filed at the CRO during the course of the study. Page 99 of 118

210 11 Study Responsibilities and Quality Assurance 11.1 Investigator Responsibility for Study Conduct The post-market release study will be conducted according to the Declaration of Helsinki or with the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual, ISO 14155, 21 CFR 822 and applicable local regulations. The adverse event collection will be focused on clinical events specific to drug eluting stents and bleeding complications. The participating investigator is responsible for adhering to this protocol, the Declaration of Helsinki, ISO 14155, 21 CFR 822, the agreement and the regulatory requirements. It is the responsibility of each study-site Principal Investigator to provide the current study protocol to all sub-investigators and other staff responsible for study conduct, as well as provide for the training of all sub-investigators or other staff involved in the conduct of this research. The study must fully adhere to the principles outlined in Guideline for Good Clinical Practice ICH Tripartite Guideline [January 1997] or with local law if it affords greater protection to the subject. For studies conducted in the EU/EEA countries, the sponsor and the investigators will ensure compliance with the EU Clinical Trial Directive [2001/20/EC]. For studies conducted in the USA or under US IDE, the sponsor and investigators will additionally ensure that the basic principles of Good Clinical Practice as outlined in the current version of 21 CFR, subchapter D, part 312, Responsibilities of Sponsors and Investigators, part 50, Protection of Human Subjects, and part 56, Institutional Review Boards, are adhered to. In other countries where Guideline for Good Clinical Practice exist the sponsor and the investigators will strictly ensure adherence to the stated provisions. Study-site Principal Investigators will acknowledge that the use of electronic signatures within the EDC system are the legally binding equivalent of traditional handwritten signatures and that they will be accountable and responsible for actions initiated under their electronic signatures. Upon completion of the trial, the Principal Investigator will submit a final written report to HCRI, and the reviewing IRB or EC. The report should be submitted to HCRI within three (3) months of completion or termination of the study. Investigator / Site selection For this study, the following investigator/site selection criteria are applicable: Center must have sufficient patient population Investigator should have adequate dedicated staff that has time to manage the study Center must be willing to comply with the protocol and data requirements Center has preferably demonstrated experience with conducting clinical (device and drug) trials that comply with applicable regulatory standards Center has an Internet connection with sufficient speed of data transfer Stents are available from hospital stock Center willing to participate in study with follow-up of subjects for 33 months All investigators will be appropriately qualified practitioners legally entitled to practice, and experienced in the diagnosis and treatment of subjects requiring a percutaneous coronary intervention (PCI) procedure with a Drug Eluting or Bare Metal Stent. The following documentation (at a minimum) must be in place before site initiation both at the participating site and at HCRI (or the designated CRO) before subject enrollment begins: Page 100 of 118

211 IRB/EC approval Signed Site Clinical Trial Agreement 11.2 Study Data Reporting and Processing HCRI will develop a study specific Electronic Data Capture (EDC) system that will capture all data as defined in the study protocol. This system will be hosted on a central, secure server provided and managed to good clinical practice (GCP) levels of security. Data entered into the system will be transmitted to the server utilizing Secure Sockets Layer (SSL) technology and 128-bit encryption. HCRI Data Management will review and clean the data on an ongoing basis for accuracy and consistency and send queries to sites as needed. Standard reports will be available on the EDC system to track such items as data entry compliance and current enrollment Training The training of appropriate clinical site personnel will be the responsibility of HCRI and/or its designees prior to or at the initiation. The Investigator is responsible for ensuring that his/her staff conduct the study according to the protocol. To ensure compliance with the protocol requirements, HCRI and/or designee will present a formal training session to study site personnel that will include review of all aspects of the study to include protocol and ecrf review, review of regulatory requirements, specific study procedures, informed consent process, and drug and device accountability. HCRI will provide training on the EDC system at a formalized, pre-study training session(s) (e.g. via online tutorial) and throughout the study as necessary. Additional assistance with ecrf data entry questions may be provided via the site monitor Confidentiality and Protection of Study Files The EDC system requires a unique combination of Username and Password for access to the study data. Access rights are governed by the role of that individual user, and only those tasks or data that are authorized will be allowed by the system. This includes Investigators, Site Personnel, Monitors, and HCRI personnel. Access to the system will not be granted to any individual until it can be demonstrated that the individual has the knowledge, skill and education to perform their expected tasks and has been positively identified in compliance with 21 CFR, Part 11. At HCRI, access rights are assigned to appropriate personnel to insure confidentiality and protection of the cleaning and analysis databases. HCRI will assign user access rights to subject data only to the appropriate qualified study personnel Source Documentation Requirements Regulations require that Investigators maintain information in the study subject s medical records which corroborate data collected on the electronic case report forms (ecrf). In order to comply with these regulatory requirements, the Investigator will maintain and make available as required Page 101 of 118

212 by HCRI or Quintiles monitors (or qualified contract monitor) and/or its regulatory inspectors the following information that includes but is not limited to: 1. Signed Informed Consent documents. 2. Medical history/physical condition of the study subject before involvement in the study sufficient to verify protocol entry criteria. 3. Dated and signed notes in the subject s medical record on the day of entry into the study that identify: the subject s date of entry into the study, the clinical site, subject number assigned and a statement that informed consent was obtained and a signed copy given to the subject.. 4. Dated and signed notes for each study subject contact with reference to the ecrfs for further information, if appropriate (for specific results of procedures and exams). 5. Description of device implantation procedure (material used, drugs administered during the procedure, date, time duration, angiographic, US and clinical findings, etc.). 6. Notations for example; clinically significant or not clinically significant on abnormal lab results and their resolution. 7. Dated printouts or reports of any special assessments, i.e., ECGs, laboratory tests. 8. Serious adverse event reporting and follow-up of the serious adverse events (minimally event description, severity, onset date, duration, relation to study device/drug, outcome and treatment for serious adverse event). 9. Source documents relative to suspected endpoint events. 10. Progress notes regarding concomitant medications taken during the study (including start and stop dates). 11.Study subject s condition upon completion of or withdrawal from the study Procedures for Database Management Data collected on each subject will be recorded on a web-based electronic Case Report Form (ecrf). A paper version of the ecrfs may be printed at the sites to use as a working copy. Instructions for proper completion of the ecrf and how the web-based system is used will be provided to the clinical site. The investigator or an authorized member of the investigational team must sign all completed ecrfs, by using an electronic signature (the electronic signatures will be provided by HCRI at the start of the study). The clinical study team at HCRI (or designated CRO) is responsible for assuring that the investigator has completed the ecrfs correctly. Data will be checked for consistency and completeness on a regular basis, both manually as well as by using computer software capabilities of the clinical database. Electronic Data Clarification Forms will be used to document the recovery of incomplete, inconsistent, or missing data Protocol Deviations A protocol deviation is defined as any instance during the conduct of the study where the clinical investigator or other site personnel changed or failed to adhere to the study design or procedures Page 102 of 118

213 specified by the protocol approved by the US Food and Drug Administration (FDA) or the equivalent applicable Competent Authority in other countries, and the Investigational Review Board/Ethics Committee that oversees the Investigative Site. Examples of protocol deviations may include: a) enrollment of a study subject who does not meet all of the inclusion/exclusion criteria specified in the protocol; b) failure to obtain a key safety procedure or lab test; or c) enrollment of a patient during a lapse in IRB approval of the study. Each Investigator shall conduct this clinical study in accordance with this clinical protocol, FDA regulations, Good Clinical Practices, and any conditions of approval imposed by their IRB/EC. Failure to comply with and/or inability to meet FDA regulations may jeopardize further participation of the Investigator or Investigative Center in this and future clinical studies. All relevant protocol deviations are submitted, reviewed and assessed for their impact on subject safety by HCRI. Each Investigative Center will receive notifications of its deviations at least annually. Investigators are required to notify HCRI/Quintiles clinical study management before initiating any deviations from the protocol, except where necessary to protect the life or physical well being of a subject in an emergency. Notification shall be documented in writing and maintained in clinical study management and investigator files. Prior notification is generally not expected in situations where unforeseen circumstances are beyond the Investigator s control, (e.g., subject did not respond to scheduled follow-up, blood sample lost by laboratory, etc.), however, the event is still considered a deviation. Specific deviations shall be reported to HCRI regardless of whether medically justifiable, preapproved by HCRI, or taken to protect the subject in an emergency. Subject specific deviations will be reported through the EDC system. Reported protocol deviations will be classified into 4 categories are as follows: 1. Issues related to subject informed consent or confidentiality 2. Deviations from protocol inclusion and exclusion criteria 3. Deviations associated with study thienopyridine medication compliance 4. Deviations associated with follow-up compliance (including deviations from protocol specified evaluations as well as subjects missing their scheduled visits) Major Deviations are defined as any unapproved change in the study procedures or study design that are within the Investigator s control that may adversely affect the participant s rights, safety or well-being, or the accuracy and reliability of the study data. Minor Deviations are defined as any unapproved change in the study procedures that are within the Investigator s control that do not have an impact on the participant s rights, safety or well-being, or the accuracy and reliability of the study data. Investigators will also adhere to procedures for reporting protocol deviations to their IRB/EC in accordance with their specific IRB/EC reporting policies and procedures. Regulations require that Investigators maintain accurate, complete and current records, including documents showing the dates of and reasons for each deviation from the protocol. Any major deviations that will be reported to the IRB/EC should also be recorded on the ecrf for collection and review by HCRI. Page 103 of 118

214 11.6 Data Transmittal and Record Retention Required data will be recorded on the appropriate ecrf at the time of or as soon as possible after the subject contact or the availability of test results. Any supporting documents must be faxed to HCRI or designee and/or retrieved from the Investigator according to the outlined time windows. Sponsor records and reports will be stored at HCRI during the course of the study. Site specific records may be stored at HCRI and/or the monitoring CRO during the course of the study. After the closure of the study, all records and reports will be archived by HCRI permanently. The investigator must be willing to give access to study monitors, auditors, EC/IRB members and FDA inspectors, and have appropriate facilities to retain relevant study documents. Investigators records will be retained for at least two years after the formal discontinuation of clinical development of the device, and according to the local IRB/EC requirements Monitoring Procedures Site Initiation Prior to subject enrollment, a remote study initiation will be conducted to ensure the following: IRB/EC approval has been obtained and documented prior to subject screening, the Investigators and study personnel are appropriately trained and clearly understand the study, the Investigators and study personnel accept the obligations incurred in undertaking this clinical investigation. Documentation of the training of key site personnel will be completed prior to or during the site initiation. Periodic Monitoring visits In order to ensure a high degree of data quality, selected clinical sites can be monitored with an onsite visit and through remote monitoring in accordance with the Monitoring Plan. An on-site monitoring visit is planned for 75% of all active sites. These on- site visits will be conducted to monitor the following on selected subjects: compliance with the protocol and adherence to the data collection procedures, to assess the accuracy and completeness of submitted clinical data, to verify that records and documents are being properly maintained for the duration of the study. The monitor will perform source data verification by reviewing original subject documents for these selected subjects. Monitoring will consist of 100% of source document data on all reported endpoint events and predefined non-event critical fields on an approximate 10% subject sampling. Pre-defined critical fields will be monitored for all sampled subjects including, but not limited to, those related to informed consent, inclusion/exclusion criteria, medical history, and post randomization study visits. Additional monitoring, including a larger subject sampling, will be conducted at any site if deemed necessary. Monitoring processes and procedures are outlined in the Monitoring Plan. Study Close Out Upon completion of the clinical study (when all subjects have completed the follow-ups, all data has been entered into the EDC system and cleaned, all queries resolved, and final electronic signatures have been obtained) a remote closeout will be conducted to support regulatory compliance with regard to record retention, proper disposition of the study drug and accountability, and most importantly that the site is audit ready. Page 104 of 118

215 11.8 Study Suspension or Study Early Termination If a center is terminated or suspended, no additional enrollments will be allowed at the center. Possible reasons for clinical investigator or center termination or suspension include but are not limited to: Non compliance to obtain patient informed consent Non compliance with adhering to the inclusion/exclusion criteria Failure to follow subjects per scheduled follow-ups Failure to submit data in a timely manner IRB/EC approval expiration IRB/EC suspension of the center If the study is terminated prematurely or suspended: HCRI will promptly inform the clinical investigators of the termination or suspension and the reasons, and inform the U.S. FDA and other Competent Health Authorities. The IRBs/ECs will also be promptly informed and provided with the reasons(s) for termination or suspension by HCRI or by the clinical investigator. The investigator will promptly inform the subjects and the personal physician of the subjects, assure appropriate therapy and follow-up for the subjects. In case of early termination the investigator agreement will be terminated. If the investigator (or IRB/EC) terminates or suspends the investigation without prior agreement of HCRI: The investigator will promptly inform HCRI and the IRB/EC, and provide a detailed written explanation of the termination or suspension. The investigator will inform the institution. The investigator will promptly inform the subjects and the personal physician of the subjects, and assure appropriate therapy and follow-up for the subjects. HCRI will inform the regulatory authority. In case of early termination the investigator agreement will be terminated. Subject follow-up in case of study early termination In case of early termination, the subjects need to be followed until at least 30-days after the index procedure. Page 105 of 118

216 12 Study Committees 12.1 Executive Committee The Executive Committee will be responsible for the day-to-day administrative management of the trial. This committee will meet periodically by teleconference to monitor subject enrollment, clinical site progress, and protocol compliance. This committee will be responsible for reviewing the final results, determining the methods of presentation and publication, and selection of secondary projects and publications by members of the Steering Committee. Committee Members: Laura Mauri, M.D., Principal Investigator Dean Kereiakes, M.D., Co-Principal Investigator Donald Cutlip, M.D. Sharon-Lise Normand, PhD Ph. Gabriel Steg, M.D. Theodora Cohen, PhD Priscilla Driscoll Shempp 12.2 Advisory Committee The Advisory Committee consists of members of the Executive Committee and others outlined below. The Advisory Committee participates in HCRI requested meetings to review study progress and conduct and to provide feedback to Executive Committee on an ad hoc basis. Committee Chairperson: Eugene Braunwald, M.D., Harvard Medical School Ralph Brindis, M.D. David Cohen, M.D. Anthony Gershlick, M.D. Paul Gurbel, M.D. David Holmes, M.D. Alice Jacobs, M.D. Michael Linkoff, M.D. Daniel Simon, M.D. Jean-François Tanguay, M.D. Douglas Weaver, M.D. Stephan Windecker, M.D. Steve Wiviott, M.D Data Monitoring Committee (DMC) The Data Monitoring Committee (DMC) or Data Safety Monitoring Board (DSMB) is composed of at least five members (physicians from the fields of cardiology and interventional cardiology and at Page 106 of 118

217 least one biostatistician), who are not directly involved in the conduct of the trial. The DMC will review the study (including reported SAEs) on a periodic basis to be defined at their first meeting. Based on the safety data, the DMC may recommend that the Executive Committee modify or stop the trial. All final decisions, however, regarding trial modifications, rest with the Executive Committee. No formal statistical rule for stopping the trial will be defined in this trial and no formal interim analysis is planned. The DMC will remain blinded to the treatment assignment (duration of DAPT) and masked to study drug (as well as study device) in their review and analysis of all endpoint events and SAEs. If the DMC requests reports that unblind or unmask the above study data, HCRI will notify the FDA of such requests. Committee Chairperson: Robert Bonow, M.D., Northwestern Memorial Hospital Charles Davidson, M.D., Northwestern Memorial Hospital James Neaton, PhD, University of Minnesota School of Public Health William Wijns, M.D., PhD, Onze-Lieve-Vrouw (OLV) Hospital Clyde Yancy, M.D., FACC, FAHA, MACP, Baylor University Medical Center 12.4 Clinical Events Committee (CEC) The Clinical Events Committee (CEC) is made up of interventional and non-interventional cardiologists and other clinical experts as required who are not participants in the DAPT Study. The CEC is charged with the adjudication of pre-specified clinical endpoint events. At the onset of the trial, the CEC will establish specific criteria used for the categorization of clinical endpoint events, explicit rules outlining the minimum amount of data required for adjudication of each event, and the algorithm followed in order to classify a study endpoint related clinical event. All members of the CEC will remain blinded to the treatment assignment (duration of DAPT) and masked to study drug (as well as study device) in their review and adjudication of all endpoint events. The CEC will meet regularly to review and adjudicate clinical endpoint events for which the required minimum data are available. The procedures by which the CEC will operate will be documented in a separate manual. It should be noted that for the primary and secondary analyses as described in Section 6, periprocedural MI will not be adjudicated with immediate association with the index procedure. Adjudication of MI events will begin 72 hours post-index procedure. All MI events will be adjudicated with the exception of those that have onset between 0-72 hours post index procedure. This protocol recommends that sites collect CK-MB preferentially over troponin in the peri- Page 107 of 118

218 procedural period subsequent to index. In the case where a site does not have CK, CK-MB available, troponin can be used. In cases in which there is clinical suspicion for peri-procedural MI based on symptoms or ECG changes, the assessment of cardiac biomarkers is strongly recommended. When biomarkers are not assessed prior to the procedure, they should be assumed to be normal, with final adjudication to be done by the CEC. All other endpoint events, including all deaths, will be adjudicated by the CEC from the index procedure. Angiographic assessment of suspected stent thrombosis is critical for CEC adjudication. Since an angiographic core laboratory is not planned for this study, appropriate expertise of the CEC membership will be utilized to provide this assessment. The determination of stent thrombosis will be based on the location of the occlusion and presence of thrombus as assessed by the CEC, composed of at least 2 interventional cardiologists. The CEC will be blinded to duration of antiplatelet therapy, and masked to drug and stent type, and investigator. In order to allow the independent assessment of the angiograms, the CEC interventional cardiologists will review the angiograms in the absence of clinical data first, before reviewing the event with the totality of the evidence with the entire committee. An attempt will be made to resolve all disagreements with consensus; however, in case of a tie, an additional interventional cardiologist will be asked to assess the angiogram and event. Independent and blinded assessment of the electrocardiogram will also be performed by board certified cardiologists who serve as members of the CEC. The electrocardiogram will be interpreted as whether ST elevation or ST depression suggestive of myocardial infarction is present and if the evolution of the electrocardiograms indicate evidence of Q wave myocardial infarction. The readers will also use electrocardiographic evidence to code the event as likely related to the target vessel territory or non-target vessel territory. The electrocardiogram will be interpreted by the CEC for all suspected myocardial infarctions that are referred to CEC for adjudication. The ECG will be interpreted first in the absence of clinical data and then utilized to provide a final adjudication based on the totality of clinical data. Adjudications for myocardial infarction and probable stent thrombosis will depend on the electrocardiographic interpretation. In the absence of an ECG core laboratory, the CEC members will use criteria based on the Minnesota code for ECG interpretation: 1. Q wave myocardial infarction will be diagnosed when newly present Q waves that measure at least 40 msec width and 1 mm depth are identified in 2 or more contiguous ECG leads. 2. ST elevation will be defined as at least 1 mm of ST segment elevation in 2 or more contiguous limb leads or at least 2 mm elevations in 2 or more precordial leads V1- V4. The relationship to study drug of each major bleeding event will be determined by the CEC while the trial is ongoing (after randomization). If, prior to the occurrence of the event, study drug was discontinued for more than 14 days, the event will not be counted as associated with the drug (this Page 108 of 118

219 analysis will be performed independently of the CEC adjudication of the event itself). The CEC will not differentiate between the comparative groups with this 14 day cut off Study Enrollment Monitoring Committee The Study Enrollment Monitoring Committee will be responsible for managing the enrollment goals including the caps and minimums to specific populations for the DAPT study. This committee will meet frequently by teleconference to monitor subject enrollment and their proportions with respect to the study limitations set forth in the protocol. The membership of this committee will be persons both familiar with and not affiliated with the conduct of the DAPT Study. In an effort to ensure the generalizability of the overall study, minimum and maximum parameters have been placed on certain patient and treatment characteristics for the DES analysis cohort (DAPT and non-dapt sources combined): e.g. at least 15% of subjects have been treated with a given DES stent type and a target maximum of 60% with a give thienopyridine type. Section shows what the exact populations restrictions are for the DAPT study. This committee will also directly monitor the proportion of subjects with complex vs. non-complex classification as well as the balance of those subjects who present with ACS according to troponin, CK-MB, and STEMI throughout the study. Based on the enrollment data from the DAPT study as well as from the contributing PMS/COA studies, the Study Enrollment Monitoring Committee may recommend that the Executive Committee close enrollment to certain groups of subjects (e.g. DES of a certain type). This committee is also charged with monitoring the characteristics of subjects who are randomized. Committee Membership pending Publication Policies Subject confidentiality and disclosure of data All records and other information about subjects participating in this study will be treated as confidential. HCRI and/or its designee CROs/AROs will collect data and monitor study records. Auditors, IRB/EC members, CEC/DMC or the U.S. FDA may also have access to the study records. Participating subjects will not be identified by name in any published reports about this study. Publication policy The results of this study will be made public and are intended to be presented and published. The study will be registered in the clinicaltrials.gov database. HCRI will form a publication committee. The committee will develop a final publication plan. The scientific validity and timing of publications will be evaluated in order to maximize the benefits derived from the publication of the clinical data of the study. In general, publications utilizing data will be managed as described below. Publication Committee Page 109 of 118

220 The Publication Committee will be defined during the course of the study and after enrollment is completed. Committee membership will include representatives of the Executive Committee and HCRI. The goal of the Committee is to ensure that the study results are published. The Publication Committee is responsible for reviewing proposals for publication, overseeing the development of manuscripts/abstracts, plus identifying and appointing the manuscript/abstract author(s)/writer(s). The Committee reviews not only main publications, but also ancillary publications. If necessary, specified authorship criteria may be applied for ancillary publications. The Committee may decide that no publications/abstracts will be prepared prior to the end of the study, and also not on individual center data. Authorship Selection Authors will be selected on the basis of the following: A significant contribution to the design of the clinical study A significant contribution to subject enrollment in the clinical study High quality of data as determined by the clinical study requirements Demonstration of a high level of interest in the outcome of the study, and the ability to write, review, edit, and present the publication A demonstration of a good publication history A willingness to contribute to the publication All investigators not listed as co-authors will be acknowledged as investigators and will be individually listed according to the guidelines of the applicable scientific journal. All publications and presentations of data from the DAPT Study should use the phrase following the listed authors for the DAPT Study investigators. Review and Communication Guidelines Investigators will receive communication regarding the authorship selection, the publication coauthors and to which scientific platform the publication will be submitted. Prior to submission of a publication (abstracts and manuscripts), the Publication Committee and all co-authors will review and authorize the publication (contents and platform). Page 110 of 118

221 13 Ethical and Regulatory Considerations 13.1 Role of the Study Sponsor As the study sponsor of this clinical study, HCRI has the overall responsibility for the conduct of the study, including assurance that the study meets and is conducted within the regulatory requirements specified by each reviewing regulatory authority. In this study, HCRI will have certain direct responsibilities and will delegate other responsibilities to other designees. HCRI will ensure adherence to the sponsor general duties, selection of Investigators, monitoring, supplemental applications, maintaining records, and submitting reports General Duties HCRI s general duties (which may be assisted by designees) include submitting the application to appropriate regulatory authorities and obtaining overall regulatory approval. HCRI is responsible for ensuring informed consent is obtained, proper clinical site monitoring is performed, providing quality data that satisfies regulations and informing study Investigators of unanticipated adverse drug and device effects events and deviations from the protocol, as appropriate. As the designated data coordinating center, HCRI will prepare written reports and a final report as directed by the protocol and will coordinate data collection and transfer with other vendors Subject Confidentiality Subject confidentiality will be maintained throughout the clinical study in a way that assures that data can always be tracked back to the source data. For this purpose, a unique subject identification code (Site number, subject number and initials) will be used that allows identification of all data reported for each subject. Data relating to the study might be made available to third parties (for example in case of an audit performed by regulatory authorities) provided the data are treated confidential and that the subject s privacy is guaranteed Institutional Review Board (IRB)/Independent Ethics Committee (IEC) It is the responsibility of the investigator to obtain approval of the trial protocol, protocol amendments, informed consent forms, and other relevant documents, e.g., advertisements, if applicable, from the IRB/IEC. All correspondence with the IRB/IEC should be retained in the Investigator File. After obtaining IRB approval, the investigator will submit the approval letter indicating the approved version of the protocol, Patient Informed Consent, and any other reviewed documentation to HCRI and/or its designee for review. The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is where the change is necessary to eliminate apparent immediate hazards to the subjects. In that event, the investigator must notify the IRB/IEC and HCRI in writing within 5 working days after the implementation. Page 111 of 118

222 13.5 Supplemental Applications If required, HCRI and/or designees will submit changes in the protocol to the appropriate regulatory authorities and Investigators to obtain IRB/EC approval to implement the changes Maintaining Records HCRI and/or its designees will maintain copies to include all trial related correspondence, regulatory documents, data, shipment of drug accountability logs, adverse device effects and other records related to the clinical trial. HCRI and/or its designees will maintain records related to the signed Investigator Agreements Submitting Reports HCRI will submit the reports required by each reviewing regulatory authority. This includes unanticipated adverse drug and device effects, withdrawal of IRB/EC or regulatory approval, current Investigators list, annual progress reports, recall information and final reports. Sites will notify HCRI within 24 hours of the time the Investigator becomes aware of any unanticipated adverse drug or device effects or withdrawal of IRB/EC approval. HCRI will also assist in the preparation of annual progress reports and a final report for the DAPT Study. HCRI will provide 6 month progress reports to FDA that include items such as the following: number of subjects enrolled, number of sites enrolled/active, anticipated conclusion of enrollment, and a summary of UAEs reported to report date. In the Clinical Study Report (CSR), HCRI will submit a listing of all subjects who died as well as all discontinuations (including discontinuations due to serious as well as other discontinuations). Included will be the start and end dates of drug treatment as well as start and end dates of the adverse events and whether or not the events were resolved, resolving, or ongoing. Electronic case report forms (ecrfs) for all patients who died and for all discontinuations will be made available to FDA if requested. Narratives will not have to be submitted with the CSR. Narratives for patients experiencing endpoint events or SAEs will be made available to FDA if requested. The CSR will also include a listing of "Investigator Reported Events" that were also adjudicated as events by the CEC as well as a listing of "Investigator Reported Events" that were reviewed by the CEC but not thought to be events. The unmasking of drug brand will only be added to the CSR submitted to FDA after blinded and masked adjudication by the CEC and review by DMC has been completed Site Record Retention Policy All clinical sites will maintain study records until HCRI notifies them and the reviewing regulatory authorities that research is completed or terminated under the clinical investigation in compliance with national law. Record retention dates will be provided to study sites by HCRI or its designee Informed Consent All subjects must provide written Informed Consent in accordance with the local clinical site s IRB/EC. A copy of the consent form from each site must be forwarded to HCRI or Quintiles for review and approval prior to submission to the site IRB/EC. Each site must provide HCRI with a copy of the study site s IRB/EC approval letter and the approved informed consent document. A signed Informed Consent must be obtained from each subject or his/her relative/guardian prior to commencing screening/baseline evaluations. Any revisions to the approved Informed Consent must be reviewed and approved by HCRI or its designee before submission to the IRB/EC. Page 112 of 118

223 The process for obtaining informed consent shall be as follows: Avoid any coercion or undue influence of subjects to participate Not waive or appear to waive subject s legal rights Use language that is non-technical and understandable to the subject or his/her legal representative Provide ample time for the subject to consider participation Include dated signatures of the subject or the subject s legal representative (or impartial witness according to IRB/EC requirements) and the investigator Show and document how informed consent will be obtained and recorded in circumstances in which the subject is unable to give it An IRB/EC approved informed consent will be given to each subject for review and signing. The approved informed consent form will include an explanation of the study, duration, expected benefits and risks or inconveniences, explanation of alternatives, medical record access and subject anonymity, if data is used for publications or submission for reimbursement support. The site Principal Investigator may delegate the responsibility to obtain informed consent to one or more of the staff members. This will be documented in the delegation of authority log filed at the site. A sample template of the patient informed consent form will be available for the IDE submission. The signed consent forms will be retained by the investigator and made available (for review only) to study monitors, auditors or inspectors on request. A copy of the signed and dated informed consent form will be provided to each study subject. In the event that the subject is unable to provide written informed consent, verbal consent from the subject or written assent from a legally acceptable representative will be accepted to facilitate enrolment. The legal representative may provide written consent on behalf of the subject only after having been fully informed about the study. Where a subject is providing verbal consent, an impartial witness must be present during the entire informed consent discussion. Once consent has been given, the witness must sign and personally date the consent form, to confirm that the information contained within the informed consent and any further information provided by the investigator, was explained to and apparently understood by the subject and that consent was freely given. Where a subject has initially verbally consented or a subject s legally acceptable representative has assented on behalf of the subject, written consent should be sought from the subject as soon as, in the investigator s opinion, the subject is capable of understanding the process and capable of signing the consent form, or as required by their IRB/EC. Page 113 of 118

224 14 References 1. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O'Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349(14): Stone GW, Ellis SG, Cox DA, Hermiller J, O'Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med. 2004;350(3): Pfisterer M, Brunner-La Rocca HP, Buser PT, Rickenbacher P, Hunziker P, Mueller C, Jeger R, Bader F, Osswald S, Kaiser C. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol. 2006;48(12): Cutlip DE, Baim DS, Ho KK, Popma JJ, Lansky AJ, Cohen DJ, Carrozza JP, Jr., Chauhan MS, Rodriguez O, Kuntz RE. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation. 2001;103(15): Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293(17): Kuchulakanti PK, Chu WW, Torguson R, Ohlmann P, Rha SW, Clavijo LC, Kim SW, Bui A, Gevorkian N, Xue Z, Smith K, Fournadjieva J, Suddath WO, Satler LF, Pichard AD, Kent KM, Waksman R. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation. 2006;113(8): Ong AT, Hoye A, Aoki J, van Mieghem CA, Rodriguez Granillo GA, Sonnenschein K, Regar E, McFadden EP, Sianos G, van der Giessen WJ, de Jaegere PP, de Feyter P, van Domburg RT, Serruys PW. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation. J Am Coll Cardiol. 2005;45(6): Mauri L, Hsieh W-h, Massaro JM, Ho KKL, D'Agostino R, Cutlip DE. Stent Thrombosis in Randomized Clinical Trials of Drug-Eluting Stents. N Engl J Med. 2007;356(10): Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Juni P, Sianos G, Hellige G, van Domburg RT, Hess OM, Boersma E, Meier B, Windecker S, Serruys PW. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 2007;369(9562): Stettler C, Wandel S, Allemann S, Kastrati A, Morice MC, Schomig A, Pfisterer ME, Stone GW, Leon MB, de Lezo JS, Goy J-J, Park S-J, Sabate M, Suttorp MJ, Kelbaek H, Spaulding C, Menichelli M, Vermeersch P, Dirksen MT, Cervinka P, Petronio AS, Nordmann AJ, Diem P, Meier B, Zwahlen M, Reichenbach S, Trelle S, Windecker S, Juni P. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. The Lancet. 2007;370(9591): Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358(9281): Steinhubl SR, Berger PB, Mann JT, 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19): Page 114 of 118

225 13. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7): Budaj A, Yusuf S, Mehta SR, Fox KA, Tognoni G, Zhao F, Chrolavicius S, Hunt D, Keltai M, Franzosi MG. Benefit of clopidogrel in patients with acute coronary syndromes without STsegment elevation in various risk groups. Circulation. 2002;106(13): Eisenstein EL, Anstrom KJ, Kong DF, Shaw LK, Tuttle RH, Mark DB, Kramer JM, Harrington RA, Matchar DB, Kandzari DE, Peterson ED, Schulman KA, Califf RM. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297(2): Spertus JA, Kettelkamp R, Vance C, Decker C, Jones PG, Rumsfeld JS, Messenger JC, Khanal S, Peterson ED, Bach RG, Krumholz HM, Cohen DJ. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation. 2006;113(24): Wiviott SD, Braunwald E, McCabe CH, Horvath I, Keltai M, Herrman JP, Van de Werf F, Downey WE, Scirica BM, Murphy SA, Antman EM. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet. 2008;371(9621): Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20): Ong AT, McFadden EP, Regar E, de Jaegere PP, van Domburg RT, Serruys PW. Late angiographic stent thrombosis (LAST) events with drug-eluting stents. Journal of the American College of Cardiology. 2005;45(12): Grines CL, Bonow RO, Casey DE, Jr., Gardner TJ, Lockhart PB, Moliterno DJ, O'Gara P, Whitlow P. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Journal of the American College of Cardiology. 2007;49(6): Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry- Ribaudo L, Booth J, Topol EJ. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16): Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin Dose for the Prevention of Cardiovascular Disease: A Systematic Review. JAMA. 2007;297(18): Garg P, Cohen DJ, Gaziano T, Mauri L. Balancing the Risks of Restenosis and Stent Thrombosis in Bare-Metal Versus Drug-Eluting Stents: Results of a Decision Analytic Model. Journal of the American College of Cardiology. 2008;51(19): Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es G-A, Gabriel Steg P, Morel M- a, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW, on behalf of the Academic Research C. Clinical End Points in Coronary Stent Trials: A Case for Standardized Definitions. Circulation. 2007;115(17): Thygesen K, Alpert JS, White HD, on behalf of the Joint ESCAAHAWHFTF. Universal Definition of Myocardial Infarction. Circulation. 2007;116(22): Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107(23): Page 115 of 118

226 27. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007;49(14): Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004;109(25): Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM, Ferenc M, Gick M, Caputo A, Buttner HJ, Neumann FJ. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol. 2006;48(9): Schwarz UR, Geiger J, Walter U, Eigenthaler M. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets--definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost. 1999;82(3): Cuisset T, Frere C, Quilici J, Morange PE, Nait-Saidi L, Carvajal J, Lehmann A, Lambert M, Bonnet JL, Alessi MC. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-st-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol. 2006;48(7): Bonello L, Paganelli F, Arpin-Bornet M, Auquier P, Sampol J, Dignat-George F, Barragan P, Camoin-Jau L. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost. 2007;5(8): Frere C, Cuisset T, Quilici J, Camoin L, Carvajal J, Morange PE, Lambert M, Juhan-Vague I, Bonnet JL, Alessi MC. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-st elevation acute coronary syndrome. Thromb Haemost. 2007;98(4): Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ, Tantry US. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol. 2005;46(10): Blindt R, Stellbrink K, de Taeye A, Muller R, Kiefer P, Yagmur E, Weber C, Kelm M, Hoffmann R. The significance of vasodilator-stimulated phosphoprotein for risk stratification of stent thrombosis. Thromb Haemost. 2007;98(6): Antman EM, Tanasijevic MJ, Thompson B, Schactman M, McCabe CH, Cannon CP, Fischer GA, Fung AY, Thompson C, Wybenga D, Braunwald E. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N. Engl. J. Med. 1996;335(18): Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N. Engl. J. Med. 2000;342(12): de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, Hall C, Cannon CP, Braunwald E. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N. Engl. J. Med. 2001;345(14): Hamm CW, Heeschen C, Goldmann B, Vahanian A, Adgey J, Miguel CM, Rutsch W, Berger J, Kootstra J, Simoons ML, for the c7e3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) Study Investigators. Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. N. Engl. J. Med. 1999;340: Morrow DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, Robertson DH, Hille DA, DeLucca PT, DiBattiste PM, Demopoulos LA, Weintraub WS, Braunwald E, for the TACTICS- TIMI 18 Investigators. Ability of minor elevations of troponins I and T to predict benefit from an Page 116 of 118

227 early invasive strategy in patients with unstable angina and non-st elevation myocardial infarction. JAMA. 2001;286: Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, Jr., Chavey WE, 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC, Jr., Jacobs AK, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation. 2007;116(7):e Montalescot G, Philippe F, Ankri A, Vicaut E, Bearez E, Poulard JE, Carrie D, Flammang D, Dutoit A, Carayon A, Jardel C, Chevrot M, Bastard JP, Bigonzi F, Thomas D. Early increase of von Willebrand factor predicts adverse outcome in unstable coronary artery disease: beneficial effects of enoxaparin. French Investigators of the ESSENCE Trial. Circulation. 1998;98(4): Eichinger S, Minar E, Bialonczyk C, Hirschl M, Quehenberger P, Schneider B, Weltermann A, Wagner O, Kyrle PA. D-dimer levels and risk of recurrent venous thromboembolism. Jama. 2003;290(8): Hron G, Kollars M, Binder BR, Eichinger S, Kyrle PA. Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. Jama. 2006;296(4): Healy AM, Pickard MD, Pradhan AD, Wang Y, Chen Z, Croce K, Sakuma M, Shi C, Zago AC, Garasic J, Damokosh AI, Dowie TL, Poisson L, Lillie J, Libby P, Ridker PM, Simon DI. Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events. Circulation. 2006;113(19): Morrow DA, Wang Y, Croce K, Sakuma M, Sabatine MS, Gao H, Pradhan AD, Healy AM, Buros J, McCabe CH, Libby P, Cannon CP, Braunwald E, Simon DI. Myeloid-related protein 8/14 and the risk of cardiovascular death or myocardial infarction after an acute coronary syndrome in the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) trial. Am Heart J. 2008;155(1): Blann AD, Faragher EB, McCollum CN. Increased soluble P-selectin following myocardial infarction: a new marker for the progression of atherosclerosis. Blood Coagul Fibrinolysis. 1997;8(7): Jansson JH, Nilsson TK, Johnson O. von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J. 1991;66(5): Ray KK, Morrow DA, Cannon CP, Sabatine MS, Guo W, Rifai N, Braunwald E. von Willebrand Factor but Not Tissue Factor or Soluble CD40 Ligand Are Associated With Increased Risk of Recurrent Events After Acute Coronary Syndrome in PROVE IT-TIMI 22. J Am Coll Cardiol. 2007;49 (Suppl A):188A. 50. Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation. 2002;105(14): Buchanan MR, Schwartz L, Bourassa M, Brister SJ, Peniston CM. Results of the BRAT study--a pilot study investigating the possible significance of ASA nonresponsiveness on the benefits and risks of ASA on thrombosis in patients undergoing coronary artery bypass surgery. Can J Cardiol. 2000;16(11): Page 117 of 118

228 52. Mega JL, Morrow DA, de Lemos JA, Mohanavelu S, Cannon CP, Sabatine MS. Thrombus precursor protein and clinical outcomes in patients with acute coronary syndromes. J Am Coll Cardiol. 2008;51(25): Geiger J, Brich J, Honig-Liedl P, Eigenthaler M, Schanzenbacher P, Herbert JM, Walter U. Specific impairment of human platelet P2Y(AC) ADP receptor-mediated signaling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol. 1999;19(8): Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome P-450 Polymorphisms and Response to Clopidogrel. N Engl J Med. 2009;360: Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres J, Danchin N, Becquemont L. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events. N Engl J Med. 2009;360: Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009:published online ahead of print. 57. de Bakker PI, Yelensky R, Pe'er I, Gabriel SB, Daly MJ, Altshuler D. Efficiency and power in genetic association studies. Nat Genet. 2005;37(11): Page 118 of 118

229 Appendix 1. Ancillary Platelet Function & Biomarker Sub-study Summary Background There exists significant interpatient variability in measures of platelet inhibition following treatment with thienopyridines, 26, 27 and patients with lesser degrees of platelet inhibition in response to clopidogrel appear to be at increased risk of cardiovascular events. 28, 29 Several methods exist for quantifying platelet function. Platelet vasodilator-associated phosphoprotein (VASP) phosphorylation quantifies phosphorylation of an intraplatelet actin regulatory protein downstream to activation of the P2Y 12 ADP receptor, and thus is specific for thienopyridine-induced platelet inhibition. 30 As measured with the VASP platelet reactivity index (PRI), patients that have a reduced platelet response to clopidogrel have been reported to have a higher incidence of cardiovascular complications, including stent 34, 35 thrombosis. Circulating biomarkers are a proven method of risk stratification , 40 and therapeutic decision-making and have been incorporated into practice guidelines. 41 There is growing data on the utility of biomarkers in identifying long-term risk and the need for more intensive or prolonged antithrombotic therapy In particular, biomarkers of thrombosis and platelet activation, including myeloid-related protein (MRP)- 14, 45, 46 P-selectin, 47 von Willebrand factor (vwf), 48, 49 serum thromboxane B 2 (TXB 2 ), 50, 51 and thrombus precursor protein (TpP) 52 may be useful for risk stratification. Objectives 1) To determine the optimal degree of platelet inhibition in patients undergoing PCI with stenting. 2) To determine the association of circulating thrombotic biomarkers with ischemic events and the benefit of prolonged dual antiplatelet therapy. Hypotheses 1) The degree of platelet reactivity will be positively correlated with the risk of ischemic events and negatively correlated with the risk of bleeding; a target range of platelet reactivity can be defined that balances these competing risks and maximizes net clinical benefit. 2) Higher levels of thrombotic biomarkers will be associated with higher rates of ischemic events and will be associated with a greater benefit from prolonged dual antiplatelet therapy. Study Procedures The platelet function and biomarker study will be performed in select subjects enrolled in the DAPT trial. Subjects who do not wish to participate in the platelet function and biomarker study may still participate in the main clinical trial. 1) One 2.7 ml citrated whole blood (blue top), one 4.5 ml plasma sample (purple top) and one 4.5 ml serum sample (red top) will be collected at the time of enrollment (and at least 6 hours after the loading dose of thienopyridine for the index PCI). 2) One 2.7 ml citrated whole blood (blue top), one 4.5 ml plasma sample (purple top) and one 4.5 ml serum sample (red top) will be collected at the time of randomization. Appendix 1 Page 1 of 2

230 Appendix 1 (Continued). Ancillary Platelet Function & Biomarker Sub-study Summary 3) The citrated whole blood specimens (blue top) will be shipped on the day of collection via overnight express courier to the TIMI Platelet Function Core Laboratory as outlined in the Manual of Operations. 4) All other specimens (purple tops and red tops) will be stored at -20 ºC and shipped in batch on dry ice via overnight express courier to the TIMI Biomarker Core Laboratory as outlined in the Manual of Operations. Assessment of Platelet Function VASP phosphorylation will be determined using a well-validated quantitative flow cytometry assay 30, 53 (Biocytex, France) and the platelet reactivity index (PRI) will be calculated in standard fashion. Biomarkers Biomarkers of platelet activation and thrombosis such as MRP-8/14, soluble P-selectin, von Willebrand factor, serum thromboxane B 2, and thrombus precursor protein will be measured. Other novel biomarkers related to cardiovascular disease may be measured as well. Analyses De-identified platelet and biomarker data will be merged with the clinical databases for statistical analysis. The association between PRI and clinical outcomes will be examined. Derivation and validation datasets will be created using a split sample approach. Receiver-operating characteristic (ROC) curves will be created and the discriminatory ability of PRI for outcomes quantified using the area under the curve. The degree of PRI that maximizes sensitivity and specificity for each outcome will be ascertained. Specific cutpoints will then be subject to validation. The association between biomarkers and clinical outcomes will be examined. Multivariable regression analyses will be used to assess for their independent prognostic utility. Stratified analyses will be performed to quantify the treatment benefit of dual antiplatelet therapy on the primary endpoint among subjects stratified by biomarker levels. Formal interaction terms (biomarker x randomized treatment) will be tested in Cox proportional hazards models. References See Main Document Section 14. Appendix 1 Page 2 of 2

231 Appendix 2. Ancillary Genetic Sub-study Summary Background Thienopyridines are prodrugs requiring biotransformation into active metabolites. Polymorphisms in genes that encode the proteins responsible for the metabolism of thienopyridines have emerged as potentially important factors influencing the response to these drugs Objective To determine the association of polymorphisms in genes involved in thienopyridine metabolism with the degree of platelet inhibition and the risk of clinical ischemic outcomes with thienopyridine therapy. Hypothesis Functional polymorphisms in genes required for thienopyridine metabolism will be associated with the degree of platelet inhibition and the risk of ischemic events in patients treated with thienopyridines. Study Procedures The genetics study will be performed in select subjects enrolled in the DAPT trial. Subjects who do not wish to participate in the genetic substudy may still participate in the platelet function and biomarker study and/or the parent clinical trial. 1) DNA can be extracted from the citrated whole blood (blue top) tube that is to be collected for the platelet function study at enrollment (see Appendix 1). If the platelet function sample is not collected, a separate 2.7 ml citrated whole blood (blue top) tube should be collected at enrollment (if unable to collect at enrollment, can be collected at the next visit). 2) If the platelet function specimen (which is to be shipped on the day of collection via overnight express courier, see Appendix 1) is not collected, the genetic specimen should be stored at -20 ºC and shipped in batch on dry ice via express courier to the TIMI Genetics Core Laboratory as outlined in the Manual of Operations. Genotyping DNA extraction will be performed using standard methodology in selected subjects using a nested casecontrol study design. Subjects will be genotyped for candidate and haplotype tagging 57 polymorphisms in genes related to thienopyridine metabolism (including CYP450 enzymes, MDR1, CES1, and CES2). In addition, samples may be genotyped for polymorphisms in known genes related to cardiovascular disease, hemostasis, and metabolism, or to search for such genes. Analyses De-identified genetic data will be merged with the clinical, platelet and biomarker databases for statistical analysis. A two-stage analytic process will be used. For the first stage, the association of variant alleles with the degree of platelet inhibition will be assessed. For the second stage, polymorphisms that were significantly associated with platelet inhibition will be tested for an association with clinical outcomes. References See Main Document Section 14. Appendix 2 Page 1 of 1

232 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE Appendix 3. Clopidogrel Package Insert Appendix 3 Page 1 of 26

