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: Kwo PY, Mantry PS, Coakley E, et al. An interferon-free antiviral regimen for HCV after liver transplantation. 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/final statistical analysis plan

3 M Protocol 1.0 Title Page Clinical Study Protocol M Open-label, Single Arm, Phase 2 Study to Evaluate the Safety and Efficacy of the Combination of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered with Ribavirin (RBV) in Adult Liver Transplant Recipients with Genotype 1 Hepatitis C Virus (HCV) Infection AbbVie Investigational Product: Date: 12 November 2012 Development Phase: 2 Study Design: EudraCT Number: Investigator: Sponsor: Sponsor/Emergency Contact: ABT-450/Ritonavir/ABT-267, ABT-333 This is an open-label, single arm, combination drug study. Multicenter. Investigator information is on file at AbbVie. AbbVie* Eoin Coakley, MD Phone: Fax: Mobile: This study will be conducted in compliance with the protocol, Good Clinical Practice and all other applicable regulatory requirements, including the archiving of essential documents. *The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial Application with the Competent Authority. Confidential Information No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 1

4 M Protocol 1.1 Synopsis AbbVie Protocol Number: M Name of Study Drug: ABT-450, ritonavir, ABT-267, ABT-333 Name of Active Ingredient: ABT-450: (2R,6S,12Z,13aS,14aR,16aS)-N- (cyclopropylsulfonyl)-6-{[(5-methylpyrazin-2-yl) carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6- yloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16 atetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4] diazacyclopentadecine-14a(5h)-carboxamide hydrate ritonavir: [5S-(5R*,8R*,10R*,11R*)]-10- Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1- methylethyl)-4-thiazolyl]-3,6-dioxo-8,11- bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester ABT-267: Dimethyl ([(2S,5S)-1-(4- tertbutylphenyl)pyrrolidine-2,5-diyl]bis{benzene- 4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3- methyl-1-oxobutane-1,2-diyl]})biscarbamate hydrate ABT-333: (sodium N-{6-[3-tert-butyl-5-(2,4-dioxo- 3,4 dihydropyrimidin-1(2h)-yl)-2- methoxyphenyl]naphthalen-2-yl} methanesulfonamide hydrate) Protocol Title: Phase of Development: 2 Date of Protocol Synopsis: 12 November 2012 Open-label, Single Arm, Phase 2 Study to Evaluate the Safety and Efficacy of the Combination of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered with Ribavirin (RBV) in Adult Liver Transplant Recipients with Genotype 1 Hepatitis C Virus (HCV) Infection Objectives: The primary objectives of this study are to assess the safety and efficacy (the percentage of subjects achieving a 12-week sustained virologic response, SVR 12 (HCV ribonucleic acid (RNA) < lower limit of quantification (LLOQ) 12 weeks following treatment) of coformulated ABT-450 with ritonavir (r) and ABT-267 (ABT-450/r/ABT-267) and ABT-333 coadministered with ribavirin (RBV) for 24 weeks in HCV genotype 1 infected adult liver transplant recipients with recurrent HCV genotype 1 infection. The secondary objectives of this study are to assess the percentage of subjects with virologic failure during treatment, and the percentage of subjects achieving a 24-week sustained virologic response, SVR 24 (HCV RNA < LLOQ 24 weeks following treatment), the percentage of subjects with relapse post-treatment. 2

5 M Protocol Investigators: Multicenter trial: investigator information is on file at AbbVie. Study Sites: Approximately 10 sites. Study Population: Adults between the ages of 18 to 70 years of age, inclusive who are liver transplant recipients with recurrent HCV genotype 1 infection. Number of Subjects to be Enrolled: Approximately 30. Methodology: This is a Phase 2, multi-center study evaluating the safety and efficacy of the combination of direct acting antivirals (DAA) ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks in adult liver transplant recipients with recurrent HCV genotype 1 infection. Approximately 30 HCV genotype 1-infected treatment naïve or treatment experienced (conventional IFN or PegIFN with or without RBV prior to transplant) liver transplant recipients will enroll in this trial. Subjects will be enrolled into the study for a total of 72 weeks not including a 35-day Screening Period and a Study Treatment Lead-In Period up to 14 days prior to enrollment into the study. This study will consist of two periods, the Treatment Period (TP) and the Post-Treatment Period (PTP). After the Screening Period, subjects who meet the eligibility criteria will undergo a Study Treatment Lead-In Period which will occur up to 14 days but no less than 2 days prior to enrollment into the TP. During the Study Treatment Lead-In Period, subjects who have met enrollment criteria will return to the site for laboratory tests to measure the CNI trough level. This trough level will serve to confirm that the CNI dose is appropriate before commencing study drugs and will form the basis for CNI dose adjustment when the subject commences the DAA-RBV therapy. During the TP, patients will receive 24 weeks of ABT-450/r/ABT-267, ABT-333 and RBV. Visits will occur during the Treatment Period at Study Day 1, 3, 7, 10 (optional), and Weeks 2, 3, 4, 6, 8, 12, 16, 20, and 24. During PTP, visits will occur at Study Day 3, 7, 10 (optional), and Weeks 2, 3, 4, 8, 12, 24, 36 and 48. The safety data will be reviewed by the sponsor, as this is an open-label study and by an independent Data Monitoring Committee during the Treatment Period of the study. The following criteria will be considered evidence of virologic failure while the subject is on study drugs and these subjects will be discontinued from direct-acting antiviral agent (DAA) therapy: Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV RNA measurements of > 1 log 10 IU/mL above nadir) at any time point during treatment, Failure to achieve HCV RNA < LLOQ by Week 6; or Confirmed HCV RNA LLOQ (defined as 2 consecutive HCV RNA measurements LLOQ) at any point during treatment after HCV RNA < LLOQ. All subjects who receive at least one dose of DAAs will be monitored for up to 48 weeks following the last dose of DAA to monitor for the durability of viral response, safety and for the emergence and persistence of resistant viral variants in the Post-Treatment Period. 3

6 M Protocol Diagnosis and Main Criteria for Inclusion/Exclusion: Main Inclusion: 1. Male or female between the ages of 18 and 70 years, inclusive, at time of enrollment. 2. Liver transplantation as a consequence of HCV infection no less than 12 months before the Screening Visit. 3. A liver biopsy which shows evidence of fibrosis F2 (Metavir scale) within 3 months prior to or during the Screening Period. 4. Screening laboratory result indicating HCV genotype 1 infection. 5. Currently taking an immunosuppressant regimen based on either tacrolimus or cyclosporine where doses of immunosuppressant drugs have not been increased over the 3 months prior to Screening and no new drugs have been added for at least 3 months before Screening. Corticosteroids such as prednisone or prednisolone are permitted as components of the immunosuppressant regimen providing the dose is not more than 5 mg/day. Main Exclusion: 1. Positive test result for Hepatitis B surface antigen (HBsAg) or anti-human Immunodeficiency virus antibody (HIV Ab). 2. Use of any medications listed below as well as those that are contraindicated for use with either ritonavir or RBV within 2 weeks prior to study drugs administration or 10 half-lives, whichever is longer, including but not limited to: Alfuzosin Amiodarone Astemizole Bepridil Bosentan Buprenorphine Clarithromycin Carbamazepine Cisapride Conivaptan Dronedarone Efavirenz Eleptriptan Eplerenone Ergot derivatives Fusidic Acid Gemfibrozil Itraconazole Ketoconazole Lovastatin Methadone Midazolam (oral) Mifepristone Modafinil Montelukast Nefazodone Phenobarbital Phenytoin Pimozide Pioglitazone Propafenone Quercetin Quinidine Rifabutin Rifampin Rosiglitazone Salmeterol Simvastatin St. John's Wort Telithromycin Terfenadine Triazolam Trimethoprim Troglitazone Troleandomycin Voriconazole 4

