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: Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012;367: DOI: /NEJMoa

2 This file contains the following items: 1. MADIT RIT protocol, dated May 21, 2009; 2. MADIT RIT statistical analysis plan, dated August 15, 2012 In both cases, these were the original, final versions used in the MADIT RIT study, and there were no prior versions used in the study and no amendments.

3 . MULTICENTER AUTOMATIC DEFIBRILLATOR IMPLANTATION TRIAL: REDUCE INAPPROPRIATE THERAPY (MADIT-RIT) CLINICAL PROTOCOL Version 2.0 May 21, 2009 Pre-IDE #: Sponsored By Cardiac Pacemakers, Inc, DBA-Boston Scientific Cardiac Rhythm Management (CRM) 4100 Hamline Ave. N. St. Paul, MN Tel: (800) CARDIAC Principal Investigator Arthur J. Moss, MD University of Rochester Medical Center 601 Elmwood Avenue, Box 653 Rochester, NY Tel: (585) CONFIDENTIAL DO NOT COPY This protocol contains confidential information for use only by physicians and their designees participating in the MADIT-RIT Study. This document should be maintained in a secure location and should not be copied or made available for review by any unauthorized person or firm.

4 MADIT-RIT Protocol Version 2.0 Page 2 of 58 Executive Committee Members Arthur J. Moss, MD (chair) Mary W. Brown, MS, RN James Daubert, MD W. Jackson Hall, PhD University of Rochester Medical Center Rochester, NY David Cannom, MD Good Samaritan Hospital Los Angeles, CA N.A. Mark Estes III, MD New England Medical Center Boston, MA Steven Higgins, MD Scripps Memorial Hospital La Jolla, CA Brian Olshansky, MD University of Iowa Hospital & Clinics Iowa City, IA Claudio Schuger, MD Henry Ford Hospital Detroit, MI David Wilber, MD Loyola University Chicago, IL Study Development Team Executive Committee Shelly Christman, PhD Arjun Sharma, MD Melissa Simones Boston Scientific CRM St. Paul, MN

5 MADIT-RIT Protocol Version 2.0 Page 3 of 58 TABLE OF CONTENTS 1. STUDY SUMMARY BACKGROUND/RATIONALE DEVICE DESCRIPTION PURPOSE/OBJECTIVE STUDY DESIGN Study Type Scale Duration Randomization Follow-up Schedule ENDPOINTS AND DATA ANALYSIS Primary Endpoint Description Hypotheses Sample Size and Follow-up Data Analysis Secondary Observations Objective Data Analysis Tertiary Endpoints PATIENT SELECTION Device Labeling Indications Contraindications Eligibility Inclusion Criteria Exclusion Criteria Optimal Pharmacologic Therapy for Heart Failure METHODS Follow-up Schedule, Data Collection and Testing Enrollment Implant Programming to Treatment Arm Programming to Treatment Arm In-Clinic Follow-up Visits Unscheduled Visits: Adverse Event Reporting in the United States International Adverse Event Reporting Hospitalizations/Emergency Department Visits Withdrawal Patient Death Source Documentation PATIENT MANAGEMENT Informed Consent... 26

6 MADIT-RIT Protocol Version 2.0 Page 4 of Patient Data Confidentiality RISKS Risk Minimization ROLES AND RESPONSIBILITIES Coordination and Data Center (CDC) Sponsor Responsibilities Role of the Boston Scientific CRM Representatives Clinical Investigators Investigator Selection Study Initiation Executive Committee Electrogram and Device Interrogation Core Laboratory Mortality Review Committee Data Safety and Monitoring Board REPORTING REQUIREMENTS Record Keeping Study Completion Discontinuation Criteria/Early Termination MAINTAINING COMPLIANCE Study Monitoring Review of Submitted Data Confidentiality Securing Compliance REFERENCES APPENDICES APPENDICES Appendix A: Protocol Abbreviations and Key Definitions Appendix B: Statistical Design and Analysis Appendix C: Executive Committee Members Appendix D: Electrogram and Device Interrogation Core Laboratory Appendix E: Mortality Review Committee Appendix F: QOL Assessment and Patient/Shock Acceptance Surveys Appendix G: Hinkle-Thaler Criteria Appendix H: Declaration of Helsinki... 55

7 MADIT-RIT Protocol Version 2.0 Page 5 of 58 TABLES Table 1: Study Summary... 6 Table 2: Data Collection and Testing Summary Table 3: Programming Requirements MADIT-RIT A Table 4: Programming Requirements MADIT-RIT B Table 5: Programming Requirements MADIT-RIT C Table 6: ATP Programming Recommendations FIGURES Figure 1: Three-arm Randomized MADIT-RIT Trial Figure 2: Study Design... 11