233 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE HIGHliGHTS Of PR SCRIBTh"GTh"f OR\. L\TIO Tbrsr highlighrs do nor iodudt au rhr informatio n nttdtd to ost PL\\TI saftl and rffrctinly. Str f ull prrscribing i.nfol"tnatioo for PL\YIX. PL\\TI (dopidogrtl bisulf atr) tablrrs Initial l".s..-\ ppr<l\ al: 1991 \YARJI<TIG: DQIDi1SH.D HfECffiLf.SS IN POOR MH.\BOUZ.RS Su frr ll pus ribirrg irrformatiorrfor omplpte bo.wd wamirrg. f.fftetinorss of Plnix dtpt nds on actintioo to an actin m rta bolite by tht cytochromr P450 (CYP) sysrrm, principally CYP2C19. (5.1) Poor mttaboliurtrrattd 1\ith Pla\i.x a t rrcommrndrd dosts rxhlbit higher rardio\"al)cular t\ tnt ratts fouowing arutt rorona1 sndromt (ACS) or pt1'<ui3nrous coronary inttn rntion (PCI) than patien ts with normal CYP2C19 function. (12.5) Te<ts arr a\ ail1blr to idrn a potiror 's CYP2C19 grnorype and can bt ostd as an aid in dttr rmioing thrraprutic srrarr (11.5) Cons:idtr ahtrnad, t trt:umtot or n t:atmtnr ur:utgits in paritnrs idtotifitd as C\'P2C19 poor mt taboliurs. ( ) R C.l\ TB.JOR CH-.\.'JiGf.S Boxed Warning Dosage and Administration (2.3,2.4) Warnings and Precautions ( , 5.3) Thl>IC ATIONS.\.'ill l"sag. Pla\il< is a P2Yu platelet inlubitor indic.aied for: Acute coronary syndrome - For patients with oon-st-segmeol ele; ation ACS (unslable angina (UA)/oon-ST-elevation myocardial infarction (NST5<ll)] including patients who are lobe managed medic.auy and those who are lobe managed with corodai)' revascularizatioo, Plavix bas been shown to decrease the rate of a c.ombined endpoint of cardio\'ascular death, myocardial infarction (MI), or stroke as weu as the rate of a combined endpoint of cardiovascular death, Ml, stroe.or refractory ischemia. (1.1) - For patients \\ th ST-ele\11tion myocardial infarction (STEMI), Plavi. bas been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarctioo, or stroke. The benefit for patients who undergo primary PC! is unknown. (1.1) Recent myocardial infarction (MI), recent stroke, or established peripheral anerial disease. Piavi.'< has been shown lo rtduci' the combined endpoint of new ischemic stroe (fatal or nol), new Ml (fatal or not), and other vascular death. (1.2) \GE A.\\'D AD:\IDilSTR.-1.TIOi'i Acute coronary syndrome (2.1) - ou-st-segment eje, ation ACS (UAr.'<STEMl): 300 mg loading dose fouowed by 75 mg once daily, in combination with aspirin ( mg once daily) - SIE.\.fl: 75 mg once daily, in combination with aspirin ( mg once daily), with or without a loading dose and with or without thrombolytics Recent M1, recent stroke, or established peripheral arterial disease: 15 mg once daily (2..2) DOSAGE FOR.I\IS.'D STR 1\GTHS Tablets: 75 mg. 300 mg (3) CO Ul\'DICATIOI\'S Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage (4.1) Hypersensitiv ty to clopidogrel or any component of the product (4.2) W.-\R.'IlNGS Al\'D PR C\. UTIOl'\S----- Reduced effectiveness in impaired CYP2Cl9 function:avoid concomitant use with drugs that are strong or moderate CYP2C19 inhibitors (e.g., omeprazole). (5.1) Bleeding: Plavi.'\ increases risk of bleeding. Disc.ontinue 5 days prior lo elecri\ e surgery. (5.2) Discontinuation of Plavi.'\: Premature discontinuation increases risk of c.ardio \ ascular events. (5J) Recent transient ischemic anacl: or stroke:combination use of Plavix and aspirin in these patients was not shown to be more effective than Pta,;_-. alone, but was shown to increase major bletdiog. (5.4) Thrombotic thrombocytopenic purpwa (ITP):TIP bas been reponed \\ith Plavi."<, including fatal cases.( 5.5) IDH:RS. R.\CTI0:'\' Bieeding, including life-threatening and fatal bleeding, is the most commouly reported adverse reaction. (6.1) To report St:SP.CT.D.ID\'f.RS[ R.-\CTIOl\S, contact Blisrol-Myers Squibb/Sanofi Pbarmactuticals Partoebip a t or FDA a t FD A-1088 o r /medwarcb DRUG IJiiiTR.-\CTIOl'\S onsteroidal anti-inflammatory drugs (NSAIDs): Combination use increases risk of gastrointestinal bleeding. (7.2) Warfarin.: Combination use increases risk ofbleeding. (7.3) US. Th' SPECIFIC POPt:I..-1.TlOl\S Nursiog mothers: Discontinue drug or nursing, laking into consideration impo rtance of drug to mother. (8J) Str l7 for PAm 'T COUJ\'SEl.Th'GThTORMATI0:-1. R<l i<ed: August 2010 Appendix 3 Page 2 of26

234 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE FULL PRLSCRIBIJ\G DiFORM.-\TIOJ\":CO!'ITI:'I'TS WAR..l\G: DThlll'iiSHED EITECIDt:.; SS IN POOR METABOLIZERS 1 Thl>IC-.\TIO:-JS.-\J'l> US-.\GE 1.1 Acute Coronary Syndrome (ACS) 1.2 Recent MI, Recent Stroke,or Established Peripheral Arterial Disea 2 DOS-.\GE.-\J'l> ADMI:'IlSIRATION 2.I Acute Coronary Syndrome 2.2 Recent Ml, Recent Stroke, or Established Peripheral Arterial Disea 2.3 CYP2CI9 Poor Metabolizers 2.4 Use with Proton Pump Inhibitors (PPI) 3 DOSAGE FOR!IS.-\J'l> SIRE:-JGIHS 4 COYTR..Wl>IC.-\TIO:-JS 4.1 Active Bleeding 4.2 Hypersensiti ity 5 WAR.l\11\GS A!'ll> PRECAUTIOJ\S 5.I Diminished Antiplatelet Acti, ty Due to Impaired CYP2CI9 Function 5.2 General Risk of Bleeding 5.3 Discontinuation of Plavi."< 5.4 Patients \\ith Receni Iransieni Ischemic Atiac.k (ITA) or Stroke 5.5 Thrombotic Thromboq1opeoic Purpura (TIP) 6.-\DYERS REACTIOJ\S 6.1 Clinical Studies Experience 6.2 Postroarketing E."tperience 7 DRUG ThTIR..-\CTIOl\S 7.1 CYP2C19lnhibitors 7.2 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 7.3 Warfarin (CYP2C9 Substrates) 8 t:se 1!\ SPECITIC POP'lL-\TIO:-JS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal impairment 8.7 Hepatic Impairment 10 0\'ER.DOS-.\GE 11 DESCRIPTIO:-< 12 CLThlCU.. PH.L-\COLOGY 12.1 echanism of Action 12.2 Pharmacod}1ll1Dlics 123 Pharmacokinetics 125 Pharmacogenomics 13 :'I'OJ\"CLI1'1'IC.U. TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis. Impairment of fertility 14 CLThlC.U. STUDIES 14.1 Acute Coronary Syndrome 14.2 Recent Myocardial Infarction, Recent Stroke. or Established Peripheral Arterial Disease 143Lack of Established Benefit ofplavi.-. plus Aspirin in Pati.enis with Multiple Risk Factors or Established Vascular Disease 16 HOW SUPPLIED/STORAGE.-\.. 1> HA.l>LIJ\"G 17 P.\TIE!\ COl'XSELG 11\TORJ\l.\IIOl\ 17.I Benefits and Risks 17.2 Bleeding 17.3 Other Signs and Symptoms Requiring edical Attention 17.4 Invasive Procedures 175 Concomitant Medications 'Sections or subsections omitted from the full prescnoing information are not listed. Appendix 3 Page 3 of26

235 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE FULL PRESCRIBING INFO L.\.TION WARNING: Dll\IThL<iHED EFFECTIYL SS11\". POOR 1IETABOLIZERS The effectivene-ss of Pla,ix is dependent on its actiyation to an acfiye metabolite by the cytochrome P-t50 (C\"P) system, principal() CYP2Cl9 [see Jfamh1gs and Precaulious (5.1)]. PJayh: at J commended dose'> form<> less of that metabolite and bas a smaller effect on platelet function in patients who are CYP2Cl9 poor metabol.izers. Poor metabolizers mth acute coronary syndrome or undergoing percutaneous coronary inten ention treated mth Pladx. at recommended dose'> exhibit higher cardio, asculu ennt rate<> than do pati.ents "ith norma] CYP2Cl9 function. Tests are ayailabje to identify a patient's CYP2Cl9 genotr:pe; these te.stcau be used as an aid in detennining therapeutic strategy {see Clinical Pharmacology (11.5)]. Consider altematin o eatmenf or treatment strategies in patients identified as CYP2Cl9 poor metabolizers {see Dosage and Admi11istration (13)]. I INDICATIONS.A!.'ID USAGE 1.1Acute Coronary SyndJ ome (ACS) For patients with non-st-segment elevation ACS [unstable angina (UA).Inon-ST-elevation myocardial infarction (NSTENIT)], including patients who are to be managed medically and those \Vho are to be managed \Vith coronary revascularization, Plavix has been shown to decrease the rate of a c.ombine-d endpoint of cardiovascular de th, myocardial infarction (MI), or stroke as well as the rate of a c.ornbined endpoint of cardiovascular death.mi, stroke, or refractory ischemia. For patients with ST-elevation myocardial infarction (STEMI), Plavix bas been sho\vn to reduce the rate of death from any cause 3lld the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo primary percutaneous coronary intervention is tmknov.rn. The optimal duration ofplavix therapy in ACS is unknow Recent lll, Recent Stroke, or E<>tablishe-d Puipberal Arterial Disea<>e For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease., Plavix has been shown to reduce the rate of a c.ombined endpoint of new ischemic stroke (fatal or not), new!vii (fatal or not), and other vascular death. 2 DOSAGE.A!.'ID ADl\IThlSTRATIOI'\ 2.1 Acut-e Coronary Syndrome Plavix can be administered with or \Vithout food [see Clinical Phannacology (12.3)} For patients with non-st-elevation ACS (UAJNSTENIT), initiate Plavix with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate aspirin ( mg once daily) and continue incombination with Plavi.x [see Clinical Sh1dies (14.1)}. For patients with STEMI, the rec.ommended dose ofpjavix is 75 mg once daily orally, administered in. combination with aspirin ( mg once daily), with or \"\rithout Appendix 3 Page 4 of26

236 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE tbrombolytics. Plavix may be initiated with or without a loading dose {see Clinical Studies (14.1)]. 2.2 Recent lfi, Recent Stl'oke, or.established Periphera] ArteJiaJ Disease The rec.onuuended daily dose ofpjavi.11: is 75 rug once daily orally, with or \Vithout food [see Clinical Pharmacology (12.3)}. 2.3 CYP2Cl9 Poor )[etaboliz.en CYP2C19 poor metabolizer status i.s associated \Vitll diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet respo.nse{see Clinical Phannacology (12.5)], an appropriate dose regimen for this patient population has not been established. 2A Use "itb P1 oton Pump Inhibitors (PPI) Omeprazole, a moderate CYP2Cl9 inhibitor, reduces the phannacological activity ofplavix.. Avoid using omeprazole concomitantly or 12 hours apart with Plavix. Consider using another acid-reducing agent with less CYP2C19 inhibitory activity. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response:an appropriate dose regimen has not been established [see Warnings and Precautions (5.1), Drog Interactions (1.1) and Clinical Phannacology (12.5)). 3 DOSAGE FORl\IS A.!"''D STRENGTHS 75 mg t1.blets: Pink, round, biconvex, film-coated tablets debossed witb..75"on one side and "1171"on the other 300 mg tablets:pink, oblong, film-roated tablets debossed with "300" on one side and "1332" on the other.t COl'HR.A.Il\-niCATIONS.t.l Actin Bleeding Plavix is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage..t.2 Hypersensithity Plavix is contraindicated in patients \\i'ith hypersensitivity ( e.g., anaphylaxis) to clopidogrel or any component of the product [.see Adverse Reactions (6.2)]. 5 WARJ'W\GS AND PRECAL-riONS 5.1Diminished Antiplatele.t Acthity Due to Impaired CYP2Cl9 Function Clopidogrel is a prodmg. Inhibition of platelet aggregation by clopidogrel is due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 [see Boxed Warning] and by concomitant medications that interfere \Vith CYP2C19. Avoid concomitant use of Plav:ix and strong or moderate CYP2C19 inhibitors. Appendix 3 Page 5 of26

237 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE Omeprazole, a moderate CYP2C19 inhibitor, has been shown to reduce the ph.anrul.cological activity of Plavix ifgiven concomitantly or if given 12 hours apart. Consider using another acid-reducing agent v.rith less CYP2C19 inhibitory activity. Pantoprazole, a weak CYP2C19 inhibitor, had less effect on the pharmacologic-.al activity of Plavix than omeprazole [see Drvg Interactions (7.1) and Dosage and Administration (2.4)}. 5.2 ue-ra] Risk of Ble-eding Thienopyridmes., including Plavix, increase the risk of bleeding. Ifa patient is to undergo surgery and an antiplatelet effed is not desired, discontinue Plavix five days prior to surgery. In patients who stopped therapy more than five days prior to CABG the rates of major bleeding were similar (event rate 4.4% Plavix + aspiri5.3% placebo -aspirin). In patients who remained on therapy within five clays ofcabg, the major bleeding rate was 9.6% for Plavix + asplrin, and 6.3% for placebo -aspirin. Thienopyridin.es inhibit platelet aggregation for the lifetime of the platele.t (7-10 days), s.o withholding a dose will not be useful in managing a bleeding event or the risk ofbleeding associated with an invasive procedure. Because the half-life of dopidogrers active metabolite is short, it may be possible to restore hen1ostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective. 5.3 Discontinuation of Phnix Avoid lapses in therapy, and if Plavix must be temporarily discontinued, restart as soon as pos.sible..pren1ature discontinuation of Plavix rnay increase the risk of cardiovascular events. 5.4 Patients "ith Recent Transient Ischemic Attack (TIA) or Stroke In patients \vith recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and Plavix bas not been shown to be more effective than Plavix alone, but the combination has been sho\vll to increase major bleeding. 5.5 Th1'ombotic Thrombocytopenic PUJ-pura (TIP) TIP, sometimes fatal, bas been. reported follov.ring use ofplavi'{, sometimes after a short exposure (<2 weeks). TIP is a serious condition that requires urgent treatment inchlding plasmapheresis. (plasma exchange). It is. characterized by tbrombocytopenia, microaugiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings,renal dysfunction., and fever [see. Adverse Reactions (6.2)]. 6 AD\I RSE REACTIONS The following serious adverse reactions are discussed bejow and elsewhere in the labeling: Bleeding [see Warnings and Precautions (5.2)} Thrombotic thrombocytopenic purpura [see Warnings and PrecmJti.ons (5.5)} 5 Appendix 3 Page 6 of26

238 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE 6.1 Oinical Studie-'i Experience B.ause clinical trials are c,onducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a dmg cannot be directly compared to rates in the clinical trials ofanother drug and may not reflect the rates observed in practice. Plav:ix has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. The dinic.ally important advetse reactions observed in trials comparing Plavix plus aspirin to placebo plus aspirin and trials comparing Plavix alone to aspirin alone are discussed below. Blemling CURE In CURE, Plavi.use with aspirin was associated with an increase inmajor bleeding (prinwily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1). The incidence of intracranial hemorrhage (0.1%) and tatal bleeding (0.2%) were the same in both groups. Other bleeding events that \Vere reported more frequently in. the dopidogrej group \Vere epistaxis, hematuria, and bmise. The overall incidence of bleeding is described in Table 1. Appendix 3 Page 7 of26

239 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE Table 1: Cltu:. Incidence- of Ble-eding Complica tions(% patie-nt-s) Event PJavix Placebo (+aspirin)* (+aspirin)* (n=6259) (n=6303) Major bleeding I 3.7 t 2.7 Life-threatening bleeding Fatal lifd.l hemoglobin drop Requiring surgical intervention Hemorrhagic strokes Requiring inotropes Requiring transft1sion P-4 units) Other major bleeding Significantly disabling Intraocular bleeding \Vith significant loss of vision Requiring 2-3 units of blood :rvlinor bleeding Other mcdard th:erapies were wed as appropriate. Life-threatening and other ma jol" bleeding p-value < Maj or bleeding ennt rate for Plavix + a:;pum "I\'3S dose-<iependent on aspirin.: <100 mg = 2.6; mg = 3.5; >200 mg = Maj or bleeding e> ent rates for Pla'-i." + aspum by age were: <65 years= 2.5%, 2:6) to <15 years = 4.1%, 15 years = 5.9'0 Maj or bleeding e.-ent rate for placebo+ aspirin wa:; dose-dependent on a:;pum: <100 mg = 2.0%; mg = 2.3; >200 mg = 4.0% Maj or bleeding e.-ent rates for placebo+ aspirin by age were:<65 years = :65 to <1.5 yems = 3.1%, 2:75 year.; = Led to interruption of study medication. Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results. COJIJ!MIT In CO:t\IRviTT, similar rates of major bleeding were observed in the Plavix and placebo groups, both of which also received aspirin (see Table 2). Appendix 3 Page 8 of26

240 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE Tab](> 2:Incidenc(> of Bleeding Ennts in COl\Il\flT (% patients) Typ(> of bleeding Pladx Plac(>bo p-value (+ aspiiin) (+aspirin) (n=2296l) (n=2289l) Major* noncerebral or cerebral bleeding** Major noncerebral Fatal Hemorrhagic stroke Fatal Other noncerebral bleeding (non-major) Any nonc.erebral bleeding O.S S MaJor bleeds were cerebral bleeds or non-cerebral bleeds thought to ha-e caused death or tha t reqmred tra=fusi.on. ** The relatin rate of major noncerebral or cerebral bleeding was independent of age. ent rates for Pla\-lx + aspirin by age l\"ere: <60 yecars = to <70 yeal:!l = 0.7%,70 yea1= O.So/e. Event rate:; for placebo+ aspirin by age l\"ere: c::60 yecars = to <70 yeal:!l = 0.6%,70 years = 0.7- CAPRIE (Plavtx vs.aspirin) In C.I\PRIE, gastrointestinal hemorrh.1.ge occurred at a rate of2.0% in those taking Plavix vs. 2.7% i:n those taking aspirin; bleeding requiring hospitalization oc.c.urred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for Plavix compared to 0.5% for aspirin Other bleeding events that were reported more frequently in the Plavix group \Vere epistaxis and hematoma. Other Adverse Events In CURE and CHARIS?vLt\, which compared Plavix plus aspirin to aspirin. alone, there was no difference in the rate of adverse events (other than bleeding) between Plavix and placebo. In C.t\PRIE, which compared Plavix to aspirin, pruritus was more frequently reported in those taking Plavix. No other difference in the rate of adverse e'-'ents (other than bleeding) was reported 6.2 Postmarketiug llp(>ji(>llc(> The following adverse reactions have been identified during post-approval use. ofplavix. Because these reactions are reported voluntarily from a population of an unkno\vnsize, it is not always possible to reliably estimate their frequency or establish a causal relationship to dmg exposure. Blood and lymphatic.system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (ITP) Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemonnage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis General disorders and administration site condition: Fever, hemorrhage of operative wound Appendix 3 Page 9 of26

241 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE Hepato-biliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver fimction test hmmme.system disorders: Hypersensitivity reactions.anaphylactoid reactions, serum sickness Musculoskeletal, connecttve tis.sije and bone disorders: Musculoskeletal bleeding, myalgia, a:rthr.tlgia., arthritis Nervous system disorders: Taste disorders, fatal intracranial bleeding Eye disorders: Eye (conjunctival, ocular, retinal) bleeding Psychiatric disorders: Confhsion, hallucinations Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleffiing Renal and urinary disor:ders. Glomerulopa.thy, increased creatinine levels Skin and subcutaneous tis.szje disorders: rvlaculopapular or erythem.1.tous rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Jolmson syndrome, angioedema, erythema nndtiforme, skin bleeding, lichen planus Vascular disorders: Vasculitis, hypotension 7 DRUG INTER-\.CTIONS 7.1 CYP2Cl9 InWbitm'S Clopidogrel is metabolized to its active metabolite in part by CYP2Cl 9. Concomitant use of drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction inplatelet inhibition {see Warnings and Precautions (5.1) and Dosage and Admini.stration (2.4)]. Proton Pwnp Inhibitors (PP]) A study was conducted witb Plavix (300 mg loading dose followed by 75 mg/day) administered with a high dose (80 mglday) of omeprazole. As shown in Table 3 below, with concomitant dosing of omepra.zole, exposure (Gnu and AUC) to the clopidogrel active metabolite and platelet inhibition \Vere substantially reduced. Sinillar reductions inexposure to the clopidogrel active. metabolite and platelet inhibition were obsenred when Plavix and omepra.zole were administered 12 hours apart (data not shown). There are uo adequate studies of a lower dose of omeprazole or a higher dose of Plavix in comparison with the approved dose of Plavix. A study was conducted using Plavix (300 mg loading dose followed by 75 mglday) and a high dose (80 mgfday) ofpantoprazole, a PPI witb less CYP2C19 inhibitory activity than omeprazole. The plasma concentrations of the clopidogrel active metabolite and the degree ofpjatelet inhibition were less than observed v.rith Plavix alone but were greater than observed \Vhen omeprazole 80 mg was co-administered with 300 mg loading dose follo\.ved by 75 mg/day of Plavix (Table 3). Appendix 3 Page 10 of26

242 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE Table 3. Comparison of Clopidogrel Achve Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole % Otangefrom Plavix (300 mg/75 mg) alone Plavixplus Cmax (ngl'ml) AUC Platelet Inhibition (0/o) Day 1 DayS Dayl Day 5** Day l DayS Omeprazole* 80 mg 46%! 42%! 45%.1.40%!39%.1.21% Pantoprazole 80 mg 24%! 28%!.20%!14%!.15%! 11% tlnh ibmo... n of platelet aggregation v.;'lth 5 mcm ADP *Similar results seen wheu Pl.avi... and o:meprnzole were administered 12 hours apart. **AUC at Day 5 is AUCo Nomteroidal Anri-Intlammatory Drugs (1\SAIDs) Coadministration ofplavix and NSAIDs increases the risk of gastrointestinal bleeding. 7.3 Wa1-farin (CYP2C9 Substratt><>) Although the administration of clopidogrej 75 mg per day did not modify the pbannacokinetics of S-\v..uiarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, coadministration of Plavix \Vith warfarin. increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitro,clopidogrel inhibits CYP2C9. 8 "CSE IN SPECIFIC POPULATIONS 8.1PJ"t>gnancy Prl!:nancv Catl!goB Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mglkg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m 2 basis), revealed no evidence of impaired fertility or fe.totoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because an.ima1 reproduction studies are not always predictive of a human response, Plavix should be used during pregnancy only if clearly needed. 8.3 NursingIothHs Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known \Vhetber this drug is excreted in human. milk Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in mming infants from clopidogrel, a decision should be trulde \"\rbe.ther to discontinue nursing or to discontinue the drug. taking into accmmt the importance of the drug to the mother. SA Pedianic Use Safety and effectiveness in the pediatric population have not been established. Appendix 3 Page 11 of26

243 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE 8.5 Getiatric Ls-l' Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with Plavix were 65 yerus of age and older, and 15% were 75 years and older. InCOMMIT, approxinl1.tely 58% of the patients treated v.rith Plavix were 60 years and older.26% of whom were 70 years and older. The observed risk of thrombotic events \Vitb dopidogrel phts aspirin versus placebo phls aspirin by age category is provided in f igures 2 and 5 for the CURE and COMMIT trials, respectively [see Clinical Studies (14.1)j. The observed risk ofbleeding events with clopidogrel phls aspirin versus pla.cebo plus aspirin. by age category is provided in Tables 1 and 2 for the CURE and COMMIT trials, respectively {see Adverse Reactions (6.1)}. No dosage adjustment is necessary in. elderly patients. 8.6 Renal Impairment Experience is limited in patients with severe and moderate renal impairment [.see Clinical Pltannacology (12.2)]. 8.7 Hepatic Impairment No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Phannacology (12.2)]. 10 OVERDOSAGE Platelet inhibition by Plavix. is irreversible and will last for the life of the platelet Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of dopidogrel at 1500 or 2000 mglkg was lethal to mice and to rats and at 3000 mglkg to baboons. Symptoms of acute toxicity \Vere vomiting, prostration, difficult breathing, and gastrointesti.nal hemorrhage i:n animals. Based on biologic.1l plausibility, platelet tra:nsfitsion may restore clotting ability. 11 DESCRJPTOI N Plavix (clopidogrel bisulfate) is a thienopyridine class inhibitor ofp2yn ADP platelet receptors. Chemically it is methyl (+)-(S)a-{2-clllorophenyt)6,7-dibydrothieno[3,2-c]pyridine-5(4H) acetate sulfate (1:1). The empiric.;l formula of dopidogrel bisulfate is CJdhsC1N02S lliso and its molecular weight is Appendix 3 Page 12 of26

244 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE The structural formula is as follows: f,j(f c 0 II '0 C- OCH3 H./' Cl H,so, C1opidogrel bisulfate is a \vhite to off-white powder. It is practicajly insoh1ble in \llater at neutral ph but freely soluble at ph 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether_ It has a specific optical rotation. of about+56 _ Plavix for oral administration is provided as either pink, round, biconvex, debosse-d, film-coated tablets containing mg of dopidogrel bisulfate which is the molar equivalent of 75 mg of dopidogrel base or pink, oblong, debossed film-roated tablets containing mg of dopidogrel bisulfate which is the molar equivalent of300 mg ofclopidogrel base. Each tablet contains hydrogenated castor oil, hydroxypropykellulose_ mannitol, microcrystalline cejhdose and polyethylene glycol 6000 as inactive ingredients _ The pink film coating contains ferric oxide, hypromellose 2910, lactose monohydrate, titanium dioxide and triacetin. The tablets are polished with Camauba wax_ 12 CLJNICAL PHARi\IACOLOGY 12.1:\le-chanism of Action C1opidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Yn class of ADP receptors on platelets_ 12.2 Pha.rmacodynamks C1opidogrel nmst be metabolized by CYP4.50 enzymes to produce the active metabolite that inhibits platelet aggregation _ The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y!2 receptor and the subsequent ADP-mediated activation of the glycoprotein GPilb!IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible_ Consequently, pjatelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days)_ Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the. amplification of platelet activation by released ADP_ Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of Plavix. Repeated doses of 75 mg Plavix per day inhibit.1\dp-in.duced platelet aggregation on the fust day, and inhibition reaches steady state benveen Day 3 and Day 7_ At steady state, the average inhibition 1eve1 observed witb a dose of75 mg PJavix per day was bet\veen 4()0/o and Appendix 3 Page 13 of26

245 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE 60%. Platelet aggregation and bleeding time gradually return. to baseline values after treatment is discontinued, genera.uy in about 5 days. Geriatric Patients Elderly P-75 years) and young healthy subjects had similar effects on platelet aggregation. Renall yimpaired Patients After repeated doses of 75 mg Plavix per day, patients with severe renal impairment (creatinine clearance.from 5 to 15 mumin) and moderate renal impairment (creatinine clearance from 30 to 60 mumin) showed low (25%) inhibition of ADP-induced pbtelet aggregation. Hepaticallv-Impail'ed Patients After repeated doses of 75 mg Plavix per day for 10 days in patients with se\rere hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. Gender In a small study comparing men and women, less inhibition of ADP-induc.ed platelet aggregation was observed in women Pharmacokinetics Clopidogrel is a prodrug and is metabolized to a pharmac logically active metabolite and inactive metabolites. Absorption After single and repeated oral doses of75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites. Effect of Food Plavi."{ can be administered with or without food. In a study in healthy male subjects when Plavix 75 mg per day \Vas given with a standard break 1St, mean inhibition of ADP-indured platelet aggregation was reduced by less than 91/'o. The active metabolite..a...uco2.4 was unchanged in. the presence of food, \Vhile there was a 57% decrease in active metabolite Cu:.n,. Similar results were observed when a Plavix 300 mg loading dose v.ras administered with a high-fat breakfast Metabolism Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circubting metabolites) and one mediated by multiple. cytochrome P4SO enzymes.. Cytochmmes first oxidize clopidogrel to a 2-oxo-dopidogreJ intermediate metabolite. Subsequent metabolism of the 2-oxo-dopidogrel intennediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet recepors, thus inhibiting platelet aggregation for the lifespan of the platelet. Appendix 3 Page 14 of26

246 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE The Caw: of the active metabolite is twice as bigh following a single 300 mg clopidogrej loading dose as it is after four days of75 mg maintenance dose. 11 occurs approximately 30 to 60 minutes after dosing. Inthe 75 to 300 mg dose range, the phamtacok:inetics ofthe active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0- and 2.7-fold increases in Cmax and AUC, respectively. Elimination Follo\"ling an oral dose of 14 C-labe1ed clopidogrel inhumans, approximatejy 500/o of total radioactivity was. excreted in urine and approximatejy 46% infeces over the 5 days post-dosing. After a single, oral dose of75 mg, clopidogrej bas a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes Phannacogeno mics CYP2Cl9 is involved in the foim.ation of both the active metabolite and the 2-oxo-dopidogrel intermediate metabolite. ClopidogreJ active metabolite ph.annacok:inetics and antiplatejet effects, as me..1.sured by ex vivo pjatelet aggregation assays, differ according to CYP2C19 genotype. Genetic variants of other CYP450 enzymes may also affect the formation of clopidogrel's active metabolite. The CYP2C19*1 allele corresponds. to fully ftmctional metabolism while the CYP2C19*2 and *3 al1eles are nonfunctional. CYP2C19*2 and *3 account for the majority ofreduced function alleles in white (85%) and Asian (9/o) poor metabolizers. Other alleles associated with absent or reduced metabolism Me less frequent, and include., but are not limited to, CYP2C19*4, *5,*6, *7, and *8. A pa.tient \Vitb poor metabolizer status will possess f\vo loss-<>f-fi.mction alleles as defined above. Published frequencies for poor CYP2C19 metabolizer genotypes are approximately 2% for whites., 4% for blacks and 14% for Chinese. Tests Me available to determine a patient' s CYP2C19 genotype. A crossover study in 40 healthy subjects, 10 each in the four CYP2Cl9 metabolizer groups, evahjated pham1acokinetic and ant:iplatelet responses using 300 mg follo\ved by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and diminished inhibition ofplatejet aggregation \\-'ere observed in the poor metabolizers as compared to the other groups. \Vhen poor metabolizers received the 600 mg/150 mg regimen, active metabolite exposure and antiplatelet response were gre.ater than with the 300 rng/75 mg regimen (see Table 4). An appropriate dose regimen for this patient population has not been established inclinical outcome trials. Appendix 3 Page 15 of26

247 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE Table 4: Acti,-e Metabolif e Pharmacokinetics and.-\.ntiplatelet Responses by CYP2C19 l\letabolizer Status Do e Ultrarapid Exten:;ive Inte1mediate Poor {n=lo) {n= lo) {n=lo) {n= lo) CIIWO (n,g/m.l) 300 mg (2:4 h) 24 (10) 32 {21) 23 ( U ) 11 (4) 600 mg (2:4 h) 36 (13) 44 {27) 39 (23) 17 (6) 75 mg (DayS) 12 (6) 13 (7) 12 (5) 4 ( l) 150 mg (Day 5) 16 (9) 19 (5) lb (7} 7 (2) IPA (%)* 300 mg(24 h) 40 (21) 39 {28) 37 (21) 24 (26) 600 mg(24 h) 51 (28) 49 {23) 56 (22) 32 (25) 75 mg (Day 5) 56 (13) 58 (19) 60 (18) 37 (23) 150 mg (Day 5) 68 (18) 73 (9) 74 (14) 61 (14) VASP-PRl) t 300 mg (24 h) 73 (12) 6S (16) 78 (12) 91 (12) 600 mg(24h) 51 (20) 48 {20) 56 (26) 85 (14) 75 mg (Da ys) 40(9) 39 (14) 50 ( l6) 83 (13) 150 mg (Day 5) 20 (10) 24 (10) 29 ( U ) 61 (18) Valuare mean (SO) * Inhibition of platelet aggregation with SmcM ADP; largernlue indicatgreater platelet inhibition t Va:;odilator-srimulated pho phoprotein -platelet reactivity index;!illlalier nlue indicates g1-eater platelet inhibition Some published studies suggest that intem1ediate metabolizers have decreased active metabolite exposure and diminished antiplatelet effects. The relationship between CYP2C19 genotype and Plavix treatment outcome was evaluated in retrospective analyses ofplavix-tre..-:tted subjects in CHARISI\t.A. (n=2428) and TRITO -TIMI 38 (n=1477)_ and inseveral published cohort studies. InTRITON-TIMI 38 and the majority of the cohort studies,the combined group of patients with either intermediate or poor metabolizer status had a higher rate of cardio\rascular events (de.ath, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolizers. In CR.A.RIS!vfA and one cohort study, the increased event rate was observed only in poor metabolizers_ 13 KONCLII\"lCAL TOXICOLOGY 13.1Carcinogenesis, Mutagenesis, Impairment of f ertil.ity There l as no evidence of tumorigenicity when clopidogrel v.ras administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mgfkg per day, which afforded plasma exposures >25 times that inhumans at the recon:unended daily dose of75 mg _ CJopidogrel \vas not gen.otoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene nmtation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice). Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mgl'kg per day (52 times the recommended hun1an dose on a mg/m 2 basis)_ Appendix 3 Page 16 of26

248 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE l-1 Cl.Jl\:lCAI. STl"DIES The dini.cal evidence of the efficacy of Plavix is derived from three double-blind trials involving 77,599 patients. The CAPRIE study (Oopid.Ogrel vs. Aspirin in Patients at Risk of Ischemic Events) was a compamon of Plavi'l: to aspirin. The CL1RE (Clopidogrel in Unstable Angina to Prevent Rec:wreot Ischemic Events) and th.e COnT/CCS-2 (Clopidogrel and Metoprolol in Myocardial Infarction Trial / Serond Chinese Cardiac Study) studies were comparisons of Plavix to placebo, giyen incombination v.ilbaspirin and other standard! therapy. 'The CHARISMA (Clopid.Ogrel for High Atherothrombotic Risk Ischemic Stabilization, Management, and Avoidance) study (n=15,603) also compared Plavix to placebo, given. in combination with aspirin and. other standard therapy. U.l Acute Coronm" S"'Dd.romt? CURE.. The CURE study included 12,562 patients \"t\h ACS \\them ST-el'ation (UA or NSTE:Nil) and presenting within 24 bmus of onset of the most Tec:ent episode of chest pain or symptoms consi.sient with isclj.emi.a. Patients were required to have either ECG c:banges compa tible with new ischemia (without ST-elevation) or el.evated cardiac enzymes or lroponin I or T to at let t\\.ce the upper limit of noijdal The patient population was larrgely Caucasian (82%) and included 38% women, and 52% patients5 yelll5 of age. Patients were randomized to receive Pla-.ix (300-mg loading dose followed by 75 mg onoe daily) or placebo, and were treated for up to one year. Patients also reoa\e' d aspirin ( mg onoe daily) and other standml therapies such. as heparin. The use of GPIIbiiiia. inhibitors was not permitted for three days prior to randomization. The number of patients experiencing the primaj)r outcome (CV death, 11' 1, or stroke) was 582 (9.3%) in the Plavix.-treated group and 719 (11.4%) in the placebo-treated gr01.1p.a 20% relali\'e risk reduction (95% CI of 10%-28"/p < 0.001) for the Pla\i.>i.-lreatedg;roup (see Table 5). 16 Appendix 3 Page 17 of26

249 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE Table 5: Ourcome Ennts in rhe CURE PrimarY Analysis Plavix Placebo (- aspirin)* (+ aspirin)* Outcome Relative Risk Reduction(%) (95% CI) (n=6259) (n=6303) Primary outcome 582 (9.3%) 719 (11.4%) 200 (Cardiovascular death. Ml ( ) stroke) p < O.OOl All Individual Outcome Events: CV death 318 (5.1%) 345 (5.5 ) 7% l'vfl 324 (5.2%) 419 (6.6%) ( ) 23% ( ) Stroke 75 (1.2%) 87 (1.4%) 14% (-17.7, 36.6) Other standard theraptm were ll!>ed as appropnate. The irubndual component do not repre!>ellt a breakdown of the pnmary md co-primary outcome!>. but rather the total number of subjet±i expenencing an event du.nng the coe of dte study. Most of the benefit of Plavix occurred in the first two months. but the difference from placebo was maintained throughout the course of the trial (up to 12 months) (see Figure 1). Fi;ure 1: Ca rdiova >t"ubr Death.:\(yo :udi::-l lnfaurion, and troke in the Ct"R.E tudr 18 CARDIOVASCULAR DEATH,MYOCARDIAL INFARCl10N STROKE l Ul i Lll Ul ;;. 1Z PLAVIX ( aapini)'!i ::I u MOHTHS OF FOLLOW-UP Appendix 3 Page 18 of26

250 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE induding heparinflm:vt/h, illtravenous glycoprotein lib/lila (GPIIb/Illa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of Plavix was obsen.red independentj y of the dose of aspirin ( mg once daily). The use of oral anticoagulants, nmrstudy anti-platelet drugs, and chronic NSAIDs was not allo\ved in CURE. Figm'e 2: Hazard Ratio for Patient Baseline CharacteJistics and On-Study Concomitant ledicationsllntejwntions for the CURE Study Percatt E\-err.s Bil6e:rll!' PLAV1X Placalo ctiafacte!uit[cs (+arir111)" (+n )" 0\ler.tl Dla!JlOSIS ttdml-'11' lln&1/!jiig er! Aqe <65 5!i9fi ;! Genller Male Female -= Race C31Jcas 1DJOII Ele<t earn EfiZy i'lall-ca'iic No ! ST DEilf >1.1lnrn Yes '10 7'll3 7.5 a.9 Yes 52S& =.s D!31:e:a; 1' Yes Pretl1006 r.t 1' Yes <: Pret110Us ke- No 121l> Yes cancornllallt,/lllffi41y HepartMJUWH No Yes Al;pll1n <100rrg D l-2d Jrrg >200rrg GPI.IlllllaAniag No Yes Be-ia-BIOC&er 1'10 2lll Yes ACEI No 4! :9.1 Yes Upfd-ltM-erlng 1'10 & Yes 8101 SA 10.5 PTCA.ICADG No Yes "'Oiler 5IJIKiardE611o-ere I.ISed ar;aj!i:iopr1ale o.a Rallo (95% CIJ The use ofplavix in CURE was associated \"\r:ith a decrease inthe use of thrombolytic therapy (71 patients [ U%] in the Plavix group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPUb/III.a inhibitors (369 patients [5.9%] in the Plavi".X group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of Plavi.in CURE did not affect the nwnber of patients treated with CABG or PCI (with or \l.r:ithout stenting), (2253 patients [36.0%] in the Plavix group, 2324 patients [36.g«/'o] in tbe placebo grouprelative risk reduction of 4.0%). Appendix 3 Page 19 of26

251 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE CO.J\.fMJT In patients with STEML the safety and efficacy ofplavi:x were evaluated in the randomized, placebo-controued, double-blind study, COMMIT COrvtMIT included 45,852 patients presenting within 24 hours of the oncret of the symptoms ofmyoc.ardiaj infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to rereive Plavix (J5 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or tmti.l hospital discharge, whichever came flrs:t The primary endpoints were death from any c.ause and the first occurrence of re-inl'u"ction, stroke or death. The patient population included 28% women, 58% age60 years (26% age70 years), 55% patients wbo received thmmbolytics, 68% w:b.o received ACE-inhibitors, and only 3% who tmderwent PCI. As shown in Table 6 and Figures 3 and 4 below, Plavix signific.antly reduced the relative ri.sk of death from any cause by 7% (p=0.029), and the relative risk of the combination ofre-i.nfarction, stroke or death by /o.002). :E-H!.nt Tabl6: Outcome Ennts in the COl\11\llT AnalYsis Plaxn (+ as pirin) (r\=:961) Phci!bo (+ aspirin) (N=229l) Odds ratio (95Cl} p-\ alu@ Compoite endpoint:dnth, MI. or Stroke 2121 (9. 2%) 2310 (10.m) (0.86, 0.97) Death 1726 (7.5%) 1845 (8.1%) (0.87, 0.99) Non-fatal MI** 270 (1.2 ) 330 (1.4%) 0.81 (0.69, 0.95) Non-fatal Slroke** 127 (0.6%) 142 (0.6%) 0.89 (0.70, 1.13) 0.33 * The differ-ence hbeen the compos1te endpomt and the sum of deaib+no.n-fatal l\..fi+non-fatal stroke mdicates that 9 pa tients (2 clopidogre1 and 7 placebo) suffered both a non-fatal strok.e and a non-fat.lll MI. ** Non-fatal MI and non-fatal troke exdude patients 'l'i-ho died (of any cause). Appendix 3 Page 20 of26

252 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE Figw e 3: Cumulath e Ennt Rates for Death in the COl\11\flT Study ',,., - 17U.. t!m(75lij tel propcnooel risk ntduc1ioo $ llrll dlsdlarge ,-- o..,. 1 a rando 14 J on IIQI 21 2J s..a mju IO 21 d<tysl All treated patients receryed aspui.n. Figure: Cumulatin Ennt Rates for the Combined Endpoint Re-Infantion, Sn ob or Death in the COl\11\llT Study II 10 l>l c.b U10 ill ount (10 '""' 9 a '%. wiwi doath, 7 ralntuclion o r, a ṭ, rọ t k. 1 diac._ re 1 % pt<>flerllonul o1otl reo.. on '" o ocm 2 o y , ll Dllfloln<o!'M'd..,.IJatlon(l.lf> t o 21 dey l All treated patients recetved aspll'id.. The efft of Plavix did not differ significantly in various pre-specified subgroups as shown in Figure 5. The effect \'\'as also similar in non-prespecified subgroups including those based on Appendix 3 Page 21 of26

253 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE infarct location. Killip class or priorn history (see Figure 6). Such subgroup analyses should be interpreted cautiously. figun 5: Effff ts of Adding Pla\u to Aspirin on th > Combin >d Ptimary Endpoint across Bas >lin > and Concomitant l\1 >dication Subgroups for th > COl\11\flT Study Baseline Etents (%} Odds ratio & CJ. eatcgot'mtiofl Clopid Plecebo Clo rcl Ptacebo (22 961) (22 891) b ette : btlter Sn:. rttra_e 7 t :r ttii1h '" : t t.ge I Mtr((yNrt},., cg (-.2'\) lijiio Q" kid 1:1'!'11'\l &:4! 1011\; IJlo.,JI ;t4 1K"") VJ l SSP (mlllh... -,.,. 11''1 ) 1416f' ) tfl)!l) cllll 41t (>II'!.),,t 4'1.) otju!i) l l l{.ll lit,tr U,{tl t\1 Hoorssilte o.-t: l/1{1 1< t;ll {Ill', < !IU '"'{tl ll'o U1J IJ.I dl(, B.fK\.'IU !.tl {I (0!\) Ml II"..J <.:;( 2'\) f'6':) HeW1rate (bpm l'f\l(l\;'\) "' '4)?4f01l ltl 10!11 ( "") 1XG 110 "' Pro po.rtlonal re<l e!ion 110flll ltj0 3J 471) 21 (5. 6,) 0.0(11)) 11k {I r'\) f:>:lf:o' ) 9t-IO 'OC:\1 :1 ''tl{l3:f.., ll'; llh il'(j.. 1'... f.. 11ool)'t C9111V t/tfl! t: t\1 {II.IK\ to-1:' NJ 1119 (ON.)!till{10 '1'<., Progi'IO$fiOlnCitW (1tqUIIg* roup$): GM:l UJ-,:l"J l H'I'Q.1 qo rqj "10" ql-"1) 'r.f''l'\1 I'M4 t)lg (17ti'Q t >'J{18X, MoiiOprolcl e»-11on ITol<ll 7121 {02%.) 2$10 {10.1%) * Blobal H«ei"'g@ lty Testi 1 =IU;p=O' <,::,!l!i'-!cn eln I I <;> 0% 3 tp.o Threemular- iu<l progno ric inde..'c groups were baed on ab!iolute ruk ofprimazy compo:ite outcome for each patlent calculated from baselme prognosllc \-an.ablec; (excluding allocate4 treatments) wtth a Cox regre->sion model Appendix 3 Page 22 of26

254 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE Figurt> 6: Effe-cts of Adding Plavi:x to Ao;pilio in rht> l'lon-prt>spt>dfi.e.d Subgroups in thl' COMl\JIT Study CategoriMtion Kl lp class: I I UJ [I:ny 14b(ll) Mil!lUl(l-& Ill)!; (IG.cr'!:.j P o?ioii$ Ml Yo'oS 1f/[!K.) 2l>t 111 1".-.1 fin 1!144 :ny 7111!l (1011-'J lnal rct location: A112n«IIIR:l [R IN.) 17 fidffi',f 'ltf-1 look 1.0 I&) 1oo:J m :!'lo) ITotal 2121 (0.2%} 10 (10.1 ) Global HotorogaRII )' Tost l-4.1;p. 0 ;1>1 $ <L" g.eorfidcmo lnlq Ockk ratio & C.l. CiofiidOiel P111celio boiler : l>cuer.i Proportional rgiiiijctlon I I I <f> O $E 3 (p = ) 0 0.7& (0) I tl(oli 18( Rec.enrIyocardial Infarction, Rect>nt Srroke, or Lo;t"''lblisht>d Pelipht>ral A.rtt>rial Disea<>l' CAPRIE The CAPRIE trial was a 19,185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing Plavix [15 rug daily) to aspirin (325 mg daily). The patients randomized bad: l) recent histories of myocardial infarction (v.ith:in 35 days):2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of3 years). The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (f..':\tal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were au classified as vascular. Table- 7: Outcoml'.E\-l'nts in the- CURIE Plimary Analrsis Patients Ischemic stroke (fatal or not) Nil (fatal or not) Other vascular death Plavi.'\. n= (4.6%) 275 (2.9%) 226 (2.4%) aspirin n= (4.SO/o) 333 (3.5%) 226 (2.4%) Total 939 (9.8%) 1020 (10.6%) Appendix 3 Page 23 of26