7 M Protocol Diagnosis and Main Criteria for Inclusion/Exclusion: Main Exclusion (Continued): 3. Clinically significant abnormalities, other than HCV infection in a subject post transplant, based upon the results of a medical history, physical examination, vital signs, laboratory profile and a 12-lead electrocardiogram (ECG) that make the subject an unsuitable candidate for this study in the opinion of the investigator. 4. Recent (within 6 months prior to study drugs administration) history of drug or alcohol abuse that, in the opinion of the investigator, could preclude adherence to the protocol. 5. Previous use of any investigational or commercially available anti-hcv agent other than IFN-based therapy, i.e., conventional (c)ifn and/or pegylated (Peg) IFN, with or without RBV, including previous exposure to ABT-450, ABT-333 or ABT-267. Investigational Products: Doses: Mode of Administration: Duration of Treatment: ABT-450/r/ABT-267: coformulated 75 mg/50 mg/12.5 mg tablet ABT-333: 250 mg tablet Ribavirin: 200 mg tablet ABT-450/r/ABT-267: 150 mg/100 mg/25 mg QD ABT mg BID Ribavirin Per local label or Investigator Practice Oral Subjects will receive ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks. Criteria for Evaluation: Patient Reported Outcomes (PROs): The change in non-disease specific Health Related Quality of Life (HRQoL), HCV-specific function and wellbeing, and Health State Utility will be assessed using the short form 36 version 2 (SF-36 V2), the HCV Patient Reported Outcomes (HCVPRO) instrument, and the EuroQol EQ-5D-5L instrument including the integral visual analogue scale (VAS), respectively. Efficacy: Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit. Resistance: The following resistance information will be tabulated and summarized for subjects who experience virologic failure: the variants at each amino acid position at baseline identified by population nucleotide sequencing will be compared to the appropriate prototypic reference sequence, and the variants at the available post-baseline time points identified by population and/or clonal nucleotide sequencing will be compared to baseline and the appropriate prototypic reference sequences. 5

8 M Protocol Criteria for Evaluation (Continued): Pharmacokinetic: Individual plasma concentrations of ABT-450, possible ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ritonavir and ribavirin will be tabulated and summarized. Individual blood concentrations of immunosuppressants, cyclosporine and tacrolimus will also be tabulated and summarized. Safety: Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical laboratory tests, 12-Lead ECGs and vital signs. Statistical Methods: Efficacy: The primary endpoint is the percentage of subjects with SVR 12 (HCV RNA < LLOQ 12 weeks after the last actual dose of study drugs). The secondary objectives of this study are to assess is the percentage of subjects with SVR 24 (HCV RNA < LLOQ 24 weeks after the last actual dose of study drugs), the percentage of subjects with virologic failure during treatment, and the percentage of subjects with relapse post-treatment. For the primary and secondary endpoints, the simple percentage of subjects meeting the endpoint will be calculated and a 2-sided 95% binomial confidence interval using the normal approximation to the binomial will be computed. PROs: Exploratory analyses of the change in non-disease-specific HRQoL, HCV-specific function and wellbeing, and health state utility will be measured using the SF-36V2, HCVPRO, and EQ-5D-5L instruments, respectively. SF-36V2 and HCVPRO will be analyzed by their total/component scores, as appropriate. The EQ-5D-5L will be analyzed by utility score and by visual analogue scale (VAS) response. Change from baseline in the patient reported outcome (PRO) summary measures will be assessed. The number and percentage of subjects with decrease that is less than the minimally clinically important difference (MCID) for HCVPRO total score and EQ-5D-5L health index score will be calculated for all subjects. MCID for HCVPRO total score is based on Receiver Operating Characteristic (ROC) curve anchored by SF-36 MCS and SF-36 PCS decrease of 5 points. Resistance: The following resistance information will be analyzed for subjects who experience virologic failure: the variants at each amino acid position at baseline identified by population nucleotide sequencing will be compared to the appropriate prototypic reference sequence, and the variants at available post-baseline time points identified by population and/or clonal nucleotide sequencing will be compared to baseline and the appropriate prototypic reference standard sequences. The most prevalent amino acid variants found by population sequencing and amino acid variants that emerge or become enriched in isolates from at least 2 subjects will be summarized and the persistence of viral resistance will be summarized. 6

9 M Protocol Statistical Methods (Continued): Pharmacokinetic: Plasma concentrations of ABT-450, possible ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ritonavir and ribavirin will be tabulated for each subject and group. Blood concentrations of cyclosporine and tacrolimus will be tabulated for each subject and group. Summary statistics will be computed for each time and visit. Safety: The number and percentage of subjects reporting treatment-emergent adverse events will be tabulated by Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. Tabulations will also be provided in which the number of subjects reporting an adverse event (MedDRA preferred term) is presented by severity (mild, moderate, or severe) and relationship to study drugs. Change from baseline in laboratory tests and vital sign measurements to each time point of collection will be summarized. Laboratory test and vital sign values that are potentially clinically significant, according to predefined criteria, will be identified and the number and percentage of subjects with potentially clinically significant values will be calculated. Sample Size: It is planned to enroll 30 subjects to this study. With a sample size of 30 subjects and an observed SVR 12 rate of 80%, the 2-sided 95% confidence interval, using the normal approximation to the binomial, will be (65.7%, 94.3%) with a width of 28.6%. Subjects who do not have data at PTP Week 12 (after performing the described imputation) count as failures for SVR 12 so no adjustment for dropout is applicable. With 30 subjects, the probability is at least 96% to observe an adverse event with an incidence rate of 10% or higher. 7

10 M Protocol 1.2 List of Abbreviations and Definition of Terms Abbreviations ABT-450/r/ABT-267 AE ALT ANC APRI aptt AARDEX AST BID BMI BUN CNI CRF cifn CYP2C8 CYP3A DAA DNA EC ECG ecrf EDC EDTA EOT EOTR EU EQ-5D-5L FDA FSH GAM GCP ABT-450 with ritonavir and ABT-267 Adverse event Alanine aminotransferase Absolute neutrophil count Aspartate aminotransferase-to-platelet Ratio Index Activated partial thromboplastin time Advanced Analytical Research on Drug Exposure Aspartate aminotransferase Twice Daily Body mass index Blood urea nitrogen Calcineurin inhibitor Case report form Conventional Interferon Cytochrome P450 2C8 Cytochrome P450 3A Direct-acting antiviral agent Deoxyribonucleic acid Ethics Committee Electrocardiogram Electronic case report form Electronic data capture Edetic acid (ethylenediaminetetraacetic acid) End of treatment End of treatment response European Union EuroQol 5 Dimensions 5 Levels Health State Instrument US Food and Drug Administration Follicle stimulating hormone Generalized additive method Good Clinical Practice 8