8 MADIT-RIT Protocol Version 2.0 Page 6 of STUDY SUMMARY Table 1: Study Summary Title of Study Multicenter Automatic Defibrillator Implantation Trial: Reduce Short Title Version and Date Name of Sponsor Principal Investigator Participating Centers Primary Objective Primary Hypothesis Study Design Number of Patients Study Duration Study Population Inclusion Criteria Inappropriate Therapy MADIT-RIT Original approval: December 19, 2008 (version 1.0, not released) Original Release: Version 2.0, May 21, 2009 Boston Scientific Corporation Arthur J. Moss, MD The study will be conducted at approximately 90 worldwide centers. The primary objective of the study is to determine if dual-chamber ICD or CRT-D devices with high rate cutoff (MADIT-RIT-B) and/or long delay (MADIT-RIT-C) are associated with fewer patients experiencing inappropriate therapies (ATP or shock) than standard programming (MADIT-RIT-A) during post-implant follow-up of patients with indication for primary prevention device therapy. ICD or CRT-D devices programmed with high rate cutoff (MADIT-RIT B) or long delay (MADIT-RIT C) will be associated with fewer patients who experience inappropriate therapies (ATP or shock) when compared to standard programming (MADIT-RIT A). MADIT-RIT is a global, multi-center, prospective, randomized, threearm, clinical study patients will be programmed to one of the three treatment arms. Patients will have scheduled follow-ups at 3-, 6-, 9-, and 12-months postprogramming to treatment arm, and semi-annually thereafter. If a sufficient number of patients have experienced inappropriate therapy episodes to provide desired power when the last enrolled patient has completed the 9-month visit, follow-up for the trial will be complete. If an insufficient number of patients have experienced inappropriate therapy episodes at this time, the trial will continue until the last enrolled patient has been followed for 12 months. The study is expected to begin in Q and continue for approximately three years. Patients > 21 years of age who give informed consent and are implanted with a Boston Scientific CRT-D or ICD. Primary prevention patient with ischemic or non-ischemic heart disease who meets current guidelines for dual-chamber ICD or CRT-D device therapy Patient in sinus rhythm Patient on stable optimal pharmacologic therapy for the cardiac condition or who has developed a recent ICD indication that necessitates ICD therapy concurrent with the optimization of pharmacologic therapy Patient 21 years of age, or legal representative, willing and capable

9 MADIT-RIT Protocol Version 2.0 Page 7 of 58 Exclusion Criteria Follow-up Period of giving informed consent Patient with an implanted pacemaker or CRT-P Patient with existing ICD or CRT-D device components Patient with a history of spontaneous sustained VT or VF (> 160 beats/minute) Patient with permanent or chronic AF, or cardioversion for AF, within the past three calendar months prior to enrollment Patient with coronary artery bypass graft surgery or percutaneous coronary intervention within the past three calendar months prior to enrollment Patient with enzyme-positive myocardial infarction within the past three calendar months prior to enrollment Patient with angiographic evidence of coronary disease who are candidates for coronary revascularization and are likely to undergo coronary artery bypass graft surgery or percutaneous coronary intervention in the foreseeable future Patient with second- or third-degree heart block Patient in NYHA Class IV Patient who is pregnant or plans to become pregnant during the course of the trial Patient with irreversible brain damage from preexisting cerebral disease Patient with presence of any disease, other than the patient s cardiac disease, associated with a reduced likelihood of survival for the duration of the trial, e.g., cancer, uremia, liver failure, etc. Patient with chronic renal disease with BUN >50mg/dl or creatinine >2.5 mg/dl Patient participating in any other clinical trial Patient unwilling or unable to cooperate with the protocol Patient who lives at such a distance from the clinic that travel for follow-up visits would be unusually difficult Patient who does not anticipate being a resident of the area for the scheduled duration of the trial Patient unwilling to sign the consent for participation Patient whose physician does not allow participation Upon device programming to each treatment arm, all patients will have scheduled follow-ups at 3-, 6-, 9-, and 12-months post-programming, semi-annually thereafter, and at study closure.

10 MADIT-RIT Protocol Version 2.0 Page 8 of BACKGROUND/RATIONALE The implantable cardioverter defibrillator (ICD) is highly effective in reducing mortality due to cardiac arrhythmias in high-risk cardiac patients. 1-3 However, inappropriate therapies caused by supraventricular tachyarrhythmias (SVTs) remain a significant side effect of ICD therapy despite medical treatment, affecting 8-40% of patients. 4-9 Inappropriate shocks can lead to pain, anxiety, depression, impaired quality of life, proarrhythmia, and poor tolerance of life-saving ICD therapy The most desirable method of limiting inappropriate therapies is appropriate rhythm detection and intervention by the ICD. Intuitively, dual-chamber detection enhancements that utilize atrial and ventricular electrograms to formulate a diagnosis were thought to be superior to single-chamber, ventricular-only detection enhancements. Although early non-randomized and small randomized studies failed to show any definitive superiority of dual-chamber over single-chamber detection, 4-6 more recent large randomized studies have shown that not only are dual-chamber devices not inferior to single-chamber devices, 14 but they are in fact superior at identifying and reducing inappropriate therapy for SVTs. 15 Dual-chamber ICDs provide better information about the atrial rhythm during tachycardia, making it easier to determine whether the rhythm originated in the atrium or the ventricle. This is important as paroxysmal atrial fibrillation (AF) is the leading cause of inappropriate shocks. 16 Presently, approximately 20-25% of ICD shock therapy is inappropriate. In addition, inappropriate and appropriate ATP therapy can trigger ventricular tachycardia and ventricular fibrillation. 17 Part of the inappropriate therapy problem relates to the fact that programming of primary prevention devices is not done significantly different than programming of secondary prevention devices. We hypothesize that increasing the rate detection to 200 bpm or increasing delay before initiating appropriate therapy in a population of primary prevention ICD and cardiac resynchronization therapy-defibrillator (CRT-D) recipients will decrease significantly the number of patients receiving inappropriate ICD therapies without affecting morbidity or mortality when compared to standard programming utilized in the MADIT II study. Further support for higher rate cutoffs and longer delays was recently highlighted in a hands on article by Spragg and Berger. 18 Presently, the best methodology to program a dual chamber ICD or CRT-D device to reduce the amount of inappropriate therapy is unknown. This trial will be the first large randomized study statistically designed to evaluate specific programming features in the implanted devices to reduce inappropriate therapy in primary prevention patients. 3. DEVICE DESCRIPTION The MADIT-RIT trial will utilize the current approved guidelines for indications and contraindications of ICD and CRT-D devices for primary prevention therapy. Only Boston Scientific ICD (TELIGEN ) and CRT-D (COGNIS ) devices and future generations of Boston Scientific ICD and CRT-D devices that are commercially available will be used in this trial.