255 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE As shown in the table, Plavix was associated v.rith a lower incidence of outcome events, primarily Ml The overall relative risk reduction (9_8% vs. 10 _6%) was 8.7%, p=0_045 _ Similar results were obtained when all-cause mortality and au-c.ause strokes were counted instead of vascular mortajity and ischemic strokes (risk reduction 6_9'1/o). In patients who sunrived an on-study stroke or myocardial infarction, the incidence of subsequent events was lo\ver in the Plavix group_ The curves showing the overall event rate are shown in Figure 7. The event curves separated early and continued to diverge over the 3-year follow-up period. Figure 7: f at.'.ll or Non-Fatal \-ascular En-nes in the CAPRIE Study f MAL Dlt lion.fatal' ASal l.nt Et EilTS MOiffitS C.: FOLLOI'f.UP The statistical significance favoring Plavix over aspirin was marginal (p=0 _045). Ho\\-ever, because aspirin is itself effective in reducing cardiovascular events in patients \"\ith recent myoc.ardiaj infarction or stroke, the effect of Plavix is substantial. The CAPRIE t rial included a population that was randomized on the basis of3 entry criteria _ The efficacy of Plavix relative to aspirin was heterogeneous across these randomized subgroups (p=().043)_ It is not clear whether this difference is real or a chance occurrence _ Although the C.t\PRIE trial was not designed to evaluate the relative benefit ofpla"vix over aspirin in. the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myoc.ardial inflrction) and \Ve.aker instroke patients _ In patients who were enrolled i.n. the trial on the sole basis of a recent myocardial infarction, Plavix was not numerically superior to aspirin_ 14.3 Lark of Established &-ue-fif of PlaYh:. plus Aspi.Jin in Patienfs with l\iultiple Risk Factors or E'itabli'ihl Yamilar Disease- CHARISMA The CHARIS:rvtA trial was a 15,603 subject, randomized, double-blind. parallel group study comparing Plavix (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis_ All subjects were treated with Appendix 3 Page 24 of26

256 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE aspirin mg daily. The me.an duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite ofcv death, Ml, o:r stroh. A total of534 (6.9%) patients in the Pla'l.-ix group versus 573 (7.4%) patients in the placebo group expetiend a primaty outcome event (p=0.22). Bleeding of all severities \Vas more common in the subjects randomized to Plavi.x. 16 HOW SL"PP.LIED/STORAGE A1\l> HA.'.IDLIJ\G Plavix (dopidogrel bisulfate) 75 mg tablets are available. as pink, rowld, biconvex.. film-c.oated tablets debossed with ''75" on one side and «1171"' on the other. Tablets are pro\rided as follows: NOC <5 NOC NOC NOC Bottles of 30 Bottles of 90 Bottles of 500 Blisters of 100 Plavix (dopidogrel bisult:'lte) 300 mg tablets are a\l3.ila ble as pink, oblong, film-coated tablets debossed with "'300"' on one side and "'1332" on the other. Tablets are provided as fouo\vs.: NOC NOC Unit-dose packages of 30 Unit-dose packages of 100 Store at 25 C (77 F)excursiOllS permitted to C (59-86 F) [see USP Controlled Room Temperature]. 17 PATIEI\""T COl.il'i'SELINGINFOR.l\IA.TION 17.1 Benefits and Risk5 Summarize the effectiveness fe.atures and potential side effects ofpjavix_ Tell patients to take Plavix exactly as prescribed Remind patients not to discontinue Plavix without fust discussing it with the physician who prescribed PJavix Ble-eding Inform patients that they: will bruise and bleed more easily. will take longer than usual to stop bleeding. should report any unanticipated, prolonged, or excessive bleeding, or blood in. their stool or urine Other Signs and Symptoms Requiring Iedical Attention Inform patients that TrP is a rare but serious condition that has been reported with Plavix and other dmgs in this class of drugs. Instruct patients to get prompt medk.al attention if they experience any of the following symptoms. that cannot otherwise be explained: fever,1.veakness, extreme skin paleness. pwp1e skin patches, yellowing of the skin or eyes, or neurological changes. Appendix 3 Page 25 of26

257 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE 17.4 lnyasiw Procedm'es Instruct patients to: infom1physicians and dentists that they are taking Plavix before any invasive procedure is scheduled tell the doctor peffonni.ng the invasive procedure to talk to the prescribing health care professional before stopping PlaviX 17.5 Concomitant Medicariolls Ask patients to list au prescription medications, over-the-counter medications, or dietacy supplements they are taking or pjan to take, inch1ding prescription or over-the-counter omeprazole, so the physician knows about other treatments that may affed how Plavix works (e.g., v.rarfarin and NSi\IDs) [see Warnings and Precautions (5)]. Distributed by: Bristol-Myers Squibb/Sanofi Phamlaceutic.als Partnership Bridgewater, NJ sanofi aventis 0 Bristol-Myers Squibb Plavixis a registered trademark. Appendix 3 Page 26 of26

258 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE Appendix 4a. Prasugrel Package Insert- United States Appendix 4a Page 1 of 17

259 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE ffighlighi'sol'piu!:scribingi!'u'orm. UOJ>; 'Illr<e bi,. b".t o,.,;. ode sjl dlt illloi'iiwia...ted "" F.fli.st moly Dll l&ninly. s..fall P"""'rih ildil...a..r..iflill'll<. 11:l'Fm\rT (pn.s..,.c)<o.hlr1s IJW:W u.s.1\ppr...:l: li!q9 W..uu-r.-c, I!l.aDil'G RISX s...fdjk6«iljdj. iil.ft>nlwfun/11< DfiiJ'lIID:ud...,m,g F.ftiat cua..>t,.._._,&uj, (5'.1.5.:2, udu). Do...ll!f lji>..,illp.&litllc willa amn p1!1toio:xoi blttcliji:or s lmtn].f irseiftiisdll!llir srtod:or so:rob (4.lllllli4 Ia palitllc2!:75 JHn of..,_ Ef&u is:e-l:lllr t"«ll-lllio.t bea'iis oftk ia.cru:ood ri:k olfsul ud iatnauillibihcb ud 1IIIUrUia b<vfit. nupt U.lli iwist politllc (oli.lboi>> o r priw MJ)....,...it> rffoct.,._.,t<> bt:r-«ud m ' Be maybf. <($.5). Do 110< sw-t [lliou:ia. p.11iso IU:l-1) 1D...S.., m coroury <nftt lrypiss!l'"sft -="'Y(C.>\BIG). l\u.pos::iblt,cliscolliaaol!fliolii ij ltssi 7 oi&j's prior ID IllY Sar::«J..o\ddilioulri:t fl<ron for bihclia:' iacboclo:: bodyt < ft pnflftl2qid illtecl COMOIIIi'IJILI...of-<ialioE llasj Uoa...t...ri:ik of Smpo<i blftdilo ia.uypm..t 'IIIIo i< lftcin Dlllu.s rec...tty...s.re.-<anoury.p«n<orlijiit illln'walio (Pa). C.<\BG, oc olber nar:;i<ol proc..t-.ia...sfltia OIC D6nu. 11poaiN.IIIWI.I! f bihdilo:...u.o.;aoajimid: Eiittat. s l!flioat.fw"!kulsrlyia lintrrw -.-b sn.r1.011e ror...,- 'J'Idr-. iarr...,,,..ri:lt.t.c: q,..at<. rdio'o'ccllllor...n(;..n INDICAnO.\'SANDIJS. GE EE-.m " r-y"f lilot illhil:imrutr...d ftho :odxti<mflmmi:>otx ;.:u u.,,,.,,(w::jndin! -:<u tdll:o:ol'!>: h)mpztiomsv.nb ><=:» «!"""'}.s)'diiroma v.!u> L'"O 0> bo -.d'iiijlci ic 6:l.b1n: "'li etm bl" ar.lllld-51' -u:io:l vca:rdwi (N'mMI) (U). p.m..:,,,.::;;, sr.u-.:j::iao UJ)'t>CoUdDl (S1EY.I)'IEhlc odl 'lri Doi: 'borm dll JlCI (lj) tGE A.\"DU'IO.'i ---- ilaitin,.-;m 60 m,;;en bodin5&:.o (:!). ot!d lij!o:>e<> d:>i!y'lri;'; a:v.iilia fcoi!. C<mrlor ) g:"""' lbilymrpatiaa!l "601;g ro. _, d al:;o abilq:itia(1'l "'!1D 32)"'!!) dti!) (Z) DOS. GF.FOIWS.V\0S'l'Rf:XGIBS---- S m,;; m:l 0 g:t>>lito (3) CO -..JU.IIw Fosl tl(4.1)!':iil!r=:.iw todlr<:::ic u:xi:or<'ll'<lko(4. ll!ld.r<! C(. U), ti<!llafef!ild:...--d. c. no W.'IRJ\D"CS:. 0 PRF.CACII0.'\0:---- C. t-& g::;:;::a:,mpuiam mmnin!efioat.& if'""' ' somt1!uo:abctoc, MI.w dod(b) AD""F.ESI! Rl!. C'IlOl'\S BI id<: Ii!,.. OIId &a:kis thom> <CGIIIIDimly nopcomd om""" to><"""- (6.!). To npo<t stspf.c'l'jid AD\'E&Sl:RL C.:l'IO.'\"S.,.. <ICE!Eli Lily Dll Colllf uy It -811$.St5-<979 or FDA It.a.FD..<\..lts!or Sft 17 foe PA'IIE?\'T OOuMELU"'G11\"l'ORM..-t1l0i'\i ud:u..lioaiio Gailo FUlL l'rescribil'i'g ORM.>\TIOS:CO!IITENI'S W-'.IJ!.'.\11\G:BLDDDi'G RISK 11\l>IC.UI0.'\0:-"D US.It.GF. 1J " CaaJW)'Sy:.±umo 2 DOS. GF.. "\DADl.lll'n"IR.TIO:'i l DOSAGF. FOIWS. 1\ID S'IRI!'IGTRS 4 CO.'\-m.ID1>IC.\DONS u Al:1M6 - PC..- J.<l.mtkmS"""" 5 W;\Rl:\r>"CS.:U".D PRF.C.otL"JIO\S S.l Gmml iti:.t O<iBI S. 9:m='J }L""'7" Ga5 Sur;,.,y Raluod Blwclins B IXl<<rnltnnuxo c:a5w H Ihumbo:;o 1lu<>omocp:<;"'mt!'r 6 AD\l!:RSE Rl!. CDONi 6.1 C1iaial Tmll 7 DRUG DiT I R.-tCD0.'\0: 1.1 w.ma. 7.2 Non-5UJ!t!O.dal Ani Iln!' C<==Jitmt Modi!Ziam S t:se V'SPECII'IC POP'IJ!.A1liDI"S 8J!To!IW"Y S.3 S.4 Nlr- ::\.-,; :Po. m:ir u,. s.s.u.. f'""""' l6 LO'a-llod1U.oi., 11.1 Rlcll II.S!.9 M<abalic. S:r.:s 10 OVERDOS. GI!!OJ Sp! u:::d S) 10.:! R.o<iLbout Spoci.5< 'l'lw.:aoat ll DL5CRIPIIO.'i 12 Cl»>lCAL PR. 'tcolog\; 1:!.1 l>lochmi.=ofamlm 12.:! IW:=coolymec 12.3 IW:=c. ll.s lw:=cc!ta<tccl IJ ISOJ\<J.d:.\'IC..U. l'oxjoologv 13.1 em;..,...,-1'...i:.. df.ruity 14 Cl»>'IC.U.STUDI!S 1 HOW!>L1PPLII!l),'S1'0EAGI: A!>"DILit..'\l>Ul'G 11 PA1lE1 it Gl>UJ'\J:>TOIWATIOl' 17.1 a.c.st. mdri-.k 17. Br-Eng 17.3 o:-horsieu md.m..r:c.:.!h rmnn. li.s CC!DCoe=t Appendix 4a Page 2 of 17

260 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE 2 FL"IL.PRESCRIBTh"G L'rrOR..U.UIO:l\ 2 3 W <\RNI!IiG: BLEED.INGRISK 4 Efli.mt c::m ca Se cant, sometimi!s fabl, bihdiag [see Wll1'llin,v and PrUtm.Iio1U (5.1 il1ld 5.2) and Adn:rs/8..Jlr<Jt:non5' 5 (6..1)]. 6 Do not list Effiot id p :ttioh 'lrilb acfu"t tbolopcal blor :a history of trusitllt.iscllemic :atbck or- strob [s'ee 7 C.onmrmlfiCilliom (4.1IHid 4.1)). 8 ID p:ttiots 2: 75 yhrs of al!:t,effient is :: ner:ad.y :aot rkobkaor tilt idcn:ased risk or fatal Uld illtrarranial. 9 b:aad nncertaia bmelit, acept id hi;h-risk situtiom (p:ai:h-uts'lrith diabetes or- a history of prior Ml) wlw:e its effk't 10 apptars to be ue:atu aad its list may be codsidtrtd {r.t't! U5'e in Specijfc: PopldJU:iotu (8.5)]. 11 Do not stju1eflifllt id tiots lib.ly to D.Ddtr"go argot coronary arte:j'}' byp:lss gn.ft surgery (C.U!G). Whea possible, 12 disco:atinlh! Effimt at least 7 d:ij"prior-!o :my s t-ij. 13 Additional risk factors for-billdudt: 14 body t < 60 k;g 15 pr-opellsity to bleed 16 co:acomit:mt 11St of medications flla:t idcre lhe risk o.f b(-e-,wa:rfari.d, bep11rid, fibriluilytic tllhapy,du-ooic 17 use of noa-stuoidal :mti-idflammatol")'[1'saidsi) 18 Snsped blill D)' pat:it:a.t 1l'ho is hypoteusin ud has H<eutl} nnw ::oue coronary upogr:aphy, perclllaus cor-onary 19 illten-.:ation (PCI), CABG, or olhu surgical proctdllns id theseofeffient 20 H possible,m:m.'lbwithout discoutiaeffie:at. l)is(outidllieflitut, particllbrly ill tht first few -ks 2fter 21 :Kllte corod:ii"}' sy11drom.illcn:asi!s the risk of subsequmt cjmtianscubr ft' {su Wand Pr«-l1ll.liom (5.3)]. 22 U.l>ICATIO:SS AND USAGE Acllleo Corollllry Sy11drome 24 Effii5indica.:ed to ll!duce lhmte oftilrombotic c:mfio \ asrular (CV) l!'i"l!id!l (" dstem thrombosis) id pad.en15 with 25 aciite conmary S)Udn:me (ACS) who are ID bell!l!uiaged wnh pertnwli!<kls COl:llmi)' imen emi.o:n (PC!) as ifollcm.-s: 26 Paliems wilb llllst:\ble :mp (UA) or noo-st-ele\1\tionmyocardial infalction (NSTEMI). 27 Paliems wub ST-ae\ lilioll:myocanlw i:d.f:m1i011 (S'IB«) v.ied lllllllllged wub prim:!ry or delaypci. 28 Effie:!K!Ia> bem silov.11(o reduce mern.of a cambioed eix!poiijt of c:ardicw-...;:cu);u- destli, oonfaialmyocardial illfuttio:n 29 11),or 1101Ifa.W siiioke c ompa...-ed co dop100grel The diiffueol:.e bl!twe:ntreamlell15 'lli:li dl:i1.-eo.predomimllllyb) with no 30 dlfferulc:e C!D strol."i!s :md linle diffbl'ell<:loo CV death [s"g Clinical SnJdiQS (14)}. 31 liis ge,:nemlly recocilii!ellded that!wipla:elet menpy be admitlisrued py m thf! lllllllllgeiiii!lli of ACS bec:au;e lll3d}' 32 c::rn:li "a5cillar cxcrur nilbin hams of initial p:re5elltltion. Inthe clfnkal ti:i3l that esrablish!!d me effic!c) ofefiiiml Effi.E!II! 3.lld 33!be comrol were 110t adl!linister!!d to UA,NS"TR>U pad.enl5 UDJil corcm.1ry :ma:rowy "'"115 estlbfor the small frllctioo of 34 patil!id!llbat required urgi!dl CABG after tre:ll!ili!llt nim Effi.ent, thri.!.k ofsigoific:mt bleeding Wli.S Sllbst:!lltial [sw Wamiand 35 Pr«.al.... tions (J.2)}. Becau;e lbe qe lll!ljorityofp:uieouare lll:!diiged. ll>itholll CI\BG,llowe\-er, treatmelll em be coll5ideredbefore 36 detej:mioi:rl.:g c:orao:uyllllll.!omyifoeedforc. Gis ccm;idered lllllikl!l). Thuges ofearlie ttuim<>..ot witheffi:m mnst tbeo 37 be bal:mci!dt thilx:reased rate ofbleedmg in!x'lil!id!l v.:bo do l!leed to lll:ldsgo mge!!ll CABG DOSAGE AJ'ID ADMI!,ISTRATIOS 39 hlitia:e EffiJ:m treammit :.;. a single 60 mg oral load:i!lg dose :md!hen coiit:ijme at 10 mg or.illy oore daily. P:ttiems t:!kiog 40 Effi.E!II! sboold. also we aspirin 05 mgto 325 mg) daily [UNJ Drug hl::aacti011s (7)and Clinit:m PkamiDt:o-i<Jgy (12.3)}. Effiem lll3)' 41 be OOmillister!!d nub or witbout OOod [sclilfkal P (11.3) ard Clilfkal SnJdifls (14)}. 42 Dosiog i:d L<m Weigl!! Patiems 43 Compared to pad.en15 -eig!liog60 k;g. patiems v.-e<60 kg b.-.1 -e :m ilk:rea;ed E'lpOsu:re to tibe aai"-e metabollie of 44 prasulllldan i.dae3sedrisk ofbleedli!!g on a 10 mg onr.e dailye dose. Considerl.Gweillgtbe m::!:ime:tw!ce dose co5 mg 45 in jl(llil!id!l <60 kg. The effectiveue»sod safety of the 5 mg dose b!\ e ool beed prospeai\'ely smdied DOSAGE FOR. 1> S'IREJ'\GTBS 47 Etfil!lll 5 mg is 3}"ellaw,elonga:bex:!.gcx13l, filln<oated, oon-scored tablet di!oossedwith "5 h1g"on one side :mel"4760" oo the other side. 4S 49 Effil!lll lo mg is a beige, ted be. oml!, :film.-ooa:ed, uon-sc:ored t:!.bler debossed wilh 90 MG" oo one side sod v.mn 50 "4759"o:o me omer side CO'i'!IR.'\Thl>ICATIO:SS Actin Bl 53 EfiiEJJJl is cmm:tindica."edinpatiems v. 1h aah'e! p:ubolo-gjcal blsudl. as pepnc ulcer or inttacr.uiial bemm:rllage [sw 54 Waming:;mrl Pr«.maions (5.l ) and AdHrr.i" l.k:oictions (6.1)} Prior TnDSiut lscbudic - or Strob Appendix 4a Page 3 of 17

261 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE 3 56 Effim1 is coo.'.illllldocmed io. patiem. wi1h a!listory- of prior tt:msiem isdlemi<: all:ick (TIA) or make.. InTIUTON-TIM! 38 ro AssessImPra>eroent in Ill OmLomes byqplimizing Pla:elf!.l InhibitiotLith!lrasugrel), patiems v.ith a histmy of 58 TIA or isdiemic make (> J lllldll.lhs prior co enrollment) hld a higher mte of Slroke OD Effimr (ci.a; of wtlkh 4.2% were lhrombolic 59 make aod :u. We e intracr.mi.31 hedjrrb.age[ich]) th3ll OD dopidogrel (1.all dlrombotic). lll patiems itlrow sud! a history-, 60!be idcidedce of sttoke was 0 9% (02olCH) 3Dd 1.0' (O.J% ICB) "ll"illl E.ffiem aod dopidogrel, re>peeth"ely. Patiems ith a histmy 61 of i;cbemic stroke "1\'i:thio. 3 montm of screenillg aod p:uiwilh a lllir.ory ofbi!m.j.'1:1:13gic SII"oke at my tim; we..-ce e:x:ludi!dfrom 62 TRITON-TIMI 38. Patiem;; "1\mexperieoce a sl!oke or TLJ\. while on Effient geiernlly sboii!ld h:we lhe:!py discolllinm.ed {LINl 63.4dl-.."RRa&rions (O.l) andclinicoj Studi(14)) WJUU\L'IiCS AND PRECAtriiOSS GeDB:al Risk of Bleeding 66 Ibienoopyridillei, idd!ding Effient, illcrea5e m ruk of bleeding. With tbe c»;mg regimens usedm.trito:m.n 38, mn 67 (Th.rombolysis ill Myocardial biful:rion) Major (clinically 01.--en blassociated with a fall in bemo,globill 2: 5 g'dl., or il!lttacnmi.al 68 bemonb.age) aodid?>.!inoa" (o\-ertbleeding:woc:irued"l\"illla full id hemogfubio of 2: 3 g.'dl. bom: < 5'dl.) bl e\"ellts wexe 69 more c.oil!llloii. oo Effi.ent1hm OD dopidogrel [.wtj.mt.!tuu;jkarnoru (6.1)). The bleedmgrisk is liighst fllitwiy, as sbowo illfigure 70 1 (a-enl5 lhrough 450 da) s;illse,t sbowse!\ Elll5 7 days) Clopidogrel J , 3 Nl.unber at nlk: z ' f ) J / I r r , - I 1.z li l Days from Randomization Efnent &74t Clopldogret 611S 8042 ecj Fit 1: No:a-CABG-IWattd md lajor or Mmor B.IHdiD!!: Enllts Suspea bleeding id my patient who is hypoteos:iw :rnd!j.a> recem!y lllldergooe coro:muy aogiogra ly,!lci, C.<WG,or ofuer 77 smgiml procedure;ena if the pa!iem does oot bsn m-en si,gm ofbl 78 Do 1101 use Effient in patiems ith acm e bleeding, prio:r IL"'- or SII"oke {sllfl C'.omraindic.nriom (4.1 and4.1)}. 79 Othi!r risk facton fo:r bleeding me: ' Appendix 4a Page 4 of 17

262 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE 80 Age 75 yea."s. Because of tire risk of bleeding(faml bleeding) and uncemin. effecth"9ei5 in patiems yem of age, usofeffien; is ge:!leilllly oot recommill tbese p:uieot;;, except insitu:;.tioo.; (patient> \\ith 82 mabetes or hh"1dry of myoc:lidi:al inmrc:ti011) '11tilen! its afec:j appe:u;10 be greater aod its nse lll3y be ccm;idel'ed [s 83 -drustl Rmcrion.r (6.1). 11.;(1 in Sp«iftc Popularions (8,5).Clinical Pllann.uolotJ (11. 3).and ain.iull Triah (J.I)}. 84 CABG or olber swgiclll procedure [:11 Warning;and Pr«.aution:; (j.2)]. 85 Body \\";ight <60 lq. Co:nillE a ID'11tw (5 mg)mtiml!ll3llce! dose {Ulf1.Do:;agtand.Mminisrration ()).Adnzr'.Al 86 RIMKrions (6.1).U:;t m S]x.-cijfc; PopWmi<NC (8..6). 87 Propmsi.t) o b!e <1 (g., recedt!illllm3, recmt surgery,recem or recmrem gnstroimestimal (Gl) bleeding, acm-e pepllic 88 ulcer dise3.si!, or se.-ere bepalit: impa.imlem) [.-lti>'.111:s11haaions (6.1) and U:11 in S;Korijk PopWmi<NC (3.8)). 89 ).femcatiom tbat illc:rm5e the risk of bleeding ( g., oml 3lliicrogullmts,cllrollic nse of IJ.OD-sterotdll :utti-illflmd:!l:!.tcuy 90 d."'lfgs [NSAIDs], andfi.brinolync agem;). Aspirin andbep3rin. '11tc CimlDOD.ly usedin 'IRITON-IThll 38 [sh Drug 91 lnimtiaion.r ( - Clinical Srudi(14)). 92 IbieDopyridille> LD!ubit platelet aggreg;uion for the lifetime of tire platelet (7-10cbyi), so v. thho ding a dose \\ill oot be 93 useful m giag a bleedillg 1!".-em or the risk of "bll!ediog :mocia-:ed wim :m im--a.m e procedllre.beamsem half-life of' s 94 aai --e metabolite is shon relati\1!to the lifetiml!of lie pla:ell!ol, N may be posiible to restore!jemost:k;is by administering aogemm 95 pla.:effis; bowe..-ei, pl:arelet lir:!ll5fusicms \\ilhia 6 b.ou:rs of m lo:ldiog do5e or 'I homs of the =.imejl.'llice dose may be less effea:i\-e Coroury Artery Bypass Gmt er} -Rftatfd The risk of bleeding iii!lcreased in p:atiems ll!cei\ing Effient v. bo I!Ddergo CABG. If possible, Effiem s!jouldbe disc Oiltimled at least 7 d3y;; prior to C.o\BG. Ofthe 437 p3tients v.ilo u:!lde vreol C.o\BG during TIUTOK TIM! 38,the rates of C.I\BG-rel:aled TIMI1-fujor or :'>fillm ble ding ""14.1, a in the Efiiem,group :md 4.5% ill the clopidogrel group {;11/l.J.thw<".AlhaaiON (6.1)]. The lliglru risk fur ble ding e.'ell!s in patiems tr!:lled with Effiem persisted up to1 days from the most ll!ci!lll dose of study drug. For patiems ll!cej!,illlg a too l01 l02 l03 l04 l05 l06 l07 los l09 llo l11 l12 l13 l14 l15 l16 l17 l18 l19 l20 l21 l22 l23 l24 l25 l26 l27 l28 l29 l30 l3l l32 l33 l34 l35 l36 l37 l38 tbi LidiD2 \\ilhid 3 days prior 10 C.I\BG, me e> of IDH Major or mwr bleedillg were 26.7'+ (12 of 45 pati!llti) illme Effiem group, compa.-oed v. th 5.0, 0. (3 of 60 patil!ll15) in m dopido,grej group. For p3tients who reci!iwd theil- last dose of tmenopy:ridid2 \\ilhin 4 to 7 days pnor to0\bg, ihe fn!quenrie> d;!creased to 113% (9 of SO pariems) ill the p=grel. group and H% (3 of89 p:!rie!dis) ill the dopidogrel group. Do 1101 stan Bffient ia ]X1tie!ll5 likely to Ullder,go urgeat CABG. CABG-felated bleedlng lll..1}'be trea:ed \\ilh lr3iibfus:iod of blood product;, indudi!!g padred red blood cell;:md pla.:elm:hcm-et.--er, platelet lr:ul5fu.sioli.s v.ithin 6 homs of!be lrodiqg dose or 4 hours of the mamtelliadce dose lll3y be less decti\-e. 5.3 Disco:aiinuatiOD of Effiellt Disc:omi!me lhieti.oj'yii s, induding Effiem, for actin bleeding, e!ea:i\-e smgery, Slroke, or TIA. The oprim:ll dtlmtioo of tbi lidine tberapy iiullbiov.u Ill patient!'11t11o are lll3lw!ged '11t th PC! 3lld stem placelm!llt, premamre clliamlilluatioo of llllliplatelet tioll, illclu:lid,g thi.enopyridine;;, COII\1!}> 8D ilx:re3.;ed risk of 5Wit il:irombosis, myocmdial idjiucti.oll, 3lld death. Prieots whopremarure disco:oriimaticm of a thil!llopyridime will be :u io.aeased risk for c:u-diac a--ems.. Lapses ill t:hentp) should be a\-oided, 3lld ifdlienopyridi!ii!s Dlll5t be Y cllicominuedbeanse of ad.:jjfyer-_,e a-en:(s),!bey should be as soon a.> possible [SC'-Q Co11I1Ylindicmions(4.1 and 4.l) and War'l'll1lp and Plw4!ni<NC (5.1)] Thrombotic I'brou:lbocytope-nic P1up 1.n IbrolJ!boti.c il:irombocytc pmpum(tip)h-is been reported wilh m me of olbn thielwpyr.idillles, some.iimes afrer a brief (< 2 weeks). 1TP is a serious condmon ilw ammml aod require mgmt trea11i!.ellt, ilx:l:u;cfiog pla=pberesi> (plasma e.uh:mg,e). TIP is d!2l:acterilli!dby lhrombocyrmicroangiopa:hi.c hemolytic :m!!mia (5Cbi5tocytl!5 [fragmem red blood cells] seen on pe.liplleral smear), neurological findings,rellal dys1i:lllaion, 3lld fe\'n. 6 ADVERSERE..o\CDONS 6.1 CliDicalTrials Experimc The following serioiiise ruaiom :ue also cliicu;.;ed elsewhere ill the labeling: Bleeding [::«BoxmWtm1171g cmd W g; cmd l'r«-nulion:; (j )} Thlumbotic th.'"ombocytopl!llic parpam [s«1 Wt11?1ing:; and Prwaurions (5.4)] S3fsy in p:uiem;v.litll. ACS Ullder,going PCI was e\-..lloated ill a clopidogruc..cmmolle:l. stody, TRITON-TTh1I 3!,in which 6741patiemi WeJ-e u-eated \\ 111Effil!lll (60mg loadin,g close and lgmg once daily) for a mediad.of 14.5 mooths (5802 patiems '1\'Efl! treated fur II\" & 6 l!idi!llb5;4136 jlcltieswareated for roore tb:m 1ye:u). The p<jpu!atioo reated with Eftient wo: s 2:7 to 96 } 35 of age,25% female, m:i92'j.o Caucasiao..olli patients in tbe 'IRITON-1111!l8 study were10 recm-e 35pirin. The dose of dopidogrel in!!us smdy \\'lli a 300 mg loading dose m:i75 m,golio! d:!ruy. Becal!Se dinic.a.l trials are cow:hktedunder widely \c:cmditions., ad!.'e!r'sl! r!octi.an rates obsen ed in m diniclll trials WIDOt be directly compued v.'ilh the rates obsm-ed inother clinical trials of aoot!ler drug and lll3y oot reflect the rates obsen ed.in p:arnce. Drug Disc:ominuation. The rate of smd) dmg cfiscomimla.liod be<ause of acfl;-ez5e reactiom\\1!5 7.2,o for Effian and 63% for clopi.dogrl Bleedin;g was the mo;z Carnma.JI ad\s se reaction leading to smdy drugdiscomimlatioo for both(2.5,.for Effi.E!Ilt aw:i 1.4% for clopido,grel). Bleed:io!: 4 Appendix 4a Page 5 of 17

263 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE l39 l40 l41 l42 l43 Blumlfg llnnlmlld to C!BG SUrgilr) -1m. TRITON-TIMI 38.o\-mill Ill."ES of IThll fajor «1\lfuwr bleedim.g adl."e!'i reaotiaos U!Irela:ed to caromry a:rt2!)' bypass gmft sur,g2!)' (CABG) were sigmticmtly bigler on Effieot thad on dopidogrel :;,; W'l'iU illtabl Ta!M 1:So.cABG-Related(TRITOS-m n JS) Effiult ClopidognJ p-l" llt ) (\) C"f.(l) C "f 6) TIMI or ar :Minor bleedi!lg p=().002 TIMI jor bleedlng" p=0.029 Lift!-mr teninl!! Fabl s lll.lmci':!lli:!l h rrhage (ICH) R.equiring iootropes R.equiring sureical imm-emion Elequ:irinf!('>4 Ullfu) 'fll\.ll moor bleedij!ot' p=().022. Pao.en.ts may be copiillli!d m DDre1h:!ll one row. Set!5.1 for dmnition. l44 l45 l46 l47 Figure 1demlmstrn:es oo:rcabg relati!d. mil Majoe- or tinor bli!edlng. Thi! blrate i;hlghe;l initially. a; shcm-n i:n l48 Figme 1(IILSet:I>.-.ys 0 to 7) {m.? Waming;sam.PNc.autions (5.1)]. l49 Bleedi!!g mes ID p:uieot; \\i.mme rut; mcro:rs of a gl!75 )'-ejrs aod w gbt < 60 kg are sbol\-n in Table 2. l50 l51 T31M 2: BlRatesfor Jli"oD-CABG-R.ebted by MajorlMilwr WeWlt add. e ("IRITON-'IIMI Fabl JS) Effi.ut Clopidognf Eflifllt Clopidop-tl () ( ) (") ( ) Wl!ie:!U < 60k{!; (N'-308 EffimN 356 cl l52 l53 l54 l55 l56 l57 l58. Weie:!U60kg (N=6313 Effiem, N=6299 dopido!1el) e < 15;-e:m (N=5850 Effient, N5J!22 d ido!1el) "' 0.1 Age75 i"e!m {N=$91 Ef!i.enN. =a94_dqlido!!jel) LO 0.1 Bl«dirtg RWtiJd to ClliG- In'IRII'ON-TIMI paliellis wbo l"i!c eda ibieoopyddine uoderv.-entcabgdur.ii!gtlle caune of the study. The rate of C.!BG-reliari!d. TIMI Ma1or or tin«bleedingv.-as 1-U% fur tile.etf:iem group 2lld4.a inme dopidogrel group (Table 3). The higbi!r risk far bleeding ad!."e!!:5:n!acliom in parient!l treari!d with Effiem pemsti!dup m 7 dayfrom the lll05t I"I!CW dose of study drog. Table 3:C.l\BG-R.ebted Bltoedi.a,_. (IRITO -mn.38) Ef:!i.tllt ( ) Clopidoutl <"> (Jii"=2ti) C"f=214) Tlllrll Ujor or Miloor bleeclijdg Tlllrll ujar bleedmg 1U 3.6 Fatal Reopenl.ticm l Til!IIBfnsion of 1lili In1!111011!1ial hemoa11a?,e 0 0 Tlllrll llil«bleedine; l59 PaD.en.t!l may be COIIlll!i!d m. DDre 1h:!ll one row. l60 l61 Blfg RqJortiJd a:;.kji.gr.;tj &actions - a-ems reponi!d a; a& e;rse re.aaicll!l5 in TRITON-m!II 38 were, for l62 Effienr luid c.lclpidogl'el, respecti\ ely: epista:ti(6.., 3.3o), gd.siii'oid.iesml.al bemorr:b.'lg!!0.5.',1.0'1 ), llemopcysi> (0.6%, 0.5%), l63 snbcmalleons bema:olll3 (0..5%, 0.2%). j)ost-procedmal bemolrll:lg(o.;,e,0.2,.)1 retroperitooe:ll h llhage (0.3'e,0.2,.), 3lld l64 retil!lal h ntag(0...0.u.). l65 M'1li nx:ies l66 During TRITON-TIMI 38, De\\"ly diag QS!!d g;naocies Wm! reponed in1. and 1.2,.of paliem;na\\i.m pra;ugr:el. l67 aoddopidogre.l, resp«li\"!ly. I*sites comnwtingo I!Je cliflmllces were primarily colon and luijg. It is IIIId!!arif se obsen"".ltions a..-e causally e!ated ar are r.mdam ootnm!dces.. l68, Appendix 4a Page 6 of 17

264 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE l69 AmEven l70 Ill1'R.ITON-IDfi 38, COilllllllll811d oilier impol'lllllliiod.-bejuol:rhagjc a&.etse 1!05 were. for Effient aod dopioogrel, l71 respeaively: s:e>.111rcmjbocjtopwa (0. 06'+, 0. 04,.),3lleuia (2 2'%, 20!-o),abo0llll21 bepalic funttion (022., 027o), :illergic l72 n!aotiocs (0.36 o.,0.3 ) 1:md aqgi.oecsema (0.+, 0.04,.). Table 4 sm:nm:uizres me adverse e.-em; npott!d by at least 2.5% of l73 pcltiellll!:. l74 l75 Tablellio:a-Hemorrb.a'TrnfmtDt Emu-u.t Adnne Ena.fs!Uportfll bv at Least 2..54il of Pa!Ma.ts ill Ei:f:lier Groap EffiEDI (%) Clopldogrel r- > (N=6741) (N=6716) Ei}'J)mmsiO:J. 7.) 7.1 es lemia! 7.0 H Headoclle Bock pain ) D)>pa!B ) Nausea Dfzzmess Cougb H\"J))Cel!SlOll Faligue NOIKMdi3c chest pain "U:rial iiibrillalion B ad)-c:rn:lia 29 2A I.eukopeai3 (< 4 X 10 WBO'L) Raill Pyrexia PeriphenU e<ena P:ril!lme.maml!)' Diardiea l76 l77 l78 l79 l80 l81 l82 l83 l84 l85 l86 l87 l88 l89 l90 l91 l92 l93 l94 l95 l96 l97 l98 l DRUG n."'ieraciioi".s 7.1 W2ri2ria. Co3dmi:nis!lllliOD of Effient a!ldv. mmm iocrelses therisk of bleeding [:Qfl Framing; and Pr«.aunOn:;(5.1) and Cliniazi Phtmrtac.o 'otj (12.3)]. 7.2 Noii-StH"oidal.U:ti,IIIfbmmatory Dn1;:s Co3dministr:ilioo of Effient aod NS..4Jlli (u5i!d chronlcally) may incll!ase the risk of bl{:unwamillg;>: and cautions (J.J)). 7.3 Otllu- Coa.comi.ta:D.t ll.!fllicatioas Effi lll CSil be a ; th drug; that are illlhll:ers oinh:ibitors of cytochrome P450[::N Cli1lical Phtmrtaa!WtJ' (12.3)]. ElffiEM CSil be ad!ltini,""ten!d ;m aspirin (75 mg to 315 mgper day),heparin. GPllbliiia inhibitors, swill;, digmin. aod dju?s!hal ele\"ste g:jomic ph, including pro:on pump Wn.l>im15!!lid H2 blocki!i:s {Wfl Clinic.al Pkarmac.o!ogy (113)]. 8 USE IN SPECillC POPtiL<\TIOXS 8..1 PT Pl'ef""'ncy C&ef!on B -There :ue DO ::dequate!!lid well<ontrolled. studies of Effiuse iii preg!llllll women. ltepnxfucti\"e aod de\'1!lopmemnl ta:tico ogy srudies iiimis al!ld rabbits at ddsei of up r.:o 30 merec OIWill!lldedlhi!n!peul:ic e:xpo5lm!s in lnirn:!n; {based ao plasm3 exposures to me lll3jor cirmjali.llg inlmallm&bolite) revealed no l!'lidence of fetal harm; ho -e\o'l!f, :mimal srudies are DOt alwsypn!dlcri'l;-e of a!mm.3n poll5e. Effient should be used dm:iijg pn! llliilty ooly iftbe potemial be:j.efu to tbe mjther justifies me potential risk m the ferns:. m emli!lyofetal de \ e!opment:ll toxkology srudies, p gi!st IlllS :md mbbin!cehed pn!sllgll!l at ma:emal.ly ta:ric oml dose; equ:i\11lem ro lllldtl!th:!n 40 time51be h=e'lposure. A sj:ighi clecre:l5e ill pup body wei:,ght was obser'l'"ed; but, tbele were DO sttucturaj malfo:rm:uions meitber specil!5. 1n prena:nj aod pos1didlllnt 5tudies, mtemlttm1m llt ;mh:ld no area on tbe beha\iaml ar reproductive d!!'i ejopllll!m of the offspt dlose5 grea:e,r than 150 times ibe h=e."':p05lll'e {:llit JVonclinical Tozicciogy (H l )]. 8.J N MofhHs II is110t ktxn\u '1\ibe!her Effient i.> e."tcreted illlnmlm milk;hollo-e.'et,membotitesofeffiem were fimod. in mt milk. Becal15e m:my cf!ugs are e:meted id bum3n milk, pra511,grel sboold. be usednmsing aaly if me po:em:w be!leiit ro me motber ju5tifies tbe potential risk co ibe ml"sing ind.mi. 6 Appendix 4a Page 7 of 17

265 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE ts PtdiatricUs S:liff>l}' :!lid&lkth-elleis inpedb.ttic p:uieot> lm"'e! oot bee! estab!:ished {SH Clinical PhamltiGOI'ogy (123)]...utru u fuiriton-id_fi 38, 3S.5o of patient;"l!.'l!rl!5 year!i of age and. 13.2o \\'e!l!75 YE!:3I5 of ag,e. Theri.s1: of b1 illcreased wilh adv(!;llding age in both rmtruent groups,al.lhrugt the rebti\-e risk of bleeding (Effie,m compared v.ith dopido,grel) was smtilal' across a g.e groop5. P:ltiSIL1575 yeru-s of age v.'!io receinrl EffiCDl bad w i:dc:re-..sed risk of fatal bl!<'-i ems (1a) compared to palien15 v.w IKei\ ed dopiclogrel (0.1,.}. Inparien1575 yem of age, 5}1llp!Onl3.lic ilitmcr:ujial OOnontage oc.ciim!d ill 7 pltieoo (O a) \libo IKei\ ed Effil!lli Slid ill3 pariem (O.l%) who r:ecei "ed d idogul. Becau;e of the risk of bt..aeding, l!lld beuuse dfeclivelll!ss i;: II:!ICennin mpaifems75 years of[sh ainic.alsrudi(u)), useof Effiem is genernllyiiiot ik.ommended inp:rtients,!!piin higb-ri5k :silu3rion.s (dlabete;and past!ji.,"'!ory of myocardial ima.."ction) where ils effect appe:us to be grej!a'and i15 use m: y be co:nsid!!red [W11 WamingJ: and 17YzcBliZion;;(J.J).Clinical Pl;ormac.o!ogy (11.3).l11ld Clilliml StJidf(14)} LowBodyW t futiuton-tl\fl 38, 4.6% of patie= cr&tedwith Effient had body weigln <60 kg Indi\idaals v.i!h body weight < 60 kg h3c:l 3ll illcll!ased ri>l ofbleedin,g and an i'llc:re:&;ed U'p()SllR to the acli...-e metabolite of(;;qq Doaag" and A.dmini&trrm<m Wami am PrtK.aurion.: (5.1).tmdCiiniroiPhamrac.ology (J'J.S)}. C :!ISider 1CI'i\memamre!l3lH:e dose ro 5 mg inpatie= kg. The effecth enss and safety of!be 5 rag do5e ha\11! nm been py srudied 8.7 Rmal lmp:lil:mmt No doge alljustmenl is necessmy for parie= 11olith l1!llal il:npclimll!m. 'Ib!!!'e is limited 1!3:pE!lience ill pa.liems"!!.i1h end-5tag;! 1l!llal disease {;H C/iniml Pharmlxology (1J.J)] Hpatic lmpairmmt No dosage adjtlsi!ilellt is :aecessary ill pat:i.enls 11o<ith mild to ll!llldern:e hc impaimjem (Child-Pugh Class A 3Dd B). The p!l:!ml:!cak:illetics :!l1d ph.uu!.'lcodymlltics ofin patiiems v. th se\'e!re hepauc disease l:m e 001been srudied, but such p:uien15 aregene'311) atrisk of bleeding {s«1 W tmd J>n>cm.uiollS (5.1) t111dainic.aj nurnmxo!ogy (J1.3)}. IU M tabolic status fuhe3lthy SQbjeas. pa.tiems 11o<i!h st:lb1e alberosderosi;:, :!l1d parien15 v.i!h ACS recei\'ill,g pr:ll.5\lgrej, there was no rui!i.'i!iit meet of generic vilriatio!l incy'y.! 6,CYP2C9. CYP2C19, or CYP3A5 on the pba.'lji:lcokioetic; ofp el's actn'e! membolite or ils inhi.biriqll of platelet ag ioll. 10 OVERDOSAGE IO.I Sipls add Symptoms Pl:mole,t illhl'b:i.lioo.by prasugn!l. is mpid l!lld il:re \ er;ful.e,for the life of the plm!!ll!l,and isud!.ikely to be idaill the e\'e!lll of an 0\'erdose. InIlllS,lethility was obsm ed aft& admiws!mrion of 2000 mglkg. S)1llilComs of :licute tooriciry in dog,s Wcluded e:t:neiis,idcre1;:ed semm alkalille pbaspkuase, :!l1d hep3iocellul1r :mopby. Symptom> of acute tolticu) ill nm idcjnded mydrias:is, im!pll3r respiration. decre3sed locomo:or acmicy, p:osis,5'u\ggerin,g gait, :!lid lacr'im:!tiod RKollllllM!a.chrions aboa.t SpKi:fic Treatme-nt Ph:!!lei II':!ll5fusian llli:iy re=redo1ring abili..'. 1Thepmsugrel. acme membolite is oot likely ro be!'e!lllo'\i!d tj.y dialpis. 11 D.ESCRIFilOS EtfieM comains pm;ugrel, 3 thil!iwp)'iidi.!le c.las; inhibitor of pliatelet :octi\'11.1ion and 3ggregsrioll-ma:ed by the P2Y12.IDP IKeptor. Etfiem i;: fuj.'!lllllated as lhehydrodiloride s:lih, aiocenute, v.11khis dlemic:illy desigllaltedas 5-{(1RS}2<yclopropyi l -{2- flwropbellyl)-2-a: :oe!hyl]-4,5.6,7-mrllhydrolbieoo(3,2-c]pyj:i.di;n.-2-y1 acemte hydrochloride. Prasugrell:rydrochloridehas the empiric:ll fojmula C O,S RC!repre;ei ting a mo1ecnlar weight of The chemical structure of pillshydrochloride is: m Plasugre.l hydrochlcride i;: a white to poetically 11otri.te solid Iris soluble at ph 2, slightly solub1 a1 ph 3 to 4,l!lld pract:ic:illy illsollll!le atph 6to 7.5. It :llso diisolves free!) illdlf!thaool andis sl:igbdy soluble in l- l!lld2-prop:mol3lldxe,;one. It is p!'8ctic:ally illsolnb!e io dil!lby1ether and efu}i acetate. EtfiSILr is ar.illab1' e for or:ll a "trrltiod. a.; 5 l!r\g or 10 mg elo a:ed B&goD31, fiilm-< o:rted,lltl'll-stmed mb1' ea, debossed 011eadi side. Eadl yellow 5 mg mblsis llll3llll!actw'ed v.il:h 5.49 l!r\g prasugrel hydrochloride,equi\'3lem to 5mg Jli'8Sllgl'el Slid e:d. beige 10 m,g rabletwi1h mgl hydrochloride, equ:i:nla1 to 10 mg ofpnrn gl'el. During m:m.ufacrure md. stonlge,p311ial con -ersion from prasugre-1hydrochloride to pmsugrel fr! base =y occm.. Other illgredieot> illc:lllde IIWl:!l.itol, b} llose, Appendix 4a Page 8 of 17