11 M Protocol GCSF granulocyte colony stimulating factor GGT Gamma-glutamyl transferase GLP Good Laboratory Practice HBsAg Hepatitis B surface antigen hcg Human Chorionic Gonadotropin HCV Hepatitis C virus HCV Ab Hepatitis C virus antibody HCVPRO Hepatitis C Virus Patient Reported Outcomes Instrument HEOR Health Economics and Outcomes Research Hemoglobin A1c Glycated hemoglobin HIV Ab Human immunodeficiency virus antibody HRQoL Health Related Quality of Life ICH International Conference on Harmonization IEC Independent ethics committee IFN Interferon IL28B Interleukin 28B IMP Investigational Medical Product INR International normalized ratio IP-10 Interferon gamma-induced protein 10 IRB Institutional Review Board IRT Interactive Response Technology IU International units LLN Lower limit of normal LLOD Lower limit of detection LLOQ Lower limit of quantification MCID Minimal clinically important difference MDRD Modification of Diet in Renal Disease MedDRA Medical Dictionary for Regulatory Activities MEMS Medication Event Monitoring System NS3A Nonstructural viral protein 3A NS4A Nonstructural viral protein 4A NS5A Nonstructural viral protein 5A NS5B Nonstructural viral protein 5B OATP1B1 Organic anion transporting polypeptide 1B1 9

12 M Protocol OL PCS PegIFN PG POR PRO PTP QD QTc QTcF r RBC RBV RNA RT-PCR RVR SAE SAS SDP SF-36V2 SGOT SGPT SUSAR SVR SVR 4 SVR 12 SVR 24 TP ULN VAS WBC Open-label Potentially clinically significant Pegylated-interferon alpha-2a or alpha-2b Pharmacogenetic Proof of Receipt Patient Reported Outcomes Post-Treatment Period Once daily QT interval corrected for heart rate QTc using Fridericia's correction formula Ritonavir Red blood cells Ribavirin Ribonucleic acid Reverse transcriptase PCR Rapid virologic response Serious adverse event Statistical Analysis System Study Designated Physician Short-Form 36 Version 2 health status survey Serum glutamic oxaloacetic transaminase Serum glutamic pyruvic transaminase Suspected Unexpected Serious Adverse Reaction Sustained virologic response Sustained virologic response 4 weeks post-dosing Sustained virologic response 12 weeks post-dosing Sustained virologic response 24 weeks post-dosing Treatment Period Upper limit of normal Visual analogue scale White blood cells 10

13 M Protocol Definition of Terms Study Drugs Study Treatment Lead-In Period Study Day 1 Treatment Period (TP) Post-Treatment Period (PTP) ABT-450/r/ABT-267, ABT-333, RBV Maximum of 14 days and minimum of 2 days prior to Study Day 1 First day a subject takes study drugs Baseline/Study Day 1 through last dose of study drugs Day after the last dose of study drugs through Post-Treatment Week 48 or Post-Treatment Discontinuation Pharmacokinetic and Statistical Abbreviations AUC AUC 24 C max C trough t 1/2 T max Area under the plasma concentration-time curve Area under the plasma concentration-time curve from time zero to 24 hours Maximum observed plasma concentration Pre-dose trough plasma concentration Terminal phase elimination half-life Time to maximum observed plasma concentration 11

14 M Protocol 2.0 Table of Contents 1.0 Title Page Synopsis List of Abbreviations and Definition of Terms Table of Contents Introduction Differences Statement Benefits and Risks Study Objectives Primary Objective Secondary Objectives Investigational Plan Overall Study Design and Plan: Description Screening Rescreening Study Treatment Lead-In Period Study Treatment Period (TP) Post-Treatment Period (PTP) Selection of Study Population Inclusion Criteria Exclusion Criteria Prior and Concomitant Therapy Prior HCV Therapy Concomitant Therapy Management of Tacrolimus or Cyclosporine Dosing Prohibited Therapy

15 M Protocol 5.3 Efficacy, Pharmacokinetic, Pharmacogenetic and Safety Assessments/Variables Efficacy and Safety Measurements Assessed and Flow Chart Study Procedures Meals and Dietary Requirements Blood Samples for Pharmacogenetic Analysis Drug Concentration Measurements Collection of Samples for Analysis Handling/Processing of Samples Disposition of Samples Measurement Methods Efficacy Variables Primary Variable Secondary Variables Resistance Variables Safety Variables Pharmacokinetic Variables Pharmacogenetic Variables Removal of Subjects from Therapy or Assessment Discontinuation of Individual Subjects Virologic Failure Criteria Discontinuation of Entire Study Treatments Treatments Administered Identity of Investigational Products Packaging and Labeling Storage and Disposition of Study Drugs Assigning to Treatment Groups

16 M Protocol Selection and Timing of Dose for Each Subject Blinding Data Monitoring Committee (DMC) Treatment Compliance MEMS Caps Drug Accountability Discussion and Justification of Study Design Discussion of Study Design and Choice of Control Groups Appropriateness of Measurements Suitability of Subject Population Selection of Doses in the Study Adverse Events Definitions Adverse Event Serious Adverse Events Adverse Event Severity Relationship to Study drugs Adverse Event Collection Period Adverse Event Reporting Pregnancy Toxicity Management Grades 1 or 2 Laboratory Abnormalities and Mild or Moderate Adverse Events Grades 3 or 4 Laboratory Abnormalities and Severe or Serious Adverse Events Management of Decreases in Hemoglobin Management of Transaminase Elevations Creatinine Clearance

17 M Protocol 7.0 Protocol Deviations Statistical Methods and Determination of Sample Size Statistical and Analytical Plans Demographics Efficacy Primary Efficacy Endpoint Secondary Efficacy Endpoints Subgroup Analysis Additional Efficacy Endpoints Patient Reported Outcomes Resistance Analyses Safety Adverse Events Clinical Laboratory Data Vital Signs Data Pharmacokinetic and Exposure-Response Analyses Determination of Sample Size Randomization Methods Ethics Independent Ethics Committee (IEC) or Institutional Review Board (IRB) Ethical Conduct of the Study Subject Information and Consent Source Documents and Case Report Form Completion Source Documents Case Report Forms Data Quality Assurance

18 M Protocol 12.0 Use of Information Completion of the Study Investigator's Agreement Reference List List of Tables Table 1. Table 2. Medications Contraindicated for Use with the Study Regimen...39 Study Activities Treatment Period...49 Table 3. Study Activities Post-Treatment Period (PTP)...53 Table 4. Clinical Laboratory Tests...59 Table 5. Identity of Investigational Products...76 Table 6. Management of Hemoglobin Decreases...99 Table 7. Table 8. Table 9. Management of Confirmed ALT Levels Greater than or Equal to 5 ULN and Greater than or Equal to 2 Baseline Sided 95% Confidence Intervals Using the Normal Approximation to the Binomial for SVR 12 Rates Probability of Not Observing an Adverse Event or Lab Abnormality for Various True Incidence Rates List of Figures Figure 1. Study Schematic...29 Figure 2. Schematic of Study Treatment Lead-In Period...33 Figure 3. Adverse Event Collection

19 M Protocol List of Appendices Appendix A. Responsibilities of the Clinical Investigator Appendix B. List of Protocol Signatories Appendix C. Clinical Toxicity Grades