11 MADIT-RIT Protocol Version 2.0 Page 9 of 58 The investigational treatment is designed to determine if dual-chamber ICD or CRT-D devices with high rate cutoff (MADIT-RIT-B) and/or long delay (MADIT-RIT-C) are associated with fewer patients experiencing inappropriate therapies than standard programming (MADIT-RIT- A) that was utilized in the MADIT II trial (See Figure 1). 4. PURPOSE/OBJECTIVE The purpose of the MADIT-RIT trial is to compare the occurrence of inappropriate therapy using high rate cutoff and/or long delay in primary prevention patients receiving an ICD or CRT-D device compared to standard programming. Inappropriate therapy is defined as the highest energy therapy delivered (ATP or shock) for non-ventricular tachyarrhythmias or for inappropriate sensing (See Appendix A). The objective of the MADIT-RIT trial is to determine if dual-chamber ICD or CRT-D devices with high rate cutoff (MADIT-RIT-B) and/or long delay (MADIT-RIT-C) are associated with fewer patients experiencing inappropriate therapies than standard programming (MADIT-RIT- A) during post-implant follow-up of patients with indication for primary prevention device therapy. 5. STUDY DESIGN 5.1. Study Type This is a global, prospective, randomized, three-arm, multi-center clinical investigation that has been classified as IDE exempt Scale The investigation will be initiated in the U.S., Europe, Canada, Israel, Hong Kong, and Japan, and will utilize approximately 90 centers, depending on enrollment rate. An average of patients per month is expected to result in 1500 patients programmed to treatment arm in approximately 12 months. The ongoing recruitment rate will be closely monitored. If the monthly recruitment rate is less than the projected average of patients per month, then new centers may be added to enhance enrollment upon Boston Scientific CRM and University of Rochester Coordination and Data Center (CDC) approval Duration The trial is expected to end in approximately 36 months with six months for full start-up, months for recruitment, 9-12 months to complete follow-up of the last patient programmed to treatment arm, and six months for data analysis. Slower recruitment will prolong study duration. Patients enrolled in this investigation must be followed per this investigational protocol.

12 MADIT-RIT Protocol Version 2.0 Page 10 of Randomization Randomization schemes can be obtained by logging onto the electronic data capture system and registering the patient. Patients with an approved primary prevention indication for ICD or CRT-D device will be randomized and programmed within one calendar month of implant to one of three treatment arms in a 1:1:1 ratio (Figure 1). Randomization will be stratified by enrolling center, device type (ICD or CRT-D), and history of self-terminating paroxysmal AF. Patients without successful device implantation will be withdrawn from the study. Figure 1. Three-arm Randomized MADIT-RIT Trial (See Tables 3-6 for more detailed programming requirements) MADIT-RIT A (Standard Programming derived from MADIT II) MADIT-RIT B (High rate cutoff) MADIT-RIT C (Long delay + Rhythm ID) Zone 1 (VT): Zone 1 (VT): Zone 1 (VT-1): 170 bpm, 2.5s delay 170 bpm 170 bpm, 60s delay Onset/stability detection enhancements ON Monitor only Rhythm ID detection enhancements ON ATP + Shock ATP + Shock Zone 2 (VF): Zone 2 (VF): Zone 2 (VT): 200 bpm, 1s delay Quick Convert ATP Shock 200 bpm, 2.5s delay Quick Convert ATP Shock 200 bpm, 12s delay Rhythm ID detection enhancements ON ATP + Shock Zone 3 (VF): 250 bpm, 2.5s delay Quick Convert ATP Shock 5.5. Follow-up Schedule Patients will have scheduled follow-ups at 3-, 6-, 9-, and 12-months post-programming to treatment arm, and semi-annually thereafter (Figure 2). If a sufficient number of patients have experienced inappropriate therapy episodes to provide desired power when the last enrolled patient has completed the 9-month visit, follow-up for the trial will be complete. If an insufficient number of patients have experienced inappropriate therapy episodes at this time, the trial will continue until the last enrolled patient has been followed for 12 months. After ICD therapy is delivered, an in-clinic visit should be scheduled within one week of the enrolling center becoming aware of the therapy, or as soon as possible. All follow-up visits will require a pulse generator evaluation with routine interrogation. Sensing and pacing evaluation will be performed for each lead. Real time electrograms, stored sensing and pacing electrograms, and pacing and tachyarrhythmias therapy reports will be analyzed and printed. Each interrogation session will be saved to two blank discs for arrhythmia episode adjudication (one disc to be kept in the patient binder, one disc to be sent to the CDC). Every effort will be

13 MADIT-RIT Protocol Version 2.0 Page 11 of 58 made to maintain patients in their randomized arm. Reprogramming can be made if clinically indicated based on safety concerns. All changes in device programming will be recorded. The patient should not be withdrawn after reprogramming and should be followed per the protocol. As available, the wireless LATITUDE Patient Management system will be utilized to monitor patients between in-clinic visits. However, LATITUDE will not replace the need for in-clinic visits. Figure 2. Study Design Enrollment Complete Inclusion/Exclusion Criteria Complete Informed Consent Process Collect Quality of Life Forms (See Appendix F) Implant Within 14 Calendar Days of Enrollment Implant ICD for primary prevention patient or CRT-D for patient with no history of VT/VF Randomization Obtain randomization from electronic data capture system Program to Randomized Arm (Day 0) Within 1 Calendar Month of Implant Collect Demographics/History, Implanted Device Components and Testing, ECG, Cardiac Medications, Physical Assessment, Device Interrogation/Programming Status, Adverse Events 3-, 6-, 9-, and 12-Month Visits and Semi-Annual Visits Thereafter Collect ECG, Cardiac Medications, Quality of Life and Acceptance Surveys (at 9-month visit only; See Appendix F), Physical Assessment, Device Interrogation/Programming Status, Adverse Events, Changes to implanted device components