266 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE crosca."lnnillose sodium. microcjysmlline cel.lulose, and,,'i!g;!table magnesium ste:mue. The colu coacamam!acrose, bypromellose, li1:!nim:n dioxide,triacetin. iroo.oxide yellow,:mdiroo <Etide red (ollly ille!i!jl!lll 10mg mblet). 11 CLDilCAL PIL<\R\. 'IACOLOGY U.J MerbDiism of Action gri!l i5 :minh"lbit ar of pb.telet aai'l."atian :mdtioo tbrrugll themreisibte bidding of its atm-1! metabolite totbe P2Yn das; of ADP l!fkoi'5 on platelet;.. U.2 Plwmacod}'llmlics Prasugri!l prod!lc:es illhibition of platelet ag;regation ro 20 pm or 5 JL'\f ADP,as me3silt'edby l:igbt a:msmission a ometty. Follo'l\>it.!; a mg loading do;e ofeffient. approximlately 90"./o ofpatienis had at least 50' + illhi.bition of platelet a :ufcmby I bour. tromum platelet i:nlllbition was abom 80%{Figuri! 2). Me:m Sl:l!"..ciy.sm:; i.ibi1fon of plai:!ie>j 31ggregation \\'8.5 3boui 7a following 3 to 5 d'!) s of dosin:g 3.ll0 mg daily after a 61}.mg loading dose ofeffiem : 80 :g at 710! aṭ 60 5:0 ḷ c. 40 Mean :I: SO I.IMADP I. Ḷ : 10 0 :e - 10 :!!.1: -20 c ZD Z2 24 Time 1hour) Ft 2:lllhibi.tion (Me) of 2011M ADP-indllced Pbteltt - tion (II'A) MusliRd byt Tr:msmission 270 omttry 1ftu Prasu tl 6Cl Phi:!l& a :uioo,grndmlly re:,ums to baseline \-aloes a ;er 5-9 da)'-s afur discomilmlaticm o prastgrel thl; time com:se 273 being a re,lleaionof new platelet production nnbenb.:m okidaics of!!l Disccmtilnmlg clclpido,grel75 mg :md 274 illitiariog pl'li.sugl'!l lo mg v.ith thi! lll.ela dose l'l!5u!ted illi:dcrmsed i:n!ubidon of pla,i!ie>j aggregation, but :oot gn1a:edl.1n tint [}J>iaill}' 275 pro:luced by 3 10mg main:en:mce dose ofprasugrellilcme. The relationsbip betweeo.illhibitian of platelet tion :md d:illical 276 acmity has 110beeD escab!isbed 277 U..3 Pblrm:Kolmle-tio 278 grel i5 a and is rapidly met!.bolm!d to a p!mlm:!colog;iaill)' acm:ell!iio:abolite :mdmacm:ell!i!om.bolite:i. The 279 aai'l.'e!!lli!taboli!i! h:!.i :metimill3tion. balf-life of abow7 boors {nuige 2-15batlls). Re:ilib.y Sllbjects,p:uiems wub. stable 280 atbe.rosderosis:, :md )XIti&lS Ullde!'goillg PCI sjxm s:imili!r pkumacokidmcs... lb:iorpfio11 cmd Bintiil!g - Following ocal administratioll, 2:. 79% of the dose f.> absoroed Tbe absorption 3lld metabolism :U'E! rnpid. '1\>i!h ped ph;ma c oncemruion;(c_j of me aai1.'e tru!tabolite:!pp:rorinately 30 ntimne; after do. The aai"l;'l! 283 meabolite's!!:xposme! (AUqincn!ases slight!)' llllm! th:m pmpon:iomlly 0\-er the dose range of mg. ed daily doses of mg cb noc le3d to accurmnl:ui011 of!he1kri.-e tru!t.abolite. In a srudy ofhe3lthy subjern gi1.'61a singj.e 15 mg dose, the AUC of tbe 8 Appendix 4a Page 9 of 17

267 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE aaive metabolire was ummecred by a high!ill,big!calorie mew, but C... was decreibedby 49% :md T,... was increased from0.5 to 286 L5 houb. Efiiem am be av;ithool: regard1d food. The acti\ meabolite is boimd abom 98o to humm serum albwuia 287 Mlllaboli.rm and Elimination - Pmsugrel is DOt detected in plasrn.1 followillg om! ad:mi!llstmrioll It is mpidly!lydrolr-ud in 288 & ill:eslille to a. thiolaaon!!,which is mencom-e11:ed to &aai'lo'l' metabolliby a smgle s-tep, pcimarily by C\'PJA4 3Dd C'YP'..B6 :!lid 289 to a lessere.'ttmtby CYP2C9 aod C:YP2C19. lbeest:iautes ofappareili volume of disttibui:ion afl's active metabolite raoged 290 from 44 to 68.L :md me estim:l:es ofderu:mre ran,from 112 to 166i.Jfu in bi!althy rubjecl!i aod paliems with. stable 291 atberosclerosi.s. The acti\ lite i5 metaboliu!d to m--oina.cm clmlp<iiiild; by S-:memyla1ion ar codjug;.tian with q5teine. The jor illacti\-e metabolites are hi,ghly boumi 1:1pla>ma proreills, Appro:tima.:ely 68,.of the pm5ugrel do'..e is excreted id. the 293 m-ille i!lld 2 in & feces as ill: d:h-e metabolite> Specffir!>qpulotiggs 295 Plldiatric - o.kine 1irs aodpharmlc.adymmics ofp Jm-eool been e\ tedin a pedi.alric pop!la.lfcmfuyj UsQ 296 in Sp«ific Populations (8.4)]. 297 Gmalric -Ill a sllldy of 32 healthy subjecjs bennen the age;of :!0 3Dd SO}'em,ge bad no sigdi:ficant effect m 298 p!lmn&okinetics ofpn!silglel' s actire m!tabolite or its imln"bilii:jn ofplati!let aggre,gation. [n TIMI38..w mean 299 me (l!.uc) of the oom:e:membolite-a'3s 19%inp:uielm75 ye:rrsofibm id.plliil!llts <l5 yea:rsofage{t-m Wam 300 md Pr«.aulions (5 1).Rtltxtion:; (6.1). and UsQ in ilk Populations (8.5)]. 301 Body Wmghr - The l!lli!:ulej!p05wi! (AUC)to aai'lo'e metabollieis appmxim:ltely JO to 401o higberid subjecantitlla body 302 wei,gbt of <60 kgt1w1in those weighing 2.60 kg [sdoa.agand.administrazion (1). Wtmli7Jg;s and rauri(lf!s (5.1),,41Jignp 303.Rmctions (6.1), and L".:-" m Spc-cjftc Popultrrion!i (8.6)]. 304 P oki.netics ofprnsugrel' s aai\-e=tabolite 2:resimila:r in men :md WOOll!ll 305 EtJmicir;y - E.iD subject; of African 3Dd Hispruric descem is simiw: ro dl3.l id Ca.. l:d clinical plwmmoolo,gy 306 srudies:, after adjustillg for body weigbt, me AUC of the acti\ e metabolite vi-as approxim.1(ely I higher illchinese,jap:mese, i!lld 307 Korean swljeci5 lhml.in Caum>lan snbjem. 308 Smoking- Pbarmat:atmedcs of pm;ngru s aai\'l' nmsbollie are si:mili!r id. Sllld eis :md IIOllSll!lQkss. 309.Rimallmpaimrl11fi - Pharmat:akineti.cs of pr:uogrers aaive metabollie aod its in!n"birion of pla:!!l.l!l a garion are simila! in 310 pa.til!llls \\<ith lllodel'ate rem! irl!pa.irmen1(crcl=30 to 50 mlimin) and healthy snl!jecjs. Ill JX11iflllS wim end stage renal disease., 311 e.to the acth e metlbolite (both c,..and A:UC(O-t... :o '1\<-:l<i about half ih:u incooo-ol.> i!lld patients 'i\titll:moder:lte rl!ll:!l 312 t {t-im [4Q in Sp«ifl.c Populations {S.7)}. 313 H'!]Xlric lmpainm;ru - l'lmm.1t:akinedcs of pm;ogrel'saai'lo'e me.:abol:i!e and illhibiriod of platelet a g gregatiod -awe simiw ill 314 patil!llls 'i\ th mild to ll!odemre hepo.tic i:mpainnmt t:to healmy sobjecjs. The okinetics :md phar:mkadynamics of 315 prasugrel' s actin:me.mbolite in p:lliam wuh se\we hepo.tic disease han DOt bee!ilstudied [""" Wam111g;o and Prromti(lfls (5.1) and H 6 U.:-tJ in S]»cfftc Population:; (8.8)}. 317 Om:lruo>moiqns 318 Po.'tllltial j/jr Othw ro J..f!«i PmsugrJ 319 lllhibftors qfcyp3..4- Ketocoo:!ZOle (400 mgdaily). a selecti\ e:and poteotill!u"bilorofc\'p1a4 :mdcyp3as, did:n«meet 320 p-asugrel-mediated illli:ibitimofplatele.i agregruion or lhe acti\ e metabolite' s AUC md T...,_, but decreased the c_ by 34% to 46%. 321 Therefore,CYPl.". m!ubitars sod!as,-pamil,clilt:i= illdma\ir,dprofloxac:in, da:dmromycill, :md juice :u-e e:ocpeaed to ha1-e :1 am effect em the pbarmat:okineti.cs of me a.ai -e metabolite of prasogrel [z!n!i>n«1nt4l7't1crions (7.3)]. 323 ofcjrodircimtjs P4JO - Rifampicin (600mg daily), apcwil illdlllce.rofc\'p3a. 3Dd C:YP2B6 mdan induice.r of 324 CYP2C9.CYP2Cl9, 3Dd CYP2C8, dld 30t si,gllil'iamliy dwlge the pha_'m:icalinetic; of I' s actn e :me.labo!:ire or Us i:nh:ibition 325 of platelet agre.garion. ore, known CYP3A iddti:ers such as rif!:mpicin, autr.,mazepille.. :md other id.ducers of 326 C}"tod!ro:mes P450 are oot expected to tm e signifiamt effea 0::1 the plwmmt:aki:nedcs ofac:ri\-e metabolite of prmogrel {:ulfl Llni:g 327 buuactions (1.3)}. 328 Drr.g; tlstr.i:.' vrt-'1ga..71'ic; ph- Daily c.o:!<t!d:inistnttion of roniridine (anblocker) or l:msoprnz.ole (a proton jlwijp inhibitor) 329 decreased lbe c_ ofthepaafl.'e metabolite by 14% 3Jid29.,,IE5pi!CI:i\'i!.ly.11m didootdlallgfthe acm e:msmbolite' sauc 330 aod T Ill TRITON-mil38, Effient was admi:nistered "iiliout reg;nd to c.o on of a. proton jlwijp inhibitor or H:zblader H1 [;{'Q Drug Jmi?rQCri01lS (7 3)]. 332 Srmins- Atar\11Stacin (80 daily). a drog me,mbolized. b) CYP \4,did 001:ili& the cokidi!lics ofp1"8511\!;!"el's 333 aai'lo'e metabolite or its in!n"bilionofplatel.et :;; gadon[$w.dn.;g lntoric;rions {7.3)}. 334 H'!JX11"in -A sillgle illmri."ejlous dose of11ilfmot:iollatedhep:;j:in (100 U)did oo:signifiaml:ly :ll:e.r t:o:j,.gola.licm or lhe 335 prasugrel-llll!!diated i:nljjbitian of pla:elsaggn!g:llion; llov.--e er,bleedillg lime was illueased comp:!zed \\<ith eithi!r drug able{stj!i 336 Drug Ilfluaroon:;(1.3)]. 337 Aspirin - Aspirin 150 dally did DOl al!bt p -mediated.inlnoitian of platelet lion: howe\"er, bleeding time w-:1; 338 increased C a:mp:!:!ed \\<ith either drug alone [u11 Drug bttuaaions (13. )}. 339 Warjbrin - A sigllificam p:olcjiiigati.ad of the bleedin,g time was obsen ed whelip!1isllp"e) wa; t:a:lldministered "idll5 rug, of 340 warf:!j:in [.:- Drug Immxrions (11. )]. 341 PD<mtia!for1'1mJ<gN! to {ff«tothadr!.i;g;:> J42 In \irro metabolism stndies de:momtt:!.te lhs:t ':;m2ill c:imllametaboli:es :u-e OOllikely to came diniailly 343 signifiamt inhlbition.ofcypl"..2,cyp2c9; CYP2Cl9, CYP2D6, orcyp3a, oridductioc!lofcyp1a.2 -orcyp3a 344 Dn;g;.\kraboli:!ld CYP2JJ6 -Pt:l.mgrel is a '1\<-eak idhl"bit«a CYP2B6. Io he:ilib) subject>, decreased 345 to bydrm..-ybupropioo, a. CYP2B6-mediated metabolite ofbtqlropion, by 23%, an amoiill! oot considered dillically Appendix 4a Page 10 of 17

268 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH INSTITUTE S n 6 o 9 m sigo:ifiaml Pn;ngrel is na antitipa:ed to hasi.g;uiti=effect oo tbe p almacokidnfcs o cfru\!? that are primarily meabolized by CYP2B6. sucb as h3lathaoe,q "Clophospbamide. propoaod Dl!\iraploe. l;.ff/lct on Digarin - The porential role of pllb-ugrel as a P.gpsnbsmne v;:.;ddt enhnted Pmsugtl!l is Dot :m illhib:itot of Pcgp, as di.gom de.lillllce '111-ai!IOI. affected by pra:;tigrel coaclrmilli;tmtioo{sw.dn;g lntllmcrions (7.3)]_ 11.5 PharmacogooJDics There is DD relevant effect of genetic vanatioo id CYP2B6, CYP2C9,CYP2CJ9, 01 CYPJA5 on the cok:illlmcs of p-asugtl!l' s actin> membolite or lis iiohibttioo of platelet ation. L3 NO:SCLUiiCAL TOXICOLOGY lj.] C:a: omis, Mub uesis,impainzlf-nt of Futility Cmrinog 1'11Kiis- No co:mpouod-!1!-h:ed tmoor> weore obsen-ed ill a 2-ye:n-Ill.! stuciy \\ilh p:r-...;ngel ar ornl dose;; up mgo'day (>I 00 times Il!C!hempeutic aid lnm!:u!s (based oopl.:is'!m ap>5ui1!5 ro me major circnlalillg hruolo. membotite). Th&e 'I!.IJIS an increrued incid<>..oce of lll!llcin (hepatoeellul:!l' adeoomas) illmice exposed far 2 year;10 bighdoses (>2j0 limes t!le bl.lm:m metabolite e,xposure). Mn m Mi; - gtl!l w:ulicii gen«ollicm m-o ini tro tem (Ames bacterial.gene lll!lt!tioo cest, cla.stogwdty assay id Cbineie hamster fibroblasts) alld id. Olll!in1-M(at (micrijdjjdeus test by mtrsperitoneal rome io. mice). lmpairmtml qf Fmflio - Pr:!sugi1!] had no iliea on feniliry of.d!3le :md female r:lls at ornl doses t1p to 300 mg 'k:'day (80 time; the lnlm.:m lltljor oretabolite l!ltposure Illd3.il} dose of 10 mg pr:asurel). 14 crna.cal STIIDIES The dillkal!!>idel!ce foi' ihe effl!cti\ueis ofeffil!lll is derived from the!riton1-tl\fl 38 (1Rial (0 Asse.u!Jupro\--ement in _!henlpemic OnI: OII!O!S b}'qp!imi:z:ing Pla:ela In!llb:itiwi1:!1. Pr-..;ngru) stndy, a 13,608-patil!lll,II!mlticemer, ill:!!rnatlooal, modomi:z.ed, double-bliod parallel-group S1ndy compatimg Bffient to a repme;a. of dopidagrel, each.to aspi:j:illsod other SWld:ud thernpy,illpatients 'IIIithACS(l:A, NSTI:h.11, or STEM!) woo were 10 be ed wi1h PCl. IWldomizstion wass!r!lliified for U!VNSTh\0:aod STii fl P:ltieoo 'IIIith UAINSIEMI pnsenling \\itllill 72 bour5 of symptom onset WeN CO be nmdoollzed after I!DdergoiDg Cora!W)' mgiogn;plly. Patients 'III th STEMI presenting '111-iihill l2 horus of symp;am Oll5et C auld be r..ndomw!d prior to coromry mgiogrnplly. P:l.lieots \\ilh STEMI pte51!nring bem 12 hoo:l!i aod I'I days of sympoo!!ll anset wete to be!l!lldamw!d after llllllhgo:iog c.oro:wy mgiogn!phy. Patients tllldern-em PCI,sod forbo1h UA'NS1'Ebin aod STB.\0:patiEIIm, the l.oadillgdose was 10 be admini;;t&ed anytime baweed r:!lldamization and I bour afta-patiem left the c:athet. eriz.alioolab. lf pati'iii th STEl\-il v.-ere trea:ed \\ilh tmombolytic therapy, r::!lldamizgtioo could.1110i occur I1Dlil at least 24 b= (fm teoecteplase, retepla;:e or al'teplase) or 48 hours (for kimse) after IE thrombolyuc '111--:l.i gi\ en. P:ltie,ni!S were l'll!ldomizl!d to recei,.'e! Effielll (60 mg loodlog dose followedby 10 mg ome daily) or dopidogi'e!l (300 mg 1dose followed by 75 mg ome daily). 'WUb.admil:llstrl!tion aod f'ouow-tlp for a mimimm.m of 6 mollih> (:a:ctiw medlan 14.5 molllh;). P:ltie,ni!S also recen ed aspmo ('15 mg to 325 mg ooce daily). Other lb!!t.l.pies., sudl:u bep:l1io and i:nlr:ivelooiiis glycoprorein Ilb.'liia (GPifu'IIIa) il!lbj.dt:on were admll!i5tered at the of metre:ilillg physiciao. Ornl aoticoo:gtiliuus. 001& pla:el& il!lbj.dt:ors, aod chronic NSAIDs v.-ere 1110t :illov;ed. The pc:imaiy on:rame lll.l!a5!lll'e Wli.S the c01llp05ite o:fc:11dio>'8scu!ar de:lth, IIIOilflt:!l:tYil. odo!ifastroke illme UA NS:1EMI populatioll. Succe;s in tlii.; group allowed :malysis of tbe s:!iile eddpoilll io. tbe o\-eall ACS :mdsid.il populalioii:i. :Koofatal MI.; induded both11-!is de:l!cted solely ahrougb :malysi;of Oi!llline lrimse musde-br:rin(ck- ffi) c:h:!nge; :md clioically appa..'1:llt (m\o-esm;gatohepomd) hfu. The pa.tiem population wa:> 9'2% C:l.ucasiao. 26o female,:md3o ;:65 year; of "ge. The me.diall time from S}1l!P:Om omet to smdy drug admillis!llltion was 7 bour5 for p:ui!!d15 \\ilh S1EMI md 30 ruts for palieots wiili UAINSTE.'.fL - tely 99% of pg.tiems tiddem-eiu PCL The study'i!.ijis admfu:dst&ed after me fin corcmary guide'l!oire was placed id approely 75% of pg.tiems. Ei!iliem sigllifkantly reduced roral ellldpoim events compared to c.jopidogrel (s"" Table 5 ll!ld Figure 3). The lion of tot:ll. e:odpoiot 1!\'E!!IiS was dt:f.-en prillwily by a decreaie id Illlllfilial as.ibo!b mose ocam:illg euly (throug)l. 3 days):md later (afta- 3 days). >\ppidximate!y 4lna of Mis occurred peri-procedm:ally sod v.-ere detected solely by c =, illck"m. Administnuioo of me dopidogtl!lloodillg dose In IRIION-TIMI l8 '111-:!B d<>.layed relam e to t!le pl3cebo-com.lioued IIial;llhat suppon!!d lis appro\"ll1fur ACS. Effiem produced higher rn.:es of dini.cally sigoifiamt blg!!=dopidogrel illtriton-mti 38{;«.dthws11 Rmaioro (6.1)]. Choice ofthempy requlre.;bala!x:iqg these c!uference;inou:come. The tre3ttl1ejl! effect of Effieot 1i\11S app;uem 'lllithio mefust few ds)s, and perllited to IE e!lld of t!le study (Fi.gme 3). The illse. sbmn result;m'e!t me fust 7 days. 10 Appendix 4a Page 11 of 17

269 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE Clopidogrel UA/NSTEMI 11 ::2: _,..._., s,_...,-- -- c - _,.,..- "#.._.. 9 r-' 0 c Q,),..li: 8 / Effient.c. /....!::,- I 7 le fl) -(!) / / 1 IJ) c: js '0 6,_ I I c 5 (.) 0 l C'O... > 4 0 ].Q "E 3 p=0.002 l P"'0.017 < I '., , Days from Randomization ' 11 Appendix 4a Page 12 of 17

270 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE wo c# -. 9 o- c Q).. 8.r; O rolil 7 I Q) _., (ij "'js 6 - c :::1 0 5 c (!) ".'_0 3 (!) 0 2 STEMI p=o 02,_ - _,r l2 Clopidogrel _...,,.- _,_--- /-- 'J,_.Jr- ' r s UA'NS!E..'fi popul.atioa tbe curves c 10 di\ ere tbrougbow tbe 15 maoth OO!low-penod Intile STEMI popu.ljcron. tbe W6 early sep:lll!rioll wu III.3IlCtined tb! 15 mo:ub follow-up period. bm!ben WIIS DO progessi\1! di\-e-gece after the firsi few W7 weeks. W8 Bfiem reduced tbe occunence of tbe P!m.liY composite endpow comp311!d 10 clopidogrel m both the UA NS1E'and W9 STEMp!oplll.mons(s""Table 5). Inpmems ""bo sm\n1!d m cm-snny myocardw i:l!:uo:ioll, tbe lllci&oce of subsequent n"'l!ms tl 0 W3.5 also lcm-er in the Efi- Ul tl2 TabJ. 5:PaO.nts1ritla O.tcom Enllh (C\" DHtlt.,!.fi,Stroke) illirito-tnll 38 Pat:iots with t'\"rh From Mpbn-MftB uah"ili ffient Oopido:rel IWatin Rnk RHactioll < r p-nblt ("} ("} (95..-cn U.VSSTDJI N=60.U :S=5030 C\" de:nh, DOilflual ::-.n, or DO:o!atal stroke ) CVcleath ( U) Konf3ta!MI ( ).001 Kon!:3cal Stnlke : smn N=l769 N=l 765 CV dea1ll, Dllllfa:lll::'-fl, or DOllfatal stnlke ( ) C\" death { } Konbta!MI H (5.2, 41.2) 0016 Kcmfatal Stnlke ( ) o.n. l 2 1 p=q.oob ' Days from Randomization 1 Fn 3:Time to first nut ofc\" dufll. MI,or strob(i'rito TD.n 38) 2 W3 ro-t tm1e m tile G"A m."!dfi aod S1E'il popul.ario. In bo:h p<lplll:uions, tbe curveswt:hm the em few hours. m the W5 The Kapl:m-Meier am-es (Figure 3) sbow m pmn:uy COIIIpOSlte eldpotm of CV de3!b. DOIIf:atal MI.. or DOIIfil:aJ stroke 0\"er Appendix 4a Page 13 of 17

271 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE fl4 f15 The efi"ect of Effieot ill,mjou;s is shou.'dinfjgures 4 aod 5. Re;ults are generally coosisteot acrosspre-specified t16 snbg:roup;, 'l!i;th the exceptiac of patients ith a.llistary aftia arstral!;e{sk' Conrmind1cm:ioru ( U)]. 'Ibetl"e:l!Dlelll em.ctv.-a.s t17 cbiven prim:lrijy by a redl:lction inco:cfallll «The l!ffi!cl inpariem;?.75 years ofwas 3il.so somev.tm 5malll!l", :md bleeding rut fl8 is higher illtbe5e illcfi\iduals (:.w.ld>.._t:!uactioru (li-j )). See belowfor malyses ofpattieol5?_75 y-=s ofag;!wubrisk f:lctoi>.. fl9 Basellne Characteristt.cs N 'i='ercent Events O ERAI.L-IlM<!iTEIII... - Etroonl CIQpi<Jo9rol 10014!U 12.1 u 10A ' l 10;1!15 "!:71' " 1- 'IU 16.1.\.... C.n.t.,...,... :wn N lo 13!.0 «rwo.-, 40hll > t.j ;:40kl to!sit 9.l 11.1 RAg loft lio:...1hafi ta 15S8 u 11t, Unhi<IS- ml 'IZJ W'"[[l.-n &-or-,. ẉ u u '".. &aulhnmr1u Elllt.mEutatM' nc 133 u 15;2, 13 t20 Drt.a,.. illllilltu :ton... ""..,. 1 Yil! u U i.l Pr.-:.utt CABO.,... Uf &:2 l!o t11t u , - 1\0 11:< -!&16 U.7, ; ȯ...!ll.l' l.. atwarp.- Drl.,..llt ;!: l &:ns IO.t - ""' ' ' t- 11!1.. l!iodof...l'ld l'o lett u 10. -$"'"*""" 'rat olli U Pl'*\lli(M,I:tMI.,.. :101$ 12-t 1$.t I!Itt u 10.1 "" Prt: tijilel Pr.wouo TW5Uol<a YtH os 1U 1U r...f-j'"'*"'o...c -;.,,." u 10.a ạ.:..,.ḷlllltaionly'. DP'IIIIll lnhiwtih' U :1 l).l e.a 1 Har.ard Ratio Effient better Clopidogrelbetter m F4:Subuoup :malyse-s for time to first en.:at of CV dfllth,mi,or stroke (BR md95cl; TRITO)Il.I1\fil8) - UANSTD.Il Patil!llts.. t22 t23 Appendix 4a Page 14 of 17

272 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE -!, "., ".,,...!T5 y "",.. IU Baseline Characteristics N Percent Events OYLRALL4TU!l """- EIDNit ClopldOQfl&l 30,. WI I ZA I IH UA II'.I lu7... ll.l :r :rm JT.2 U. l IU JoOII... "'" Ụ Ị.Sbltl,_. IU WII...IOUV,PI tel :I,.., n... - "".. ""' Yoo IDA Dll... I>.I , l'rwwtau1cadg Yoo II,... IU 1.1 GP tli..._u '" _- BMr 11'16gt1t Milllllbaill:!l..._ Prntclu1TliUS4roMI nn.rnxn SJft'J*mt On..t...tlMI!I. : nọ... IU u IU I Z.I b:a.tlr:ll uuz,... IU llliiiiii'igf WDdd... lu IU l l.l IU 1.1..,..,... l....,..,... I Z..I.!,12 ft a a..-.lld an t' - r,.., IU,... IU, y.. lu,.., n.l' lt'11 ll.l m IU r- I Ill 11.2 IU []14 ILl IIU IU -t o-s_ Rio t24 Effient ber Clopidlogrel better t25 F5:SabuoliJI anlyses for time to first ennt of CV deat.ll, MI,or stroke (BRmd CI; TRITON-Innl8) -S"ID!I t26 Pa timls_ t27 t28 Effienr isy oonecomm.ended inpalients?:;75)ll!a."soh,ge.!!pi in bigh-ii;k sifll:iiions (diabete>mellims orprior t29 Ml) wbiu effea appears ro be gibater :!lidi3 ll5e! may be amsid<>-il!d. 'Ihe5e reco!l!jm"'nd"'iolls m1! based 011subgr01q> 3.ll:!.!yses (Table 6) a:od lllll5l be intezpre."ed '1\idl amtiod, bw 1bdat.1suggest!bat EffieiJ! rechces iscb.o.m:it 1!\"!mS in such p:ltiel!g. f3q m t32 Tabl6: So11p -l or r to First Enut or CV.!Dutil,!.D,or stroke: PatitJ als < or5 Yen-s of Age, ± Diabetes, U3 ±Prior History' of!.d, All ACS P:atif.llt:Populatioll Effimt Qoe] N "with N {) with HuardRatio p--"-alll um t\"dis {95%oC1) A. e 5 Diabete> - ';""ei (0.42, 0.97) Diabete> Ll ( VB) NS A<75 Diabet6 -}""ei (0.58_ ) Diabete> ( ) A7. 5 Appendix 4a Page 15 of 17

273 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE Prior«- Yl!S (0.47, 1.09 ) 0.12 Priorg (0..80, 137) NS A. :e <75 Appendix 4a Page 16 of 17

274 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE t34 B5 t36 U7 t38 t39 wo :t41 :t42 :t43 :t44 :t45 :t46 :t47 :t48 :t49 t50 m t52 t53 t54 t55 t56 t57 t58 t59 t60 t61 t62 t63 t64 t65 t66 t67 t68 t69 t70 m t72 f73 t74 t75 t76 t77 t78 f79 0 m There v.we 5 few!!! 5tent tllrombo5e; (9o C.l 32' - 64o;p< 0.001) reponed 3lllDIIg pariems randomized m Effiem (0.9, }1hm llll!dllgpa.1i!l!is randomized ro c:lopidogrel (1.8%). The diffum:e auaifested early :md w:umailltainlhrough tm }'ear of follow-up. Wl!!e sfmllar v.ifu 00..'"11! metal and -ellrting em.. llllluton-tl\fi 38, prreduc.ed i;cbemjc e\'l!ms (maillly oonfu13111js) luidincre!3sed b'lf!ding e.-en1s (s(h}.-l.til:-..11 &actions (6.J )] rejam e to clopidogru. The filldings are c.onsis'. JJI with the illtellded greater illhi.biri.ao. of platelet ag ticm by jl05ugvei a.1 tbedo>e>used ill the srudy {:a ainical P1ttrrmfXo!ogy (l2.1)]. ThH!is, blm-e> a,:malte.'!pwwi<m: botb. (ld5ugvel l!.llld dopidd,g "el an p1ha.lllllb-t be metabolized to their actin mois es. WbereJs lhe okil!lero of (ld5u' s a.cm e:m!aoolite a..'"e! wt knlm-n to be mectedby gl!olletit \'Jriatiom incyp2b6, CYP2C9, CYP2C19,or CYPJA5.the p!lmn!lcokil!lero of dopidogn!l' s acth-e ll!:!!tabolite :=affi!cledby CYP2Cl9 gi!lldtype, =l.appraximgtely 10% of Cau::asian;; are reduc.ed-membol:izen. {oreo,w,cmain proton pump mbibiton, "'idel>' used in1m ACS pa.liem popl]arioo lllld used ill'iriion TIMI 18, inbibit CYP2Cl9, thueby decre:lsillg foil!latioll of dopidd,g:rel's actin metabolite. Tim;, redlt:ed metabol:izer sm1us 3lld use of procoo pump inhibit= lllil}' diminish clopidog;rel's :!.Cri.\ity id a frn.ctiod.of tile popolatiod, and 1113Y hm:e ccm:tn'buted to jl05ugvei'.s greater IIl!alll!lem effect illld. t& bleedimg mte illtriton-11\fi38. The e.." JJJ towbicb. lb.ese fac:ton were opemticx131, bo\\'i!>'l!l",is lllllmlmu. 16 HOW SUPPliED/STORAGE Al\D K.U\DLING Effima (pmsugrel) 5 mg is supplied as a yellow, elo.c,gated h!!l1.gon:11, film..cooted, oon-sc.ored tablet debowith "5 {G" oo one side alld v.ifu. "4760''on the oth<er side. 5tablet;, are supplied 3.5 full.ows.: Bottles of7 - hdc Bottles oflo - NOC Effiem (pmsug "el) 10 mg is supplied 3.5 a beige. elooga:ed he.'t!lfihn..coated, DIID-SCored mble sed \\oith"10 {G" 0111 ODe side and "4759"OD cmv side.. I0mg tablets are supplied 35 foll.o\\o-,. Bottles of 30 - NDC Bli5t".rsID 90 NDC n ( Jdemi Dose:t, Wlit dose medkalicm. Lilly) Store at 25"C (77"F); excut>iolis pem!itted to ly to 30'C (59P lo 86'"F). Di;pellse alld keep product m origillal c;odl:!.iner:. Keep camaiijer dosed aod do wt remo>-e deii.oomr trom bottle. Do DOt break tablet. 17 P. 'T COG INFOIUL '-110::"( See fedit:lliod Guide 17J Bomts :md Risks Sll Wlm'ize the effecti\ l!lle5s fi!alu11!5 1md potemial side effirn ofeffiem. Tell p;:!1iems to take Effieot edc!ly a; prescn'bed. Rmtimd patie!!!lls 1101 to dl5cominue ElffiE!!ll \\oirhoul fusi dlscnssillg it v.ith the pb}-sicin whoprescribed Effiem. Rl!COIIlll!lelld that paliedis read the:medicari.oo Guide Blftiful: Imanupuialt> that they: \\<ill btui.>e luid bleed ll!jji'e e35ily. v.ill take looga tli2jlllill:!.lro stop ble!dio?, should repon :my lmsillitipa:ed, proklnged, or e:u:essh:e bleediog, or blood m tb!!lr srool or u...me. 17.J Oth.e: Si:;ns udsymptomsmmk:ll Attmtio.o l:tlfmm pari.ems lhaj ITP [;a rnre but seriru.; CODdiriOD that lw bee!reponed '1\ilb medic:ufollis in this c.la.ss of drugi.. In5tt1lci patiems to gal prompt medlc3l attelltiod ifthey e.'!pl!rieoce ally of th-e following 5}'1Iql(Oli!S mt CllmiO!otherwi;;e be c:b.mges lln-a.sin Pnx:Nores lllstniict pa.liems to: infunu pb)'iici3ns aod cmtt:isu that IIley :!Tl! t!kiog EffiE:IIl before!!ii}' im."ssin proc.ed!.:ue L5 scbfduled tell tbe doctor pe!fol1llillg the W\ e pmcedure to talk ro the pil!scn'bbfiilih c.:= professioll3l. before stoppf:lg Effi.ent. -ed!m-er, weakoess, atreme slidpali!dfss.. pwple skin patches, yei!cm±!!g of the slidor eye5.or oeurologjc:ll 17.5 CoDComitaDI MMica tio:as Ask palieots lo list all ptl!sa:iptiod tnedicaticids. 0\-ei-the<OUDter medlcatiom., ar diet!ry supplsiilllti they 3ll! wing Or pl3ll lo tlke sop!ly>ici.m knlmsabout ot.rea1:1ded!s that ctt:y affect blrisk (11.g.,\\o-:u:fuill aod NSAID>). 9 I..itE:lnue Issued:July 10, 009 Appendix 4a Page 17 of 17

275 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE t90 t91 t92 t93 ifv7310 A.\fiJ Manmctund by Eli lilly :mel Comp.my, IDdiaJaapo.lis,Il'i,46285 l\hrbted by Da:iidli S:ml). o,ilk.:meleli Lilly add. Comp:l.ll)' S:rnl.'.}'O,Inc.and.EliLilly :!lid Comp:my.All rights resen-ed. PRINTED IN US..!\ 16 Appendix 4a Page 18 of 17

276 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE Appendix 4b. Prasugrel Package Insert- Europe Appendix 4b Page 1 of 44

277 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE A.". il\ex I SUMMARY OF PRODUCI CHARACI'ERISTICS Appendix 4b Page 2 of 44

278 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE 1. X.UIE OF THE l<ie.dicikal PRODL"CT Efient 5film-coated t:ab)e,ls_ 2. QUAllTAT I\'E QU".-.'ITITA'ITI'E COMPOSITION E:u:h tablei comains 5 mg pnsogrel (as hycfrochlori} Excipient:Each tablec<ontains 2.7 mg lac:to5e. For a fullli.;:t of ac:ipiems, see section 6.L 3. PH.!\RAL!\CEUTICAL FORM Film.-coa;ed mblet (tablet). Yettem :md dooble-anuw-".haped tablets, debo55ed lliih ''5, on one side!!lid "4760"' on the othe. <t. <t.l CUNICALPARTICULJUS Thu-a pt-uik illdica tions Efient, co-adm:mistered with acetyls:!ilicylic :!Od (ASA), is indkated for the pw;emon of atherolhromboric e\-enli ill.patients with. acme coroiwj syndrome (i.e. m>-ublenons T segmeat elenri011 myocudial inflrrtion. (UAINSTE.\ti] or ST segment elention myocardial i:nfarct:ion [STEMI]) tllldergoing primary or delayed percut:aneou; corona.ry inte.-.,."ell.lion (PCI). For funher :im.fonnalion. please reru tosection 5.L <t.l Po<!OioaDd me-tlli.od of admill.istration..j.tijjll:i Efieot sb.auld be illitia:ed with a s e- 60 mg loading dose 3liJd lilen continued at I 0 mg ollce a day. Pmems tlkmg Efieor s!wnld also mke ASA daily (15 mg to 325 mg). Ill pati.ents \\th :lrn:e caroiiiuy syl!d.'1!me! (ACS) wllo l!fi! I!l.:!ll8ged with. PCI, premarure discontinnation of 811}' allliplatelet agent, illduding Efient, could result in an :increjsed ri.sk of Cb:roml:lo5is,myocazdial illfaiction or death due ro 1he patient' s ll.lldo.>.dying disease. A tte:umflll of up ro 12 months is recunless me disco:n.rinnalion of Efient is clinically Uldicated (see secnom 4.4 aod 5.1}- Pmi11nts >75\"'ars old The use of Efient iii. patieats ::: 75 years of 3ge i> gener:illy.dot recomm:edcied. If.after a careful inditidual belle.fitrisk eraluation by the presa:ibi:n,g p!lys1d.an (see section4.4), tteatment is deemed llll!ce»aa)' i:n lb:eparients age gtoup ;:75 }"e:u:s, thea following a 60mg loadi.dgdo.;:e a reduced lll.aiml!llisike do.>e of 5 mg should be presmded P:ltients;:75 years of a,ge han greaca sl!lillmity co bl:eedi!lg :md higj!er e:q>asure co 1he acrin metabolite of pr.lsngrel (see s:ection; 4.4, 4.8, 5.1 3liJd 52). The e\idellce for the 5 rug dose is based ollly an pllamucodynamiclphannxol:idenc all.31y.>es and DO cl.imcal data cum!mly e.on me safl!1}' of this do.;:e in the patients age group:::75 yl!sj5. Pari11m;wcig:trinr: <50 /ig Efient sll.oold be gi-..."eel as :1 sidgl.e 60 rug loading dose :md men contimled at a 5rug once daily dose. Appendix 4b Page 3 of 44

279 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE The 10 m,g mainceiit!oc.e dose is 110t recollmlii!dd!d. This is duto m illlcreasin e..'q)oiure to me acti\-e lll!tl.bollie of pra grel, md ao illcre:lsed risk of ble-eding id patimi!: v.ith body weight <60 k,g "'ohen gn en a 10 :mg onc.e daily dose compari!d llith p:uiems0 k,g. Effie:!C)' lmd safely of dle 5 :mg dose bavnot been prospect:h-ely a;sessed (ssections 4.4, 4.8 a:!l.d 5.2). RRnal im pairm"ni No dosl! adjusimmt is nessary for patient> widl relll31 impaiiml!lli, fodpatimts wi.lh el!ld stage renal diieaie (Si!!! si!cti.on 52).'Th!O!E! i;limlted th<!r.ipewic ence inpatients wfth renal impairment (see section 4.4). Hparic impairmror No dosl! adjus'l!iwlt is necessary id subjects wi.lh mild. to ll!ioderate hepatic fmpai:rme>'!l.l (Child Pugh class.4. aijd B) (ssection 52). There is linililbe;rapeutic 1!-Xperience m pati.ems wim mild aijd ra.:e be,patic dysfimaion (section 4.4). C hi/drrn amfndo!qu4f!rs Efimt is110t.reco=dfor use illchildren below age 18 dol! to :1 lack of data on Wei)'lmd efficacy. Method of admi lll1 1r3.11on For or3l usefiem may be adlnin.istered wilh or \\ithow food. Acbmniitrlllion. of me 60 mg pra;ugrel loading dose ill me f:b"ted state may pl"oiiide most rapid onset of action (see section 5.2). Do 110t crush 01 break the tab!& 4.3 Contr:lill.dic:alions Hypmensit:i\ityo the aai\'1! subst:mce or co aoy of the excipiellis. Acti ;-.e palbological b1i!!!dimg. History of stroke or twisint iscbaemic atmr:k (I1A). Sl!\-ere hepatic imp::limlem (Child. Pugh class C). 4.4 SpK:ial w.u-uids a nd precautions for 1IS4! B!flfding ri&k Ill me pbase 3 di:mc31 Dial key exdnsioll criteria indt».!d. m illcre35ed risk of bleeding; :!Daemi:l; lhromljoc}lop3eni3;a history of patholo,gical mmcranial findings.patients with arn:coronary S)'DdJ"omes Wldergoillg PC1tteated \\ith.efient a:!l.d ASA sbowed an incre3sedrisk of lll3jor :md minor bleediing ac.cordingo th@ TThfi ch:isffic.arion sysc!!m. Therefore, the use of Efie:nt in patient5 at im:rea.sed risk of blg s!lonld only be con;juohen tbe benms id temjs of p1o?\'entioll.of ischaemic ents a.-re deemed ao oum-.eigh the risk of seriol!is b1e.this conc.em applies esperislly to pariems:?:1, 5 years of age (see below). v.im a pr l)' to bleed (e.,g. due to recent t:r1imua, recem smgl!,ry',recnt or l1!<1im!nt g)!qtrointestil!al b'leeding. or acm e peptic. ulcer disease) v.iab. body weight <60 kg (see sections 421!1ld 4.8). In these padems me 10 mgmaintmance doseis 110:olllllll!nded. A 5 :mg maimel!wlcdose sbould be IISed. wi.dl. concomita.l:u admini.smltion of med.icill:l.l prodnct5 that ll13)' increasthe riik of bl,g, im:lndmg or:jil. amic.oagulam.15,dopidogrel II.OIHteroida.l anti-imlmnm.atory drugs {KSAIDs), lmd fibril101ytics. For palie;m \\ith aai\ e blfor wbom reu al of me plw:m.jco1ogjcal eff.em of Efien1is required. platelt tra.llsfui;on IJ!3Y be appropria The use of Efient in. patients?:,75 ye315 of age is genenill)' oot r:ec'oaijd sbould only be lllldm:!ken wilh caution after a c:!.ieful in.cli1iidual benf!fulrisk o?\'almtion b)' the p:rescribillg pbysicim indicates that bensfin ill terms of p:re..-ention of isdlaemic e\"l!llls Ol!Uweigh!berisk of serious bli!edings. In me phase clinical trial lbse patients \\'ere a.t greater risk of"bleed.ing, mc!ud.infall1l Appendix 4b Page 4 of 44

280 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE bleeding,c.omp:ued to patient> <15 years of age. Ifpre;cribed, a lower llt3inteiiwi.< e dose of 5 mg should be w:ed; ihe 10 mg!i!3i:oteuajke dose i.;iioi recoiiilllellded (see section> 4.2 and 4.8}.. Thempeuac experibnce \\ith prasugrel. i.> LimitEd in JX!.tient> v.l]th re:tml fmpai:tmem ( UK!uding ESRD) and inpati!!lll!i 'l'>ilh mod<>...r:!!e! hep:uic. impairment These pariems may have an illcreased bleeding risk. Therefore, pra:;ugrel should be used with c:awioc inthse p:uiellls. Thempemic experibnce \\ith prasugrel. i.; li:mi{ed in Asi:m patienl!i, Ths-efore,pra:;ugrel sbotdd be used ' '>ilh catrtion in these JX!.tients.. PariaiS shcrulcl be told!hal' ilmit!ke longer thm usual to stopbleeding whee they mke prasogrel (incombination \\ith ASA), and that they should repon any unusual bleedlc.g (site or duration) to their pl!yskim. Sw-gey PariaiS should be achised t o illfoim physidm; and dentists ibat they are t:!.ki.ng pmbefore any sur,gery i.; scheduled lll!dbefore lilly new medic:idal produd is taken. If a patient is to uod&go electn e sur,gery, and an aotiplatelea!feo is not di!sired, Efiens!ioold be cfucontinlli!d at le3si 7 days prior to surgery. I:ca:eased freqtwlc}' (3-fold) and 51:\-eril}' of l!'leelwty occur id p31iect> WldergoiDg C.G surgery 'l'>iwd 7 day.; of discollliiima.lion of(see 4.8). The benefit,; and risks of prasugrel should. be carefully consid&ed inpatients in whom the coro:wy anatomy has not been def'med alld urgent CABG is a possibility. 'i"hrmpjbotic Tltromlux:\7opatmic l' rprim (TTPJ ITP has ll reported v.rith i!he use of other thiecopyrictille.;_ TIPJS a seriou,; condilion and reqllil'es prompt treatment.efi.elll was not associated \\ith TIP inclinical Dials suppo:l'timg.regi:suaticm. Pll.liems wit!ij. mre bered:ill!jy problem; of ga:laoose intolerance, ihe Lapp lactase defidency Ol' gj]uc.o'.>eg;ili!c.tose b;orptioll should no< take Efiem <t.5 lll.ttnciion with other medicidal prod ucts and othtr forms of illteraction Wmj/1rin: Coocomitml 3dmim.istra.tion of Efi\\ith towuarill dei'\'ll.li'\ es other than w:ufarill ba:i DOf been stndied. Because of t!ie po:enti31 ol' iccre:>.ied ll5k of bleeding, wlllfaml (or olher colllllibria d.erinrin.>) :mel prasugrel should be co-:!idmillistered wid!caution (se.! secnoo. 4.4'). Non-zwroidal mtri-illflammatory drog;> (NS.4!Ds):Comomitlllll sdmillismltioll wifu chro:nic NSJ. \llli ba:i 1101 been studied. Becau;e of lb.e po'l!lltial for increa;ed risk ofbleedimg, chrollic NSAID.> (illdudilj.g COX. -2 inhibitors) and Efiem should be c.o-adl:uini.stered v.rith cawion (see.secti0ll4.4). Efieot Cllll be c.o:ncomimntly a ered M!b. medic:i.dal producrs mel:lbotised by cytochrome enzyme,; (idclwllilg statids), or medidoal produr1. 5 that are id.duc.ers or inhibitors O'f cytochrome P450 ejiiz1'1!lei. Efi:e.n;Cllll also be coccomit:uut'}' administered. witb ASA, heparim., digo-:'litl, md medicmaa pl'odu>cts!mt ele>-ate glistric ph, illc.ludi.llg prololl pump i.tibibitols :melh,blockers. AUb.oU?b not studied in spec:i:fic inter:ktion studies, Efi.ect been. co-:ldminis'tered ill the phas: 3 clinical trial wilh low molecular 'l'i!ight heparin, bh'\!l.irucli.n. and GP lib/ida inbibiton (no inform: tioll a\"allabte regarding ibe type of GP IIbi!IIa inhl'bitor used) \\ithow e\ida ce olf di'dically siginjficam ache rse idternct:ions.jc;;nylsali.cylic acid: EDect i.; to be admim.ist&ed co:ncomitlllld)' \\ifu acel}'lsalicylic acid (ASA). pha:m:!acodynmli.c mternction \\itb ASA leadimg to :m idcrea;ed risk of bleeding ii possible, ihe demo:nstr:ltion of the efficacy :md.safety oj pra5ugffi comes from patients concomitantly III'E!a:ed wiib ASA. Appendix 4b Page 5 of 44