20 M Protocol 3.0 Introduction End-stage liver disease secondary to chronic hepatitis C virus (HCV) is one of the most common indications for liver transplantation worldwide. 1 However HCV infection of the new graft occurs in almost all recipients, typically pursuing a more aggressive disease course than in other HCV infected populations. Graft cirrhosis occurs in 10% to 20% of recipients in as little as 5 years. In addition, more than 40% of those with cirrhosis develop complications within 1 year with less than 50% surviving a year after decompensation. The options for those with advancing disease of the transplanted liver may be limited and re-transplantation may not be an option for all patients. Several factors have been associated with the accelerated disease of the transplanted liver including being a female organ recipient, the presence of HCV subtype 1b, higher levels of fibrosis in the explanted liver, treatment of rejection with high dose steroids and the presence of IL28b ( ) non-cc genotype in both host and graft. Nonetheless, treatment induced clearance of HCV in the post transplant setting has been associated with improved 5-year survival and lower rates of progression to cirrhosis and graft decompensation. 2 When considering treatment of HCV post liver transplant there is a consensus that those with evidence of chronic HCV on a liver biopsy as evidenced by inflammation and/or fibrosis may be considered for a trial of pegylated interferon (pegifn) and ribavirin (RBV) therapy and those with fibrosis levels of F2 (Metavir) merit a trial of PegIFN-RBV therapy. However, treatment outcomes in the post transplant setting are not optimal. A pooled analysis of over 40 trials of RBV combined with either conventional (c)ifn or pegylated (Peg)IFN noted low sustained virologic response 24 weeks (SVR 24 ) rates (24% to 27%) and high discontinuation rates (24% to 26%). The overall low SVR rate in transplant recipients is in part because exposure to PegIFN/RBV is typically associated with significant treatment limiting toxicities, particularly anemia and other cytopenias. The high frequency of anemia is in part attributed to greater RBV exposures in this patient population. The calcineurin inhibitors 18

21 M Protocol (CNIs) tacrolimus or cyclosporine, are widely used as immunosuppressants in liver transplant recipients but are typically associated with some degree of renal impairment. Such renal impairment may augment RBV exposures, potentiating the risk for anemia. Because of the high frequency of anemia with PegIFN/RBV therapy lower doses of RBV are typically used at the outset of therapy and the use of erythropoiesis stimulating agents and even transfusion to manage anemia are relatively common in liver transplant recipients. A recent advance in the treatment of those with HCV genotype 1 has been the availability of the HCV protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC). These direct-acting antiviral agents (DAA) must be used in combination with PegIFN with RBV for up to 48 weeks. However, they are not approved for use in the post transplant setting. Ultimately, it is anticipated that regimens combining multiple DAAs may be curative without the need for PegIFN/RBV. Exploratory studies in otherwise healthy individuals with HCV using such PegIFN/ RBV sparing combination regimens have been initiated, and promising short-term antiviral efficacy has been reported from IFN-free combinations (either with or without RBV) of an HCV protease inhibitor with a nucleoside polymerase inhibitor, 3 a nonnucleoside polymerase inhibitor, 4 and a nonstructural viral protein 5A (NS5A) inhibitor. 5 Additionally, studies evaluating the combination of a nonstructural protein 5B (NS5B) nucleotide polymerase inhibitor and RBV have been initiated. Sustained virologic response 12 weeks post-dosing (SVR 12 ) rates as high as 90% (9/10 subjects) have been observed in genotype 1b infection with an NS5A plus protease inhibitor combination and 100% (10/10 subjects) in genotype 2 or 3 infection with a nucleotide polymerase inhibitor plus RBV. 6,7 In the post transplant setting, the potential to add the DAA's TVR or BOC to PegIFN/RBV therapy is complicated by the potential for interaction with the CNIs, e.g., tacrolimus or cyclosporine. Tacrolimus and cyclosporine have their exposures considerably increased by these DAA's. Tacrolimus dose normalized exposures are increased by 70- and 17-fold, for TVR and BOC, respectively. 8,9 Cyclosporine dose 19

22 M Protocol normalized exposures are increased by 4.6- and 2.7-fold, for TVR and BOC, respectively. 8,9 This interaction may be managed by monitoring CNI levels, which is the standard of care in this setting and provides a means of monitoring changes in CNI exposure in order to make appropriate dose adjustments. Currently, there are only limited preliminary data from small observational studies describing outcomes with the addition of one of the newly approved DAA's TVR or BOC to PegIFN-RBV therapy in liver transplant recipients Preliminary data presented by Kwo et al evaluated 7 subjects a median of 3.5 years post liver transplant. Each subject had a prior null response to PegIFN/RBV in the post transplant setting and had histologic fibrosis levels ranging 3 4 (Metavir). Subjects were scheduled to receive 48 weeks of PegIFN/RBV with 12 weeks of TVR. RBV doses at the start of therapy ranged 800 to 1000 mg/day. At the end of TVR dosing 5/7 subjects had HCV RNA < LOQ. All subjects also required further RBV dose reduction on study and transfusion and EPO use were common. All of these subjects were taking cyclosporine with mean dose reductions from 193 mg/kg at baseline to 68 mg/kg to the end of TVR dosing consistent with the observed interactions described above. AbbVie currently has a number of DAA compounds in clinical development: ABT-450 is a nonstructural protein 3/nonstructural protein 4A (NS3/NS4A) protease inhibitor, ABT-267 is a nonstructural viral protein 5A (NS5A) inhibitor and ABT-333 is a nonstructural viral protein 5b (NS5B) non-nucleoside polymerase inhibitor. These agents have the potential for coadministration in the treatment of HCV infection. This study is intended to examine the efficacy and safety of 24 weeks of treatment with ABT-450/r/ABT-267 with ABT-333 coadministered with RBV in treatment-naïve or treatment-experienced (cifn or PegIFN with or without RBV prior to transplant) adult liver transplant recipients with recurrent HCV genotype 1 infection. ABT-450 ABT-450, (2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-{[(5-methylpyrazin- 2-yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-yloxy)- 20

23 M Protocol 1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2- a][1,4]diazacyclopentadecine-14a(5h)-carboxamide hydrate, is a NS3 protease inhibitor with nanomolar potency against genotype 1 HCV in vitro. ABT-450 is metabolized primarily by cytochrome P450 3A4 (CYP3A) and thus is dosed with ritonavir, (the combination is denoted as ABT-450/r) a potent CYP3A inhibitor, in order to enhance exposures. ABT-450/r has a favorable safety, tolerability, and pharmacokinetic profile at doses administered to date and has shown potent antiviral activity at doses of 50/100 mg QD and greater in HCV genotype 1-infected subjects. Additional detailed information about preclinical toxicology, metabolism, pharmacology and clinical data can be found in the Investigator's Brochure for ABT ABT-267 ABT-267, dimethyl ([(2S,5S)-1-(4-tert-butylphenyl) pyrrolidine-2,5-diyl]bis{benzene4,1- diylcarbamoyl(2s)pyrrolidine-2,1-diyl[(2s)-3-methyl-1-oxobutane-1,2- diyl]})biscarbamate hydrate, is a novel NS5A inhibitor, with inhibitory concentrations in the picomolar range against genotypes 1a and 1b in subgenomic replicon systems. ABT-267 has a favorable safety, tolerability, and pharmacokinetic profile at all doses administered to date, and has shown substantial antiviral activity during 3 days of monotherapy in HCV genotype 1-infected subjects. Additional detailed information about preclinical toxicology, metabolism, pharmacology, and clinical data can be found in the Investigator's Brochure for ABT ABT-333 ABT-333, (sodium N-{6-[3-tert-butyl-5-(2,4-dioxo-3,4 dihydropyrimidin-1(2h)-yl)-2- methoxyphenyl]naphthalen-2-yl}methanesulfonamide), is a non-nucleoside NS5B polymerase inhibitor with inhibitory concentrations in the nanomolar range against genotypes 1a and 1b NS5B in subgenomic replicon systems. ABT-333 has been welltolerated in single and multiple dose studies in healthy volunteers, and when administered 21