14 MADIT-RIT Protocol Version 2.0 Page 12 of ENDPOINTS AND DATA ANALYSIS 6.1. Primary Endpoint Description The primary endpoint, after programming of a dual-chamber ICD or CRT-D device to treatment arm, is the time to first episode receiving inappropriate therapy (highest-energy therapy delivered, classified as ATP or shock). See Appendix A for definitions of episode and highest-energy therapy delivered Hypotheses ICD or CRT-D devices programmed with high rate cutoff (MADIT-RIT B) or long delay (MADIT-RIT C) will be associated with fewer patients who experience inappropriate ATP or shock therapies when compared to standard programming (MADIT-RIT A). A design has been chosen that allows conclusions of: 1) B is superior to A; and 2) C is superior to A. The null hypothesis is that of "no effect" on risk of first inappropriate therapy episode in patients in B vs. A or in C vs. A, while the only alternative of interest is that the risk ratio B:A or C:A is less than one. Nevertheless, we will use a two-sided alternative, with a 5% significance level (or 2.5% one-sided). The two trials (B vs. A and C vs. A) are in parallel, with inference to be made about each, and hence no adjustment for multiplicity is deemed appropriate. H 0 : After programming of a dual-chamber ICD or CRT-D to treatment arm, the ratio of ongoing risks of an inappropriate therapy episode, in patients alive and without prior inappropriate therapy, for those in arm B relative to those in arm A = 1. H A : After programming of a dual-chamber ICD or CRT-D to treatment arm, the ratio of ongoing risks of an inappropriate therapy episode, in patients alive and without prior inappropriate therapy, for those in arm B relative to those in arm A < 1. H 0 : After programming of a dual-chamber ICD or CRT-D to treatment arm, the ratio of ongoing risks of an inappropriate therapy episode, in patients alive and without prior inappropriate therapy, for those in arm C relative to those in arm A = 1. H A : After programming of a dual-chamber ICD or CRT-D to treatment arm, the ratio of ongoing risks of an inappropriate therapy episode, in patients alive and without prior inappropriate therapy, for those in arm C relative to those in arm A < 1. We focus on power to detect a value 0.5 for the ratio of risks, but consider values in the range 0.67 to The hypotheses are common to both B vs. A and C vs. A comparisons. These hypotheses are only relevant if mortality is unaffected by B or C relative to A.

15 MADIT-RIT Protocol Version 2.0 Page 13 of Sample Size and Follow-up Based on the calculations in Appendix B, the sample size for this study is 1500 patients programmed to randomized treatment arm, with approximately 500 patients in each arm. This enrollment phase is expected to require approximately 12 months. Once this phase is complete, patients will continue to be followed in the continuing follow-up phase for at least another 9 or 12 months, depending on accumulated numbers of endpoint events; see below. Hence, these two phases will require months, with potential active follow-up for patients averaging months Data Analysis There are three "treatment arms" labeled A, B, and C, with A using standard programming as determined from programming in MADIT II, B using high rate cut-off, and C using prolonged delay and Rhythm ID detection enhancements (Figure 1). The trial will be treated as if it were two simultaneous two-arm trials, B vs. A and C vs. A. Arms B and C also will be compared, but without pre-specified hypotheses, or expectation of adequate power to discern meaningful differences. The primary analysis will be based on a proportional-hazards analysis for risk of a first inappropriate therapy episode, recognizing mortality as a competing (and possibly related) risk; 19 as a consequence, follow-up for inappropriate therapy will be censored upon death. The analysis will be stratified by enrolling center, by history of paroxysmal AF at baseline and by device type (ICD or CRT-D). To achieve 90% power at a hazard ratio of 0.5, representing a 50% reduction in risk, a total of 88 events are required in two arms being compared, both in B and A together and in C and A together; 85% power requires 75 endpoints. The hazard ratios considered here are assumed to include any effects of crossovers. Based on data from recent and on-going trials (see Appendix B for more details), we expect cumulative rates of mortality and withdrawals at one year to be 6-7% and 1-2%, respectively, leading to an accumulated loss of patients from active follow-up over the trial duration of 10-12%. Also, we expect the cumulative rate of endpoints (first inappropriate therapy episode) at one year to be 10%. Taking into account potential deaths and withdrawals, and assuming a 50% reduction in risk of endpoints in B relative to A, and likewise in C relative to A, we estimate that 88 endpoint events will be accumulated, in B and A together and in C and A together, by the end of a 12-month continuing enrollment phase, and possibly by the 9-month point in this phase. If this target number is reached at the 9-month point (with information conveyed to the Principal Investigator by the Data Safety and Monitoring Committee), the trial will be terminated but otherwise continued for 3 additional months. Accumulation of 75 endpoints at termination, assuring 85% power, is deemed almost certain. Details of this analysis are provided in Appendix B.