281 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE H parin: A s lilltm\-enous bolus do:..:e of WlfractiODoSted heparin (100 Ulkg) dld DOt significantly alter the p!llsugrel-m!!diated inmbition olfplau;lt awegatio:!l Likewlie,prasugrel did I!IQi signiii=lly a.l.r me effect of llep:uin ou measures of c.oogulalioll. Therefore.. botih m c.in31 products am be acilninisrered c.oocomill!lltly.au mcreasm ris.k of b'gl is po5:sib!e when Efiem is co :l Cfmi!ristelrl!d \\ith b!p3rill_ Szarins: Aton1151atin (80 mg daily) did nc» Slter the phaml:!cokin&ics ofpn;and its inlnbition of platelet 3ggregatiou. Therefore. stat:in> that are substrates of CYPJA are no;anticipa:ed to m e llll effea OD mepbannar.ol;inet:ics of pr:l!sugrel Or its i.nhibiliod of platelet :ll,ggreggtfod. M"dici7Jal products that Q/(rl_ym gtmric ph:daily co-admi:ai>ttlltio!l of ranitidle (mblocker) or lamopr:!zole (a p:romn pump i:nlnbiror) did DOt change the pn,-ugrel scth-e Waboli's AUC and r_, bm det:re:ised the C...by 14% md 29%, re5pecth:e}y.in llrepba;;e 3 c.linlnl trial, E.fiem Vi'35 3dlnimist. \\ithout reg,ard to co-acfminimatioc of a protem pwup illhlbitor or H! blocker. Acfminisc::uiou of lhe 60 mg prasugrelloadlcg do-oe \\itlhom concomim.nt use of protod pwup inhibitors may pr ide most n pid oll5et of action. Jnhibiwr.; ofcypm : Ke:, oco:u.azole (400 mg daily), a selecid;e andpotem inmbttorof CYPlA4and CYPlA.5, did DOt affect pmsugrel-medi:jjted idillbition of platelei aggreg:l.liou or me pmsugrel acti\-e t:1bolile.s AUC :mel Tbm decrea;.ed tile c_ by to 46 - fore, CYP3A illb!.bitols such as azol antifull;ggls, mvprotease inbj.bitors. da.ridlromyciii, telithromycill. nnpamll, dilliazem, indina\ir,dprofloncin, and juice are not amidparm to!13.-e a s:ignifi.atm effect on tile p!i:!imacoldn&ics of me acti\-e metabolite. lndjwb:: qf CJlDChrtmrm P4JO: Rifampicic (600daily), a poteet induceof CYP3A :mel CYP2B6, :mel 3ll id.dccer of CYP2C9, CYP2Cl9,3IDd CYP2C&, did not signiiit.81llly c:hacge the pll3rmacoldno&ics of prasugrel Therefore,!mown CY"P3A inducers S1ICh :.; rifampicin, c::a.rbslmzepfue, :md other lllduce,rs of cytochromes P450are DOt :mridp:;ted ro ha\ e signifi.c!llt l!f' fecl on the pharm:locokid&ir.s of the acm:e metabolite. Ettff t:i ofeftmt on othllr mvdicinal f!1'0duds: Mv.dici7J al producr:; tmmrbolbtd b;} C1P JC9: ptasugrel did 1101 illhibit CYP2C9.as ildid cot affect the p!j.mnacok:inetks of S-'1'>-arfarii:L Because of the potential for inc:re: sed risk of bleedlcg,v.r:ufarin md E.fiect should be co-admimscered v.ith cauticm (sel!' section4.-t). M dici7j al producrs mt.rabolbtld b;} C1P1B6: PI:i5'11igrel iia weak inhibitor of CY"P2B6. m healthy subje<t:s, pra;ugrel decreased e:tposure 10hydroxybupropion, a CYP2B6-medlated 11110t:1bolile of bupropion. by 23 'o. Tbi5 l!f' fecl is likely to be of cl:ii!ucal c occem. only when pmsugrel is co- 3dlnimist\\ith medic.in31 p:roduct5 for which CYP2B6 li lire outy t:lbolic pathway and ba\ce a n=ow lb tic window (e.g. cydop!lo5pll:!mi.de. efm.i:rem). 4.6 Pre:IIIC)' add bctation No clil!lic.al study bas bec.ondncted. illpregcam or lacmiicg women. Animal srudies do DOt iddicate dil'ea lwmful effects \\oitb respect 10 pn,g:u.ancy,embryonal'foetal de\ elopmem, p:litllriticm or postllt!m! de\-elopme!lt (see section 5.3). Becaus:e :mimal reproduction studie5 are not always pl'ediainolf a h=response, Efiellt should be USMpn!giii3Dcy olll>y if lb!!potemlal bene.fit to me mothejusti.fies lhe po::atial risk ro the foeo:us. It iillllkno'l\111 w ther pra5ugrel is excreted in hiiiwid. brel5t milk.animal studies b' o-e slxmu excreticm ofprasugrel ill b:rea;r miilk.the we of prasugrel during bleastfeedil:lg is IIOire<ommended. Appendix 4b Page 6 of 44

282 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE Pmsu,grn had 110 ef!ea 011 fenility ofm.'lle allld female rae at o:ral dose> up to e:xposme 240 rimes ihe recomml!llded daily bumm maintej a!iice dose (based on mg/m). <t7. EffKts OD ability to drin:md IISI!' madudi!s No srudies 011!be effects on ability to cm \ e :md use machines lwr;;e bl!ec perfo!lllied. Pr:l.;ugl-e! is expected to ba\-e 110 or ne gt"b1e infillellle on ihe abilliy to dri\-e 3lld use machines. <t.8 Undesirable effkts Safeillp:lliems \\ilh acute c oronary sycdrome ucds,going PC1 -as e\'3l113.ted illone clopidogrelconirolled smdy (TIUTON) in ilich p:llielus were treated v-. iih pmmgrn (60 mg1oodicg dose :md 10 m;g O!IICe daily m:rina!.dadce dose) for 11rm!dian of 14.5 mont!is (5802 paliems were treated for O\-er 6 moctll;.4130 patients -.;, ere ireated for more than I year). The mte of srudy drug ctisconticuation dui! to ad\-.erse e-..ellls v-.as 7- for prll51lgrel and 6.3% for doptdol Of lhese, bleeding was the most common ad\-erse.reaction for both cln.lg; legding ro sro.dy drugdi;:cominualioc (2.5% for pnsugrel md 1.4o fordopidogrel). Non-Cm'O!JLU)' ArUtl)' Bypass Grqfl (C..llJG) nlm"d b1hding Ill TRITOK,frequency of patients experil!.iicing a non-c'abg related bleeding evem is sbo'iw in Table 1. The i:dcide!iiceof K od-ca.bg-relllted milmajor bleeding, includicg life-lbre3tmiag and fatal, :l> well as ldu IllliDor b'leediog,was stati-,-tically siglli:fic:mtly bigbe in snbjects lrea!ed wilb pillcompared ro dopidol, ill!be UAJNSTE:I.and All ACS popal:>tiolis.no significant diffne.dte wasin!be STEM] population. Thmascommon site of sporuanus bleedlng w as th p;trointestinaliiljci 0.7,o 111-.;, lh pmd 1.3% 1111v.ilh clopidogrel); the most frequ<>.di site of prcr;-oked bleeding WllS anerial pu:licture site 0.3% lllte with pra.sugrel :md 12% \\ith dopidognl}. Enat.'\11.'\CS L'A/NSTE..UI S'l'EJ.IT Pr3SU Clopid Pr-asu:veJ Clopidogrel P'nsa Clopido;;reJ +AS.A +AS..... (N'=-6741) -AS..>. \. (:S=51001) +A.SA (N'=1740) +.-\.SA (N=6716) ::.{g80) (N=l736) TIMI m1jor bleedillg' l..ife-<1hrerlurlm!," 1.3 u 13 O.S u 1.0 Fatal OJ 0.1 OJ S}m:ptor:naric OJ OJ 1) ICF' EW(11iring il:otrope; EW(11iring surg!l il:!m-.enrion EW(11iring crm;fu;foo Ul!fu) TIMitll!!!.or blee.itng I T b1e 1:lncidencof Non--C.o\BG rfl2ted bl(palie11ts) OJ OJ OJ O.S O.S 2.4 1: a Ctwmrlly adjr Jtcaw...,.tkjiMrJ by rn! l'flmow!w) as "",\ OC<Jtd.ul bifa rn JJ (TIJ.D) SnJyGJattfJ crt "" I>Orlot!r rmrd:jni rlr<rapu,..,.,...was. c A.oy tltmrlwltal <11 M a ydjiucdly_,.tked!itf a.utxjar rj ajall1lr bftlog/,omt;:)grjj.. Appendix 4b Page 7 of 44

283 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE d1jfo-d!naril11114g!'-lilrgt amw.af17mtat'!/oil"bi JaMUOcll.durlflti)JX'S Niot..PI>llCJJts.W CIOkPIT..!dtil JIIIOil"'e tjidt t:jiv I'Olt. YCH "'"I b"'""mg'- fci11ucdly " "'l*.<djw, cu.soc ar d"'''"'a fall il'llltj.bt"lllooil'l of "l:)r,jl. b r J df_ Pwjanr< > nl'(qz:; old Ill me phase 3 ilillin1dial, oon-cab lated TIMI major or lllioor b1eedillg:rates for patimrs in two a,ge groups were as follow.>: Patillnn < 60.tg Ill tbe phase 3 dillkal Dial, oon-cab lated. TIMI major or lllioor b1eedil!lg rates for patients in w;o weight gl"oup5 were as follows: ID pati.en1skg mrd age <15 }"MIS, coo-cabrelated TIMI major or mmor b!eedill.g rates were 3. 6.for pnsugrel:llld 2.8% for clopidogrel; I:li:e.> for fatal blewl!le 0.2% or prasugrel2ll.d 0.1,. for dopidogrel. C.tBG-rv!awd llrmtm: Ill me phase 3 cfulical Dial,437 paiiellis llllcrern-e.o:t C..l\.BG <furi:og me COUI5e of the smdy.of tl!!ose p:;.ti.eots,1llle rate<ofc.abrelated ID!l.!D:8jorormiD.orbleed:ingwas 14_ l,hor the pra.;ngrel group 2ll.d 4_5,0.in the dopidogrel. gro1q1. The higher risk for bli!!!dmg e\ ent:s in subject;. ;reatl!d <ilh pn1persisted up to 7 days from the IIIQSt recem dose of srudy drug. For patiems who received their mil'iiop-yiidide wi1bio. 3 day.> prior ro CABG, llle frequeocie..> oftl\!1m:jor or midor trleedillg v.-ere (12 of 45 patients) io.1he prasugrel.compared with 5.0% (3 of 60 paril!llls) in m dcpid.ogrel group. For pati.ems who recei\-ed 1llle1r l:h""t dose of thienop}'ridio.e \lltthill 4 ro 7 days prior ro CABG,the frequencie.> de<re3sed to 1 LJ,. (9 of lw patients) in1he pmsugrel2ll.d 33a (J of 90 p:uiellis) in the dopidogrel gr01q1. Beyolld 7 days after drog disconlioua'lion, the otr.>m ed ra:e; of C..l\.B related b-leeding v.-ere similar beweeo treatment groups (sectiod. 4.4) Ad:r li!i'ul Rmcrion:; Table 2 summarise..> hs.l'lllioiih:l,gic aod non-hs.emorrb3.gic adl. l!bi! reaaions in TRITOc.Wsified by frequeocy 3lld S}'Stem organ class. Freq)leocies are delioed a.>!allows: Very commoo (? 1110);commo::J. (? l/100 to < l/10); UJK OimlliDD (? ro < 1/100); rare (? 1110,000 to <111,000); \-ery rare (< 1110,000): oot koov.-11 (CillllOi be estimated from!he available dat:l). SHttlll Table 2: ()r:p,ad R:.emorrba. Clas5 CollllltOD. :md :Soll-haemorrlla=:ic adnrtactioas t"dcoiiuiida Rare B1'ood arrd1,)-mplrtr.ic - SJS.rur distmkrs Er di!rmjqs :l!.lemcmbage 14uc1ar Disorihrs HDI!IIIAtO!Il4 hspirt11.r!joracic Epi11Lm!lai!IlilOpey>is atrd mdia!irintli di!ordln Chrsrroim1t1rilfal Gib&roiote5tinal hamwlihage R.e mperitoilo<.ll.la g_e di!ordln R.edal l!a=onb.age!lai!iiiatochl!zia Appendix 4b Page 8 of 44

284 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE SJ:in QIIQ SllilcJmmrOII! l!imfr riiumiqn ]U JtQ) (!JidL'Ti1lar; disorrkn lklfcal disorrin-s tmii admi11iluatirlll siyj COJJdiJioll! lrljury,poisolling and rjtoc«jlraj "cojtfpjkaiit»>! hih Ecchvmo.;i; H =arl!u \re;.;el plldcilin! sire ha=ato= Jlw:.citure sire m e Gillti\1111 blel!d:in! Con.nmoc Po1;-proc.edural hae!:ooiii!j..g;e Subruw:.eou5 hdemaum:a Ill patients 'l'otith or v.ithom a history oftia Or stroke, m ldddence of stroke iiitbe phase 3 clinical lri:u W:li :15 follow'> (see se<tion.4): Historyof nor stroke Pn;-agrel. Clopidogrel Ye.-!N=51S) 6.5(D% ICE u \ {()!' CH'} :s'o (N=B090) 0.9 ( 0.2 ICH ) L. (0_3ICH ) *JCH=mrraorm.ral hagmol'rltng. 4.9 Onrd 0\-erd.o!ie of Efiem may le:lld to prolonged bl.eediing time and subsequent bl-ung complication;. No data are a\--ai!.a ble oc 1!ie m rnaj of die pb3j:m.jcological effect of pra:roue-1; howe> er,if prompt correcriod of pml011,ged bleeding time is required. plate:lt tnllisfu"..ion 3.lld.'or olb& blood. products may be con;id«..red. 5. PHAR!.L.<lCOLOOICAL.PROPERTIES 5.1 Pbarmacodyumic pro rties Pharmaa rfjmamic:. Pt.-.g; rel is 3ll i:nhi.biror of platelet acth--ati.on and a,gg egation throughthe m "i!!!iible billdin,g of its xli'\ e metabolite to the P2Y 12 dass of ADP receptor.s on platelecaillce pla telets pa:rtici;pate id tm iciliati.on :mel'or e'\ olution of thrombotic complianion; of a:bhoscl:roti.c disease, ill!ubiti.on Of platelet flmclio!l em Te'SUli in the reduction of tbe mte of cardlo\1&ular e.--eats such :15death, myocardial icfarction, or stroke. Followill;g a 60 mg loading, do;e of plllsup'e i:nhibinoo of ADP-indUICed pl:atl:let a,ggreg;!lti.on oc.curs at 15 minwe; witb 5 J.l}\1ADP and lo mi:ml!es will!j f ADP. The.lll4'1:imum iohibirioc. by prasugrel of ADP-ind:llced plal:let &greg;j.tio:j. i.s Sl,.w1tb 5 J.l}li ADP aod mo \\ith 20 JL\f ADP, id both case> vi. lha of he:rlmy subje!o!:is :md pati.ecl5 \\<iib. smble :llthero;clero51s a.chieli. n.g at least.54n inhibitioo of platelet a_ggre;gatioll by 1 hom. P!!a.supel-media.ted tchibition of pla:telsagyegatione:shibits low between-.subject (12o) aod 'l'o thill-subje!o!:l(9, ) n.r.iability 'l'otith bom5!1-i :md 20.4DP.:Me31l st!<lldy-state tchibiti.on or pl.atel :t aggregation was 74,.and69! a respeclh:ely for 5 JL\f ADP 3.llid 20 p.l.l4 ADP,aod was achie>ed following 3 to 5 days -of admillismltion of tm I 0 mg pra.sugrel ma.imell!!lll.(e do;e preceded by a 60 mgloading dose. More dian 98% of subjeel!i had20'! o i:nlnlrition of platelet aggre;gatioll dwingmaiiotel!ij!d.ce do.>io.g. Platelet awegation gr:!duafiy rerumed to baseliol!\-alue; after t Htllt"..ot m. 7 to 9 day;after 3odministr.J.tion of a sillg1je 60 mg LOado;e of prasugrel and m 5 day;follo\\<idg d&octi.uuatioii of ma.imell!!lll.(e dosing a1seady-smte. Appendix 4b Page 9 of 44

285 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE Qopidooo:Followmg adm:im.is11r.1tion of75 mg dop.idogrel ollc.e d.:lily fo10 days, 40 bealmy mbject> 'l'i'ere switched to pr:151lgl'el 10 mg o:nceo daily withor \\itbout a loading do;e of 60 mg. Simil:u olrir in!uoiti.on of plat elet agg!'!g;ltio::t wa.; obse,n;ed. with pr.15ugr!!l S\\itching pmsugrel60 mg loading dose resull1!d in!he ll!idst rapid oli.set of highs- plat!!let inlllditio:n. Followmg :lldmilristration of a 900 mg, loadilig dose of dopidogrel ('aim ASA), 56 subjec.ls \\ith ACS were reared for 14 days with eilheri 10mg o:nce daily or do;pidogrel 150 mg o:nce daily,:md tbm rnitthed to eitber dopidogrel l50 mg or pmsugrel lo fo llliiomer 14 d.:lys. Higller illhibilioo of dlrerny to platelet aggregation 'li-t as o05en;ed i:o palieot!; switched ro prasogrel 10 mg compared 'lltilhthose reared with dopido,grel l50 In? No d3.l:!l :m! a -ailable on swirrhing from a dopidogrel loadmg do;e directly ro a pnsugrello:l.ding dose. mrary mtd Sqffty in AcurQ Coronary Sp!dmmQ {ACS) The phase 3 TR.ITON sto.dy comp:m!d Efient (prasugrel) \\ith dopidogrel, both co-admfol".teredilh A.S..>. \ and other stam.dwi therapy. TRITOK was a paliem, multicentre intemstio:n.a!, lmldomi;ed, double blind, panillel group study. ParieJm had ACS 'llt idl m...mte to hi,gh risl UA, NSTE.\fl, or STE.\fl :md were 11l3.113ged with PCI. Pariems '1\itm. U.!t.INSTR.\fl witbi:d 72 hours of symp:dill5 or STEMIceen 12 hams to 14 days of symptom; ere Fdldoll!lised mer k.oowledge of corolw)"anatomy.palil!lll!i \\ith STEMl \\itlrin 12!law:; of.s)'ilqltoms and plrumed foprimary PCI could be randomised \\ithout knowledge of corolll!i}' 3llillromy.For all p:nim, ililoading do;e c ould be administered mzytime between mlildomisalion :md 1 hour after me patient left iliatheieriia'tioll. lab. Panems r:m.domist!d 10 recm-e pll!su.grel (60 mg loading dose followed by 10ollC.e daily) or do;pidogrel (300 mg loadillg dose followed by 75ollC.e daily) were tteated for a mediad of mollibs (1113:ltimum of 15 lliiollth; \\itb alllidimmnof 6 mow:lls follow-up). Patiems also recei\-ed ASA (75to 315OD e d.:liily).t:se of my thiedopyrididwithill 5 days before emolmellt Wll.i an e.'ociusiod aiterioll. Other thpies, such as lr.!p:uin and GPilb.iiiia mmoilors,wert! admlni.stered at me discretion oftbe phpiiciall. Approxil:n.ltt!ly 40% of patients (im. eoch of me 1reatl!n!!m,group5) recei t!d GPDbiiiia idbibitojs id snppon of PCI (:oo iofo=tion a\-:illable reg:miiog the type of GP IIbiiiia inhibitor used).appro :tima:ely ofpaliems ( w eacll of the treatmellt groups) rec.ei>-ed 3lltililrombills (bep:jirio, low mole<uiar weight bepario, bn alimdln, ootll 1 agem) dirt!ctly i:o support ofpcl The uial' s prim:!iy outc ome me3sllre was me lime to fimocci!lnllci!' of aidio\'ascular (CV) death, oon-f.atll myocardial inf.arclion (Ml), or.non-fatal stroke. Allilll)'lli of!he composite endpoint to lhe AJI ACS population (combim.ed UA NSTElYfi:md STE il cohort>) was cootinge:ot on sbo\\iog siatistical 511pi!liority of pl \"er5us dopidogrel im. the UAINS'IE.Il conan.05)..ml ACS pcpu /atiqn.: Efiem showt!d superior efficxy c.omp:ued to dopidogrel illredudiilhe primary composite ourcome 1!\"etm a:> well as the p e-specmed sec ocdary oli!come e\ l!lll!i,idclldiog Yent lbromlxl5is (see!table 3). TbbeJiefit of pmsugrel wa> apparent witbi!l lhl! fi.rsi 3 days :md it pernsted. m me end of study. The superior efficacy was accomp:mlt!d by 3ll im.crease in majobleedin,g (see seclion; 4.4 2l!d 4.8). The patiem population was 92% Cauca;ian, 26'0. female,:md 39'0.5 } 'em's of age.the beoefus associated wim pra;ugrel were illldepell.deot of the u;e of olher acute and Jo.g-tenn c:ardio\'llscohr lherapie;, im.c.ludid.g be.parinl!ow molecul.u weight bt!pario, bi l lliru.clm, imravedous GPIIbiDia illlhibiton, lipid-lmnri.d.g mt!dkim.al product;.bi!3-blocken. a!l.d angjotmsm cooyerting ellz}'illl! inbjd. i.ros.the efficacy of pmsugrel 'llt'l!os ill.depecde.nt of the ASA dose (75 mg m 325 mg OD e d3ily). The of oral anticoagul3.llis, co!l smdy anlipl>ul!let UL<>ditim21products and thionic KS>, \IDs was oot an 'edin TRITON. Ic me.'ill ACS popuhnicm, prasugrel was associated 'llti.lb a lower illcideoce of CV death, oon-f.at:tl a,ooon-f.atal s!i'oi!t! compared to dqpidogrel,.reg:ndl.ess of b:l6elille clw:'actmstics sudl:u age, sex, body wei,ght,,geogmpbical.regicm, use of GPIIMila idhloitors, and stelll i)'jii!. TbbeJiefit was primarily dne to a significant decrease illiiod-futal fl (see mble 3). Snbjects w:idl diabe:l!.'s bad s[.gnifi.cant recfuction5 ill the primluy and all secondaly c ompoendpoints.. Appendix 4b Page 10 of 44

286 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE The o&.ien-ed bene.fir of prasugrel in parimls?: 75 }'ears was less lhall tb.aj obsene d illpaliems <15 yem. Pati?: 75 years we;e at illaeased risk of bleeding, illduding fatal (see section> 42., 4.4, 3Dd 4.8}. Patients?:75 ye:m im. whom lb!!beaeftt 'lllilh el was DKJre e\ident illlduded those \\ith diabetl!s, S"'ThU, hipri;k of stan wom.boois, or rectu110!l e ents.. Pal!iems \\ith a bh'"tolj' of TIA or a h.is!oi) of ischaemic strolte more ihan J DKJndls prior to p!llsiigrel mernpy bad uo redlllctionill the plim:uy compos:iie elldpoint. TablA! 3: Pa timts with. 011tcome Ennb in TRITON Primary Anal)'sis Prasagfl Oopido el H:uard Ratio (HR.) p- + ASA +ASA (95 CI) nln Outcome EnD!s (N=6SB) =6795) ADACS Pri:Dwy CompositOu.ltoDLt Ev01b " O.ll U (0.7l2, 0.9()2) <0.001 Ca!'dio\oa;cW.U (C\1)' &!1h. lloilfatl.j or con fatal ;uob Primn'v Illdrndllal Ou.trome E'I'Hits CV death leo S6 ( ) 0307 Nonfatll W (0.672,0.853) <0.001 Nonfatal stroie OJ> 0..9 LOl ls o.m }0 t'ainstemi (N=50U) 30) Pri:man Composite Ou.ftoDLt E'I'Hits C\1death. nonfa1lll Ml or nollfatal ;.trob " O.B ' CVde>l.tl: La u O.llS5 Noll.fatal W D.a73 <0.001 Nonfatal strob 0.& OS O.!H9 :0.633 L:il S'JL\ ) =1765) Priman Co.mposite Ou.f rome E.v01ts C\l death. nonfatal M1or nollfatal moke 9.& 12, (0.649 O.S'l CVde>l.1h & ( ) 0.12'9 Nonfatal W 6.7 u (0Sl!S..O.!l'4&) ll.oto Noll.fatal stroke Ll Ll L097 (0590.,2.040) Ill!be All ACS poplllarioll, malysis of e-.ac:ll of!hi! sec.ondaty mdpoims showed a si amt beumt -001) foprasugrel '\'ej:su> <lopidogrel. Tbl!Se idcluded dei'illite or probable stem thrombosis at sludy ead (0.9% \"S 1.8".<0; HR 0.498;C , 0.683);CV de:uh, nonfatal MI, or urgent target \'e>sel m; a>eul.:arisation d!routh 30 days ( 5. s 7.4HR 0.784;CI 0.688,0.894);all canse death, nomtal ornonfa.<al.stroke through study end (10.2% H 12.nHR ; CI 0.751,0..919); CV dmth, oonf:aml :Ml,oollfar.al srroke or rebospitalisarion for cardiac i5cbaemic e-. em tllrough smdy l!ll.d (1L7 % \'S l3.8o; HR O.JB8;CI 0.762, }- Amll) si;.ofall c:anse deam did not sbow ally siguific:mt diffhedce between. prasogrei3dd dopidogrel im. the AU A.CS population{2.76% n 2.i),in me UAINSTEM:I pcpulati.on (2.58,.1;'5 2.41%), and im. me STEMl popmlarion Q.28% n 4.3l%)c Pr:b"l!grel was assoc:iated \\ith a :recfuction id saent th:rombo.s:i;. through the 15 momb follow-up period The reducrioc illstem dlrombosis with Elient wasobsen.--ed both early aoo beyond lo days for both bare metll 3Dd d."l,lg stents.. Ill :m :mal)-si;. of panents who soni1.-ed SD ischaemic e1-. ent pr-=was assotil;.ted with a reduction illthe incicfo--dr.e of snbsequem p:r.im!jy el!dpoiut e.ems (7.8% for prasugrej \'S 11.9 for dopidogrel). Altllongh blel!di.llg was illlcreased 'lllilhpm..;uue}', au analysis of the compo5ite I!JldpoiDI of dealh from :my cause, nonfatll myocmlialinfarcl!ion, nanfu1:ll strolte, and non-0\bg- a:-ed TIMI major bl!.emoll'hage fin oured Efi:em c ompa:red ro clopidogrel (Hazard mtio, 0.87; 9:m.CI, 0.79 ro 0.95; p=0.004). In TIUTON,for H'ery 1000 patieuts treated v.ith Eiieot, W>_re were 22 fewer patients with III)'Ocardial infarcrioc., 3Dd 5 DKJre \\ith cojh:abg-retated Tl?!1. I major baemm:rll3ges,com]x!ied wim. patiedts treated with dopidogjel ' Appendix 4b Page 11 of 44

287 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE 5.2 Ph:mnacoki:Jlttic proptrties Pm; grel is a prodrug :!llid is rapidly membolised in ln'o to :m oclive metabolite and imocn e mt:lbollib. The active metabolite' s e.'tposure (AUC}has moderate ro Ic.w between-subjec.t (2no) :md v.ilhill-snbje<t (l o) nriabilir).pmiugrel's pbamiac.okin.etics are similm in healthy subjects., palim'!s v.;dt stable atherosclero5is, :md patients ucdergoin,g pernttaceoos COI'OIIII!I}' inten ection. dbsomnon The abso:rpli.oo 2I!d m:t:ibolis:m of pn1sugrel are mpid, v.ith peak pl!ill!l3 coilcentnl.lloo (C...) of tbe xm e D!ll!tabolite occunicg m3p11ro::tim:llel)' 30 mill.we;. The acm-e metabolite' s ee (AUC) increases propomooally over the therapemic dcr,e nmge.in a study of healthy subjects. AUC of tbe xm e Illi!tabolite was unaffected.by a high fa!, high alorie meal, but c_ was decreased by 4a9d!he time 10 read!. C... (T.,.,) was mcreased from how:s. Efiem was adminis1ered v.>lthout reg:!rd to food illtriton. Therefore, Efiem C3ll be admidb-w-ed wilbout reg:!rd to food; howe,er, tbe iiicfministnltion of prasl lo:ldijig dose in me flsied smte my p Q ;ide lll05i rapid 0115et of actioii (see se<licm 4 2). DinribJlti07l Acm-e metabolite billding to lnimrm serwn album.il!. (4'!.o buffered solnrion}w:!s 98,.._ Mrabolimt Pmg; rel is oot detected in. plasm.a followil!.,g on!. admlci5tra!ioo. ll is rapidly hydrolysed in me intesliice to 3 lhiolacro:ne. wbic:h i;; tbm (0:11\-erted to tbe acth-e metabolile IJ.y a smgle srep of cytochrome P450 mmbolism,primarily by CYP1A4 3.DdCYP2B6 aod to a lesser e.':tect bycyp2c9 :md CYP2Cl9. 'Il1f! ac th e n:wabolire metabolised 10 two inacti\'e compowlds by S methylation or c ocjuglllioo. v.ith cy eim.e. In healthy snbjec:g, patienls v.im stable atlm'o.;derosi.s, :md patients >with A.C!. recehin.g Efiem, th<>_re was oo relennt!ffea of gen dc -ariatio n in CYP3A5, CYP2B6, CYP2C9, ocyj?2c19 oo. the p!l:uma.cakill tics of prasugrel oit> idhibilion of plate!aggregation. Elfminariqn Apprmrimatel)' oflbe pmsugreldose i;; excreted in thm:id.e alll.d 27% in the faeces., as illlacm e m:t:lbolli!!i.. Thac:ti1;unembolit!! bas an elimination half-life ofabout 7A holm (I:lll!ge 2 to 15 how:s). Spedal Pop11lariow Eidoh : Ic.a srudy ojhe:lllhy subjec.'!s between the ages of20 :md 8() years, a.ge had no si.goific:mt effect OD p!w:rn.jcokilledcs of p1'1151lgfel or it> idhibirioc of platelet agg:regalioo the brge p!we 3 dillia!l tri3l, 1he mean estimated ej..-posttre (AUC) of lbe acth-e membol:ite 'lll11s 19% higher in elderly paliems 75 years of age) compared ro subjects <75 year> of a,ge.prnsragre.j should be used wid!. caution illpatients75 ye:m of age due co the poteotiaj risk of bleed:illl.g illtllli popularion (see se<licm5 42 :md H). H patic impa.irm mt.no dose adjustmellt is ece:;;my for patients \\iitb mild to modem7e impaired hepalifunctio:!l (Child Pugh Class A :!llid B)- Pb.a..TID3Coklics of pra,-ugrel alll.d its inhfuilion of platelet 3gg:regation were similar insubjec.ts v.ith mild 10 m te hepatic imp:wment comp:!il!d to health)' snbjeas. Pllarmacokilletics aod pharmacodyu.mics of pn15ugrel in pariems v.ith m-ere hepatic imp:titment ba\ e 1101 been srudied. Pr:uugrel Dlll5t be used in patients \\ tb se -ere hepalic imp:titment (see seclioo4. 3). R.Rnal imuairmtmi: No d05.3.ge adjlli"tmellt 9e.CBS:ll)' for paril!llts v.ith re:ca.j imp:llim!.em, iiid.uding patients with end s'lllge fl!ll3l disease (ESRD). Plwmacolcin tics of pllis1lgrel 2I!d irs illhlbition of platelet 3gg:regation llll! 5imilar in. patients v.itib. moderate rem! impai:r:melll.l (GFR l0-<50 mllmllllfl.73m") 31ldhealthy snbjecis. PrasugrelLmediated id.hibition of platelet agregation was also 11 Appendix 4b Page 12 of 44

288 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE similar inpari.ents \\ith ESRD who requiredhaemodia!ysis c.ompared to b.eallhy subjeas, a!!hough C... :md AUC of the' acth e meiabolite decreaseil 51,.8lld 42,., respectively, ill ESRD patieoti. Bodll IH1ighr: The!!lll!ml expostire (AUC) of me acth'e met:lbolite of prasugrel is approxim.ltely 30 co. highl!r in h11:ilihy subjem aod parii!ms wi.lh a body weight of <.60 kg comp:!led to chose wei,ghing 0 kg. Pr.lsugrel uld be used 'llliilicanrioo m p:uials \\i1h a body weiof <60 k,g dne co the poientialrisk ofblee m ibis population (see seciiod -*.4). ErhnicilJI: In dinkal pl!.:!:rmacology smdies, aft;!adjwfor body weight, the AUC of thi! actin! m.et:lboj.ke W:li :!ppiojrim.1tel)' 19% higher iiichillese., Japanese,:md Ko:re3llsubject5 COmpared to mat of C:tna si3.lis, predomilwllly mated. ro high11r aposme in AsiB.ll rubjects <60 kg. There i5 110 difference in aposure IUIIIOilg Chinese. Japamese, :md K.oreim snbjects. Exposme fd snbject> of.1\fj:icad :md Hisp:uric descent is comparable to that of CancasiallsNo dose adjusmlli!m is IKon:mended based O:!l edmkiry alone. ndgr: In beallhy subjecli :md pati.ents, lbe plwm.jcokillletics of pmsugm l!l'e similar inm.en :md women. Childre! and ado!t>.sulll<s: Pll:mnaco!.."inl!iics aod pharmacodynmrics of pr:b ba\'e! oob een evaluated ill. a paediatric populariod (see secrion4.2). 5.3 Pndillical s fety data NOIKliDical dat:l r!!'l."eal oo spedal h:!z.url for hum:ms b:lied OD con10'emional stnd:ies of 5afety pl!.:!:rmacology, repeattoxid.ly, genotoxidty, can:inogellic po:en.ti31., or coxic.i.l) to reproductioll. Effects illdolh.iidfcal srudies were obsen ed onl'y at e..'j)oim:es collsidered suffid.emly fd e::tces;; of'lbe ll11lxinmm b.mnan apo;me illdic,atillg little rell!'\'lmce to dillkal use. Embry-o-foetal denloptoxicology smdjes ill rats :md rabbrts "'-ed oo e1.idence of ma.1fm:mati0115 dne r.o prasllgl'el. Ala '-e!y bi,gh dose (>240thi! rec ommended d.ail}' hlidi2ll mai!l:enmce dose on afm' basis) that caused effecls on ma c!mlll body we.i,ght a.ndlor food coibiiiiiprion, tbere was a slight decrez.e in offsprill,g body we.ight (relative tocontrols). ID pre- and poshlaral rar smdies:, l!ll.3.ten13l tteatmenl bd oo effect on 1he beha\ioo..'lil or reprodncti --e de\ elopmem of the offspring at dose> up to ml!'xposure 240 limes the recommended daily human maimemnc.e dose (based oo mg.'m. No compolllld-related tnmours "1\ ere obsm-ed in a1 -yelll' rat smdy \\i1h p:ra;ugrel exposures rto greater than 75 time5 lbe reco=l!ded lb.empelftic exposure5 illlmmalls (based od plasl!ll.3. exposn:res ro the acm-e 8lld :lll>ljor circulating l!um:m metabolites). There was B.ll i:!lm!ased idrideoc.e of tuii!otli5 (hepatocl!'ltu!m aden.ollli1s) ill mice O:.'.."JXY>i!d for 2 yesj:s to high do;es (>75 times human l!j.'j)05me). but Ibis was considered second:!ly to p:ra;ugrel-induced l!nz)tl!o!!-mdw:tioll. The ro-!ipeci1ic as.sociation of livl!f IUtiiiOIID and. drug-induced edz}ll!e ioduc:tion is well docu:men:edillthe liter:mn. The im.c:rease id li\-er mmoujs with p!lisiigrel admillist:tarioo m mice i5 oot consict->..red a rele\'lmt hmwm risk. 6. PHAIULI\CEUTICAL PARTICUlARS 6.1 List of ucipints TablerCo:re: ficroay.;ta.ll.ine cellulose M:umitol (E421) Crosamnellose sodium Hypromellose (E464) f.:l.gnsli!:u:a:e 12 Appendix 4b Page 13 of 44

289 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE Film-Coat: LActose mm10h}'drate Hypro!Di!llose (E464) Tilllilimudia-:ltide (El7l) Triacerill (El51B)!roo oxide yeilow (E172) Talc 6.2 llu:ompatibilioo Not applicable. 2 years. 6.4 SpKial precautiod:s for storage This :m.edidda.l product does not require 3.llY special tempemtl.tre stodjge collditiolls. Store ill me ori,gill:!l package ro pro:ect from ail :!lid mol-.--nm Satan md contents of container.4.1nmiinitlm foil bliste;r.; ill cartolls of 14, 2-8, 30 (x1),56,84, 90 (x1) :!lid 98 table<s. Not all pack sizes Dla1}' be nw:kected 6.6 SpKial preca vtiod:s for disposal No special requirem'ellts. 7. MARKETING AUI'HORIS.<\.TIO:!\ HOLDER EliLilly Neder!Jmd BV, Grootsla,g 1-5, NL R.l\ HomeD, The Nectherl3llds. S. MARKETING AUI'HORIS.<\.TIO:!\ SlJMBER(S) 9. DATE OF FIRST AUTHORISATIONIREI'\EWAL OF THE AUTHORISATIOS <{DD mooth YYYY)> 10. DATE OF REVISIOS OF THE TID."."I' {MMJ'YYYY} 13 Appendix 4b Page 14 of 44

290 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE 1. X.UIE OF THE l<ie.dicikal PRODL"CT Efient 10 mg film-<o&ted mble6. 2. QUAllTATI\'E - QU."-.'ITITA'ITI'E COMPOSITION E:u:h tablei comains 10 mg pnsogrel (as hydrochloride). Excipient:Each tablec<ontains 2.1 mg lac:to5e. Fora fullli>t of excipie=, see section 6. L 3. PH.!\RAL!\CEUTICAL FORM Film-<oa;ed mblet (tablet). Beige :md doobll!-3."1'0'0\'sllaped mblets, debo"ued \\ithlom;g' on ODe sid!! and "4759"OD!he omer. <t. <t.l CUNICALPARTICULJUS Tnnpt-uiK illdications Efient, ca-adm:mistered wilh acetyls:!ilicylic =d (ASA), is indkaled for!be pw;emon of atherolhromboric e\-enli in.patients wilb. acme coroiwj syndrome (i.e.1m>'1:1blenon-st segment elenrion mycic1lldi31 inflrrtio.n. (UAINSTE..\ti] or ST segment elentio.n myocardial infarction [STEMI]) tllld.ergoing primary or delayed percutaneou; corona.ry intl!."''enlion (PCI). For fur1her :im.fojmll.tio.n. please reru tosection 5.L <t.l Posolo ad m.ttlllod of ad:mid.i.stntiou..j.duhs Efieot sb.auld be illitia:ed with a s e- 60 mg loading dose :md lilen continued at I 0 mg once a day. Pmems tlkmg Efienr s!wnld also mke ASA daily (75 mg to 325 mg). Ill pati.ents \\th :!m:e coroiiiuy syl!d.."'me (ACS) wllo l!fi! I!I.:!JI8ged with. PCI, premarure discontinnation of any alllipl.atelet agem, illduding Efient, could result in an :increjsed ri.sk of Chroml:lo5is,myocazdial illfaict:ion or dealh due ro!he patient' s ll.lldo>.dying disease. A ttea.!lllflll of up ro 12 monlh.> is recunless me discollridnalio.n of Efient is clinically Uldicated (see secnom 4.4 and 5.1). Pmi11nts >75\"'ars old The use of Efient iii. patients ::: 75 years of 3ge i> gen.not recommedcied. If.after a canful inditidual bene.fitrisk e\"'aluation by the prescribi:n,g phys1dan (see section4.4), ll:eatment is deemed llll!ce»aa)' i:n me patients age group ;:75 ye:u:s, theafollovri:ng a 60mg loa.di.dg do.;:e a redoc.ed lll.aiml!dsik.e do.>e of 5 mg should be presm"bed P:ltients;:75 years of a,ge bm e greaca seiillti\ity co bleeding :md higj!er e:q>a.sure co!he acri..-e- metabolite of pr.lsngrel (see section; 4.4, 4.8, 5.1 :md 52). The e\ideoce for the 5 mg dose is based only on phannacodyuamiclph:arm.xokideric :lll31y.>es and no cl.imcal data cum!mly e.on me safei}' of!his do.;:e in the patients age group:::75 yea.j5. Pari11m;wcig:trinr: <50 kg Efient sll.oold be gi"o.". 'ell as :1 sidgl.e 60 rug loading dose :md men contimled at a 5rug once daily dose. Appendix 4b Page 15 of 44

291 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE The 10 m,g mainceiit!oc.e dose is 110t recollmlii!dd!d. This is duto m illlcreasin e..'q)oiure to me acti\-e lll!tl.bollie of pra grel, md ao illcre:lsed risk of ble-eding id patimi!: v.ith body weight <60 k,g "'ohen gn en a 10 :mg onc.e daily dose compari!d llith p:uiems0 k,g. Effie:!C)' lmd safely of dle 5 :mg dose bavnot been prospect:h-ely a;sessed (ssections 4.4, 4.8 a:!l.d 5.2). RRnal im pairm"ni No dosl! adjusimmt is nessary for patient> widl relll31 impaiiml!lli, fodpatimts wi.lh el!ld stage renal diieaie (Si!!! si!cti.on 52).'Th!O!E! i;limlted th<!r.ipewic ence inpatients wfth renal impairment (see section 4.4). Hparic impairmror No dosl! adjus'l!iwlt is necessary id subjects wi.lh mild. to ll!ioderate hepatic fmpai:rme>'!l.l (Child Pugh class.4. aijd B) (ssection 52). There is linililbe;rapeutic 1!-Xperience m pati.ems wim mild aijd ra.:e be,patic dysfimaion (section 4.4). C hi/drrn amfndo!qu4f!rs Efimt is110t.reco=dfor use illchildren below age 18 dol! to :1 lack of data on Wei)'lmd efficacy. Method of admi lll1 1r3.11on For or3l usefiem may be adlnin.istered wilh or \\ithow food. Acbmniitrlllion. of me 60 mg pra;ugrel loading dose ill me f:b"ted state may pl"oiiide most rapid onset of action (see section 5.2). Do 110t crush 01 break the tab!& 4.3 Contr:lill.dic:alions Hypmensit:i\ityo the aai\'1! subst:mce or co aoy of the excipiellis. Acti ;-.e palbological b1i!!!dimg. History of stroke or twisint iscbaemic atmr:k (I1A). Sl!\-ere hepatic imp::limlem (Child. Pugh class C). 4.4 SpK:ial w.u-uids a nd precautions for 1IS4! B!flfding ri&k Ill me pbase 3 di:mc31 Dial key exdnsioll criteria indt».!d. m illcre35ed risk of bleeding; :!Daemi:l; lhromljoc}lop3eni3;a history of patholo,gical mmcranial findings.patients with arn:coronary S)'DdJ"omes Wldergoillg PC1tteated \\ith.efient a:!l.d ASA sbowed an incre3sedrisk of lll3jor :md minor bleediing ac.cordingo th@ TThfi ch:isffic.arion sysc!!m. Therefore, the use of Efie:nt in patient5 at im:rea.sed risk of blg s!lonld only be con;juohen tbe benms id temjs of p1o?\'entioll.of ischaemic ents a.-re deemed ao oum-.eigh the risk of seriol!is b1e.this conc.em applies esperislly to pariems:?:1, 5 years of age (see below). v.im a pr l)' to bleed (e.,g. due to recent t:r1imua, recem smgl!,ry',recnt or l1!<1im!nt g)!qtrointestil!al b'leeding. or acm e peptic. ulcer disease) v.iab. body weight <60 kg (see sections 421!1ld 4.8). In these padems me 10 mgmaintmance doseis 110:olllllll!nded. A 5 :mg maimel!wlcdose sbould be IISed. wi.dl. concomita.l:u admini.smltion of med.icill:l.l prodnct5 that ll13)' increasthe riik of bl,g, im:lndmg or:jil. amic.oagulam.15,dopidogrel II.OIHteroida.l anti-imlmnm.atory drugs {KSAIDs), lmd fibril101ytics. For palie;m \\ith aai\ e blfor wbom reu al of me plw:m.jco1ogjcal eff.em of Efien1is required. platelt tra.llsfui;on IJ!3Y be appropria The use of Efient in. patients?:,75 ye315 of age is genenill)' oot r:ec'oaijd sbould only be lllldm:!ken wilh caution after a c:!.ieful in.cli1iidual benf!fulrisk o?\'almtion b)' the p:rescribillg pbysicim indicates that bensfin ill terms of p:re..-ention of isdlaemic e\"l!llls Ol!Uweigh!berisk of serious bli!edings. In me phase clinical trial lbse patients \\'ere a.t greater risk of"bleed.ing, mc!ud.infall1l 15 Appendix 4b Page 16 of 44