24 M Protocol to HCV-infected subjects at doses up to 800 mg twice daily (BID) for up to 12 weeks. The mean t1/2 in healthy volunteers ranged from approximately 5 to 8 hours. ABT-333 has a favorable safety, tolerability, and pharmacokinetic profile at doses administered to date and has shown antiviral activity in HCV genotype 1-infected subjects at doses greater than 100 mg BID. Additional detailed information about preclinical toxicology, metabolism, pharmacology and clinical data can be found in the Investigator's Brochure for ABT Combination Dosing in HCV-Infected Subjects in Study M Study M is an ongoing multicenter, open-label Phase 2b study evaluating the antiviral activity, safety and pharmacokinetics of multiple ABT-450/r-based DAA combination regimens in HCV genotype 1-infected adults who are either treatment-naïve or are previous null responders to PegIFN and RBV. This study consists of 14 arms: 9 arms with planned enrollment of 440 treatment-naïve subjects and 5 arms with planned enrollment of 120 null responders. The primary and secondary efficacy endpoints compare the percentage of treatment-naïve subjects achieving a sustained virologic response at 24 weeks post-dosing (SVR 24 ) across the various regimens. Preliminary efficacy data suggest that all regimens demonstrate rapid suppression of HCV-1 RNA levels. All subjects in all 8- and 12-week treatment arms have completed study treatment and are in post-treatment follow-up. Among the treatment-naïve subjects, the SVR 12 rate in those treated with 4 drugs (ABT-450/r + ABT ABT-333 with RBV) for 12 weeks is 97.5% (77/79 subjects). The SVR 12 rates, although still high, are numerically lowest in the 8-week treatment group and the ABT-450/r + ABT-333 +RBV group at 88% (70/80) and 85% (35/41), respectively. The SVR 12 rates in the 12-week groups without ABT-333 and without RBV are 90% to 87%, respectively. Preliminary resistance testing in Study M suggests that in the majority of subjects who experienced virologic failure, viral mutations were selected in the target regions corresponding to the DAAs each subject was receiving with the exception of those treated 22

25 M Protocol for 8 weeks, among whom most had populations at the time of relapse that were identical to their baseline sample. Preliminary safety analysis showed that all study drugs regimens were well-tolerated for up to 24 weeks in treatment-naïve and prior null responder subjects. Approximately 1.2% discontinued study drugs treatment due to adverse events. The majority of adverse events reported have been mild or moderate in severity, the most frequent including nausea, headache, fatigue, insomnia and diarrhea. Laboratory abnormalities included decreases in hemoglobin, most likely related to RBV, since mean decreases in hemoglobin from baseline to the end of treatment were greater in arms with RBV than in the arm without RBV ( g/dl versus 0.7 g/dl). Grade 3 (or higher) elevations of alanine aminotransferase (ALT) occurred in 5 subjects (all without bilirubin elevation) all of whom were asymptomatic. In all 5 cases ALT normalized without intervention or study drugs modification or interruption. Four of these subjects were receiving ABT-450/r at a dosage of 200/100 mg which is greater than the planned ABT-450/r dose in the current study. The highest ALT level in Study M was 408 U/L. To date, the majority of subjects randomized to 24 weeks of treatment in Study M are still receiving study treatment. However, preliminary assessment of safety and efficacy suggest that these treatment regimens are comparable to the corresponding 12-week treatment regimens. Combination Dosing of DAAs with Immunosuppressive Agents Commonly Used in Liver Transplant Patients Phase 1, drug-drug interaction studies of AbbVie DAA combinations with immunosuppressive agents in healthy volunteers are currently ongoing. Available preliminary pharmacokinetic and safety data, to date, from these studies are summarized below. 23

26 M Protocol Cyclosporine: The pharmacokinetics of a single 30 mg dose of cyclosporine in combination with ABT-450/r, ABT-267 and ABT-333, dosed to steady-state was compared to a single dose of 100 mg cyclosporine dosed alone in healthy individuals in the Study M Effect of ABT-450/r + ABT ABT-267 on Cyclosporine: Cyclosporine C max was not affected by DAA coadministration as dose normalized cyclosporine C max with and without DAAs were comparable. The dose-normalized AUC of cyclosporine, when coadministered with DAAs, was 5.8-fold of cyclosporine exposures when administered alone. Dose normalized C24 of cyclosporine, when coadministered with DAAs at steady-state, was 15.8-fold of the C24 of cyclosporine when administered alone. Cyclosporine T max was delayed by 3 to 4 hours when coadministered with DAAs and t 1/2 increased from 8 to 25 hours. Effect of Cyclosporine on ABT-450/r, ABT-333 and ABT-267: Single dose of cyclosporine did not affect steady state exposures (C max and AUC) of ritonavir and ABT-267; however, ABT-333 and ABT-333 M1 exposures slightly decreased ( 35%) and ABT-450 exposures increased by approximately 44% to 72%. On starting the study regimen the total daily cyclosporine dose should be reduced to one-fifth of the prestudy dose to achieve a C 24 (trough) equivalent to prestudy levels over the first week of the study. At the beginning of Week 2 (Study Day 8), it is anticipated that a further dose reduction (by approximately half) may be needed. Thus, the total daily cyclosporine dose at the beginning of Week 2 should be reduced to half of the dose administered in Week 1. Cyclosporine trough levels are expected to stabilize from Study Week 3 (Day 15 onwards). Details of dose recommendation for cyclosporine and its concentration management when administered with DAAs are given in the Guidelines for Tacrolimus and Cyclosporine Management Document. 24