16 MADIT-RIT Protocol Version 2.0 Page 14 of 58 Results of all data will be analyzed for an intended submission to the appropriate regulatory bodies in support of a new programming algorithm for primary prevention patients Secondary Observations Objective The secondary observations of this trial are to evaluate and compare all-cause mortality and syncope in the three arms. Mortality and syncope attributable to cardiac causes will likewise be evaluated Data Analysis One source of information on mortality is from device interrogation of patients prior to death. If no therapy was offered by the device, interrogation may offer information on whether such therapy would have been offered had the patient been in a different arm of the study. Although any such incidents may provide cause for concern, such incidents are unlikely to be sufficiently frequent to provide statistical evidence for or against differences in mortality risk. The Data Safety and Monitoring Board (DSMB) will have the option of recommending termination of the trial should such meaningful mortality imbalance develop during the trial. The Morbidity and Mortality Review Committee will review all deaths and classify the cause and suspected mechanism of the terminal event according to established criteria (Appendix E). The Electrogram and Device Interrogation Core Laboratory will review all device interrogations (Appendix D). The data from the Morbidity and Mortality Review Committee and the Electrogram and Device Interrogation Core Laboratory will be provided to the DSMB. To compare mortality and syncope among the three arms, Kaplan-Meier mortality curves will be constructed for each arm and hazard ratios derived, comparing B to A, C to A, and B+C to A. To provide the greatest power, data from all three arms will be analyzed together in a proportional hazards analysis and not limited to competing-risk mortality (that prior to any inappropriate therapy). Similar analyses will be done for cardiac mortality and cardiac syncope, as classified by the Morbidity and Mortality Review Committee. Potential average follow-up for mortality is expected to be 18 months at most. With 6-7% cumulative mortality expected at 12 months, a total of 135 deaths are expected by trial termination. If mortality is the same in all three arms, there will be approximately 45 deaths in each arm. To compare mortality between two arms (B versus A or C versus A), with 90 total deaths in two arms, the power to detect a hazard ratio for mortality is very limited (see Appendix B). Even a 25% increase in risk of mortality has at most a 50% chance of being detected, even at a one-sided significance level of 10%, and even upon pooling together arms B and C.

17 MADIT-RIT Protocol Version 2.0 Page 15 of 58 Similar rates of syncope are expected. Hence, this trial cannot be expected to provide confirmation of an assumption that the differing programming algorithms will have no effect on mortality or syncope. Further analyses and details appear in Appendix B Tertiary Endpoints The tertiary objectives of this trial are, but are not limited to, the following: Evaluate the effects of MADIT-RIT-B vs. MADIT-RIT-C programming schemes on risk of first inappropriate therapy episode. Evaluate the effects of MADIT-RIT-A, MADIT-RIT-B, and MADIT-RIT-C programming on quality of life as well as on Florida Patient Acceptance and Florida Shock Anxiety surveys. Evaluate whether recurring inappropriate therapy is significantly different among the three arms of the trial. The validity of this analysis will be dependent on the frequency of reprogramming after an initial inappropriate therapy episode. Evaluate the influence of a history of paroxysmal AF on inappropriate therapy in the three arms of the trial. Evaluate the influence of ischemic heart disease vs. non-ischemic heart disease on inappropriate therapy in the three arms of the trial. Evaluate the time to first appropriate therapy in each of the three arms of the trial. Evaluate the total shocks delivered in each of the three arms of the trial. Evaluate total energy delivered in each of the three arms of the trial. Evaluate the stroke rate in each of the three arms of the trial. Evaluate the relative healthcare costs in each of the three arms of the trial. Evaluate the frequency of arrhythmic hospitalizations in each of the three arms of the trial. Evaluate the frequency of heart failure hospitalizations in each of the three arms of the trial. Evaluate differences in inappropriate and appropriate therapy in ICD vs. CRT-D devices. Evaluate the frequency of untreated sustained VT in each of the three arms of the trial. Data for the tertiary objectives will be censored at the time of reprogramming if a patient is reprogrammed away from the randomized arm.

18 MADIT-RIT Protocol Version 2.0 Page 16 of PATIENT SELECTION 7.1. Device Labeling Indications The CRT-D is indicated for patients with: 1. NYHA class III/IV, AND 2. LVEF 35%, AND 3. QRS width 120 ms, AND 4. Remains symptomatic despite stable, optimal heart failure drug therapy. The ICD is indicated for primary prevention patients with: 1. Prior MI and LVEF 30%, OR 2. Ischemic or non-ischemic dilated cardiomyopathy, LVEF 35%, and NYHA class II/III, OR 3. Prior MI and LVEF 35% and documented, non-sustained VT and inducible VT at EP testing. Should the indications for ICD/CRT-D implantation change during the MADIT-RIT trial, patients who meet the new indications will be eligible to participate. Please note that for purposes of the MADIT-RIT trial, CRT-D patients with an NYHA Class IV indication will be excluded Contraindications Use of ICD systems are contraindicated in patients whose ventricular tachyarrhythmias may have reversible cause, such as 1) digitalis intoxication, 2) electrolyte imbalance, 3) hypoxia, or 4) sepsis, or whose ventricular tachyarrhythmias have a transient cause, such as 1) acute myocardial infarction, 2) electrocution, or 3) drowning. Use of ICD systems also are contraindicated in patients who have a unipolar pacemaker. There are no contraindications for the CRT-D device. Use of LV leads are contraindicated in patients with a hypersensitivity to a nominal dose of 0.7 or 1.0 mg dexamethasone acetate drug. Some LV lead models are contraindicated in patients with mechanical tricuspid heart valves, or obstructed or inadequate vasculature for intravenous catheterization. WARNING: For specific warnings and cautions refer to the Device Systems Guide.