292 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE bleeding,c.omp:ued to patient> <15 years of age. Ifpre;cribed, a lower llt3inteiiwi.< e dose of 5 mg should be w:ed; ihe 10 mg!i!3i:oteuajke dose i.;iioi recoiiilllellded (see section> 4.2 and 4.8}.. Thempeuac experibnce \\ith prasugrel. i.> LimitEd in JX!.tient> v.l]th re:tml fmpai:tmem ( UK!uding ESRD) and inpati!!lll!i 'l'>ilh mod<>...r:!!e! hep:uic. impairment These pariems may have an illcreased bleeding risk. Therefore, pra:;ugrel should be used with c:awioc inthse p:uiellls. Thempemic experibnce \\ith prasugrel. i.; li:mi{ed in Asi:m patienl!i, Ths-efore,pra:;ugrel sbotdd be used ' '>ilh catrtion in these JX!.tients.. PariaiS shcrulcl be told!hal' ilmit!ke longer thm usual to stopbleeding whee they mke prasogrel (incombination \\ith ASA), and that they should repon any unusual bleedlc.g (site or duration) to their pl!yskim. Sw-gey PariaiS should be achised t o illfoim physidm; and dentists ibat they are t:!.ki.ng pmbefore any sur,gery i.; scheduled lll!dbefore lilly new medic:idal produd is taken. If a patient is to uod&go electn e sur,gery, and an aotiplatelea!feo is not di!sired, Efiens!ioold be cfucontinlli!d at le3si 7 days prior to surgery. I:ca:eased freqtwlc}' (3-fold) and 51:\-eril}' of l!'leelwty occur id p31iect> WldergoiDg C.G surgery 'l'>iwd 7 day.; of discollliiima.lion of(see 4.8). The benefit,; and risks of prasugrel should. be carefully consid&ed inpatients in whom the coro:wy anatomy has not been def'med alld urgent CABG is a possibility. 'i"hrmpjbotic Tltromlux:\7opatmic l' rprim (TTPJ ITP has ll reported v.rith i!he use of other thiecopyrictille.;_ TIPJS a seriou,; condilion and reqllil'es prompt treatment.efi.elll was not associated \\ith TIP inclinical Dials suppo:l'timg.regi:suaticm. Pll.liems wit!ij. mre bered:ill!jy problem; of ga:laoose intolerance, ihe Lapp lactase defidency Ol' gj]uc.o'.>eg;ili!c.tose b;orptioll should no< take Efiem <t.5 lll.ttnciion with other medicidal prod ucts and othtr forms of illteraction Wmj/1rin: Coocomitml 3dmim.istra.tion of Efi\\ith towuarill dei'\'ll.li'\ es other than w:ufarill ba:i DOf been stndied. Because of t!ie po:enti31 ol' iccre:>.ied ll5k of bleeding, wlllfaml (or olher colllllibria d.erinrin.>) :mel prasugrel should be co-:!idmillistered wid!caution (se.! secnoo. 4.4'). Non-zwroidal mtri-illflammatory drog;> (NS.4!Ds):Comomitlllll sdmillismltioll wifu chro:nic NSJ. \llli ba:i 1101 been studied. Becau;e of lb.e po'l!lltial for increa;ed risk ofbleedimg, chrollic NSAID.> (illdudilj.g COX. -2 inhibitors) and Efiem should be c.o-adl:uini.stered v.rith cawion (see.secti0ll4.4). Efieot Cllll be c.o:ncomimntly a ered M!b. medic:i.dal producrs mel:lbotised by cytochrome enzyme,; (idclwllilg statids), or medidoal produr1. 5 that are id.duc.ers or inhibitors O'f cytochrome P450 ejiiz1'1!lei. Efi:e.n;Cllll also be coccomit:uut'}' administered. witb ASA, heparim., digo-:'litl, md medicmaa pl'odu>cts!mt ele>-ate glistric ph, illc.ludi.llg prololl pump i.tibibitols :melh,blockers. AUb.oU?b not studied in spec:i:fic inter:ktion studies, Efi.ect been. co-:ldminis'tered ill the phas: 3 clinical trial wilh low molecular 'l'i!ight heparin, bh'\!l.irucli.n. and GP lib/ida inbibiton (no inform: tioll a\"allabte regarding ibe type of GP IIbi!IIa inhl'bitor used) \\ithow e\ida ce olf di'dically siginjficam ache rse idternct:ions.jc;;nylsali.cylic acid: EDect i.; to be admim.ist&ed co:ncomitlllld)' \\ifu acel}'lsalicylic acid (ASA). pha:m:!acodynmli.c mternction \\itb ASA leadimg to :m idcrea;ed risk of bleeding ii possible, ihe demo:nstr:ltion of the efficacy :md.safety oj pra5ugffi comes from patients concomitantly III'E!a:ed wiib ASA. 16 Appendix 4b Page 17 of 44

293 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE H parin: A s lilltm\-enous bolus do:..:e of WlfractiODoSted heparin (100 Ulkg) dld DOt significantly alter the p!llsugrel-m!!diated inmbition olfplau;lt awegatio:!l Likewlie,prasugrel did I!IQi signiii=lly a.l.r me effect of llep:uin ou measures of c.oogulalioll. Therefore.. botih m c.in31 products am be acilninisrered c.oocomill!lltly.au mcreasm ris.k of b'gl is po5:sib!e when Efiem is co :l Cfmi!ristelrl!d \\ith b!p3rill_ Szarins: Aton1151atin (80 mg daily) did nc» Slter the phaml:!cokin&ics ofpn;and its inlnbition of platelet 3ggregatiou. Therefore. stat:in> that are substrates of CYPJA are no;anticipa:ed to m e llll effea OD mepbannar.ol;inet:ics of pr:l!sugrel Or its i.nhibiliod of platelet :ll,ggreggtfod. M"dici7Jal products that Q/(rl_ym gtmric ph:daily co-admi:ai>ttlltio!l of ranitidle (mblocker) or lamopr:!zole (a p:romn pump i:nlnbiror) did DOt change the pn,-ugrel scth-e Waboli's AUC and r_, bm det:re:ised the C...by 14% md 29%, re5pecth:e}y.in llrepba;;e 3 c.linlnl trial, E.fiem Vi'35 3dlnimist. \\ithout reg,ard to co-acfminimatioc of a protem pwup illhlbitor or H! blocker. Acfminisc::uiou of lhe 60 mg prasugrelloadlcg do-oe \\itlhom concomim.nt use of protod pwup inhibitors may pr ide most n pid oll5et of action. Jnhibiwr.; ofcypm : Ke:, oco:u.azole (400 mg daily), a selecid;e andpotem inmbttorof CYPlA4and CYPlA.5, did DOt affect pmsugrel-medi:jjted idillbition of platelei aggreg:l.liou or me pmsugrel acti\-e t:1bolile.s AUC :mel Tbm decrea;.ed tile c_ by to 46 - fore, CYP3A illb!.bitols such as azol antifull;ggls, mvprotease inbj.bitors. da.ridlromyciii, telithromycill. nnpamll, dilliazem, indina\ir,dprofloncin, and juice are not amidparm to!13.-e a s:ignifi.atm effect on tile p!i:!imacoldn&ics of me acti\-e metabolite. lndjwb:: qf CJlDChrtmrm P4JO: Rifampicic (600daily), a poteet induceof CYP3A :mel CYP2B6, :mel 3ll id.dccer of CYP2C9, CYP2Cl9,3IDd CYP2C&, did not signiiit.81llly c:hacge the pll3rmacoldno&ics of prasugrel Therefore,!mown CY"P3A inducers S1ICh :.; rifampicin, c::a.rbslmzepfue, :md other lllduce,rs of cytochromes P450are DOt :mridp:;ted ro ha\ e signifi.c!llt l!f' fecl on the pharm:locokid&ir.s of the acm:e metabolite. Ettff t:i ofeftmt on othllr mvdicinal f!1'0duds: Mv.dici7J al producr:; tmmrbolbtd b;} C1P JC9: ptasugrel did 1101 illhibit CYP2C9.as ildid cot affect the p!j.mnacok:inetks of S-'1'>-arfarii:L Because of the potential for inc:re: sed risk of bleedlcg,v.r:ufarin md E.fiect should be co-admimscered v.ith cauticm (sel!' section4.-t). M dici7j al producrs mt.rabolbtld b;} C1P1B6: PI:i5'11igrel iia weak inhibitor of CY"P2B6. m healthy subje<t:s, pra;ugrel decreased e:tposure 10hydroxybupropion, a CYP2B6-medlated 11110t:1bolile of bupropion. by 23 'o. Tbi5 l!f' fecl is likely to be of cl:ii!ucal c occem. only when pmsugrel is co- 3dlnimist\\ith medic.in31 p:roduct5 for which CYP2B6 li lire outy t:lbolic pathway and ba\ce a n=ow lb tic window (e.g. cydop!lo5pll:!mi.de. efm.i:rem). 4.6 Pre:IIIC)' add bctation No clil!lic.al study bas bec.ondncted. illpregcam or lacmiicg women. Animal srudies do DOt iddicate dil'ea lwmful effects \\oitb respect 10 pn,g:u.ancy,embryonal'foetal de\ elopmem, p:litllriticm or postllt!m! de\-elopme!lt (see section 5.3). Becaus:e :mimal reproduction studie5 are not always pl'ediainolf a h=response, Efiellt should be USMpn!giii3Dcy olll>y if lb!!potemlal bene.fit to me mothejusti.fies lhe po::atial risk ro the foeo:us. It iillllkno'l\111 w ther pra5ugrel is excreted in hiiiwid. brel5t milk.animal studies b' o-e slxmu excreticm ofprasugrel ill b:rea;r miilk.the we of prasugrel during bleastfeedil:lg is IIOire<ommended. 11 Appendix 4b Page 18 of 44

294 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE Pmsu,grn had 110 ef!ea 011 fenility ofm.'lle allld female rae at o:ral dose> up to e:xposme 240 rimes ihe recomml!llded daily bumm maintej a!iice dose (based on mg/m). <t7. EffKts OD ability to drin:md IISI!' madudi!s No srudies 011!be effects on ability to cm\ e :mduse machines lwr;;e bl!ec perfo!lllied. Pr:l.;ugl-e!is expected to ba\-e 110 or ne gt"b1e infillellle on ihe abilliy to dri\-e 3lld use machines. <t.8 Undesirable effkts Safeillp:lliems \\ilh acute c oronary sycdrome ucds,going PC1 -as e\'3l113.ted illone clopidogrelconirolled smdy (TIUTON) in ilich 6741 p:llielus were treated v.-iih pmmgrn (60 mg1oodicg dose :md 10 m;g O!IICe daily m:rina!.dadce dose) for 11rm!dian of 14.5 mont!is (5802 paliems were treated for O\-er 6 moctll;.4130 patients -.;, ere ireated for more than I year). The mte of srudy drug ctisconticuation dui! to ad\.-erse e.-.ellls v.-as 7- for prll51lgrel and 6.3% for doptdol Of lhese, bleeding was the most common ad\-erse.reaction for both cln.lg; legding ro sro.dy drugdi;:cominualioc (2.5% for pnsugrel md 1.4o fordopidogrel). Non-Cm'O!JLU)' ArUtl)' Bypass Grqfl (C..llJG) nlm"d b1hding Ill TRITOK,frequency of patients experil!.iicing a non-c'abg related bleeding evem is sbo'iw in Table 1. The i:dcide!iiceofkod-ca.bg-relllted milmajor bleeding, includicg life-lbre3tmiag and fatal, :l> well as ldu IllliDor b'leediog,was stati,--tically siglli:fic:mtly bigbe in snbjects lrea!ed wilb pillcompared ro dopidol, ill!be UAJNSTE:I.and All ACS popal:>tiolis.no!iigni.ficlldt diffne.dte wasin!be STEM] population. Thmascommon site of sporuan us bleedlng was th p;trointestinaliiljci 0.7,o ;, lh pmd 1.3% 1111v.ilh clopidogrel); the most frequ<>.di site of prcr;-oked bleeding WllS anerial pu:licture site 0.3% lllte with pra.sugrel :md 12% \\ith dopidognl}. Enat.'\11.'\ CS L'A/NSTE..UI S'l'EJ.IT Pr3SU Clopid Pr-asu:veJ Clopidogrel P'nsa Clopido;;reJ +AS.A +AS..... (N'=-6741) -AS..>. \. (:S=51001) +A.SA (N'=1740) +.-\.SA (N=6716) ::.{g80) (N=l736) TIMI m1jor bleedillg' l..ife-<1hrelrurlm!," 1.3 u 13 O.S u 1.0 Fatal OJ 0.1 OJ S}m:ptor:naric OJ OJ 1) ICF' EW(11iring il:otrope; EW(11iring sur G!l il:!m-.enrion EW(11iring crm;fu;foo Ul!fu) TIMitll!!!.or blee.itng I T b1e 1:lncidencof Non--C.o\BG rfl2ted bl(palie11ts) OJ OJ OJ O.S O.S 2.4 1: a Ctwmrlly adjr Jtcaw...,.tkjiMrJ by rn! l'flmow!w) as "",\ OC<Jtd.ul bifa rn JJ (TIJ.D) SnJyGJattfJ crt "" I>Orlot!r rmrd:jni rlr<rapu,..,.,...was. c A.oy tltmrlwltal <11 M a ydjiucdly_,.tked!itf a.utxjar rj ajall1lr bftlog/,omt;:)grjj.. 1B Appendix 4b Page 19 of 44

295 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE d lifujrn.arilfftiijl!.i<lrlijl tj"mw.oftliid81'!/01" ludu!g ajoi... r..d..._. rlk ()J'X'.S I»>J...Ud tilllt4l'l!...om n:nr. < TCH -...l b"'"" fciiiij cd /y_, bl<rjj'r t.ar.socrarzd wrrh a fall'".l.u<otogwrlf of "l:j r.jl. bur <.J ll d!_ z...rm.. P.:murs"""Y!;,. Patjqnr; > 7 hwars old Ill ibe phase 3 dilliul trial, oon-cabg--re.bted TIMI major or minor blee<wig rates for patients ill two a.ge groups wel\!! as follows: Patimn < 60 J:;g Ill ibe phase 3 dinka!. trial, oon-c.'\bg--i!!lated 'IThfi major or mi:dor bleedi!lg ntes for paliems ill two '1!.-e,ghl group> V.'ere as follows: Ill patientskg and age <75 }'e&s,.ooc-cabg--rel:lted TIMI major or minor bleeding rates v.-ere 3_6, for pn;ugii!l3lld 2.8. for clopido,g;m;ra:l5 foe fatal bleeding wee 0.2o for pmsugrel :mel 0.1a for dopidogrel C!BG-I"!l!gtpa blfwinr Ill ibe phase 3 di:di<:al. trial, 437 paliellls tmdo...rn-ect C-1\BG dmiog dte com:se of the srndy.of lho5e patiems,the rate oc!abg--related TL\-!1 llll!ljor or min.or bl!!edi.n,g was 14.1 for!he pr.uugrel group :mel 4.5,.in!he dopidogrel group. The higher risk for b1eed:img e\"ellts in subjects reated with prssugrel peni5ted up 10 7 days li'om the most rece111t dose of srudy c:!rug. For paliellls who received ibeir ibieoopyridille 'llo"itllic. 3 day;prior to C.I\BG, ihe frequeocie> ofid-!1 major or minor b-leeding '1!.-ere 26_7, 02 of 45 patients) intile prssugrel grotrp, compared \\ith 5.()1!.-a (3 of 60 parienjs) ill ibe d dogrel group. Forpariems whorec.et\"e!d tlleirl:l5tdose ofthienwilhin 4 to 7 days prior ro CABG,lhe frequenrie; decre3sed 10 l lj' (9 of ao pati!!llts) ill the prssugrel group :mel 33% (lof 90 pariems) id the dopidogrel group. Beyo:nd 7 days after drng discolllidualio:o,!he ob-..en ed ra:l5 Of C.I. \BG-related bl' eedi:dg were sil:niil.3r iberne eo trealment groups (see sectiou4.4).lth wu1rlll1aion:; Table 2 5UIDill.lrise.> bae.m!lllbgic aod non-haem gic ad\ erse re1ctioos illlrito."l da;.sified by frequeocy 3lld system o gan class. Frequ.enries aje deiml!d a; foro ws: Very common1110);common11100 to < 1110); mk OIJliJitOII lf looo io < 11100); rme1110,000 to <1/1,000); \"li!i!y rare (< 1110,000): DOl!Ww.'ll (ClllUlO: be estimated from tile available data). SysttDIliD Table 2: Ra.emorrhaPc Chs5 CoDUDOD. nd Soll-hnmorrhaadnrse nactiods L'ncommoa Rare Br'ood a1ld1,}-mpira:ic - Sysmr disordtm f.}diswdm Eve ha.emoaha rmn.-jar DisordQ7l H I!I!!Illtoma hspiroror;.tllomcic Epi '1ll.'!is HaemoJlcy>is tjlfd li'u'diastinal tfisorligr Ggs_troi1JititDraJ Gb"troilltestinal haemoliha.,g.e R.ettoperitcmeal g;e tfisorligr R.edal l!:aen::onhage Hai!I!!Illtochi!Zia 19 Appendix 4b Page 20 of 44

296 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE SJ:in QIIQ SllilcJmmrOII! l!imfr riiumiqn ]U JtQ) (!JidL'Ti1lar; disorrkn lklfcal disorrin-s tmii admi11iluatirlll siyj COJJdiJioll! lrljury,poisolling and rjtoc«jlraj "cojtfpjkaiit»>! hih Ecchvmo.;i; H =arl!u \re;.;el plldcilin! sire ha=ato= Jlw:.citure sire m e Gillti\1111 blel!d:in! Con.nmoc Po1;-proc.edural hae!:ooiii!j..g;e Subruw:.eou5 hdemaum:a Ill patients 'l'otith or v.ithom a history oftia Or stroke, m ldddence of stroke iiitbe phase 3 clinical lri:u W:li :15 follow'> (see se<tion.4): Historyof nor stroke Pn;-agrel. Clopidogrel Ye.-!N=51S) 6.5(D% ICE u \ {()!' CH'} :s'o (N=B090) 0.9 ( 0.2 ICH ) L. (0_3ICH ) *JCH=mrraorm.ral hagmol'rltng. 0 Onrd 0\-erd.o!ie of Efiem may le:lld to prolonged bl.eediing time and subsequent bl-ung complication;. No data are a\--ai!.a ble oc 1!ie m rnaj of die pb3j:m.jcological effect of pra:roue-1; howe> er,if prompt correcriod of pml011,ged bleeding time is required. plate:lt tnllisfu"..ion 3.lld.'or olb& blood. products may be con;id«..red. 5. PHAR!.L.<lCOLOOICAL.PROPERTIES 5.1 Pbarmacodyumic pro rties Pharmaa rfjmamic:. Pt.-.g; rel is 3ll i:nhi.biror of platelet acth--ati.on and a,gg egation throughthe m "i!!!iible billdin,g of its xli'\ e metabolite to the P2Y 12 dass of ADP receptor.s on platelecaillce pla telets pa:rtici;pate id tm iciliati.on :mel'or e'\ olution of thrombotic complianion; of a:bhoscl:roti.c disease, ill!ubiti.on Of platelet flmclio!l em Te'SUli in the reduction of tbe mte of cardlo\1&ular e.--eats such :15death, myocardial icfarction, or stroke. Followill;g a 60 mg loading, do;e of plllsup'e i:nhibinoo of ADP-indUICed pl:atl:let a,ggreg;!lti.on oc.curs at 15 minwe; witb 5 J.l}\1ADP and lo mi:ml!es will!j f ADP. The.lll4'1:imum iohibirioc. by prasugrel of ADP-ind:llced plal:let &greg;j.tio:j. i.s Sl,.w1tb 5 J.l}li ADP aod mo \\ith 20 JL\f ADP, id both case> vi. lha of he:rlmy subje!o!:is :md pati.ecl5 \\<iib. smble :llthero;clero51s a.chieli. n.g at least.54n inhibitioo of platelet a_ggre;gatioll by 1 hom. P!!a.supel-media.ted tchibitionof pla:telsagyegatione:shibits low between-.subject (12o) aod 'l'o thill-subje!o!:l(9, ) n.r.iability 'l'otith bom5!1-i :md 20.4DP.:Me31l st!<lldy-state tchibiti.on or pl.ate:lt aggregation was 74,.and69! a respeclh:ely for 5 JL\f ADP 3.llid 20 p.l.l4 ADP,aod was achie>ed following 3 to 5 days -of admillismltion of tm I 0 mg pra.sugrel ma.imell!!lll.(e do;e preceded by a 60 mgloading dose. More dian 98% of subjeel!i had20'! o i:nlnlrition of platelet aggre;gatioll dwingmaiiotel!ij!d.ce do.>io.g. Platelet awegation gr:!duafiy rerumed to baseliol!\-alue; after t Htllt"..ot m. 7 to 9 day;after 3odministr.J.tion of a sillg1je 60 mg LOado;e of prasugrel and m 5 day;follo\\<idg d&octi.uuatioii of ma.imell!!lll.(e dosing a1seady-smte. Appendix 4b Page 21 of 44

297 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE Qopidooo:Followmg adm:im.is11r.1tion of75 mg dop.idogrel ollc.e d.:lily fo10 days, 40 bealmy mbject> 'l'i'ere switched to pr:151lgl'el 10 mg o:nceo daily withor \\itbout a loading do;e of 60 mg. Simil:u olrir in!uoiti.on of plat elet agg!'!g;ltio::t wa.; obse,n;ed. with pr.15ugr!!l S\\itching pmsugrel60 mg loading dose resull1!d in!he ll!idst rapid oli.set of highs- plat!!let inlllditio:n. Followmg :lldmilristration of a 900 mg, loadilig dose of dopidogrel ('aim ASA), 56 subjec.ls \\ith ACS were reared for 14 days with eilheri 10mg o:nce daily or do;pidogrel 150 mg o:nce daily,:md tbm rnitthed to eitber dopidogrel l50 mg or pmsugrel lo fo llliiomer 14 d.:lys. Higller illhibilioo of dlrerny to platelet aggregation 'li-t as o05en;ed i:o palieot!; switched ro prasogrel 10 mg compared 'lltilhthose reared with dopido,grel l50 In? No d3.l:!l :m! a -ailable on swirrhing from a dopidogrel loadmg do;e directly ro a pnsugrello:l.ding dose. mrary mtd Sqffty in AcurQ Coronary Sp!dmmQ {ACS) The phase 3 TR.ITON sto.dy comp:m!d Efient (prasugrel) \\ith dopidogrel, both co-admfol".teredilh A.S..>. \ and other stam.dwi therapy. TRITOK was a paliem, multicentre intemstio:n.a!, lmldomi;ed, double blind, panillel group study. ParieJm had ACS 'llt idl m...mte to hi,gh risl UA, NSTE.\fl, or STE.\fl :md were 11l3.113ged with PCI. Pariems '1\itm. U.!t.INSTR.\fl witbi:d 72 hours of symp:dill5 or STEMIceen 12 hams to 14 days of symptom; ere Fdldoll!lised mer k.oowledge of corolw)"anatomy.palil!lll!i \\ith STEMl \\itlrin 12!law:; of.s)'ilqltoms and plrumed foprimary PCI could be randomised \\ithout knowledge of corolll!i}' 3llillromy.For all p:nim, ililoading do;e c ould be administered mzytime between mlildomisalion :md 1 hour after me patient left iliatheieriia'tioll. lab. Panems r:m.domist!d 10 recm-e pll!su.grel (60 mg loading dose followed by 10ollC.e daily) or do;pidogrel (300 mg loadillg dose followed by 75ollC.e daily) were tteated for a mediad of mollibs (1113:ltimum of 15 lliiollth; \\itb alllidimmnof 6 mow:lls follow-up). Patiems also recei\-ed ASA (75to 315OD e d.:liily).t:se of my thiedopyrididwithill 5 days before emolmellt Wll.i an e.'ociusiod aiterioll. Other thpies, such as lr.!p:uin and GPilb.iiiia mmoilors,wert! admlni.stered at me discretion oftbe phpiiciall. Approxil:n.ltt!ly 40% of patients (im. eoch of me 1reatl!n!!m,group5) recei t!d GPDbiiiia idbibitojs id snppon of PCI (:oo iofo=tion a\-:illable reg:miiog the type of GP IIbiiiia inhibitor used).appro :tima:ely ofpaliems ( w eacll of the treatmellt groups) rec.ei>-ed 3lltililrombills (bep:jirio, low mole<uiar weight bepario, bn alimdln, ootll 1 agem) dirt!ctly i:o support ofpcl The uial' s prim:!iy outc ome me3sllre was me lime to fimocci!lnllci!' of aidio\'ascular (CV) death, oon-f.atll myocardial inf.arclion (Ml), or.non-fatal stroke. Allilll)'lli of!he composite endpoint to lhe AJI ACS population (combim.ed UA NSTElYfi:md STE il cohort>) was cootinge:ot on sbo\\iog siatistical 511pi!liority of pl \"er5us dopidogrel im. the UAINS'IE.Il conan.05)..ml ACS pcpu /atiqn.: Efiem showt!d superior efficxy c.omp:ued to dopidogrel illredudiilhe primary composite ourcome 1!\"etm a:> well as the p e-specmed sec ocdary oli!come e\ l!lll!i,idclldiog Yent lbromlxl5is (see!table 3). TbbeJiefit of pmsugrel wa> apparent witbi!l lhl! fi.rsi 3 days :md it pernsted. m me end of study. The superior efficacy was accomp:mlt!d by 3ll im.crease in majobleedin,g (see seclion; 4.4 2l!d 4.8). The patiem population was 92% Cauca;ian, 26'0. female,:md 39'0.5 } 'em's of age.the beoefus associated wim pra;ugrel were illldepell.deot of the u;e of olher acute and Jo.g-tenn c:ardio\'llscohr lherapie;, im.c.ludid.g be.parinl!ow molecul.u weight bt!pario, bi l lliru.clm, imravedous GPIIbiDia illlhibiton, lipid-lmnri.d.g mt!dkim.al product;.bi!3-blocken. a!l.d angjotmsm cooyerting ellz}'illl! inbjd. i.ros.the efficacy of pmsugrel 'llt'l!os ill.depecde.nt of the ASA dose (75 mg m 325 mg OD e d3ily). The of oral anticoagul3.llis, co!l smdy anlipl>ul!let UL<>ditim21products and thionic KS>, \IDs was oot an 'edin TRITON. Ic me.'ill ACS popuhnicm, prasugrel was associated 'llti.lb a lower illcideoce of CV death, oon-f.at:tl a,ooon-f.atal s!i'oi!t! compared to dqpidogrel,.reg:ndl.ess of b:l6elille clw:'actmstics sudl:u age, sex, body wei,ght,,geogmpbical.regicm, use of GPIIMila idhloitors, and stelll i)'jii!. TbbeJiefit was primarily dne to a significant decrease illiiod-futal fl (see mble 3). Snbjects w:idl diabe:l!.'s bad s[.gnifi.cant recfuction5 ill the primluy and all secondaly c ompoendpoints.. Appendix 4b Page 22 of 44

298 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE The o&.ien-ed bene.fir of prasugrel in parimls?: 75 }'ears was less lhall tb.aj obsene d illpaliems <15 yem. Pati?: 75 years we;e at illaeased risk of bleeding, illduding fatal (see section> 42., 4.4, 3Dd 4.8}. Patients?:75 ye:m im. whom lb!!beaeftt 'lllilh el was DKJre e\ident illlduded those \\ith diabetl!s, S"'ThU, hipri;k of stan wom.boois, or rectu110!l e ents.. Pal!iems \\ith a bh'"tolj' of TIA or a h.is!oi) of ischaemic strolte more ihan J DKJndls prior to p!llsiigrel mernpy bad uo redlllctionill the plim:uy compos:iie elldpoint. TablA! 3: Pa timts with. 011tcome Ennb in TRITON Primary Anal)'sis Prasagfl Oopido el H:uard Ratio (HR.) p- + ASA +ASA (95 CI) nln Outcome EnD!s (N=6SB) =6795) ADACS Pri:Dwy CompositOu.ltoDLt Ev01b " O.ll U (0.7l2, 0.9()2) <0.001 Ca!'dio\oa;cW.U (C\1)' &!1h. lloilfatl.j or con fatal ;uob Primn'v Illdrndllal Ou.trome E'I'Hits CV death leo S6 ( ) 0307 Nonfatll W (0.672,0.853) <0.001 Nonfatal stroie OJ> 0..9 LOl ls o.m }0 t'ainstemi (N=50U) 30) Pri:man Composite Ou.ftoDLt E'I'Hits C\1death. nonfa1lll Ml or nollfatal ;.trob " O.B ' CVde>l.tl: La u O.llS5 Noll.fatal W D.a73 <0.001 Nonfatal strob 0.& OS O.!H9 :0.633 L:il S'JL\ ) =1765) Priman Co.mposite Ou.f rome E.v01ts C\l death. nonfatal M1or nollfatal moke 9.& 12, (0.649 O.S'l CVde>l.1h & ( ) 0.12'9 Nonfatal W 6.7 u (0Sl!S..O.!l'4&) ll.oto Noll.fatal stroke Ll Ll L097 (0590.,2.040) Ill!be All ACS poplllarioll, malysis of e-.ac:ll of!hi! sec.ondaty mdpoims showed a si amt beumt -001) foprasugrel '\'ej:su> <lopidogrel. Tbl!Se idcluded dei'illite or probable stem thrombosis at sludy ead (0.9% \"S 1.8".<0; HR 0.498;C , 0.683);CV de:uh, nonfatal MI, or urgent target \'e>sel m; a>eul.:arisation d!routh 30 days ( 5. s 7.4HR 0.784;CI 0.688,0.894);all canse death, nomtal ornonfa.<al.stroke through study end (10.2% H 12.nHR ; CI 0.751,0..919); CV dmth, oonf:aml :Ml,oollfar.al srroke or rebospitalisarion for cardiac i5cbaemic e-. em tllrough smdy l!ll.d (1L7 % \'S l3.8o; HR O.JB8;CI 0.762, }- Amll) si;.ofall c:anse deam did not sbow ally siguific:mt diffhedce between. prasogrei3dd dopidogrel im. the AU A.CS population{2.76% n 2.i),in me UAINSTEM:I pcpulati.on (2.58,.1;'5 2.41%), and im. me STEMl popmlarion Q.28% n 4.3l%)c Pr:b"l!grel was assoc:iated \\ith a :recfuction id saent th:rombo.s:i;. through the 15 momb follow-up period The reducrioc illstem dlrombosis with Elient wasobsen.--ed both early aoo beyond lo days for both bare metll 3Dd d."l,lg stents.. Ill :m :mal)-si;. of panents who soni1.-ed SD ischaemic e1-. ent pr-=was assotil;.ted with a reduction illthe incicfo--dr.e of snbsequem p:r.im!jy el!dpoiut e.ems (7.8% for prasugrej \'S 11.9 for dopidogrel). Altllongh blel!di.llg was illlcreased 'lllilhpm..;uue}', au analysis of the compo5ite I!JldpoiDI of dealh from :my cause, nonfatll myocmlialinfarcl!ion, nanfu1:ll strolte, and non-0\bg- a:-ed TIMI major bl!.emoll'hage fin oured Efi:em c ompa:red ro clopidogrel (Hazard mtio, 0.87; 9:m.CI, 0.79 ro 0.95; p=0.004). In TIUTON,for H'ery 1000 patieuts treated v.ith Eiieot, W>_re were 22 fewer patients with III)'Ocardial infarcrioc., 3Dd 5 DKJre \\ith cojh:abg-retated Tl?!1. I major baemm:rll3ges,com]x!ied wim. patiedts treated with dopidogjel 22 ' Appendix 4b Page 23 of 44

299 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE 5.2 Ph:mnacoki:Jlttic proptrties Pm; grel is a prodrug :!llid is rapidly membolised in ln'o to :m oclive metabolite and imocn e mt:lbollib. The active metabolite' s e.'tposure (AUC}has moderate ro Ic.w between-subjec.t (2no) :md v.ilhill-snbje<t (l o) nriabilir).pmiugrel's pbamiac.okin.etics are similm in healthy subjects., palim'!s v.;dt stable atherosclero5is, :md patients ucdergoin,g pernttaceoos COI'OIIII!I}' inten ection. dbsomnon The abso:rpli.oo 2I!d m:t:ibolis:m of pn1sugrel are mpid, v.ith peak pl!ill!l3 coilcentnl.lloo (C...) of tbe xm e D!ll!tabolite occunicg m3p11ro::tim:llel)' 30 mill.we;. The acm-e metabolite' s ee (AUC) increases propomooally over the therapemic dcr,e nmge.in a study of healthy subjects. AUC of tbe xm e Illi!tabolite was unaffected.by a high fa!, high alorie meal, but c_ was decreased by 4a9d!he time 10 read!. C... (T.,.,) was mcreased from how:s. Efiem was adminis1ered v.>lthout reg:!rd to food illtriton. Therefore, Efiem C3ll be admidb-w-ed wilbout reg:!rd to food; howe,er, tbe iiicfministnltion of prasl lo:ldijig dose in me flsied smte my p Q ;ide lll05i rapid 0115et of actioii (see se<licm 4 2). DinribJlti07l Acm-e metabolite billding to lnimrm serwn album.il!. (4'!.o buffered solnrion}w:!s 98,.._ Mrabolimt Pmg; rel is oot detected in. plasm.a followil!.,g on!. admlci5tra!ioo. ll is rapidly hydrolysed in me intesliice to 3 lhiolacro:ne. wbic:h i;; tbm (0:11\-erted to tbe acth-e metabolile IJ.y a smgle srep of cytochrome P450 mmbolism,primarily by CYP1A4 3.DdCYP2B6 aod to a lesser e.':tect bycyp2c9 :md CYP2Cl9. 'Il1f! ac th e n:wabolire metabolised 10 two inacti\'e compowlds by S methylation or c ocjuglllioo. v.ith cy eim.e. In healthy snbjec:g, patienls v.im stable atlm'o.;derosi.s, :md patients >with A.C!. recehin.g Efiem, th<>_re was oo relennt!ffea of gen dc -ariatio n in CYP3A5, CYP2B6, CYP2C9, ocyj?2c19 oo. the p!l:uma.cakill tics of prasugrel oit> idhibilion of plate!aggregation. Elfminariqn Apprmrimatel)' oflbe pmsugreldose i;; excreted in thm:id.e alll.d 27% in the faeces., as illlacm e m:t:lbolli!!i.. Thac:ti1;unembolit!! bas an elimination half-life ofabout 7A holm (I:lll!ge 2 to 15 how:s). Spedal Pop11lariow Eidoh : Ic.a srudy ojhe:lllhy subjec.'!s between the ages of20 :md 8() years, a.ge had no si.goific:mt effect OD p!w:rn.jcokilledcs of p1'1151lgfel or it> idhibirioc of platelet agg:regalioo the brge p!we 3 dillia!l tri3l, 1he mean estimated ej..-posttre (AUC) of lbe acth-e membol:ite 'lll11s 19% higher in elderly paliems 75 years of age) compared ro subjects <75 year> of a,ge.prnsragre.j should be used wid!. caution illpatients75 ye:m of age due co the poteotiaj risk of bleed:illl.g illtllli popularion (see se<licm5 42 :md H). H patic impa.irm mt.no dose adjustmellt is ece:;;my for patients \\iitb mild to modem7e impaired hepalifunctio:!l (Child Pugh Class A :!llid B)- Pb.a..TID3Coklics of pra,-ugrel alll.d its inhfuilion of platelet 3gg:regation were similar insubjec.ts v.ith mild 10 m te hepatic imp:wment comp:!il!d to health)' snbjeas. Pllarmacokilletics aod pharmacodyu.mics of pn15ugrel in pariems v.ith m-ere hepatic imp:titment ba\ e 1101 been srudied. Pr:uugrel Dlll5t be used in patients \\ tb se -ere hepalic imp:titment (see seclioo4. 3). R.Rnal imuairmtmi: No d05.3.ge adjlli"tmellt 9e.CBS:ll)' for paril!llts v.ith re:ca.j imp:llim!.em, iiid.uding patients with end s'lllge fl!ll3l disease (ESRD). Plwmacolcin tics of pllis1lgrel 2I!d irs illhlbition of platelet 3gg:regation llll! 5imilar in. patients v.itib. moderate rem! impai:r:melll.l (GFR l0-<50 mllmllllfl.73m") 31ldhealthy snbjecis. PrasugrelLmediated id.hibition of platelet agregation was also Appendix 4b Page 24 of 44

300 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE similar inpari.ents \\ith ESRD who requiredhaemodia!ysis c.ompared to b.eallhy subjeas, a!!hough C... :md AUC of the' acth e meiabolite decreaseil 51,.8lld 42,., respectively, ill ESRD patieoti. Bodll IH1ighr: The!!lll!ml expostire (AUC) of me acth'e met:lbolite of prasugrel is approxim.ltely 30 co. highl!r in h11:ilihy subjem aod parii!ms wi.lh a body weight of <.60 kg comp:!led to chose wei,ghing 0 kg. Pr.lsugrel uld be used 'llliilicanrioo m p:uials \\i1h a body weiof <60 k,g dne co the poientialrisk ofblee m ibis population (see seciiod -*.4). ErhnicilJI: In dinkal pl!.:!:rmacology smdies, aft;!adjwfor body weight, the AUC of thi! actin! m.et:lboj.ke W:li :!ppiojrim.1tel)' 19% higher iiichillese., Japanese,:md Ko:re3llsubject5 COmpared to mat of C:tna si3.lis, predomilwllly mated. ro high11r aposme in AsiB.ll rubjects <60 kg. There i5 110 difference in aposure IUIIIOilg Chinese. Japamese, :md K.oreim snbjects. Exposme fd snbject> of.1\fj:icad :md Hisp:uric descent is comparable to that of CancasiallsNo dose adjusmlli!m is IKon:mended based O:!l edmkiry alone. ndgr: In beallhy subjecli :md pati.ents, lbe plwm.jcokillletics of pmsugm l!l'e similar inm.en :md women. Childre! and ado!t>.sulll<s: Pll:mnaco!.."inl!iics aod pharmacodynmrics of pr:b ba\'e! oob een evaluated ill. a paediatric populariod (see secrion4.2). 5.3 Pndillical s fety data NOIKliDical dat:l r!!'l."eal oo spedal h:!z.url for hum:ms b:lied OD con10'emional stnd:ies of 5afety pl!.:!:rmacology, repeattoxid.ly, genotoxidty, can:inogellic po:en.ti31., or coxic.i.l) to reproductioll. Effects illdolh.iidfcal srudies were obsen ed onl'y at e..'j)oim:es collsidered suffid.emly fd e::tces;; of'lbe ll11lxinmm b.mnan apo;me illdic,atillg little rell!'\'lmce to dillkal use. Embry-o-foetal denloptoxicology smdjes ill rats :md rabbrts "'-ed oo e1.idence of ma.1fm:mati0115 dne r.o prasllgl'el. Ala '-e!y bi,gh dose (>240thi! rec ommended d.ail}' hlidi2ll mai!l:enmce dose on afm' basis) that caused effecls on ma c!mlll body we.i,ght a.ndlor food coibiiiiiprion, tbere was a slight decrez.e in offsprill,g body we.ight (relative tocontrols). ID pre- and poshlaral rar smdies:, l!ll.3.ten13l tteatmenl bd oo effect on 1he beha\ioo..'lil or reprodncti --e de\ elopmem of the offspring at dose> up to ml!'xposure 240 limes the recommended daily human maimemnc.e dose (based oo mg.'m. No compolllld-related tnmours "1\ ere obsm-ed in a1 -yelll' rat smdy \\i1h p:ra;ugrel exposures rto greater than 75 time5 lbe reco=l!ded lb.empelftic exposure5 illlmmalls (based od plasl!ll.3. exposn:res ro the acm-e 8lld :lll>ljor circulating l!um:m metabolites). There was B.ll i:!lm!ased idrideoc.e of tuii!otli5 (hepatocl!'ltu!m aden.ollli1s) ill mice O:.'.."JXY>i!d for 2 yesj:s to high do;es (>75 times human l!j.'j)05me). but Ibis was considered second:!ly to p:ra;ugrel-induced l!nz)tl!o!!-mdw:tioll. The ro-!ipeci1ic as.sociation of livl!f IUtiiiOIID and. drug-induced edz}ll!e ioduc:tion is well docu:men:edillthe liter:mn. The im.c:rease id li\-er mmoujs with p!lisiigrel admillist:tarioo m mice i5 oot consict->..red a rele\'lmt hmwm risk. 6. PHAIULI\CEUTICAL PARTICUlARS 6.1 List of ucipints TablerCo:re: ficroay.;ta.ll.ine cellulose M:umitol (E421) Crosamnellose sodium Hypromellose (E464) f.:l.gnsli!:u:a:e Appendix 4b Page 25 of 44

301 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE Film-Coat: LActose mm10h}'drate Hypro!Di!llose (E464) Tilllilimudia-:ltide (E17l) Triacerill (E151B)!roo oxide red (E172)!roo oxide yellow (E172) Ia!c 6.2 Incomp:atibilioo Not applicable. 6.3 Shelf life 2 }'1!3TS SpKi:al pnu utiojb for ston This mediciml produddoes not require :my special temper:ltur.storage ccmdi.tions. Store ill me oll,gin31 package10 pro:ect from air :md mol.--rure_ 6. 5 S3tun :uul contmb of contm.er.ojnmioium roil bliste;s ill caltolls of 14, 28, 30 (x1),56,84, 90 (:d) :md 98 tllblm. Not all padt 5ius m.1)' be DWketed 6. 6 SpKi:al pnu utiojb for disposal. No special requiremens. 7. MARKETING AUTHORIS..<\.TIO!'i HOLDER EliLilly Nederl:mdBV, Groots)ag 1-5, NL RA Hoolen, Tbe Netherl3llds.. 8. farketing AUTHORIS..<\.TIO!'i SU!.ffiER(S) 9. DATE OF FIRST AUTHORIS. TIONIREKE.WAL OF THE AUTHORISATIO!'i <{DD month YY '! :> 10. DATE OF REVISIOS OF THE TE:\.1 {MMIYYYY} Appendix 4b Page 26 of 44

302 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE A.. M.lliliFACTIJRil'iG AUTHORIS.ATIO:o-1 HOLDER RESPOSSIBLE FOR BATCH REI.Ll\SE B. CONDmOl"S OF THE M.UKETING AtiTHORISATIOS Appendix 4b Page 27 of 44

303 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE A. MA.i.'IUFACTURING AUTHORISATIOSHOLDERRESPOSSIBLE FOR BT. CH RELEASE Nam-e and add:ress of!ire rn..mubr:mrer r e yowi"ble for b:;tch ;release Lilly SA A "'da de Ia Indu;iria 30 B Alcobmdas (Maand) Spain B. COSI>ffiO "S OF TilE MARI..::ETISG AUTHORISATIOI'\ COSI>mONS OR RESTRICTIOI'\S RECARDISG SUPPLY A.". 'D USE DIPOSED OS TilE M.-. \BKETJlliG Al lti'horisatiosholder edicmal produa subjecr to medical prescriptioll.. COSI>ffiONS ORRESTRICTIO:I'iS WITH REGARD TO THE SAFE AJtooD EFFECTIVE USE OF THE MEDICISAL PRODUCT The :\f.ah should lifo\'ide educational material to :illpbys:ici3ll5 whomy be m\-oh ed in Ire patiem; withpnsugrel. The fomw md me3lll5 of dis millatio11, of!bi5 Dl.J Iial should be disrussed with the appropriate leam<!d socienes... The re;ulls of lhe disciission, 8.l!ld where approprme die material, should be agreed with the nrional compe:ent :m.m.ori.l) al!ld be a\':lilable prior to launch in eachr sate. The educational ma1erial s!ioul.d iddude: A copy of the SPC Empbasis mat o Se\ ere haemon:b.a,gic e\' are 11110re freql!leut in patieots75 ye= of age (idc.lndiog futal enm:s) or those 'Qo-eig < 60 kg o Tre:IBlll:ll.l with pra.;ugrel i.; gen<!r:illy!lot recommel!lded for patiems of 75 years of age. o If, after a c.ar&ul i:ndividtw ben<!fit/risk enlwtion by me prescribing pbys:ic.i!l.ll, treatm<'...llt is oecess:!.!}' inthe75 yeafs age group!hen folloa loadiog odo.se of 60 mg,a redur.ed maimedadc.e dose of 5mg should be pre;aibed.. o Patients weighi:ll,g <60 kg s!ioul.d:b:n-e a reduced mai.nteno:mce do-..e of 5mg o 'The ideo.te for a 5mg dose is based only on PKIPD :mal) ses al!ld no dil!liral data,aurentjy l!3ist on the safety of!bi5 doi:o me at risk snb g:roops.. OTHER co:snrno:ss Pharmacq, igzlanc"q SJ'SIQJN The t!\h llm5t ensure dl.a1 the system of plmmac O\'igilame.. as desaibed invernon 'i.-2.1presem!!d i:o odnle of the Ma... etin,g Autborisati.oD.<\pplication, is iiiplace al!ldfimd:ioniog before al!ld whilst lhe product is on the I:llait et. RiskManagOillliii Plan The t...6ji commits eo performing die studies 3lld 3dditional pb:armac.o\igjlanre acti\ities detailed iii ibe i> ianw;co\igihmc.e Plan, :;s agreed mre>i'b"ion 1.4 of the Risk Managemp...m PW!. (RMP) pre5e!m!!d id Module of me W:kAmhorisalioo.4. -.pplic:ation :md my snbse!cjtem updates of the R.MP a._!:reed by me CHMP.. n:: Appendix 4b Page 28 of 44