27 M Protocol Tacrolimus: The pharmacokinetics of a single dose of 0.5 mg tacrolimus co-dosed with 2 DAA combinations, ABT-450/r + ABT-333 and ABT-450/r + ABT-267, each at steady-state was compared to a single 2 mg tacrolimus dosed alone in healthy subjects in Study M The magnitude of the observed drug-drug interactions for both DAA combinations were comparable. Below are the summaries of the preliminary results from these drug-drug interaction studies: Effect of ABT-450/r + ABT-267 or ABT-450/r + ABT-333 on Tacrolimus: Dose normalized Cmax, AUC and C24 of tacrolimus, when coadministered with 2 DAAs (ABT-450/r + ABT-333 or ABT-450/r + ABT-267), was 3.6- to 4.2-fold, 67- to 86-fold and 22- to 24-fold that of tacrolimus exposures when administered alone, respectively. Tacrolimus T max was delayed by 4 to 5 hours and terminal phase elimination half-life (t 1/2 ) increased from 29 to 253 hours when coadministered with DAAs. Effect of Tacrolimus on ABT-450/r + ABT-267 and ABT-333: A single dose of tacrolimus had minimal effect on DAA steady state exposures. ABT-450, ritonavir, ABT-333 and ABT-333 M1 exposures (C max, AUC and C trough ) decreased by 11% to 43% when coadministered with tacrolimus. ABT-267 exposures were not affected by coadministration with tacrolimus. The magnitude of interaction of tacrolimus with the 3 DAA combination (ABT-450/r 150/100 mg QD + ABT mg BID + ABT mg QD with single dose of tacrolimus 2 mg) in the currently ongoing Arm 3 is expected to be similar to that observed with the 2 DAA combinations of (ABT-450/r + ABT-333 and ABT-450/r + ABT-267). Based on the preliminary pharmacokinetic data from this study, a tacrolimus dose of 0.5 mg/week is recommended when coadministered with the study drugs. It is anticipated that this will maintain the tacrolimus levels in the therapeutic range. Subsequent dosing and dose frequency modifications will be further informed by the individual drug level data. 25

28 M Protocol Details of dose recommendations for tacrolimus and its concentration management when administered with DAAs are given in the Guidelines for Tacrolimus and Cyclosporine Management Document and include recommendations for the use of tacrolimus in a setting where a lower dose formulation, i.e., 0.2 mg, is approved and available. For liver transplantation recipients with recurrent HCV, the low cure rates and high frequency of treatment limiting toxicities with PegIFN/RBV highlight the need for more efficacious, better tolerated therapies. This study proposes to explore the efficacy and safety of an IFN-free regimen of ABT-450/r/ABT-267 and ABT-333 combined with RBV for 24 weeks in those subjects at least 12 months post liver transplant on a stable cyclosporine or tacrolimus regimen. It is anticipated that this regimen will yield higher SVR rates than have been observed to date, with a lower frequency of adverse events. The study will be conducted with consideration for events of special interest in this unique patient population including the potential for alterations in tacrolimus or cyclosporine levels, RBV associated anemia, and tacrolimus or cyclosporine associated renal impairment as well as other standard safety assessments. Additional discussion and justification of study design may be found in Section Differences Statement The regimen planned for this study was evaluated in the Study M11-652, which is currently active and in which ABT-450/r, ABT-267 and ABT-333 are coadministered with RBV for as long as 24 weeks in treatment-naive and treatment-experienced subjects without cirrhosis. The proposed study, Study M12-999, will be the first study in which ABT-450/r/ABT-267 and ABT-333 coadministered with RBV will be evaluated in HCV infected adult liver transplant recipients. The DAA formulations used in this study also differ from those used in Study M11-652, see Section

29 M Protocol 3.2 Benefits and Risks Study M is a single arm study in which an IFN-free regimen of three DAAs and RBV are coadministered for a period of 24 weeks. AbbVie is conducting several trials, which incorporate IFN-free regimens for up to 24 weeks treatment duration. In the largest of these trials, Study M11-652, which is ongoing, after 12 weeks of ABT-450/r, ABT-333, and ABT-267 coadministered with RBV in treatment-naïve noncirrhotic subjects, the SVR 12 rate was 97.5% (77/79 subjects). The treatment regimen in Study M was well-tolerated with few treatment discontinuations or adverse events. Details about the safety of the DAAs, including data from Study M are provided in the Investigator's Brochures for the individual DAAs. Adverse events that are known, and those not previously described, may occur with the DAAs or RBV as detailed in the ICF for this study. In addition, subjects may experience inconvenience or discomfort related to the study visits or study procedures. In the post liver transplant population the risks associated with ABT-450/r/ABT-267 and ABT-333 coadministered with RBV, including the risks of toxicity and virologic failure, are anticipated to be limited and manageable based on the results of ongoing trials. The potential for alterations in exposure to the CNIs, tacrolimus and cyclosporine, when DAA's are started during the Treatment Period and when study drugs are stopped will be mitigated by guided CNI dose reductions and frequent estimates for CNI levels throughout the study particularly within the first weeks of DAA exposure. A similar approach will be followed when DAAs are discontinued or interrupted. Given the potential high rate of cure in this population of HCV-infected subjects, the risk-benefit comparison is favorable. 27

30 M Protocol 4.0 Study Objectives 4.1 Primary Objective The primary objectives of this study are to assess safety and efficacy (the percentage of subjects achieving a 12-week sustained virologic response, SVR 12 (HCV ribonucleic acid [RNA] < lower limit of quantification [LLOQ] 12 weeks following treatment) of coformulated ABT-450/r and ABT-267 (ABT-450/r/ABT-267) and ABT-333 coadministered with RBV for 24 weeks in HCV genotype 1-infected adult liver transplant recipients. 4.2 Secondary Objectives The secondary objectives of this study are to assess is the percentage of subjects with SVR 24 (HCV RNA < LLOQ 24 weeks after the last actual dose of study drugs), the percentage of subjects with virologic failure during treatment, and the percentage of subjects with relapse post-treatment. 5.0 Investigational Plan 5.1 Overall Study Design and Plan: Description This is a Phase 2, open-label, multi-center study evaluating the safety and efficacy of ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks in adult liver transplant recipients with recurrent HCV genotype 1 infection. Approximately 30 HCV genotype 1 infected treatment-naïve or treatment-experienced adults (cifn or PegIFN) with or without RBV prior to transplant) will be enrolled into the study at approximately 10 sites. The duration of the study for an individual subject will be up to 72 weeks (not including a screening period of up to 35 days duration and a Study Treatment Lead-In Period of up to 14 days duration). This study will consist of two parts: a 24-week Treatment Period (TP) and a 48-week Post-Treatment Period (PTP). During the 28

31 M Protocol Screening Period, subjects will be evaluated for entrance criteria. If all entrance criteria are met, the subject may enter a Study Treatment Lead-In Period. Figure 1. Study Schematic During the Study Treatment Lead-In Period, subjects who have met enrollment criteria will return to the site for laboratory tests to measure the CNI trough level. This trough level will serve to confirm that the CNI dose is appropriate before commencing study drugs and will form the basis for CNI dose adjustment when the subject commences the DAA-RBV therapy. If the investigator considers that the CNI trough level is not within the appropriate range, then the investigator will adjust the CNI dose and if the subsequent CNI trough level, drawn at steady-state, is within the appropriate range the subject may enter the study. Further information regarding the Study Treatment Lead-In Period can be found in Section and is depicted in Figure 2. During the 24-week TP, all enrolled subjects will receive ABT-450/r/ABT /100/25 mg QD + ABT mg BID coadministered with RBV. RBV dosing will be weight based; however, in this special population with an increased risk of RBV associated anemia, RBV dosing may be managed at the discretion of the investigator. Upon completing the TP or at premature discontinuation of the TP, subjects will enter the 48-week PTP and be followed for safety, durability of viral response and emergence or persistence of resistance to DAAs. 29