19 MADIT-RIT Protocol Version 2.0 Page 17 of Eligibility Patients selected for the trial must meet the indications provided in Section Only primary prevention patients (prophylactic treatment for ventricular tachyarrhythmia) will be enrolled. Patients will be enrolled based on the inclusion/exclusion criteria. The Investigator is responsible for screening all patients to determine eligibility for the trial Inclusion Criteria Patients who meet all of the following criteria at enrollment may be given consideration for inclusion in this clinical investigation: Primary prevention patient with ischemic or non-ischemic heart disease who meets current guidelines for dual-chamber ICD or CRT-D device therapy Patient in sinus rhythm Patient on stable optimal pharmacologic therapy for the cardiac condition or who has developed a recent ICD indication that necessitates ICD therapy concurrent with the optimization of pharmacologic therapy Patient 21 years of age, or legal representative, willing and capable of giving informed consent Exclusion Criteria Patients who meet any one of the following criteria at enrollment will be excluded from this clinical investigation: Patient with an implanted pacemaker or CRT-P Patient with existing ICD or CRT-D device components Patient with a history of spontaneous sustained VT or VF (> 160 beats/minute) Patient with permanent or chronic AF, or cardioversion for AF, within the past three calendar months before enrollment Patient with coronary artery bypass graft surgery or percutaneous coronary intervention within the past three calendar months prior to enrollment Patient with enzyme-positive myocardial infarction within the past three calendar months prior to enrollment Patient with angiographic evidence of coronary disease who are candidates for coronary revascularization and are likely to undergo coronary artery bypass graft surgery or percutaneous coronary intervention in the foreseeable future Patient with second or third degree heart block Patient in NYHA Class IV Patient who is pregnant or plans to become pregnant during the course of the trial Patient with irreversible brain damage from preexisting cerebral disease Patient with presence of any disease, other than the patient s cardiac disease, associated with a reduced likelihood of survival for the duration of the trial, e.g., cancer, uremia, liver failure, etc. Patient with chronic renal disease with BUN 50mg/dl or creatinine 2.5 mg/dl Patient participating in any other clinical trial Patient unwilling or unable to cooperate with the protocol

20 MADIT-RIT Protocol Version 2.0 Page 18 of 58 Patient who lives at such a distance from the clinic that travel for follow-up visits would be unusually difficult Patient who does not anticipate being a resident of the area for the scheduled duration of the trial Patient unwilling to sign the consent for participation Patient whose physician does not allow participation Optimal Pharmacologic Therapy for Heart Failure All patients who participate in the study should be prescribed to optimal pharmacologic therapy for heart failure (if indicated) for at least one month prior to enrollment, unless they have developed a recent ICD indication that necessitates ICD therapy concurrent with the optimization of pharmacologic therapy. Optimal pharmacologic therapy should include loop diuretics, ACE inhibitors, aldosterone antagonists, and beta-blockers as described below assuming no intolerance or allergic sensitivity. Loop diuretics - All patients should be prescribed to a loop diuretic (e.g., furosemide, bumetanide, or torsemide) unless the patient is not indicated, is contraindicated, or is intolerant of loop diuretics. Angiotensin Converting Enzyme (ACE) Inhibitors - All patients should be prescribed to an ACE inhibitor (or angiotensin receptor blocker (ARB)) unless the patient has previously failed, is not indicated, or is contraindicated for ACE inhibitors or ARBs. Aldosterone Antagonists - All patients who are candidates for an aldosterone antagonist should be prescribed to an aldosterone antagonist unless the patient is not indicated, is contraindicated, or is intolerant of aldosterone antagonists. Beta-blockers - All patients should be prescribed to beta-blockers unless the patient is not indicated, is contraindicated, or is intolerant of beta-blockers. The choice of selective or nonselective beta-blocker use is left to the Investigator s discretion. 8. METHODS 8.1. Follow-up Schedule, Data Collection and Testing The date of programming to treatment arm will be considered the time of origin (Day 0) for the patient. Table 2 summarizes the required testing in this trial.

21 MADIT-RIT Protocol Version 2.0 Page 19 of 58 Table 2: Data Collection and Testing Summary Reportable Data Items Timeframe Enrollment / Consent After Initial Screening Implant Randomization Program to Assigned Treatment (Rx) Arm (Day 0) Within 14 Calendar days After Informed Consent Signed Within 1 Calendar Day Prior to Programming Within 1 Calendar Month After Successful Implant 3-, 6-, 9-, and 12-Month Visit 3 Calendar- Month Increments After Programming to Assigned Rx Arm (+ 30 days) Semi-annual Visits Thereafter (18 and 24 months) 6 Calendar- Month Increments After Programming to Assigned Rx Arm Following 12 Month Visit (+ 60 days) Unscheduled Visits Therapy Delivered from Device (within 1 week of reporting delivered therapy to enrolling center) Inclusion / Exclusion Informed Consent Demographics / History ECG (standard of care) Device Implant Conversion Testing Cardiac Medications Quality of Life (9 mo only) Physical Assessment Device Interrogation/ Programming Status Disks Adverse Events 8.2. Enrollment Prior to possible entry into the trial, the patient s medical record including the most recent 12- lead ECG prior to the date of screening will be examined to determine if the patient meets the study inclusion/exclusion criteria. Patients who meet all of the entry criteria and agree to participate in the study will be given written informed consent approved by the investigational center s Institutional Review Board (IRB) / Ethics Review Committee (ERC). For patients who have a limited proficiency of the English language, the Sponsor will assist the center in obtaining a Non-English written consent translation if one is needed. Translated consent forms