304 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE As pe111hl! CHMP Guid!!line oo Risk lt.1aoagemem SystelllS for medicmal producu forhum:m me, i:hi! updated R.'\fP should be subntitted at ihe same lime as ihe oext Periodic Safety Update Report (PSUR). Ill :!:ddi.tioo, 2l1 updated R\.fP should be snbmirted When D.i!W i:nfollwition i.;receh-edt m:!.y imp:!ici on tb.l! <OL."Tmm Safety Spedfic.alioo, Plwm:Ko\igil.aoce Plan or risk micimisatioo acti\ities Wi1bin 60 days of a.n impommt (pba.."'d3co\iglla11ce or ti;;k minimisaliou) mile.>tone being reacbl!d t-hi! request ofi:hi! EME.. Appendix 4b Page 29 of 44

305 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE.29 Appendix 4b Page 30 of 44

306 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE A. L-\BE1LINC Appendix 4b Page 31 of 44

307 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE I PARTICUlARS TO APPEAR 0THE OUTER PACKACI!\C C,\RTO:l\ OF 5mg FU."I-COATED TABLETS I- S..UIE OF THE MEDICJX.U. PRODUCT Efieot 5 film-coat ed table:s prasugrel I 2_ SI'ATEMEOF ACTIVE SUBSTA_"lCE(S) Each table: comaim 5 rug pr35ogrei (as llydrocllloride} 1 3- LIST OP EXCIPIEl'ITS Coma.ins 13cto5!!._ S.!!! leaflet for furthinformatio!l I "- PHARAL<lCEUTIC.U. FORA1CONTE:sTS 14 film-coated tablets s film-coated tab 30:1.1 film-coatable 56 film-coated tablets 84 film-coated tablets 90xl film-coatablet 98 film-coated tab 1 5- METHOD AJiD ROUI'E(S) OF _WJI.fl!'oUSI'RATIO Read me packagi! leafletfori! U5l!_ ()r,a] u;e 6_ SPECLU. WAR.l\"'ll\C TILJ\T THE li.jiedicinalproductji.fust BE STORED OUT OF TilE REACH A.."lD SIGHT OFCHUDRE:l\ Kp om of ri!llc:h md sight of c:hild."'i!ll_ I ' - OTHER SPECIAL WARC(S), IF SECESS.ARY I s _ EXPIRY DATE E.XP 31 Appendix 4b Page 32 of 44

308 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE I 9. s SPECIAL STORAGE cmm:rnoss fn die oligioal package co protect from air :mdii!!oi5mre. 10. SPECIAL PRECAL"I'IO'SS FOR DISPOSAL, OF U:SUSED MEDICL'l.'\L PRODUCTS OR WASTE M.<lTERIALS D.ERIVED FROM SUCH MEDICL'lAL PRODUCTS,IF APPROPRE.UE I 1L NAME AA.DDRESS OFTHE L.\RKETll\G AUTHORISATIOS HOLDER Eli Lilly K!!derl:md BV, Grootsla,g 1-5, NL RA Homen, The N!!ctherl:mds MARKETING AUTHORISATIO:!\ SUMBER(S) EUiX/XXfXXX.'XXX 14 film-.coall!d 1llblets EUX 'XXXXXIXXX 28 film-.coall!d mblets X XX:XXX. XXX 30x1 film-<oall!d tablet X'XX XXX.XXX 56 film-.coall!d mblets 'Xi'XX :XXX. 1 XXX 84 film-.coall!d 1llblets X 'XX:XXX. XXX 90x1 film-.coall!d tablet X 'XX :xxx. xxx 98 film-.coall!d mblets Lot I u. m:er...u. CLASSIFlCAnos ror SUPPLY tedicinal product subject to!m!dical prescription L'lSTRUCTIO:!\S ON USE INFOR..\iATIO:S IN BRAILLE Efimt5 mg 12 Appendix 4b Page 33 of 44

309 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE I Mnm.IUM PARTICUlARS TO APPEAR OSBLISTERS OR STRIPS BUSTER OF 5 m:g FILM-COATED TABLETS I- S..UIE OF THE ME:DICJX.U. PRODUCT Efieot 5 film-coat ed table:s prasugrel I 2_ S..UIE OF THE MARAETISGAUTHORISATIOK HOLDER liuy 1 3- EXPIRYDATE EXP I "- BATCH S UMBER. Lot I 5_ OTHER <MO!-l, Th"E, WED, TIID, FRl, SAT, St."l\, > 33 Appendix 4b Page 34 of 44

310 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE PARTICULARS 1'0 APPEAR ON THE OUIER PACKA.GI?\C CARI'O:K OF 10 mg:rn.m-coated TABLETS I. SAME OF THE IEDICIKAL PRODUCT Efteut 10film-<Oated tablen prasugrel I 2. sramfeof ACIJVE SUBST. 'ICE(S) Each tabla colllllins 10- prnsugrel ( as hydrocllloride) I 3. UST OF E."\:CIPIE!\J'S Contains betas. S!eal!Jet for furths- info!ll!latioll I 4. PHAR!.L"-CEUTICAL FORM Ai\ID CON1'E:sTS 14 fibn--c.ooted tablets 28 fitm--c.oated tablets 3011 film.<oated tablet 56 film-<oated tablets 84 film-<oated tablets 9011 film-c.oated table 98 film-<oated tablets I 5. THOD Al\1> ROlfTE(S) OF AD!.IINISI'RATIO:S RI!Gd me pxka,ge le:1flet bl!fore nse. 6. SPECIAL WARl\lliC THAT THE!.fEDICIN.UPRODUCTMUS1' BE STORED OU'F OF THE REACH. '10 SIGHT OFClULDRE:K Kee-p out of ihe reach :!llld sight of c:hild.te!il. I '- OTHER SPECL.U. WAR.'l!SG(S), IF :secessary I S. EXP:IRY DATE Appendix 4b Page 35 of 44

311 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE I 9. SPECIAL STORAGE cmm:rnoss s fn die oligioal package co protect from air :mdii!!oi5mre. 10. SPECIAL PRECAL"I'IO'SS FOR DISPOSAL, OF U:SUSED MEDICL'l.'\L PRODUCTS OR WASTE M.<lTERIALS D.ERIVED FROM SUCH MEDICL'lAL PRODUCTS,IF.'\PPROPRE.UE I 1L NAME AA.DDRESS OFTHE L.\RKETll\G AUTHORISATIOS HOLDER Eli Lilly K!!derl:md BV, Grootsla,g 1-5, NL RA Homen, The N!!ctherl:mds MARKETING AUTHORISATIO:!\ StrMBER(S) EUiX/XXfXXX.'XXX 14 film-.coall!d 1llblets EUX 'XXXXXIXXX 28 film-.coall!d mblets X XX:XXX. XXX 30x1 film-<oall!d tablet X'XX XXX.XXX 56 film-.coall!d mblets 'Xi'XX :XXX. 1 XXX 84 film-.coall!d 1llblets X 'XX:XXX. XXX 90x1 film-.coall!d tablet X 'XX :xxx. xxx 98 film-.coall!d mblets I U. CE1'\ER.U..C1..ASSIFICATIOSFORSUPPLY Medicinal product subject to medical prescription L'lSTRUCTIOl'i'S ON USE l lti. INFOR.\iA.TIOS IN BRAilLE Efieot 10mg 35 Appendix 4b Page 36 of 44

312 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE I Mnm.IUM PARTICUlARS TO APPEAR OSBLISTERS OR STRIPS BUSTER OF lo mg FILM-COATED TA.BLETS I- S..UIE OF THE ME:DICJX.U. PRODUCT Efieot 10 mg illm<oated tableis prasugrel I 2_ S..UIE OF THE MARAETISGAUTHORISATIOK HOLDER liuy 1 3- EXPIRYDATE EXP I "- BATCH S UMBER. Lot 1 5- OTHER <::\{ON_ Th"E, WED, 1BU, FRI, S.<U,SL"'N, > 35 Appendix 4b Page 37 of 44

313 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE R PACKAGE LEAFLET Appendix 4b Page 38 of 44

314 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE PACKAGE LEAFLET: INFOR\i.<tTIOS FOR THE USER Efient 10 m; film-<o:a t@d t:abjeb Efiu.t 5 mg: film..coat@d fabl@ts Pm;ngrel Read :all of this le-aflet canfudy b@fore you start t:aki:dg illis mediri.de. Keep tb.i> le3!flet.yon 1It3}' need to re:!d it a,galn. If you ba -e Sll)' fiinbet questioli.s, ask yam doctor or phan:uaci:t This medicille has been presaibed for you. Do oot pass it Oil 10 others, It tllib}' balm them, e\ en if their symp1oms are tbe sajill! as yours. If:my of the side effl!ct> gets serious, or if you 110tice 3liY side effects IIOl list l!d in ibis leaflet, please tell yam doctor or p.bal:m3c:ist Ill llll5 leaflet: L What Bfiellll is alld wbal it i> usl!d for 2. Before }'OU bk e E.fient 3. How to t!ke Efient 4. Possib!le side effects 5. How to Slore Efiem 6. Furtb& infollll3ti.od 1. WHAT EFIEPi'l' IS A.'.ID WH.. IT IS t:sed FOR Eiient, belongs to a group of medicines called anti-platelet agena Platelets are very mull ceu particles mat circul.ate in ilif' blood 'Wbeo 3 blood vessel i> d:un:lged, for e.umpte if i t is em, pla:elets dolllp togetl!ler to bejp fonn a blood clot (tbrombus),therefore,platelets are esselltial to belp stop blg.if dots form \\ithin a.bar<fe.:aed blood oesselsucb. as :m :l.itl!ij'!bey CBD. be \-e!)' d:mgerous as they c:m em off the blood supply, causing a hean :mad (myocardial infarction), moke or death. Clo;s m aneries supplying blood to ibebean may :ilio redoce lbe blood. supply, causing lm.lfable 3lllgi:Da (a sl!\e re chest paid). Efieot i.n!ubits tbe c!ump:in,g of pla:elets :md so!'educes the chance of a blood d01 forming. You ba"-e been prescribed Efieot berous.e )'"OU lm'l;already had a he:m attlck or tm>table:md yon baye bel!lll treated \\itli a procedui'e! to open blocked :meries in the heart. You. may also ha\ e bad one or more stl!lllls placed to keep opell a blocked or =v.-ed artery supplying blood 10 the!lean. Efieot reduces the challces of you ba illg a fu.""'her he:ut attack or :>troke or of dying from Oil!! of thesl! atherollrrom.ljoric l!\"eot>.your docrorv.-ill alsogiw you acely!lsa.litylic :!Cid (e.,g. aspirin), :mother milplatelet ag JN. 2. BEF{)RE YOUTAKE EFIENT Do a.ot take EfiBt If you are all&gic (h} th e) to pn,-ugrel or my of the other ingrediems of Efiem. All allergic reactioo may be recognised as a rash, itdlin,g. a swoueo face, swolll!lll lips or shortoess of breath. If this has h!!ppi!lled ro you, tell yonr doctor. If you ba -e a medical collditi011 tbal is Clll.lfl!D.tly cal6il!lg bleeding. sncb as lrleedfog from your stomach or intestines. If you.ba -e i!\'bad a molr;e or a 1I':!niieot isdw!mic alt3ak (TIA). If you.bao-e senre!i\'l!t disease. 39 Appendix 4b Page 39 of 44

315 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE Take spkial can with Efim.t You sb.ou.ld iell your doctor fore ia.kefist if :my of lhe siiualions omuiooed low apply to yon: lf you bao""e an ill.cre:ased risk of bleeding such :15: age of 75 yem:s or older. Yom doctor sboold prl!!lcna dail') dose of 5as there is. a greaier risk of bleediiilg in patiellt> old& iba.d 75 }""Ears a recent serions inju.ry recent surgery (DKludi!lg sollll' dst:ll procedures) recent or rectmemlbl.eediog from the s ojjlo"lch or imestins(e.g. a stom3chul.ce, colon poljps) bod)' weight ofless than60 kg. Your doctor shouldpresaibe a daily dose of5 mg of Elient if you ""Eigh le;s tbao 60 kg renal (kidney) dise:ue or moderate liwr problems ral!ice.-rt:ain l)'}les of medicine; (see 'T:!!±lg oth& medkille5' belem pl.mned sur,gery (inclnding some denral proc:edm) in the I!Le..'l:t l.""e!il days. Yom doctor may ish yoo to srop taking Efient temp<jmrily dim! to the illc:re3sed risk of bleedillg lf you are Asiai!L- tb&e is l:imited e:tperieli!ce of Efiei!Li use ii!l Asians -no c:sses ba\ e been seen wilb Efiem, with ce."'1:rin ofu& :mtiplatelet agems 3 \"EI)' rnre condft:ioa c:ill.ed Th!ombotic Th.llmlhocytopenk i>uipur3 (TIP) am occur. TTP is a sociated. wilh fe\'er, tidy rotmd pin-poim purplis!j.-red bruise;., sm:ill to medium-med bruise;., confusioa, headxhei :md a dec.rea;:e ii!l the number of plateles. If yoo ootice tii!ly TOWldpfo-point pmplish-red bruise.;, pli!<i!se collbct your doctor imll!edia!ely. TaL:iDotbu mmirides Plea;.e tell your docror if you are taltiog or ha\ e recently ral!ien any oilier medicines, iocludiog medi.c:in<>_s obtained. "1\it!liool a pre.;cription. dietary supplements add hejbal remedia It is particularly impo!wlt to tell your doctor if yon are being1nated with dopido,grel (:m anti-platelet agent), w:u:fum (an anti"-<oagul.am), or D sl!roidal anti i:n&mma:ory drugsfor pam :md fi!'l er (such as ibuprofl!n. lll!.pro: ::en, e:oricoxj."b).if givi!ll to.geth& with Efiem these medidnes IDS)' increase the risk of bleedin,g Only take oilier IUEdicines while you are on Efiem if your doctor tells you th:!t you ca111.. TaL:iDJ!: Efiut witlil. food a Dd drilll:: Efient may be mken wimor without food. Pr ancy ud bnast-f Tell your -doctor if you becomepregn:w orare to becollll'pregd:biii.l while you are takiog Efi.elll.l. You sb.ou.ld nse Efiem only after discussing with yom doctor the po.lential bsefus :md :my po:enti31 risks to yom wl.bom child. lf you :!l"ebreast-feedii!lg, 35k yom doctor or p!i:!jma.for ad\i.ce betore tal..""ing :my medic:in Dm nd usiamadaill.ts No srudies on the effect> ofesent od.1he :ibilit}' to drin add use m.lc.hinl!i ba"o""e been pemmned. Efient islllllikely to affect your ability to dji\0! or nse mac:hins. Importmt i.dformalioo about some of tile ill.gmisats of Efiot Efient comains lactose.lf you bave been told by a doctor that you bave an ii!l:oleraiice to some sugars, contac t your doctor before mkii!lg this medicillal prodi!lct. 39 Appendix 4b Page 40 of 44

316 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE 3_ HOW TO TAKE EFIEJ\T AJ. p. -ays t!ke Efiem exxdy a; yam doctor ha.; cold yon. You s!wuld dlkk with JOur docror or cisl: if you are Dot sure. You:rdocrorwill ti!.ll yonbow many Efi!!Dl 1:1blet:i to 1:!ke.The 11511:!l dose ofefient i.;10 mgjii!" cby. You will swt ihe tteatment '\\Ill a single dose of 60 mg. If you '11;-ei,gb less th!m 60 kg or are more liwl 75 yi!wl of age, me dose is 5 mg Efient per day_ You:rdoctoru-ill also 1ell you to take ace.-yisalicylit acid- (s)be will rej.i you me l<.'llltt do.->e to take (usual!ly bem een 75 r::n,g and l25 mgdaily) You may tak e Efiem " oitb or wid1ow food Tlike you:r dose at around the srune rime every da) _ J:lo Dot break or crulll the tablet. It i.; importslll that yon tell yonr doctor, dmlist :!Dd p!mrmacisl:,lha.t you :!Ie llllking Dent. Efiem shonld DOt be used ill children and adolescems belm\- Ul years of age,. If )"Oil t2b m.ort Efient thu yo11 should Cootact your doctor or hospital snight av.-ay,a; yon may be at risk of e:oocesm""e bleedil!lg. You should sh.gw the doctor your pack of Efi!!Dl. If you forge!to tab EfiHit If you miis }'OUI scheduled. daily do5e, tak e Ei'i.ent when yoo.reme.mber_ If you foiget }'our dose for an entire day,just resiiill.i! taking Efient at it;; orual dose the lll.i!'.tt cby. Do oot take lwodo.ses in ode day. For the 14, and 98 crblet pack sizl!s, yoo.c:mch!!d: me day on u-hith JOU l3o"t rook a mblet of Efient by referring to the cl!!l.eodar prim.:ed on the blist&. If )"ou stop t:lk:ing Em:a.t Do.ooi Slop taking Efie:w \\i1honl co:nsultin,g yom d.octor. Il is especially illqlortalli to discuss '1\ith yonr doctor be!ore stopping Efiem.t becauseboth me risks and the benefits are based on regular nse. If you h.::i1"."e any fu:nher question; on the nse of tbi5 m.edidlle, ast your doctor or pllam!2cist 4.. POSSDn.E SIDE EITECI'S Like 2!l.l medicines, Efieot can t:luse side effeas,:ili!!ooghdot 1! -ecybody gets them. Frequencies of theobsen'ed side erens 3il'e defined as: \"er}' cojjilll)oll; affects more lha.n 1 u.ser ill I 0 commo111: affects 1eo 10 osen in 100 mu:o:mmo:n: affects 1 m 10 nsers in 1,000 rare: affecis 1 to lo usersill 10,000 \"er}' rare: affects less IW 1 u.ser ill 10, !known: fteque.ory c:moot be '1im:l:ed iiom the ay:jijable data Cooract your doctor immedi2tfly if yoo. ootice any o the following: Suddl!;noumbness or v.-eakm.es5 of the am!, le,g or fuce_ especially if ool)' on one side of ibebody sudden confusio:n, difficulty spe.alriog or Wldersta:ndillg others Slldd<.>.o diffirnlry in walking or loss of balance or co-ordilliarion Sllidld<.>.o dizzioe5s,or sud\de;n se; ue beruiache \lith DO koo\\u cause All of the aoo\-e may be sign; of a stroke-. Smlke is an UDCommo:n sid\! effect of Efient ill patient; wbo h!n-e never bad a stroke or trlmsiem ischaemi.c 3tt3Ck (TIA.) Appendix 4b Page 41 of 44

317 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE TeU yomdoctor promptly if you nooce :my of m following:!blood in your m:in BlE!I!dmg fi'om your r:ectum, blood in yom sr.ools or black SIOOls Unconrrollabrblfor e:wnpl!rom a mr All of tile abon may be si@lls of bleeding, m mo5t common. side efieci 'llitil Efient..OJthoagih llllc Ommon. sew l! bleeding can be liftenfng. Side effects sin. dinkal trial5 \'lith Efiw include: Common sick cjs Bleedling in!he stomach or bmr, els Bleeding.!rom a lll!edle ptmcrure slli! No.se bleeds Skin rash Small rbruiies on the skin (ecch)'.no.ses) Bloodmmfne Hal!llllltoma l eedmg tmcf<>..r thskill al the sire of 1111 injeclioo, or into a mu;de,causing swell:illg) l..gw lmemogjobin or red blood c ll cowll (a aemia) Bruising Uncommon s.itkr b. Spootaneou:.; ttleeding from me eye,recrum, guill5 or in me abdomen :rroudd tile mremal organ5 Bleeding after surgery Coughlng up blood. Blood in stools Ran side effects Subc:nw!.eous hal!l!l!ltodi3l eedmg UDder thskinaming a sw If my of tile side effkg gets serious, or if you IIIOtice :my side effects l!loi lisr.ed in ihis leaflet, pleas rell you doctor or pll:umaci.>"t. 5. HOW TO STORE EFIENT Kp out of m reach :md sight of chilchen. Do cot nse Efi.ent ::fw me apiry date,-nlirich is sta:ed on tile blister and carton after EXP. The:pi:ry date IefeJS to mlast dey of mat D!Ollth. Store in die original package to protect from air and moi.;mre. 6. fljr.ther Th"FORM.'\TION What Efita.f coa.taias Ib.e acfu $Ub5tmce is prasugrel. Efient 10 mg: Each 1ablet COllt:afns 10mg of pr.liugrel (a5 hyd.tochloride). Etient 5 mg: Each1ablet COllt:afns 5 mg ofpr-..;(shydrochloride). Appendix 4b Page 42 of 44

318 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE Ib.e olherems are microcrystallide cellulose, ma!lllitol (E421). croscannellose sodium, hypromellose (E464) magnesium ste:ar.1te, lacto.s:e mo:oo!j.ymare, ritllllium dlolride (E1'11), lriacetio (El 518), iron olride red (10 mg mblets o) (E172), fro"'oxide yellow (El72) ajj.d tak.. What Efit11f looks lika:ad co:atmts of th pa.ck Efieot 10 mg :The iablets are beige sad double-mo\\' shaped, wuh n10 mg" debossed on O"-f side sad 4759" ou the olbl!r. Efiem 5: The tablets are ::-ret.low :md double-=w-5haped, \\ith "5" debossed OD one side :!lid "4760" on the oilier. Efient is m:ailable mpack> oh:,28, 30, 5<i,84, 90 ajj.d 98 mb1ets. Not all pack siz.es mey be lll:!lketed Ma.rbti:ar; Aut!Lorisatio:a. Hold r Eli Lilly Kl!derland BV Grooulag 1-5 NL-3991 R.O.. Houtea The Nethe,rlands. Muufamuu: Lill)' S.A A da. de la Iadnsttia >Uc.OOEn.das bdrid Spain. For my information about 1bis medicine, please c.on:ad the loc:al repre;entalfn of the l>1atletidg Atrthoris:rti.on Bold.er. BquBelgi.'BffPm Daii.c.hi Sankyo gium N.V.-S.A TMe!: -+32 (0) l>1>!.1r.tpaa ITI ''Elm JlmmRe:tepmm:!" SB. -:&l>lii'i!paa Cf.sk.l n publika ELI LillY CR., s.r.o. Tel.: Daumuk Eli Lilly Dammadi - m <io OO Du ts.cblod Dai:ic.bi Sankyo Deutschhmd GmbH Tel.+49 (0) E.sti Eli Lilly Holdings Limill!dEe,Li fifual Tel.:+3' E.)l.aOcr AF..tAIEPB-AlAAY AE.B.E. I'ljl: Espana Dai:ic.bi Sllllkyo Esp:cl.a, SA.. Tel.:.-34 (0) Lanmbourg/Luumblll'l; D:ilic.bio.BelgiumN.V.- SI\ TeLtTel: +32 (0) M:agya.rorsz:ir; D:ilic.bi Sl\mk} o Europe GmbH Tel.: -+49 (0) Malta Cil3l'1es de Gior.gioLtd Tel.: Nf.dubu.d Daric.hl Samkyo N l:!lldb.v. Tel.: +31 (0) 20 4 CH Nor t Eli Lill)' Norge- AS. Hf: +47 n oo Ostunich D:ilic.biAnscia GmbH Tel.: -+43 (0) Polska D:ilic.bi Sankyo Europe GmbH Tel..:+49 (0) Portu;:al D:ilic.bi o Portugal,Lcb. Tel.: Appendix 4b Page 43 of 44

319 er-7 oapt '\l,..-/ S T U D Y HARVARD CLIN I CAL RESEARCH I N STIT U TE Fr.uce Daiic.hi Santyo Frlll!Ce S.:\5 Tel:+33 (0) Irelllld Daiic.hi Swyo UK Ltd Tel:+44 (0) islud Icep!wmahi Sin:ti: lblia I>ilicbi SankyolDl.ia S.p.A.. Tel:+39 (0) K.unpo; Pb.adisc.o Ltd. Ttjl: L:a t\.ija Eli Lilly Ho1di:ng:s Limi.ted parni\meaoo I..anija Tel: Littvn Eli Lilly Holdi:ng:s Limin!d atstnj-be Tel.+370 (5) Romiai.'l Eli Lilly Romiltia S.RL. Tel: ? S1onaija Eli Lill') f a..'=ce.""t5k:1j druztm,do.o. Tel:+386 (0) S1onaski npublib Eli Lill) Slonkia. SI.O. Tel: Su.omi/F"mlllld Oy Eli Lilly Finland.4Jb PuhtTel:+358-(0) Sne Eli ill ;Swedea AB Tel:+46 (0) UDited Kmgdom D:ilichi Santyo UK ltd Tel: +44 (0) This 1e:a1let W25 lllst :apprond ia. Detailed information on this medicme is a\"a.ilab1e on!he Europea:o Medic:ioE Agency (E 1EA) web site:http{j' Appendix 4b Page 44 of 44

320 DAPT Study Protocol Key Changes from version 4.0 to version 9.1: Eligible thienopyridine drug expanded to include prasugrel upon FDA approval in 2009 Eligible drug-eluting stents expanded to include TAXUS Element paclitaxel-eluting stent and Xience PRIME everolimus-eluting stent Follow-up and adjudication for all subjects, not just those randomized, for 0-33 months as part of the revised bare metal vs drug-eluting stent analysis, in order to improve statistical power, in the setting of a higher than expected DES:BMS enrollment ratio. Endpoint assessment for MI revised to a) exclude peri-procedural MI associated with the index procedure or 72 hours after index from the 0-33m MACCE endpoint for DES vs. BMS comparison, and b) recommended that sites collect CK-MB preferentially over troponin when evaluating suspected peri-procedural MI occurring subsequent to index Inclusion of a platelet function substudy

321 The DAPT Study A prospective, multi-center, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy (DAPT) in subjects undergoing percutaneous coronary intervention (PCI) with either drug-eluting stent (DES) or bare metal stent (BMS) placement for the treatment of coronary artery lesions. A POST MARKETING STUDY STUDY IDE # G Protocol Version: 9.1, STATISTICAL ANALYSIS PLAN Sponsor: Harvard Clinical Research Institute 930W Commonwealth Ave, 3 rd Floor Boston, MA USA SAP Version: Draft V1 Date Prepared: May 10, 2013 By Prepared By: HCRI (Harvard Clinical Research Institute) Boston, MA

322 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, APPROVAL SIGNATURES AND SIGNATURE MEANING HCRI Signatures Approvals below indicate that the individual has reviewed and agrees with this document as written. Any/All deviations will require amendments to this document. Name Signature Title/Department Date Joe Massaro, PhD Senior Statistical Consultant Investigator Signatures Approvals below indicate that the individual has reviewed and agrees with this document as written. Any/All deviations will require amendments to this document. Name Signature Title Date Laura Mauri, MD, MSc Principal Investigator May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 3

323 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, DOCUMENT HISTORY: Revision Author Date Reviewed/Revised Changes Reason for Changes Draft, Version: 1 Joseph Massaro May 10, 2013 New SAP N/A May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 4

324 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, TABLE OF CONTENTS 1 INTRODUCTION Trial Objectives Trial Design Co-Primary Effectiveness Endpoints Primary Safety Endpoint PMS/COA (Post Marketing Surveillance/Condition of Approval) Subjects Subject Populations Primary Analysis Sample Size Calculations ANALYSES PLANNED General Analysis Definitions Analysis Populations Methods of Analysis Baseline Characteristics Primary Effectiveness Endpoints Primary Analyses on Primary Effectiveness Endpoints Secondary Analyses on Primary Effectiveness Endpoints Primary Safety Endpoint Major Bleeding Primary Analysis on Primary Safety Endpoint Secondary Analyses on Primary Safety Endpoint Powered Secondary Endpoints BMS vs. DES Comparisons Additional Endpoint Analyses Analysis of Rebound Effect Sensitivity Analysis of Non-compliance with Randomized Treatment (12 to 30 Months) Additional Subset Analysis Additional Analyses May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 5

325 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, 1 INTRODUCTION This statistical analysis plan (SAP) contains definitions of analysis populations, derived variables and statistical methods for the analysis of the dual antiplatelet therapy (DAPT) clinical study. This SAP specifies the pre-planned analyses and serves as the base for the clinical study report. 1.1 Trial Objectives The objectives of this study are to evaluate the composite of all death, myocardial infarction (MI) and stroke (Major Adverse Cardiovascular and Cerebrovascular Events, or MACCE) and the survival free from ARC definite or probable stent thrombosis (ST) in subjects treated with drug eluting stents (DES) and extended dual antiplatelet therapy. The primary analyses will be performed on the primary analysis set (all randomized DES subjects). Secondary analyses will be performed on secondary analyses sets defined below. The primary study hypotheses are: a. Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with DAPT for an additional 18 months (total 30 months) will have increased survival free from death, myocardial infarction or stroke compared with subjects treated with only 12 total months of dual antiplatelet therapy, over the month post-stenting period. b. Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with DAPT for an additional 18 months (total 30 months) will have increased survival free from ARC definite/probable stent thrombosis (ST) compared with subjects treated with only 12 total months of dual antiplatelet therapy, over the month post-stenting period. 1.2 Trial Design This study is designed as a prospective, multi-center, randomized, double-blind trial. Study enrollment will consist of subjects who in the opinion of the investigators are candidates for extended dual antiplatelet therapy (DAPT), treatment with either drug eluting stent(s) (DES) or bare metal stent(s) (BMS), provide consent to participate in the study, and who receive at least one stent and dual antiplatelet therapy. Subjects with ischemic heart disease due to stenotic lesions in either native coronary arteries or coronary artery bypass grafts undergoing PCI with stent placement and no contraindications to prolonged DAPT are eligible to be enrolled in this study. Subjects may have multi-vessel treatment. Subjects may be enrolled into the study either before or after the index procedure of percutaneous coronary intervention (PCI) with stent placement. Enrollment of qualified subjects can occur up to 3 calendar days after index procedure. May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 6

326 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, For the purposes of stratification, subjects are considered complex if they have any of the following risk factors for stent thrombosis, either clinical, e.g. acute coronary syndrome (ACS), renal insufficiency or failure, ejection fraction <30%, greater than two vessels stented, in-stent restenosis of a DES, prior brachytherapy, or anatomic, meaning a anatomically complex lesion treated with a stent, at the time of the index procedure. ACS is defined as ischemic symptoms occurring at rest and lasting 10 minutes or more and occurring within 72 hours before index procedure and either ST-segment deviation of 1 mm or more or elevated levels of a cardiac biomarker of necrosis (CK-MB or troponin T or I greater than the upper limit of normal (ULN). If CK-MB or troponin is not available, total CK >2 times ULN). Subjects with STEMI can be enrolled and will be classified as ACS and complex if the index procedure is performed within 14 days after onset of symptoms. Renal insufficiency is defined by Creatinine 2.0 mg/dl and renal failure is defined as being dialysis dependent. The lesion is to be considered anatomically complex if it involves: Unprotected left main >2 lesions per vessel Lesion length 30 mm Bifurcation lesion with sidebranch 2.5 mm Vein bypass graft (segment or anastomosis) Thrombus-containing lesion Subjects who do not meet the criteria for complex will be considered non-complex for the purposes of stratification of randomization and analysis. All enrolled subjects will be treated with either drug eluting stent(s) (DES) or bare metal stent(s) (BMS) (per their respective Instructions for Use) and assigned to 12 months of open label thienopyridine treatment in addition to aspirin. Operators will select the thienopyridine either Clopidogrel or Prasurgrel. Thienopyridine treatment dose will be according to the standard of practice and prescribing information for the selected medication (see Appendix 3 and 4 of the protocol). Aspirin treatment is recommended to be mg for the first 6 months after the procedure and mg subsequently, to be continued indefinitely. Subjects who are treated with 12 months of DAPT post index procedure and who are event free (from death, myocardial infarction, stroke, repeat coronary revascularization, stent thrombosis, and major bleeding severe or moderate by GUSTO classification) and who are compliant with DAPT (see Section 1.6 below) during that time will be considered 12 Month Clear. Repeat PCI, stent thrombosis, or MI within the first 6 weeks of the index procedure will not be considered exclusionary events for the definition of 12 Month Clear. Operators are strongly encouraged to use the same stent type (BMS or DES) at any secondary procedure within 6 weeks of the index procedure. May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 7

327 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, Subjects who receive both types of stent (BMS and DES) during the index and subsequent PCI(s) will be considered DES subjects in the study. Only major bleeding events, stroke, or CABG should be exclusionary events for the definition of 12 Month Clear prior to 6 weeks. All subjects treated with DES or BMS who are considered 12 Month Clear (defined in Section 1.6 below) are eligible for randomization to either 18 months of placebo ( 12m DAPT arm) or an additional 18 months of thienopyridine treatment ( 30 m DAPT arm). Both arms will continue aspirin therapy. Randomization for subjects will be performed at 12 months post procedure in eligible subjects and will be stratified according to DES/BMS, hospital site, subject complexity and thienopyridine drug type. Eligible subjects will be randomized 1:1 to receive placebo or thienopyridine treatment for an additional 18 months. Subjects will be followed for an additional 3 months of observational follow-up at the end of the 18 month randomized treatment phase. In summary, the total follow-up for each randomized patient is scheduled to be through 33 months post index procedure. Randomization will take place at 12 months post index procedure for subjects considered 12 Month Clear. Randomized patients are to be followed and are to take randomized treatment from 12 to 30 months post-procedure. After randomized treatment is discontinued following 18 months of treatment, randomized patients are to be followed for an additional 3 months post-procedure. According to Version 9.0 of the protocol (the final protocol version), subjects not randomized at 12 months are to be followed through 33 months post index procedure. All prior versions of the protocol, however, required non-randomized subjects to be followed only through 12 months post index procedure at most, or i.e., at the time when the decision is made to not randomize the patient. The protocol was amended to Version 9.0 in order to maximize follow-up for the secondary comparisons of DES to BMS on effectiveness and safety endpoints (the DES-BMS comparisons are performed on randomized and non-randomized patients combined). 1.3 Co-Primary Effectiveness Endpoints This study has two co-primary effectiveness endpoints that will be assessed. They are: composite of all death, myocardial infarction (MI) and stroke (defined as MACCE) - 12 through 30 months post-stenting period ARC definite or probable stent thrombosis (ST) - 12 through 30 months post-stenting period 1.4 Primary Safety Endpoint The primary safety hypothesis for this study is described as follows: Subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 8

328 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, 18 months (total 30 months) will have a major bleeding (GUSTO classification, severe and moderate bleeding combined) rate not inferior to the bleeding rate of subjects treated with only 12 total months of dual antiplatelet therapy over the month post-stenting period. 1.5 PMS/COA (Post Marketing Surveillance/Condition of Approval) Subjects There are significant challenges to enrolling into any randomized study of this size in a timely manner in the current clinical trials environment. In order to complete this study in a timeframe that would allow relevant information on patient care to inform current practice, and in response to a true clinical concern regarding the optimal duration of DAPT therapy, we anticipate that patient level data will be obtained from pre-specified non-randomized (to stent) studies whose primary objective is to assess FDA approved stents (e.g. post market surveillance or condition of approval studies). This will decrease the total number of patients that would need to be enrolled de novo in the DAPT Study at the time of their index procedure. DES subjects enrolled in separate manufacturer-run PMS and/or COA studies will be included as part of the DES-treated analysis population. Only studies not randomizing to stent type and that are pre-specified and listed to the FDA will be eligible to contribute data. In this protocol, it is assumed that uniform treatment and data collection processes will be performed within the original study protocol with relevant data transfer to HCRI for analysis. Such study data may be contributed either 1) at completion of follow-up within these external studies, in which case subjects would not be enrolled in the DAPT study, but data would be contributed after 33 months of follow-up, or 2) relevant baseline data and eligibility data to 12 months could be contributed and subjects could be enrolled under the DAPT protocol from 12 month for the purposes of randomization and completion of follow-up. Required data would be transferred to HCRI as clean SAS datasets to be merged with the DAPT database for statistical analysis. The following requirements have to be met by a study that is intended to provide patient level data for DAPT: 1. The determination of eligibility for enrollment and randomization is the same as in the DAPT study. 2. Data definitions are the same. 3. The same data are collected at the same time points. 4. Adjudication (or readjudication) of all endpoint events according to a central DAPT clinical events committee. 5. Contributed data are from consecutive patients meeting the specified requirements. May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 9

329 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, The total numbers of contributed patients, and their poolability with patients who are enrolled and randomized in the DAPT study will be assessed at regular intervals in order to confirm adequate enrollment of patients from the DAPT study. Data will be obtained from these studies at regular intervals so that clinical events adjudication under DAPT will occur throughout the duration of the study. The study will accept up to randomized 8500 DES patients from four manufacturer companies contributed after completion of 33 months of follow-up from their index procedure as a part of the various post-marketing studies and/or condition of approval studies. The study will also accept DES patients from the manufacturer companies where relevant baseline and eligibility data to 12 months from the post-marketing study will be collected and then the subjects will be transferred at 12 months post-procedure to the DAPT study for the purposes of randomization and completion of follow-up per the DAPT protocol. A total of up to 2439 DES patients will be accepted via this approach. The PMS/COA studies contributing data for the analysis are the Cordis CYPRESS study, the Medtronic EDUCATE study, the Abbott Xience V study, and the Boston Scientific Liberté post-approval study. 1.6 Subject Populations All Enrolled Subjects All subjects enrolled in the study (under the DAPT protocol or under a PMS/COA study protocol for purposes of contribution to DAPT). 12 Month Clear This population consists of subjects enrolled in this DAPT study and in the PMS/COA studies who are free from death, MI, stroke, repeat coronary revascularization, major bleeding severe or moderate by GUSTO classification, and ST 12 months after stent implantation and who are compliant with 12 months of DAPT following stent implantation. A subject is considered compliant with the thienopyridine therapy for the purposes of eligibility if they take between 80% and 120% of the prescribed drug in the 0-6 month and 6-12 month periods without an interruption of therapy longer than 14 days. 12 Month Not Clear This population consists of those subjects enrolled in the study who do not meet the requirements of 12 Month Clear. During the open label portion of this study (time 0-12m), a subject is considered compliant with the thienopyridine therapy for the purposes of eligibility if they take between 80% and 120% of the prescribed drug in a given period without an interruption of therapy longer than 14 days. This information will be ascertained via data collected at May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 10

330 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, the subject interviews at 6 and 12 months post-procedure. Compliance at both time points is required to be considered clear. The primary analysis population used to test the study hypotheses will be subjects with DES who are 12 month clear and are randomized to either 12 or 30 months of DAPT. 1.7 Primary Analysis As will be detailed further below, the primary analysis set is all randomized subjects who received DES at the index procedure. The primary study conclusions will be based on this analysis set. Primary Effectiveness Co-Primary Endpoints: The primary objective of the study is to compare 12 months of DAPT with 30 months of DAPT between 12 and 30 months post index procedure 1 on the clinical and thrombosis endpoints for DES subjects. Specifically, the primary hypotheses are: Clinical: In subjects treated with DES free from MI, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 m after PCI, DAPT for an additional 18 m (total 30 months) will increase survival free from death, MI or stroke compared with only 12 total months of DAPT (or i.e., 18 months of placebo) over the month post-index procedure period. Stent Thrombosis: In subjects treated with DES free from MI, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 m after PCI, DAPT for an additional 18 m (total 30 months) will increase survival free from ARC definite/probable stent thrombosis (ST) compared with only 12 total months of DAPT over the month post-index procedure period. The study will be considered a success for 30m DAPT if at least one of these two hypotheses is statistically proven using the Benjamini-Hochberg approach on the DES Randomized ITT sample at an overall familywise error (FWE) rate of 0.05 (i.e., if each objective is proven at the two-sided 0.05 level of significance, the study is considered a success for 30m DAPT; otherwise, if one hypothesis is proven at the two-sided level of significance, then the study is considered a success for 30m DAPT). Note that the above co-primary effectiveness endpoints are modified from those specified in the protocol. In the protocol, the co-primary endpoints of ST and MACCE were to be assessed over 1 The 30 month visit is scheduled for 540 days (+/- 30 days) post-randomization for the de novo study and 30 months (+/- 30 days) post-index procedure for the PMS/COA studies. However, the 30-month visit will simply be referred to as 30 months post-index procedure in this statistical analysis plan for ease of reading. A similar algorithm is applicable to other study visits mentioned in this plan. May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 11

331 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, the month post-index procedure period. However, the investigators, in discussion with the study committees and approved by the FDA, modified the primary effectiveness time period to be months post-index procedure since it was felt this period was more clinically relevant (since it does not include the month post-index procedure treatment period during which randomized treatment was not given). There was no inspection of data prior to making this modification. Primary Safety Endpoint: Major Bleeding The null hypothesis is that subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have major bleeding rates between 12 and 30 months post-index procedure that exceed that of the control arm (subjects treated with only 12 months of DAPT) by at least a pre-specified margin of δ (delta). The alternative hypothesis is that subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization. stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have major bleeding rates between 12 and 30 months post-index procedure that are no more than that of the control arm, or exceed that of the control arm but by less than δ. Rejection of the null hypothesis will signify that the 30m DAPT arm is non-inferior to the control arm (12m DAPT) with respect to major bleed rate between 12 and 30 months post-index procedure. Specifically, the null (Ho) and alternative (H A ) hypotheses are: Ho: π 30m-DAPT π 12m-DAPT + δ Ho: π 30m-DAPT < π 12m-DAPT + δ where π 30m-DAPT is the true major bleed rate for the 30 m DAPT group and π 12m-DAPT is the true major bleed rate for the control arm over the month post-index procedure period, and δ = (0.8%). Note that the above primary safety endpoint is modified from that specified in the protocol. In the protocol, the safety endpoint was to be assessed over the month post-index procedure period. However, the investigators, in discussion with study committees and approved by the FDA, modified the primary safety time period to be months post-index procedure since it was felt this period was more clinically relevant (since it does not include the month postindex procedure treatment period during which randomized treatment was not given) and to match the revised month post-index procedure period over which the primary effectiveness endpoints will be assessed. There was no inspection of data prior to making this modification. May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 12

332 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, 1.8 Sample Size Calculations Primary Effectiveness Co-Primary Endpoints: The following is an estimate of DES sample size for the DAPT Study to compare the 12m DAPT regimen to 30m DAPT regimen under the following assumptions: i. Two primary outcomes: a. Time to MACCE between months post-procedure; hypotheses are H o : λ 12m-DAPT = λ 30m-DAPT H A : λ 12m-DAPT λ 30m,-DAPT where λ is the hazard rate of MACCE over the month period. b. Time to ST between months post-procedure; hypotheses are H o : γ 12m-DAPT = γ 30m-DAPT H A : γ 12m-DAPT γ 30m,-DAPT where γ is the hazard rate of ST over the month period. ii. Time to each endpoint follows an exponential distribution, with a. Incidence of MACCE = 2.9% and incidence of ST = 0.5% for 12m-DAPT annually for the 18 months following randomization (12-30 month post-procedure period). b. Incidence of MACCE = 2.175% and incidence of ST = 0.225% for 30m- DAPT annually for the first 18 months following randomization (12-30 month post-procedure period); (The hazard ratio (30m DAPT to 12m DAPT) under these assumptions is 0.75 for MACCE and 0.45 for ST across the 12m 30m period). iii. Randomization is 1:1 into the 12m and 30m arms (randomization occurs at 12m post-index procedure time point). iv. Annual lost to follow-up rate of 3% after randomization. v. A statistically conservative assumption that all patients who experience ST will experience MACCE. vi. Familywise (FWE) error rate is controlled at the 0.05 level using the Benjamini-Hochberg approach (reject both null hypotheses if both are significant at the 0.05 level; otherwise, if one null hypothesis is significant at the level, then that null hypothesis is rejected). vii. The primary analyses for each endpoint will be carried out using the log-rank test. May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 13

333 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, For each endpoint separately, 9,800 DES subjects randomized at 12 months postprocedure yields at least 85% power to reject the null hypothesis for that endpoint under the above assumptions at a two-sided 0.05 level of significance. Mathematically, it can then be shown that 9,800 DES subjects randomized at 12 months post-procedure will yield at least 85% power that the study has statistically met its objective under the assumption of a treatment effect in both outcomes using the Benjamini-Hochberg approach to declare the study a success for these two endpoints. This has also been shown via computer simulations. (Since 9,960 DES subjects are required to be randomized in order to have adequate power to compare randomized treatments on the primary safety endpoint, as will be discussed below, 9,960 subjects will be randomized). Note that when the study was initially designed (with the month post-index procedure follow-up period that included the month post-index procedure nontreatment period, where it was assumed the hazard ratio between the 30m DAPT and 12m DAPT groups was 1), 12,196 patients were reported to be required in order maintain at least 80% power to reject at least one primary effectiveness null hypothesis using the Benjamini-Hochberg approach. However, this was calculated theoretically under a very conservative approach: assuming the ST and MACCE endpoints were perfectly correlated. It was decided to relax the correlation assumption to a more clinically realistic, but still conservative, assumption where all patients who experienced ST experienced MACCE, but not vice-versa. This yielded a required sample size of 9,800 subjects to maintain 80% power for the primary effectiveness endpoints. When the month post-index randomized treatment period was removed from the definition of the primary effectiveness endpoints, power for the primary effectiveness endpoints increased to 85% In order to justify the validity of DAPT power and sample size calculations across the range of possible MACCE and ST estimates, a series of computer simulations were run to determine how much power would be retained if various event rates were realized. Under the worst case (i.e., lowest) assumptions of a 2.3% annual MACCE rate and 0.4% annual ST rate for the 12m DAPT group, there is still at least 80% power under Benjamini- Hochberg (still assuming hazard ratios of 0.75 for MACCE and 0.45 for ST). The assumption above that all patients who experience ST will experience MACCE is a conservative, but possibly realistic, assumption in the sample size calculations. If not all ST patients experience MACCE, then the correlation between MACCE and ST is decreased, which increases statistical power. The assumed MACCE rate is based on published rates of cardiac death, MI and stroke 2,3 and are adjusted to reflect that deaths from all causes are included in the primary 2 Stone GW, Moses JW, Ellis SG, Schofer J, Dawkins KD, Morice MC, Colombo A, Schampaert E, Grube E, Kirtane AJ, Cutlip DE, Fahy M, Pocock SJ, Mehran R, Leon MB. Safety and efficacy of sirolimus- and paclitaxeleluting coronary stents. N Engl J Med. 2007;356(10): May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 14