32 M Protocol Safety and efficacy evaluations will occur throughout the study. The safety data will be reviewed by the Sponsor, as this is an open-label study, and by an independent Data Monitoring Committee (DMC) during the Treatment Period of the study; see Section Virologic failure criteria, as detailed in Section , will be evaluated and applied by the investigator Screening At the Screening Visit, subjects who provide written (signed and dated) informed consent prior to any study specific procedures, will receive a unique subject number via Interactive Response Technology (IRT) system and will undergo the study procedures identified in Section associated with the Screening Visit. The investigator will evaluate whether the subject meets all of the eligibility criteria specified in Section and Section and record the details of the informed consent process and the results of the screening assessment and the details of the informed consent process in the subject's medical records. Eligible subjects have up to 35 days following the Screening Visit to enter the Study Treatment Lead-In Period. The study is designed to enroll 30 subjects to meet scientific and regulatory objectives without enrolling an undue number of subjects in alignment with ethical considerations. Therefore, if the target number of subjects has been enrolled, there is a possibility that additional subjects in screening will not be enrolled Rescreening Subjects may be rescreened only once as follows: Subjects who meet all eligibility criteria with the exception of one exclusionary laboratory parameter may rescreen once without prior AbbVie approval with the exception of exclusionary genotype, a positive drug screen (without prescription for the positive drug or as noted below), or a positive HIV, HBV or pregnancy test. Subjects who test positive at Screening for any of these parameters are not eligible to rescreen. 30

33 M Protocol Subjects who otherwise meet all eligibility criteria, but have a positive urine alcohol screen, may have only the urine drug screen repeated. If the repeat urine drug screen is negative (except for cases in which the screen is positive for a prescribed drug), the subject may be considered eligible. Subjects who otherwise meet all eligibility criteria, but have a creatinine clearance < 55 ml/min but 50mL/min (by Cockcroft-Gault) may have the creatinine clearance repeated, and if the repeat creatinine clearance is 55 ml/min, the subject will be eligible for enrollment. Subjects who have multiple exclusionary laboratory results require approval from the AbbVie Study Designated Physician prior to rescreening the subject. Subjects being rescreened because of an exclusionary laboratory parameter must be rescreened for all laboratory (excepting the tests listed above) and eligibility criteria, not just those that were exclusionary at the first screening attempt (with the exception of HCV genotype, HIV test and liver biopsy which do not need to be repeated). Subjects being rescreened because of a failure to establish appropriate CNI levels during the Lead-In Period (Lead-In Period failure) must be rescreened for all laboratory and eligibility criteria, not just those that were exclusionary at first screening attempt (with the exception of HCV genotype, HIV test and liver biopsy which do not need to be repeated). Liver biopsies will be read by a central pathologist. Subjects with biopsies determined to have a level of fibrosis > F2 by Metavir score will be excluded and may not rescreen. For subjects who do not meet the study eligibility criteria, the site personnel must register the subject as a screen failure in both the IRT and EDC systems Study Treatment Lead-In Period Subjects who meet the study eligibility criteria will be able to enter the Study Treatment Lead-In Period which will last not more than 14 days before Study Day 1. On Study Day 14, subjects will have a tacrolimus or cyclosporine level measured. The blood sample will be drawn as a trough level, i.e., before the subject's next scheduled 31

34 M Protocol CNI dose. The date, time and dosage of the last CNI dose and the date and time of the sample collection will be recorded in the electronic case report form (ecrf). From this blood draw, samples will be submitted to both the central and local laboratories. The local laboratory CNI trough level will serve to confirm that the CNI dose is appropriate in the investigator's opinion prior to commencing study drugs and will form the basis for CNI dose adjustment when the subject commences study drugs. Subjects with a CNI trough level drawn at Study Day 14 that is considered by the investigator to be within the therapeutic range may directly proceed to Study Day 1 of the TP. If the investigator considers that the CNI trough level is not within the appropriate range, then the investigator will adjust the CNI dose and a second CNI trough level will be drawn at steady-state, 7 days later for tacrolimus and 3 days later for cyclosporine, as shown in Figure 2. Subjects with a repeat CNI trough level drawn no later than 2 days before study entry (Study Day 2) which is considered by the investigator to be within the therapeutic range may proceed to Study Day 1 of the TP. If in the investigator's opinion the subject's repeat trough level at steady-state is not within an acceptable therapeutic range, the subject will be considered a lead-in failure and may not enter the study. Study treatment lead-in failures will be allowed to rescreen once using the procedure as outlined for rescreening subjects who had one exclusionary lab as outlined in Section , Rescreening. Refer to Figure 2 for more information. 32

35 M Protocol Figure 2. Schematic of Study Treatment Lead-In Period Study Treatment Period (TP) Subjects with HCV genotype 1 who meet the eligibility criteria and who successfully complete the Study Treatment Lead-In Period will be enrolled via IRT into the study. The TP of the study consists of 24 weeks of open-label treatment with ABT-450/r/ABT ABT-333 coadministered with RBV. Subjects should be instructed not to take their morning dose of CNI medication on Study Day 1. Subjects will be administered study drugs and their adjusted dose of CNI medication concurrently at the site on the morning of Study Day 1. Subjects will receive instructions about the study drugs and the dosing schedule at the Day 1 Visit. The study drugs (ABT-450/r/ABT ABT-333 coadministered with RBV) will be dispensed during the TP as indicated in Table 2 during the study visits; sites should ensure that subjects adhere to the study visits. Subjects who cannot complete their study visit per the visit schedule should ensure they do not run out of study drugs prior to their next study visit. Compliance is critical to ensure adequate drug exposure. 33

36 M Protocol Investigators can choose to do additional unscheduled visits at any time for the management of CNI medications as described in Table 2 (refer to the Guidelines for Tacrolimus and Cyclosporine Management Document and Section for CNI management). Following completion or discontinuation of study drug therapy, all subjects will enter the PTP Period consisting of 48 weeks of post-treatment follow-up. Subjects who prematurely discontinue from the TP should return for a Treatment Discontinuation Visit and undergo the study procedures as defined in Table 2 and as described in Section Ideally, this should occur on the day of study drug discontinuation, but is recommended to be no later than 2 days after their final dose of study drugs and prior to the initiation of any other anti-hcv therapy. The PTP will begin the first day after the last day of study drug dosing. Because of the potential impact of interruption/discontinuation of study drugs on CNI levels, investigators should contact the Study Designated Physician (SDP) when an interruption/discontinuation is anticipated or required by the protocol to ensure that a plan for appropriate CNI dose modification is in place. Similarly for those subjects recommencing DAA's after an interruption the investigator should contact the SDP to ensure that a plan for appropriate CNI dose adjustment is in place. Refer to the Guidelines for Tacrolimus and Cyclosporine Management Document and Section on the management of CNIs Post-Treatment Period (PTP) All subjects who receive at least one dose of study drugs will be monitored for HCV RNA, safety, PRO's and for the emergence and/or persistence of resistance-associated viral variants for an additional 48 weeks following the last dose of study drugs. Subjects will return to the study site as outlined in Table 3 for PTP procedures. The PTP will begin the day after the last dose of study drugs. Subjects who prematurely discontinue the PTP should return to the site for a PTP Discontinuation Visit as outlined in Table 3. Refer 34