22 MADIT-RIT Protocol Version 2.0 Page 20 of 58 must have IRB/ERC approval prior to use. All patients who meet the eligibility criteria and give written informed consent are considered enrolled in the study. The patient will complete the Mark3 and EuroQOL quality of life assessments and then be scheduled for appropriate device implantation Implant Patients will have a Boston Scientific commercially-available TELIGEN (ICD) or COGNIS (CRT-D) or future generation of Boston Scientific ICD and CRT-D device implanted by a qualified physician 14 calendar days after enrollment. All devices in the MADIT-RIT trial are market-released products and should be implanted per physician and/or center standard operating procedure. Conversion testing per physician and/or center standard operating procedure is recommended at implant. Following implant, patients should be programmed per physician discretion until they are randomized and programmed to treatment arm (within 1 calendar month of implant). The patients will be followed in accordance with the follow-up schedule after programming to assigned treatment arm Programming to Treatment Arm Randomization will be obtained within 1 calendar day prior to programming by creating the unique patient identification in the electronic data capture system and entering the type of device (ICD or CRT-D) and whether the patient had a history of paroxysmal AF. Patients must be programmed to their randomized treatment arm 1 calendar month after implant. The date of programming to treatment arm will be considered the time of origin for the patient (Day 0). The specific programming parameters are presented in Tables 3-6. Note: For patients randomized to arm C, perform a Rhythm ID Manual Update if no automatic update has occurred in the previous 24 hours. Once a patient is programmed to treatment arm, every effort will be made to maintain the patient in the study. However, in a trial of this scope and duration, it is inevitable that some patients will decline to participate further, change geographic location, become non-compliant with the follow-up protocol, or lose contact despite the investigator s best efforts to locate the patient.

23 MADIT-RIT Protocol Version 2.0 Page 21 of Programming to Treatment Arm Table 3: Programming Requirements for MADIT-RIT A MADIT-RIT A Parameters Programming Ventricular Tachy Therapy Zones 2 Zone 1 (VT) Zone Rate Cutoff 170 Zone 1 (VT) Zone Duration 2.5 seconds Zone 1 (VT) Zone Redetection Duration Nominal Zone 1 (VT) Zone Post-Shock Duration Nominal Rhythm Detection Enhancements (Onset/Stability) ON VT Detection ON SRD 3 minutes Post-Shock Detection: SRD 15 seconds Zone 1 (VT) Zone Therapy ATP + Shock Zone 2 (VF) Zone Rate Cutoff Zone 2 (VF) Zone Duration Zone 2 (VF) Zone Redetection Duration Zone 2 (VF) Zone Post-Shock Duration Zone 2 (VF) Zone Therapy 200 bpm 1 second Nominal Nominal Shock + Quick Convert ATP Table 4: Programming Requirements for MADIT-RIT B MADIT-RIT B Parameters Programming Ventricular Tachy Therapy Zones 2 Zone 1 (VT) Rate Cutoff 170 bpm Zone 1 (VT) Zone Rate Therapy Monitor Only Zone 2 (VF) Zone Rate Cutoff Zone 2 (VF) Zone Duration Zone 2 (VF) Zone Therapy 200 bpm 2.5 seconds Shock + Quick Convert ATP

24 MADIT-RIT Protocol Version 2.0 Page 22 of 58 Table 5: Programming Requirements for MADIT-RIT C MADIT-RIT C Parameters Programming Ventricular Tachy Therapy Zones 3 Zone 1 (VT-1) Zone Rate Cutoff 170 bpm Zone 1 (VT-1) Zone Duration 60 seconds Rhythm Detection Enhancements (Rhythm ID): ON; Program Passive and Active Methods ON with Fallback LRL AF Threshold 170 bpm Stability 20 ms SRD OFF Post-Shock Detection: ON SRD OFF Zone 1 (VT-1) Zone Therapy ATP + Shock Redetection Duration Nominal Zone 2 (VT) Zone Rate Cutoff Zone 2 (VT) Zone Duration Rhythm Detection Enhancements (Rhythm ID): Zone 2 (VT) Zone Therapy Redetection Duration Zone 3 (VF) Zone Rate Cutoff Zone 3 (VF) Zone Duration Zone 3 (VF) Zone Therapy 200 bpm 12 seconds ON, Same as VT-1 Zone ATP + Shock Nominal 250 bpm 2.5 seconds Shock + Quick Convert ATP

25 MADIT-RIT Protocol Version 2.0 Page 23 of 58 Table 6: ATP Programming for Arms A and C (recommended): ATP1 Scan Number of Bursts 4 Pulses per Burst -- Initial 8 Increment 1 Maximum 16 Coupling Interval 81% Decrement 0 ms Burst cycle Length 81% Ramp Decrement 0 ms Scan Decrement 20 ms Minimum Interval 200 ms ATP2 Ramp Number of Bursts 4 Pulses per Burst Initial 10 Increment 1 Maximum 15 Coupling Interval 81% Decrement 0 ms Burst Cycle Length 81% Ramp Decrement 10 ms Scan Decrement 0 ms Minimum Interval 200 ms ATP Time-out 360 seconds It is recommended that brady programming parameters for ICD devices include the use of the AV Search+ algorithm for optimization of AV delay and AV Search Hysteresis ON to prevent unnecessary RV pacing. It is recommended that brady programming parameters for CRT-D devices include the use of the SMARTDelay algorithm for optimization of AV delay and VRR and BiV Trigger ON to maximize biventricular pacing In-Clinic Follow-up Visits In-clinic visits are required at 3-, 6-, 9-, and 12-months post-programming to treatment arm, semi-annually thereafter, and at study closure. During all office/clinic visits, the device will be interrogated and the information will be documented on the follow-up form. The following testing is required at all office/clinic visits: Physical as directed on the follow-up case report form Adverse Events, including heart failure events, emergency department visits, hospitalizations, and deaths