334 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, endpoint rather than cardiac deaths only. These rates are 2.4% - 3.4%, with a median of 2.9% (12 to 30 months post-pci) and the assumed ST rate is based on published data 4,5,6. Primary Safety Endpoint: For the primary safety endpoint of major bleeding, the null (Ho) and alternative (H A ) hypotheses are: Ho: π 30m-DAPT π 12m-DAPT + δ H A : π 30m-DAPT < π 12m-DAPT + δ where π 30m-DAPT is the true major bleed rate for the 30 m DAPT group and π 12m-DAPT is the true major bleed rate for the control arm over the month post-index procedure period, and δ = (0.8%). With a sample size of 9,960 randomized subjects and a non-inferiority test at an = (1-sided) significance, the power is 80% to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with major bleed in the 30 m DAPT arm compared to 12 m DAPT arm, when the major bleed rate of the 30 m DAPT group between 12 and 30 months post index procedure is 1.9% and that of the 12 m DAPT group is 1.9% over the same time period, using a noninferiority margin (δ) of 0.8%, assuming 3% loss to follow-up annually and 1:1 randomization. Power Analysis and Sample Size (PASS) was used to compute the power, using the Farrington-Manning test. 7 Note that the original sample size of 12,196 randomized DES subjects yielded 82% power to claim non-inferiority over the month period, where the assumed major bleeding rate over the month period was 2.22% in both the 30m and 12m DAPT groups and the non-inferiority margin of 0.8%. With the follow-up period reduced from months to months and hence the major bleeding rate during the follow-up period reduced linearly from 2.22% to 1.9%, the reduced sample size of 9,960 randomized DES subjects yields 80% power to claim non-inferiority of 30m DAPT to 12m DAPT. 3 Steinhubl SR, Berger PB, Mann JT, 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19): Mauri L, Hsieh WH, Massaro JM, Ho KK, D'Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med. 2007;356(10): Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20): Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Juni P, Sianos G, Hellige G, van Domburg RT, Hess OM, Boersma E, Meier B, Windecker S, Serruys PW. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 2007;369(9562): Farrington CP, Manning G. Test Statistics and Sample Size Formulae for Comparative Binomial Trials with Null Hypothesis of Non-zero Risk Difference or Non-unity Relative Risk. Statistics in Medicine. 1990; 9: May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 15

335 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, 2 ANALYSES PLANNED 2.1 General Analysis Definitions Unless otherwise specified (e.g., for non-inferiority analyses), statistical analyses and confidence intervals will be presented as two-sided. P-values less than 0.05 will be considered statistically significant; p-values will be presented to 3 decimal places. Analysis will be conducted using SAS version 9.2 or greater. Descriptive statistics of continuous outcomes will be presented as sample size, mean, median, standard deviation, minimum and maximum; descriptive statistics of categorical variables will be presented as counts and percents. The primary analyses set is the set of randomized DES subjects, comparing the 30m DAPT group with the 12m DAPT group on the primary effectiveness, primary safety, and secondary outcomes. There is no adjustment for multiple comparisons across the secondary outcomes; each will be tested at a one-sided level or a two-sided 0.05 level of significance. Primary study conclusions will be based on this analysis set. Further secondary analyses will focus on comparisons of endpoints between 30m DAPT and 12m DAPT for BMS patients and for DES+BMS combined. Further secondary analyses will compare DES vs. BMS on select outcomes. Due to the non-randomized nature of DES vs. BMS comparisons, adjustment for baseline covariates through propensity-score adjustment will be made, as detailed below. 2.2 Analysis Populations The DES Randomized - ITT sample includes all DES subjects randomized to either 12 months of DAPT or 30 months of DAPT (This is the primary analysis population). Randomization will occur at the 12 month post-stent implantation time point. Subjects randomized to the 12m DAPT arm will receive placebo for 18 months following randomization; subjects randomized to the 30m DAPT arm will receive additional DAPT for 18 months following randomization. All subjects will receive aspirin while on randomized treatment. All follow-up data will be included in the ITT statistical analyses regardless of post-randomization compliance with the assigned treatment. Subjects will be analyzed for the primary endpoints according to the treatment to which they were randomized. The DES Randomized - On Treatment (OT) sample will be the subset of the DES Randomized ITT subjects who were On Treatment over the post-stenting month period. After randomization, a subject is considered On Treatment with the randomized therapy if they take between 80% and 120% of the randomized drug the month post-stenting period (assessed via quarterly, or i.e., every-3 months, examination of study medication used, based on the bottles of unused study treatment pills the subjects return at 3-month study visits; if a subject does not return study medication bottles, then the medication used will be based on the subject-reported amount of study pills taken) and do not have an interruption of therapy longer than 14 days (assessed via subject interview). To calculate percent compliance, the total number of doses taken is divided by the number of doses required for continuous treatment during each three month May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 16

336 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, period, all multiplied by 100. Between 80% and 120% compliance at all six threemonth intervals over the month period is required to be considered On Treatment for the entire month period. The BMS Randomized - ITT sample includes all BMS subjects randomized to either 12 months of DAPT or 30 months of DAPT. Randomization will occur at the 12 month post-stent implantation time point. Subjects randomized to the 12 m DAPT arm will receive placebo for 18 months following randomization; subjects randomized to the 30 m DAPT arm will receive additional DAPT for 18 months following randomization. All subjects will receive aspirin while on randomized treatment. All follow-up data will be included in the ITT statistical analyses regardless of post-randomization compliance with the assigned treatment. Subjects will be analyzed for the primary endpoints according to the treatment to which they were randomized. The BMS Randomized - On Treatment (OT) sample will be the subset of the BMS Randomized ITT subjects who were On Treatment as defined above for the month time period. The BMS subjects versus DES subjects, propensity score matched sample will include all BMS subjects and all DES subjects who match the BMS subjects on clinically relevant baseline demographic and disease characteristics and duration of DAPT treatment. It is anticipated that the minimum matched DES:BMS ratio will be at least 2:1 (this ratio is anticipated to be achieved given the number of enrolled DES subjects available for matching is anticipated to be approximately 5-6 times greater than the number of available BMS subjects) This sample will be used to assess non-inferiority of DES to BMS with respect to MACCE and ST rates for the 0-33 month period as discussed below. Further details of the matching are provided in the sections below. The BMS subjects versus DES subjects, propensity score adjusted sample will include all enrolled BMS subjects and all enrolled DES subjects. This sample will be used to assess noninferiority of DES to BMS with respect to MACCE and ST rates for the 0-33 month period as discussed below, adjusting for clinically relevant baseline demographic and disease characteristics and for duration of DAPT treatment through propensity scores. Further details of the propensity score calculation are given below. 2.3 Methods of Analysis Baseline Characteristics Baseline demographic, clinical, angiographic, procedural and device data will be summarized using descriptive statistics presented by treatment group (30m DAPT and 12m DAPT) for each of the DES Randomized ITT and BMS Randomized ITT analysis sets. For continuous variables (e.g., age, percent diameter stenosis, and lesion length), results within treatment arm will be summarized with the numbers of observations, means, medians, standard deviations, minimums, and maximums. For categorical parameters, the treatment-specific number and percentage of subjects in each category will be presented. Continuous variables will be compared using the two-sample t-test; categorical parameters will be compared using the chi-square test or Fisher s exact test as appropriate. May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 17

337 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, Primary Effectiveness Endpoints Primary Analyses on Primary Effectiveness Endpoints The primary analyses will compare both the survival free of MACCE and ST between DES subjects randomized to the 30m DAPT arm versus DES subjects randomized to the 12m DAPT arm using the stratified log-rank test (where the strata are the randomization strata; specifically hospital site, subject complexity and thienopyridine drug type). These analyses will be performed on the DES Randomized - ITT sample defined above. The family-wise error (FWE) rate will be controlled at the two-sided 0.05 level of significance as discussed above using the Benjamini- Hochberg approach. The study will be considered a success for 30m DAPT if 30m DAPT is shown to yield a significantly lower rate than 12m DAPT for at least one of the two primary endpoints using the Benjamini-Hochberg approach on the DES Randomized ITT sample at an overall FWE rate of 0.05 (i.e., if 30m DAPT has a significantly lower rate than 12m DAPT on both endpoints using a two-sided 0.05 level of significance for each endpoint, the study is considered a success for 30m DAPT; otherwise, if 30m DAPT has a significantly lower endpoint rate than 12m DAPT on one endpoint using a two-sided level of significance, then the study is considered a success for 30m DAPT on that endpoint). Kaplan-Meier estimates of MACCE and ST will be presented for each treatment arm, as will a two-sided 95% confidence interval of the treatment difference in Kaplan-Meier rates (30m DAPT minus 12m DAPT). All subjects will be included regardless of time to follow-up. The Lakatos method 8 for calculating asymptotic mean and variance of the log-rank statistic will be used for comparison of the survival curves. Subjects not achieving the co-primary endpoints months post-procedure will be censored in the analysis at the time of last known contact or 30-months post-procedure, whichever is earlier. For each randomization stratum separately (hospital site, subject complexity and thienopyridine drug type clopidogrel and prasugrel), assessment of consistency of treatment difference across the stratum categories will be assessed using Cox proportional hazards regression. Specifically, Cox regression will be used to assess if there is a significant treatment-bystratum interaction on each of MACCE and ST. Separate interaction models will be run for each stratum and each endpoint; the Cox models will include the main effects of treatment and all randomization strata, and a treatment-by-stratum interaction term for the stratum of interest. A 0.15 level of significance will be used to assess the significance of the interaction term. For each stratum and endpoint, a non-significant interaction term or a statistically significant but quantitative-only interaction will support the poolability of results across the stratum categories for the analysis on that endpoint. In this Cox analysis, patients not experiencing the endpoint of interest will be censored at the last known follow-up or at 30 months post-index procedure, whichever is earlier. 8 Lakatos, Edward Sample Sizes Based on the Log-Rank Statistic in Complex Clinical Trials, Biometrics, Volume 44, March, pages May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 18

338 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, Missing primary effectiveness endpoint data (MACCE and ST) due to premature withdrawals before end of follow-up (30 months post-index stenting procedure) for randomized DES patients will be imputed as follows for each endpoint prior to carrying out the primary comparisons of 30m DAPT with 12m DAPT on MACCE and ST; the sensitivity of the results to the various imputation methods will be assessed descriptively. Note that prior to performing any imputation, vital status for premature withdrawals will be collected as best as possible using available public information outside the study (e.g., national death index). If information on a patient s vital status is found by this outside research, then such information, including relevant dates and causes of death, will be entered into the database and the patient will be considered non-missing with respect to that status. 1. As discussed above, patients not experiencing the event will be censored at 30 months post-procedure or last known follow-up, whichever is earlier. This is the primary analytical method on the MACCE and ST endpoints. The remaining imputation methods discussed below are considered secondary and supportive. 2. For each of MACCE and ST, only patients who completed the 30 month follow-up within the allowable time window (within one month before the actual 30 month time point) or who experienced the event will be included in the stratified log-rank analysis (i.e., based on the observed data). 3. Missing MACCE and ST endpoint data due to premature withdrawal will be imputed via multiple imputation using the logistic regression approach; baseline characteristics to be used in the imputation model are listed in Appendix A; in addition, randomized treatment group will be included in the imputation model. Specifically, for each missing component of MACCE and for missing ST status, a total of 50 datasets will be imputed. The imputed datasets will be merged by imputed data set number (1-50) and patient, and for each patient within each imputed dataset, the incidence of MACCE (yes/no) will be re-calculated based on observed and imputed component data. For each multiply-imputed dataset and each endpoint, an assessment of treatment effect size on the endpoint incidence, and the standard error of the effect size, will be calculated for each of MACCE and ST using logistic regression. For each endpoint, these 50 assessments statistics will then be combined into one overall test statistic, using multiple imputation methodology, to obtain one overall logistic-regression-based test statistic to compare 30m DAPT and 12m DAPT on that endpoint. It has been shown via computer simulations that assessment of the treatment difference on MACCE and ST using logistic regression maintains at least 80% power under the above assumptions, using the Benjamini-Hochberg approach to control the FEW rate at A tipping point analysis will be carried out, where all premature withdrawals from 12m DAPT will be assumed to have not experienced MACCE or ST by 30 months postindex procedure. At the first step, all premature withdrawals from 30m DAPT will also be assumed to have not experienced MACCE or ST by 30 months post procedure, and under these assumptions, the stratified log-rank will be used to compare 30m DAPT to 12m DAPT on each of time-to-macce and ST. At the second step, one premature May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 19

339 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, withdrawal patient from 30m DAPT will assumed to have had MACCE and ST at the time of withdrawal, and all remaining premature withdrawals from the 30m DAPT group will be assumed to not have had MACCE or ST by the end of the 30 month follow-up; the stratified log-rank will be re-calculated to compare 30m DAPT to 12m DAPT on time-to-macce and ST under these assumptions. At the third step, two premature withdrawal patients from 30m DAPT will assumed to have had MACCE and ST at the time of withdrawal, and all remaining premature withdrawals from the 30m DAPT group will be assumed to not have had MACCE or ST by the end of the 30 month follow-up; the stratified log-rank will be re-calculated to compare 30m DAPT to 12m DAPT on time-to-macce and ST under these assumptions. This process will continue, imputing an additional 30m DAPT premature withdrawal as a MACCE and ST failure, one at a time, until all 30m DAPT premature withdrawals are exhausted. Note, that a patient may be missing MACCE status but not ST status (because ST occurred before premature withdrawal but not MACCE); in that case missing MACCE will be imputed but observed ST status will of course be used in the analysis. A similar algorithm will be applied if the subject is missing ST but not MACCE Secondary Analyses on Primary Effectiveness Endpoints There will be no adjustment of significance level across the secondary analyses described below. Also, there will be no imputation of missing data; in these analyses, patients will be censored at the last known follow-up or at 30 months post-index procedure, whichever is earlier. The difference between 30m DAPT and 12m DAPT with respect to survival free of MACCE and ST will also be analyzed by Cox Proportional Hazard regression adjusting for randomization strata factors. The validity of the proportional hazards assumption will be assessed prior to carrying out the analysis. The hazard ratio (30m DAPT vs. 12m DAPT) and its two-sided 95% confidence interval will be reported. Assessment of consistency of treatment difference across studies (de novo-enrolled cohort DAPT and PMS/COA studies) will be assessed using Cox proportional hazards regression for the DES Randomized ITT analysis set. Specifically, Cox regression will be used to assess if there is a significant treatment-by-study interaction on each of MACCE and ST. The Cox models will include the main effects of treatment, all randomization strata, and study, and a treatment-by-study interaction term. A 0.15 level of significance will be used to assess the significance of the interaction. For each endpoint, a non-significant interaction term or a statistically significant but quantitative-only interaction will support the poolability of results across the studies for the analysis on the endpoint. Interaction analyses will be performed to assess treatment-by-des stent-type interaction as described in Section However, DES stent-type will be masked as A, B, C and D within this analysis. Sample sizes may be excluded from any analyses on DES stenttype to avoid inadvertent unmasking. These analyses involving DES stent-type analyses will only be performed on patients who received only one DES stent-type. Also, per the request of the DAPT Study Advisory Committee, the treatment-by-des stent-type interaction will be assessed at the 0.10 level of significance. May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 20

340 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, As an additional analysis to assess the appropriateness of pooling across the studies, the following analysis will be performed for each primary endpoint: for each individual a propensity score for cohort ( de novo vs. not de novo study) membership will be calculated using logistic regression, with cohort as the outcome and clinically relevant baseline variables as the independent variables (see discussion of propensity matching for DES- BMS comparisons in the Power Secondary Endpoints section below for a complete list of independent variables to be used in calculations of propensity scores). Patients will then be categorized into quintiles based on this propensity score. Cox regression will be used to assess if there is a significant treatment-by-cohort interaction on each of MACCE and ST. The Cox models will include the main effects of treatment, propensity quintile, and cohort, and a treatment-by-cohort interaction term. A 0.15 level of significance will be used to assess the significance of the interaction. For each endpoint, a non-significant interaction term or a statistically significant but quantitative-only interaction will support the poolability of results across the cohorts for the analysis on the endpoint. If an interaction is found to be significant and qualitative, descriptive analyses will be undertaken to assess a possible cause of the interaction as much as the data allow (for example, for a significant treatment-by-study interaction, we will assess if the interaction is in reality due to an interaction of treatment effect with a demographic characteristic that may vary across studies). All above primary and secondary analyses on the primary endpoints (not including interactions analysis or sensitivity analysis for missing data) will be performed on each of the DES Randomized ITT, DES Randomized - On Treatment (OT), BMS Randomized ITT, and BMS Randomized - OT analysis sets. In addition, for the DES randomized ITT analysis set, a Cox regression will compare 30m DAPT and 12m DAPT on each of MACCE and ST in a similar manner as described for the primary endpoint, but actual randomized treatment usage (yes/no) will be treated as a time-dependent covariate to determine if the pattern of randomized treatment usage affected the outcome Primary Safety Endpoint Major Bleeding Primary Analysis on Primary Safety Endpoint The null hypothesis is that subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization, stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have major bleeding rates between 12 and 30 months post-index procedure that exceed that of the control arm (subjects treated with only 12 months of DAPT) by at least a pre-specified margin of δ (delta). The alternative hypothesis is that subjects treated with drug-eluting stents who are free from myocardial infarction, repeat coronary revascularization. stroke, stent thrombosis, or bleeding in the first 12 months after stenting and DAPT, and are treated with dual antiplatelet therapy for an additional 18 months (total 30 months) will have major bleeding rates between 12 and 30 months post-index procedure that are no more than that of the control arm, or exceed that of the control arm but by less than δ. Rejection of the null hypothesis will signify that the 30m DAPT arm is non-inferior to the control arm (12m DAPT) with respect to major bleed rate between 12 and 30 months post-index procedure. May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 21

341 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, Specifically, the null (Ho) and alternative (H A ) hypotheses are: Ho: π 30m-DAPT π 12m-DAPT + δ H A : π 30m-DAPT < π 12m-DAPT + δ where π A is the true major bleed rate for the 30m DAPT group and π C is the true major bleed rate for the control arm (12m DAPT) over the month post-index procedure period, and δ = (0.8%). The testing of the null hypothesis will be carried out using the Farrington-Manning test for noninferiority (risk difference approach) at a one-sided level of significance. The number and percentage of patients in each treatment group with major bleeding, the risk difference and twosided 95% confidence interval of the difference will be presented. The primary analysis set is the DES Randomized ITT analysis sets. As discussed in Section 1.8, there is 80% power to claim non-inferiority of 30m DAPT to 12m DAPT with a sample size of 9,960 randomized subjects and under the assumption of a 1.9% bleeding rate in both groups over the months post-index procedure period. However, based on the latest knowledge, 30m DAPT could be inferior (i.e., has a higher bleeding rate) than 12m DAPT in the population. If the true 30m DAPT bleeding rate is 2.8% or higher over a month post-index procedure period, then there is an 80% probability that there will be a significant difference between 30m DAPT and 12m DAPT with respect to bleeding rate in this study. For each randomization stratum separately (hospital site, subject complexity and thienopyridine drug type), assessment of consistency of treatment difference across the stratum categories will be assessed using logistic regression. Specifically, logistic regression will be used to assess if there is a significant treatment-by-stratum interaction on major bleeding. Separate interaction models will be run for each stratum; the logistic regression models will include the main effects of treatment and all randomization strata, and a treatment-by-stratum interaction term for the stratum of interest. A 0.15 level of significance will be used to assess the significance of the interaction. For each stratum, a non-significant interaction term or a statistically significant but quantitative-only interaction will support the poolability of results across the stratum categories for the analysis on major bleeding. Missing major bleeding endpoint data due to premature withdrawals before end of followup (30 months post-procedure) for randomized DES patients will be imputed as follows; the sensitivity of the results to the various imputation methods will be assessed descriptively: 1. Only patients who completed the 30 month follow-up within the allowable time window or who experienced major bleeding will be included in the assessment of noninferiority (i.e., based on the observed data). This will be the primary analysis for major bleeding. 2. Missing major bleeding status due to premature withdrawal will be imputed via multiple imputation using the logistic regression approach; baseline characteristics to be used in the imputation model are listed in Appendix A; in addition, randomized May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 22

342 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, treatment group will be included in the imputation model. Specifically, for missing major bleeding status, a total of 50 datasets will be imputed. For each multiply-imputed dataset, an assessment of treatment effect size on the bleeding incidence, and the Farrington-Manning-based standard error of the effect size, will be calculated. These 50 assessments will then be combined into one, using multiple imputation methodology, to obtain one overall Farrington-Manning test statistic to assess non-inferiority of 30m DAPT to 12m DAPT on major bleeding. 3. A tipping point analysis will be carried out, where all premature withdrawals from 12m DAPT will be assumed to have not experienced major bleeding by 30 months postindex procedure. At the first step, all premature withdrawals from 30m DAPT will also be assumed to have not experienced major bleeding by 30 months post procedure, and under these assumptions, the Farrington-Manning test of non-inferiority will be carried out. At the second step, one premature withdrawal patient from 30m DAPT will assumed to have had major bleeding at the time of withdrawal, and all remaining premature withdrawals from the 30m DAPT group will be assumed to not have had major bleeding by the end of the 30 month follow-up; the Farrington-Manning assessment of non-inferiority will be re-executed under these assumptions. At the third step, two premature withdrawal patients from 30m DAPT will assumed to have had major bleeding at the time of withdrawal, and all remaining premature withdrawals from the 30m DAPT group will be assumed to not have had major bleeding by the end of the 30 month follow-up; the Farrington-Manning assessment of non-inferiority will be re-executed under these assumptions. This process will continue, imputing an additional 30m DAPT premature withdrawal as a major bleeding, one at a time, until all 30m DAPT premature withdrawals are exhausted Secondary Analyses on Primary Safety Endpoint As a secondary analysis, the above major bleeding analysis will be repeated for each of the DES Randomized OT, BMS Randomized ITT and BMS Randomized OT analysis sets. As an additional secondary analysis, the above major bleeding analysis will be repeated for the DES Randomized ITT and BMS Randomized ITT combined analysis sets, and for the DES Randomized OT and BMS Randomized OT combined analysis sets. For analyses on the OT analysis sets, any bleeding event occurring 14 days after randomized treatment has stopped will not be counted as a major bleeding event for the respective group. Prior to combining DES and BMS patients, an assessment of stent-type-by-randomized treatment interaction (where stent-type is defined as DES and BMS) on major bleeding will be assessed using Cox proportional hazards regression at the 0.15 level of significance. If not significant at the 0.15 level of significance, or if significant and only quantitative in nature, the pooling of DES-BMS patients will be carried out; otherwise, the DES-BMS combined analyses will not be performed. Note that the non-inferiority assessment for the DES+BMS combined analysis sets will be repeated from the above-mentioned risk difference approach (with an absolute margin of 0.8%) and from a relative risk approach. For the relative risk approach, the null and alternative hypotheses are May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 23

343 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, Ho: π 30m-DAPT /π 12m-DAPT λ H A : π 30m-DAPT /π 12m-DAPT < λ where π 30m-DAPT is the true major bleed rate for the 30m DAPT group, π 12m-DAPT is the true major bleed rate for the control arm (12m DAPT) over the month post-index procedure period, and λ is the relative non-inferiority margin of 1.42 (1.42 corresponds to an absolute margin of 0.8% when the assumed bleeding rates are 1.9% in each of 30m DAPT and 12m DAPT over the month follow-up period). Assessment of consistency of treatment difference across studies (native DAPT and the PMS/COA studies) type will be assessed using Cox proportional hazards regression for the DES-Randomized ITT analysis set. Specifically, Cox regression will be used to assess if there is a significant treatment-by-study interaction on major bleeding. The Cox models will include the main effects of treatment, all randomization strata, and study indicator, and a treatment-by-study interaction term. A 0.15 level of significance will be used to assess the significance of the interaction. A nonsignificant interaction term or a statistically significant but quantitative-only interaction will support the poolability of results across the studies for the analysis on major bleeding. 2.4 Powered Secondary Endpoints BMS vs. DES Comparisons There will be no imputation of missing data for the analysis described in this section. Patients who experienced the event of interest or who had adequate follow-up will be included in the analysis. There will be no adjustment for multiple comparisons in this analysis. MACCE The null hypothesis is that DAPT subjects treated with drug-eluting stents will have MACCE rates between 0 and 33 months post-index procedure that exceed that of the control arm (subjects treated BMS) by at least a pre-specified absolute margin of δ. The alternative hypothesis is that DAPT subjects treated with drug-eluting stents will have MACCE rates between 0 and 33 months post-index procedure that are no more than that of the control arm (BMS), or exceed that of the control arm but by less than δ. MI events occurring < 72 hours after the index procedure will be excluded from this analysis. Rejection of the null hypothesis will signify that the DES arm is non-inferior to the BMS arm with respect to MACCE between 0 and 33 months post-index procedure. Specifically, the null (H o ) and alternative (H A ) hypotheses are: Ho: π DES π BMS + δ HA: π DES < π BMS + δ May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 24

344 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, where π DES is the true MACCE rate for the DES group and π BMS is the true MACCE rate for the BMS arm (control arm) and δ= Assessment of the null hypothesis will be performed on the BMS subjects versus DES subjects, propensity score matched sample. Specifically, due to the non-randomized nature of DES vs. BMS comparisons, there will most likely be a difference between DES and BMS patients with respect to baseline characteristics. Those baseline characteristics need to be adjusted for in the assessment of non-inferiority of DES to BMS with respect to MACCE. Thus, a propensity score for stent type (DES or BMS) will be calculated for all enrolled patients based on the baseline characteristics listed in Appendix A; a subset of enrolled DES patients will then be matched to the enrolled BMS patients based on propensity score and Mahalanobis distance. Further details of the matching process are provided below. The goal is to match BMS to DES in a ratio of at least 1:2. With 1,965 evaluable BMS subjects (randomized or not), a non-inferiority test at an α= (1- sided) significance has at least 82% power to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with MACCE in the DES arm compared to the BMS arm, when (a) assuming the true MACCE rate of the DES and BMS arms is 9.5% over the 0-33 month period, (b) using a non-inferiority margin of 2.28%, and (c) assuming a minimum matched DES:BMS ratio of 2:1. Power Analysis and Sample Size (PASS) was used to compute the power. It is anticipated that up to 9,500 evaluable DES subjects (randomized or not) will be available for the matching with the 1,965 evaluable BMS subjects. An evaluable subject is defined as a subject who experienced the event of interest prior to the end of 33 months follow-up or a subject who was followed for 33 months (minus the allowable one month visit window). Note that at least one PMS/COA study is not following non-randomized DES subjects for the full 0-33 month post-index procedure period if the subjects are not 12 Month Clear or if they have an event in the randomized phase. Hence to avoid bias in the results, all DES subjects from such PMS/COA studies will be excluded from the matching process and the analysis. However, given anticipated enrollment and a assuming a 3% annual dropout rate, it is anticipated an evaluable sample size of 1,965 BMS and 9,500 DES subjects will be achieved with the planned enrolled sample size. The anticipated MACCE rate of 9.5% over the 0-33 month period is calculated as follows: As discussed in the primary endpoint power analyses above, the annual MACCE rate is assumed to be 2.9% for the 12m-DAPT group and 2.175% for the 30m-DAPT group for the month post-procedure period; the average of these two annual rates is %; thus, the month post-procedure MACCE rate is anticipated to be 1.5*2.5375% = %. Over the 3 month month period, where it is anticipated the annual 30m-DAPT group MACCE rate = annual 12m-DAPT group MACCE rate = 2.9%, the event rate is expected to be 2.9%/4 = 0.725%. Thus the total anticipated rate across the month post-procedure period is *( ) = or 4.5%. It is further anticipated the MACCE rate for DES and BMS patients in the 0-12 month post-index procedure/pre-randomization period will be approximately 5-5.5%%. Thus the 0-33 month MACCE rate is anticipated to be approximately 9.5%. Stent Thrombosis May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 25

345 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, The null hypothesis is that DAPT subjects treated with drug-eluting stents will have ST rates between 0 and 33 months post-index procedure that exceed that of the control arm (subjects treated BMS) by at least a pre-specified absolute margin of δ. The alternative hypothesis is that DAPT subjects treated with drug-eluting stents will have ST rates between 0 and 33 months post-index procedure that are no more than that of the control arm, or exceed that of the control arm but by less than δ. Rejection of the null hypothesis will signify that the DES arm is non-inferior to the BMS arm with respect to ST between 0 and 33 months post-index procedure. Specifically, the null (H 0 ) and alternative (H A ) hypotheses are: Ho: π A π C + δ H A : π A < π C + δ where π A is the true ST rate for the DES group and π C is the true ST rate for the BMS arm (control arm) and δ= As with the DES-BMS comparison on MACCE, assessment of the null hypothesis will be performed on the BMS subjects versus DES subjects, propensity score matched sample. With 1,965 evaluable BMS subjects (randomized or not), a non-inferiority test at an α= (1- sided) significance has at least 81% power to reject the null hypothesis of inferiority in favor of the alternative hypothesis of non-inferiority of the proportion of patients with ST in the DES arm compared to the BMS arm, when (a) assuming the true ST rate of the DES and BMS arms is 1.67% over the 0-33 month period, (b) using a non-inferiority margin of 0.97%, and (c) assuming a minimum matched DES:BMS ratio of 2:1. Power Analysis and Sample Size (PASS) was used to compute the power. It is anticipated that up to 9,500 evaluable DES subjects (randomized or not) will be available for the matching with the 1,965 evaluable BMS subjects. An evaluable subject is defined as a subject who experienced the event of interest prior to the end of 33 months follow-up or a subject who was followed for 33 months (minus the allowable one month visit window). Note that at least one PMS/COA study is not following non-randomized DES subjects for the full 0-33 month post-index procedure period if the subjects are not 12 Month Clear or if they have an event in the randomized phase. Hence to avoid bias in the results, all DES subjects from such PMS/COA studies will be excluded from the matching process and the analysis. However, given anticipated enrollment and a assuming a 3% annual dropout rate, it is anticipated an evaluable sample size of 1,965 BMS and 9,500 DES subjects will be achieved with the planned enrolled sample size. The anticipated ST rate of 1.67% over the 0-33 month period is calculated as follows: As discussed in the primary endpoint power analyses above, the annual ST rate is assumed to be 0.5% for the 12m-DAPT group and 0.225% for the 30m-DAPT group for the month postprocedure period; the average of these two annual rates is %; thus, the month postprocedure ST rate is anticipated to be 1.5*0.3625% = %. Over the 3 month month period, where it is anticipated the annual 30m-DAPT group ST rate = annual 12m-DAPT group ST rate = 0.5%, the event rate is expected to be 0.5%/4 = 0.125%. Thus the total anticipated rate May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 26

346 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, across the month post-procedure period is *( ) = or 0.67%. It is further anticipated the ST rate for all DES and BMS patients in the 0-12 month postindex procedure/pre-randomization period will be 1%. Thus the 0-33 month ST rate is anticipated to be approximately 1.67%. Analysis DES patients are those patients who received DES at the index procedure, regardless of any other type of stent received at or after the index procedure. Patients who received only BMS at the index procedure are consider BMS patients, regardless of any other type of stent received at or after the index procedure. The number and percentage of subjects experiencing each of MACCE and ST will be presented by treatment group, as will the risk difference between treatments (calculated as DES rate minus BMS rate). The DES-to-BMS non-inferiority analyses will be carried out using the Farrington- Manning approach at a one-sided level of significance for each of MACCE and ST. Given that subjects receiving each type of stent (DES vs. BMS) are not randomized to the type of stent and thus may not have similar baseline characteristics, the non-inferiority assessment on each endpoint will be carried out on the propensity-matched DES:BMS sample as mentioned above. Specifically, for each enrolled DES and BMS individual available for matching, a propensity score (or i.e., predicted probability between 0 and 1) for group (DES, BMS) membership will be calculated using logistic regression, with group as the outcome and the baseline variables in Appendix A as the independent variables. Matching of at least one DES patient to each BMS patient will be carried out using propensity matching with the Mahalanobis' distance approach. Once a DES subject is matched to a BMS subject, the DES subject is no longer available for future matching with any other BMS subject. As a secondary non-inferiority analysis, all available DES (including unmatched DES subjects) and BMS subjects will be used in the non-inferiority analysis. Subjects will first be categorized into quintiles based on the calculated propensity score. Non-inferiority will then be carried out on the rate of each endpoint using a Mantel-Haenszel risk difference stratified across the propensity quintiles at a one-sided level of significance. In addition, endpoint rates will be presented for each treatment group within each propensity score quintile in order to assess comparability of treatments within groups of subjects with similar values of baseline characteristics. As a sensitivity analysis comparing DES subjects to BMS subjects in this secondary analysis will only include subjects who have exclusively received DES compared to those that have exclusively received BMS. Stent type used during any repeat or staged procedure within 6 weeks of the index procedure will be captured to assist in determining if a subject has received both stent types. Additionally, record of any prior PCI(s) performed within 1 year prior to the index PCI, including stent type used, will be collected for the purposes of determining whether mixed stent types are present. If mixed stent types are used in a subject, then they will be excluded from this sensitivity analysis. May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 27

347 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, 2.5 Additional Endpoint Analyses Table 1 summarizes the additional endpoints, analysis populations and treatment comparisons that will be performed. For the analyses presented in this table below, risk differences, relative risks or hazard ratios, as specified, will be estimated with a two-sided 95% confidence interval; no formal statistical hypothesis testing will be carried out, hence no treatment comparison p-values be generated. There will be no imputation for missing data, there will be no adjustment for multiple comparisons, and there will be no formal assessment of treatment interactions with randomization stratum or study. Table 1. Additional Analyses Endpoint Time period Sample (s) MACCE DES Randomized - ITT, OT BMS Randomized ITT, OT ST DES Randomized - ITT, OT BMS Randomized ITT, OT Major Bleed DES Randomized - ITT, OT BMS Randomized ITT, OT DES + BMS Randomized ITT and BMS Randomized ITT combined DES Randomized OT and BMS Randomized OT combined MACCE DES Randomized - ITT, OT BMS Randomized ITT, OT ST DES Randomized - ITT, OT BMS Randomized ITT, OT MACCE BMS Randomized versus DES Randomized, propensity score adjusted ST BMS Randomized versus DES Randomized, propensity score adjusted MACCE 0-33 BMS Randomized versus DES Randomized, propensity score matched Comparison/Effect Size of Interest Hazard Ratio 30m vs. 12 m Hazard Ratio 30m vs. 12 m Relative Risk, Risk Difference, Hazard Ratio 30m vs. 12 m Hazard Ratio 30m vs. 12m Hazard Ratio 30m vs. 12m Relative Risk, Risk Difference, Hazard Ratio 30m vs. 12 m Relative Risk, Risk Difference, Hazard Ratio 30m vs. 12 m Relative Risk, Risk Difference, Hazard Ratio 30m vs. 12 m May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 28

348 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, ST 0-33 BMS Randomized versus DES Randomized, propensity score matched MACCE 0-33 BMS Randomized versus DES Randomized, propensity score adjusted ST 0-33 BMS Randomized versus DES Randomized, propensity score adjusted Relative Risk, Risk Difference, Hazard Ratio 30m vs. 12 m Relative Risk, Risk Difference, Hazard Ratio 30m vs. 12 m Relative Risk, Risk Difference, Hazard Ratio 30m vs. 12 m Analysis of Rebound Effect After discontinuation of dual antiplatelet therapy it is possible that a rebound phenomenon will occur where the hazard of either MACCE or ST is increased during the period immediately after discontinuation. The following analyses will be performed to estimate the magnitude of this possible phenomenon. The analysis will focus on the DES subjects from the randomized portion of the study; however, the analysis will also be performed separately for the BMS randomized subjects. Subjects will be followed for 3-months following the end of assigned treatment (or i.e., for a maximum of 33 months post procedure). Estimating the rebound effect The percentage of subjects who experience MACCE in the 3 months following discontinuation of randomized treatment (regardless of when the treatment is discontinued) and the corresponding exact 95% confidence interval will be calculated by treatment group (12m DAPT and 30m DAPT). In addition, the percentage of subjects who experience MACCE during randomized therapy will be calculated and the incident rate per person-quarter (where one quarter = 3 months) will be calculated within each treatment group. The difference between the percentages will be compared descriptively. If a rebound effect is present the percentage of subjects with events in the 3 months following interruption of DAPT therapy will be higher than the percentage of subjects experiencing the events during DAPT treatment. This analysis will be performed separately for DES and BMS randomized patients; specifically, it will be performed for the DES-Randomized ITT and BMS- Randomized ITT analysis sets; it will also be performed for the corresponding OT subsets. The above analyses will be repeated for ST. In addition, the relationship between the percentage of subjects experiencing each of MACCE and ST events during rebound period and the actual observed length of DAPT treatment will be assessed using logistic regression adjusting for the randomization strata. The odds ratio of the given event per one month increase in DAPT, and the two-sided 95% confidence interval of the odds ratio, will be presented. May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 29

349 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, Sensitivity Analysis of Non-compliance with Randomized Treatment (12 to 30 Months) The effect of randomized treatment compliance on treatment effect for the co-primary effectiveness endpoints and the primary safety endpoint will be assessed via the secondary analyses performed on the DES-Randomized - ITT and BMS Randomized ITT samples. For example, for subjects randomized to 30m DAPT, we will assess differences on endpoint events for subjects who were less than 80% compliant versus subjects who were at least 80% compliant (including those that may have been over 120% compliant) over 18 months post-randomization (12-30 month post-index procedure period) and 21 months post-randomization (12-33 post-index procedure period). Percent compliance is the total number of doses taken divided by the number of doses required for continuous treatment. The number of doses taken is obtained by examination of study medication used, based on the bottles of unused study treatment pills the subjects return at 3-month study visits; if a subject does not return study medication bottles by the end of the study, then the medication used will be based on the subject-reported amount of study pills taken. In addition, for subjects randomized to 30 months of DAPT, compliance will be determined for each 3 months treatment period both as a binary variable (yes/no) and a continuous variable (%compliance). For subjects randomized to 12 months of DAPT compliance will be set to yes for the binary variable and to 100% for the continuous variable. Data for subjects who are discontinued from their randomized treatment will be excluded post-discontinuation for this analysis. The incidence of MACCE, ST and major bleed in each 3-month time period will be compared between treatment groups using repeated measures models (general mixed model) with compliance as a factor in the model (for the binary variable) and separately as a covariate (for compliance expressed as a %) over the 18 and 21 month post-randomization periods Additional Subset Analysis All primary and secondary endpoints will be compared between treatments using descriptive techniques within a-priori identified subsets of the randomized patients. Specifically, two-sided 95% confidence intervals for the differences between randomized treatments will be presented within each subset of randomized patients; no p-values comparing treatments will be generated for subset analyses. However, consistency of randomized treatment difference across each of these subgroups separately will be assessed using Cox Proportional Hazards regression models with the effects of subgroup, randomization strata, randomized treatment, and randomized treatment-bysubgroup interaction. An interaction p-value <0.15 will indicate a potential differential effect of treatment across the subgroup; the nature of any such effect (e.g., quantitative vs. qualitative) will further be investigated by inspecting the treatment differences within the relevant subgroups. The subgroups to be inspected are: SUBGROUP CATEGORIES NOTES Drug Brand Masked Clopidogrel, Prasugrel Drug Brand will be masked as A and B; in the descriptive analysis, sample sizes within any descriptive May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 30

350 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, Study HCRI Native, Abbott Xience V, Boston Scientific Liberté PAS, Cordis CYPRESS, Medtronic EDUCATE statistics tables may be excluded in order to prevent inadvertent unmasking. Region ASA (at baseline) Complexity(at baseline) Anatomic Risk Factors for ST Clinical Risk Factors for ST Demographics US vs. OUS (Western EU, Eastern EU, ANZ) 100 mg, >100 mg Presence of any Risk Factors for ST A patient is considered as having anatomic risk factors for ST if the patient has at least one of: Unprotected left main, > 2 lesions per vessel, lesion 30mm, Bifurcation with side branch 2.5mm, SVG, Thrombus A patient is considered as having a clinical risk factor for ST if the patient has at least one of: ACS, Renal Insufficiency, EF <30%, > 2 vessels stented, DES ISR, Prior Brachytherapy Each of: Age, Race (White/NonWhite), Sex, BMI Prespecified interaction term will be treatment-by-any Anatomic Risk Factor for ST (yes/no). Interaction of treatment with the components of this subgroup will not be tested unless the treatment-by-anatomic Risk Factors for ST interaction term is significant. Pre-specified interaction term will be treatment-by-any Clinical Risk Factor for ST (yes/no). Interaction of treatment with the components of this subgroup will not be tested unless the treatment-by-anatomic Risk Factors for ST interaction term is significant. Age will be dichotomized as < 75, 75; BMI will be dichotomized as <median and median Medical History Each of: Diabetes, Current tobacco use, Bleeding history, Prior MI, Prior PCI, Prior CABG, CHF, LVEF<30% Homogeneity Assessment for DES Type: The DAPT Study primary analysis is designed assuming homogeneous treatment effect regardless of stent type on co-primary endpoint comparisons of 30 vs. 12m of dual antiplatelet therapy. The DAPT Study is not designed to compare differences in risk of the co-primary endpoints according to stent type (lack of randomization, lack of power, and censoring of events during months 0-12 may all introduce bias). However, evidence of qualitative differences of treatment effect across stent type (e.g. different directions of benefit), may be considered clinically relevant. As discussed in Section , we plan an assessment of homogeneity of treatment effect on the co-primary endpoints to evaluate the generalizability of the main study finding across DES types. Our main concern relates to effects that have different directions, e.g., a beneficial effect of 30m DAPT vs. 12m DAPT associated with one stent type and a negative effect of 30m DAPT vs. 12m DAPT associated with another stent type. For MACCE, ST, and major bleeding: hazard ratios adjusted for pre-treatment characteristics (see Appendix A) of 30m versus 12m DAPT by DES type (DES type will be presented blinded as A, B, C etc.) will be displayed as a forest plot. In addition, Cox proportional hazards regression with adjustment for pretreatment characteristics (see Appendix A) will be performed to assess the significance of the treatment-by-stent type interaction. If p > 0.10 for interaction, or if < 0.10 but all HR are > 1 or all are < 1, then this May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 31

351 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, will support the pooling of subjects across stent type for purposes of the analyses on the endpoints. 2.6 Additional Analyses Death, Cardiac Death, MI, stroke, and repeat revascularization for each treatment arm will be compared between 30m DAPT and 12m DAPT using similar techniques as for the primary effectiveness endpoints of MACCE and ST. This will be performed for the DES Randomized-ITT, BMS Randomized-ITT, DES Randomized-OT and BMS Randomized-OT analysis sets. Further, using the propensity-matched and propensity-adjusted analysis sets, BMS will be compared to DES on these individual endpoints in a manner similar to how DES and BMS were compared on MACCE and ST. In addition, the effect of the switching of thienopyridine or thienopyridine dose within the first 6 months post-index procedure on the primary outcomes will be examined in an exploratory fashion. No p-values comparing treatments will be generated for these additional analyses. Specifically, patients will be categorized as to whether, in the first 6 months post-index procedure they (a) switched thienopyridine treatment; (b) stayed on the same thienopyridine but had an increase or decrease in dose; and (c) did, not change thienopyridine treatment or dose. Cox proportional hazards regression will be used to assess the relationship of this categorization to the incidence of the primary endpoints for the set of randomized patients. A stepwise regression will be performed, using a significance level of 0.05 to enter and stay in the model. Included as covariates will be the above-mentioned baseline characteristics used in the creation of the propensity scores and multiple imputation. May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 32

352 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, APPENDIX A Baseline Variables to be Used in the Creation of the Propensity Score for the DES-BMS analysis, and in the Multiple Imputation Model for Missing Data Demographics Age Sex Race Ethnicity BMI Medical History Diabetes Hypertension Stroke Transient Ischemic Attack (TIA) Congestive Heart Failure (CHF) Peripheral Arterial Disease (PAD) Percutaneous Coronary Revascularization Coronary Artery Bypass Graft (CABG) Atrial Fibrillation Myocardial Infarction (MI) Cancer Major Bleeding Current Smoking Status Indication for PCI Positive Stress Test Stable Angina ACS STEMI Acute STEMI STEMI 24hrs - 14 days NSTEMI Enzyme Negative ACS Other Other Complexity Factors Renal insufficiency/failure LVEF <30% > 2 vessels stented at IP ISR of DES at IP Prior brachytherapy Unprotected Left Main > 2 lesions per vessel Lesion length 30 mm Bifurcation lesion with sidebranch 2.5 mm Vein Bypass Graft Thrombus containing Lesion May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 33

353 Harvard Clinical Research Institute DAPT Study Statistical Analysis Plan May 10, 2013 Protocol Version: 9.1, Other data Lesion data (per patient) Stent Type (for propensity only; not for multiple imputation) Region ASA dose at discharge Theinopyridine Type, at Randomization (masked) Randomization status (only for Propensity score creation) Lesion Length Reference Vessel Diameter (RVD) Lesion class Lesion type TIMI Flow, Pre Procedure TIMI flow, Post Procedure % Stenosis, Pre Procedure % Stenosis, Post Procedure Vessel Type Vessel (Native Location) Number of Stents, Implanted at Index Procedure Stent Diameter Total Stent Length Number of Treated Lesions Number of Treated Vessels May 10, 2013 DRAFT, Version: 1.0 HCRI Confidential Page 34

354 The DAPT Study A prospective, multi-center, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy (DAPT) in subjects undergoing percutaneous coronary intervention (PCI) with either drug-eluting stent (DES) or bare metal stent (BMS) placement for the treatment of coronary artery lesions. A POST MARKETING STUDY STUDY IDE # G Protocol Version: 9.1, STATISTICAL ANALYSIS PLAN Sponsor: Harvard Clinical Research Institute 930W Commonwealth Ave, 3 rd Floor Boston, MA USA SAP Version: Draft V2.2 Date Prepared: June 18, 2014 Prepared By: HCRI (Harvard Clinical Research Institute) Boston, MA