26 MADIT-RIT Protocol Version 2.0 Page 24 of 58 Device Events: inappropriate and appropriate device therapy for events ECG (per standard of care) Record all cardiac medications At the 9-month visit only: EuroQOL, Florida Patient Acceptance Survey and Florida Shock Anxiety Scale For patients in arm C, perform Rhythm ID Manual Update if no automatic update has occurred in the previous 24 hours Save all device data to two discs (one to be kept in patient binder, one to be sent to CDC) as well as one printout to be kept in patient binder 8.6. Unscheduled Visits: ICD/CRT-D Interrogation and Evaluation after ICD Therapy After a patient reports ICD therapy, or LATITUDE indicates therapy was delivered, an inclinic visit should be scheduled within one week or as soon as possible. The following is required at all unscheduled in-clinic visits: Physical as directed on the follow-up case report form Adverse Events including heart failure events, emergency department visits, hospitalizations, and deaths Device Events: inappropriate and appropriate device therapy for events ECG (per standard of care) Record all cardiac medications For patients in arm C, perform Rhythm ID Manual Update if no automatic update has occurred in the previous 24 hours Save all device data to two discs (one to be kept in patient binder, one to be sent to CDC) as well as one printout to be kept in patient binder 8.7. Adverse Event Reporting in the United States Adverse events will be reported in accordance with Medical Device Regulations. An adverse event is defined as an event that affects device performance, cardiovascular function and/or study endpoints. Information collected on the adverse event electronic case report form includes the classification of the adverse event and whether the event was patient- or pulse generator-/lead-related and the outcome of the event International Adverse Event Reporting An adverse event is any untoward medical occurrence in a subject. Investigators will be asked to classify whether an adverse event is considered serious or non-serious and whether they consider it device related or not.

27 MADIT-RIT Protocol Version 2.0 Page 25 of 58 Adverse Device Effect (ADE) - any untoward and unintended response to a medical device. This definition includes any event resulting from insufficiencies or inadequacies in the instructions for use (IFU) or the deployment of the device This definition includes any event that is a result of a user error Adverse Event (AE) - any untoward medical occurrence in a subject This definition does not imply that there is a relationship between the adverse event and the device under investigation Serious Adverse Device Effect (SADE) - adverse device effect that has resulted in any of the consequences characteristic of a serious adverse event or that might have led to any of these consequences if suitable action had not been taken or intervention had not been made or if circumstances had been less opportune. Serious Adverse Event (SAE) - adverse event that a) led to a death, b) led to a serious deterioration in the health of the subject that: 1. resulted in a life-threatening injury, or 2. resulted in a permanent impairment of a body structure or a body function, or 3. required in-patient hospitalization or prolongation of an existing hospitalization, or 4. resulted in medical or surgical intervention to prevent permanent impairment to body structure or body function, or 5. led to fetal distress, fetal death or a congenital abnormality or birth defect 8.9. Hospitalizations/Emergency Department Visits All hospitalizations and emergency department visits will be recorded as adverse events; there is no separate case report form for hospitalizations in this investigation Withdrawal The patient status case report form is completed when a patient is withdrawn from the study. Reasons for withdrawal include: Patient did not meet inclusion/exclusion criteria, Patient not implanted, Patient withdrew consent, Patient lost to follow-up, Patient withdrawn by Physician, or Device explanted. Withdrawals can only occur after consent is obtained Patient Death The patient status case report form is completed when reporting a patient death. Collected death information includes details about cause of death, device functioning, and other relevant details. The device should be interrogated (if possible) and the case report form listed above must be completed and transferred to the electronic data capture website as soon as possible after notification to the center. Every attempt should be made to return Boston Scientific CRM system components to sponsor. Collected death information that will be reported to the Mortality Review Committee includes, but is not limited to: Was an autopsy performed?

28 MADIT-RIT Protocol Version 2.0 Page 26 of 58 Was the patient pacemaker dependent? Was device active at the time of death? Was device interrogated in situ after death? Primary organ cause (Cardiac: Arrhythmic, Cardiac: Pump Failure, Cardiac: Ischemic, Cardiac: Other Cardiac, Cardiac: Unknown, Non-cardiac, Unknown) If ischemic (Acute MI, No Acute MI, MI Unknown) Temporal Course (Sudden, Non-sudden, Unknown) Antecedent worsening HF? Death witnessed? Death monitored? If death monitored (VT, Bradyarrhythmia, Pulseless electrical activity, Other, Unknown) If bradyarrhythmia (Sinus bradyarrhythmia, High degree AV block with slow ventricular response, Asystole, Unknown) Operative related (Pre-Operative, Peri-Operative, Post-Operative, Unknown) Death-related to (Procedure, Pulse generator, Lead/Catheter, Unknown, None) Source Documentation A participating Investigator must maintain accurate, complete and current records, including record of each patient s case history and exposure to the device. Source documentation is required during acute testing, post-implant and chronic device evaluation, and adverse events. Source documentation is per Investigator s discretion but must include patient medical records, worksheets, case report forms, parameter reports, and electrograms. 9. PATIENT MANAGEMENT 9.1. Informed Consent Patient participation in this clinical investigation is voluntary. Informed Consent is required from all patients or their legally authorized representative, and the Investigator is responsible for ensuring that Informed Consent is obtained in accordance with 21 CFR 50. Patients who meet all the eligibility criteria and agree to participate in the study must read, sign, and date an Informed Consent form prior to any study procedures/testing/data collection. The Informed Consent form must also be approved by the Investigator s IRB/ERC. For patients who have a limited proficiency of the English language, the Sponsor will assist the