37 M Protocol to the Guidelines for Tacrolimus and Cyclosporine Management Document and Section for further details on management of CNIs. Subjects who receive at least one dose of study drug and who do not achieve and maintain virologic suppression (HCV RNA < LLOQ), or who relapse post DAA therapy, may be offered another AbbVie-sponsored study. Subjects may also be offered another non-abbvie treatment as determined appropriate by the investigator. 5.2 Selection of Study Population HCV genotype 1-infected adult liver transplant recipients who are treatment-naïve, or treatment-experienced with conventional (c) IFN and/or PegIFN, with and without RBV treatment at any time prior to transplant, and who meet the inclusion criteria and who do not meet any of the exclusion criteria will be eligible for enrollment into the study upon successfully completing the Study Treatment Lead-In Period Inclusion Criteria 1. Male or female between 18 and 70 years of age, inclusive, at time of enrollment. 2. The subject is a recipient of a cadaveric or living donor liver transplant. 3. Liver transplantation as a consequence of HCV infection no less than 12 months before the Screening Visit. 4. Female who is: practicing total abstinence from sexual intercourse (minimum 1 complete menstrual cycle) sexually active with female partners only not of childbearing potential, defined as: postmenopausal for at least 2 years prior to screening (defined as amenorrheic for longer than 2 years, age appropriate, and confirmed by a 35

38 M Protocol follicle-stimulating hormone [FSH] level indicating a postmenopausal state), or surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy or hysterectomy) or has a vasectomized partner(s); of childbearing potential and sexually active with male partner(s): currently using at least one effective method of birth control at the time of screening and two effective methods of birth control while receiving study drugs (as outlined in the subject information and consent form or other subject information documents), starting with Study Day 1 and for 7 months after stopping study drug as directed by the local ribavirin label. (Note: Contraceptives containing ethinyl estradiol are not considered effective during study drug treatment.) 5. Females must have negative results for pregnancy tests performed: at Screening by serum specimen obtained within 49 days prior to initial study drug administration, and at Baseline (prior to dosing) by urine specimen. 6. Sexually active males must be surgically sterile or have male partners only or if sexually active with female partner(s) of childbearing potential must agree to practice two effective forms of birth control as outlined in the subject information and consent form or other subject information documents throughout the course of the study, starting with Study Day 1 and for 7 months after stopping study drug or as directed by the local ribavirin label. 7. Currently taking an immunosuppressant regimen based on either tacrolimus or cyclosporine where doses of immunosuppressant drugs have not been increased for at least 3 months before Screening and no new immunosuppressant drugs have been added for at least 3 months before Screening. Corticosteroids such as prednisone or prednisolone are permitted as components of the immunosuppressant regimen providing the dose is no more than 5 mg/day. 36

39 M Protocol 8. Subjects with liver transplantation as a consequence of hepatocellular carcinoma (HCC) in the setting of chronic HCV may be eligible if a. Prior to transplantation the HCC is not known to have ever exceeded the Milan Criteria including on the pathologic examination of the explanted liver (Milan Criteria defined as either a single HCC lesion 5 cm or up to three separate HCC lesions none larger than 3 cm, and with no evidence of gross vascular invasion, and no regional nodal or distant metastases) and b. Post transplantation there is no evidence of recurrence of HCC 9. Screening laboratory result indicating HCV genotype 1 infection. 10. Subjects must be able to understand and adhere to the study visit schedule and all other protocol requirements. 11. Body Mass Index (BMI) is from 18 to < 38 kg/m 2 at the time of Screening. BMI is calculated as weight measured in kilograms (kg) divided by the square of height measured in meters (m). 12. Must voluntarily sign and date an informed consent form, approved by an Institutional Review Board/Ethics Committee (IRB/EC), prior to the initiation of any screening or study specific procedures. 13. Must have a liver biopsy which shows evidence of fibrosis F2 (Metavir scale) without evidence of rejection within 3 months prior to or during the Screening Period. 14. Subject has plasma HCV RNA level > 10,000 IU/mL at Screening. 15. Subject has either never received treatment for HCV or if the subject has received treatment (s), it was limited to cifn and/or PegIFN with or without RBV at any time prior to liver transplantation. 37

40 M Protocol Rationale for Inclusion Criteria (1 3, 7 9, 11, 13 15) To select the appropriate subject population with sufficient disease severity for evaluation. (10) For the safety of study subjects. (4 6) RBV has known teratogenic effects. (12) In accordance with harmonized Good Clinical Practice (GCP) Exclusion Criteria 1. History of severe, life-threatening or other significant sensitivity to any drug. 2. Use of any herbal supplements (including milk thistle) within the 2-week period prior to the first dose of study drugs. 3. Use of everolimus, sirolimus or azathioprine as part of the stable immunosuppressive regimen within three months of Screening. 4. Use of any medications listed in Table 1 as well as any other medications that are contraindicated for use with either ritonavir or RBV within 2 weeks prior to study drugs administration or 10 half-lives, whichever is longer, including but not limited to those medications listed in Table 1: 38

41 M Protocol Table 1. Medications Contraindicated for Use with the Study Regimen Alfuzosin Amiodarone Astemizole Bepridil Bosentan Buprenorphine Clarithromycin Carbamazepine Cisapride Conivaptan Dronedarone Efavirenz Eleptriptan Eplerenone Ergot derivatives Fusidic Acid Gemfibrozil Itraconazole Ketoconazole Lovastatin Methadone Midazolam (oral) Mifepristone Modafinil Montelukast Nefazodone Phenobarbital Phenytoin Pimozide Pioglitazone Propafenone Quercetin Quinidine Rifabutin Rifampin Rosiglitazone Salmeterol Simvastatin St. John's Wort Telithromycin Terfenadine Triazolam Trimethoprim Troglitazone Troleandomycin Voriconazole Not all medications contraindicated with ritonavir or ribavirin are listed above. Refer to the most current package inserts or product labeling of ritonavir and ribavirin for a complete list of contraindicated medications. 5. Use of known strong inhibitors of cytochrome P450 3A (CYP3A), inhibitors of P450 2C8 (CYP2C8) cytochrome (e.g., gemfibrozil, montelukast) or inducers of CYP2C8 or CYP3A (e.g., phenobarbital, rifampin, carbamazepine, St. John's Wort) within 2 weeks prior to study drugs administration. 6. Consideration by the investigator that the subject has a prior history of intolerance to PegIFN or has a contraindication to PegIFN. 7. Females who are pregnant or plan to become pregnant, or breastfeeding, or males whose partners are pregnant or planning to become pregnant within 7 months (or per local RBV label) after their last dose of study drugs. 39

42 M Protocol 8. Recent (within 6 months prior to study drug administration) history of drug or alcohol abuse that, in the opinion of the investigator, could preclude adherence to the protocol. 9. Positive test result at screening for Hepatitis B surface antigen (HBsAg) or anti-human immunodeficiency virus antibody (HIV Ab). 10. History of re-transplantation of the liver. 11. Recipient of a liver transplant from a donor with known HIV infection, HBV surface antigen-positive and/or HCV antibody-positive test results. 12. Documented history of post transplant complications directly involving the hepatic vasculature, e.g., thrombosis of the portal vein, the hepatic artery and/or hepatic vein, which in the opinion of the investigator has not resolved at the time of Screening. 13. Documentation of gastro-esophageal varices, ascites and/or hepatic encephalopathy following liver transplantation. 14. HCV genotype performed during screening which indicates a mixed genotypic infection. 15. Positive result of a urine drug screen at the Screening Visit for opiates, methadone, barbiturates, amphetamines, cocaine, benzodiazepines, phencyclidine, propoxyphene, or alcohol, with the exception of a positive result associated with documented short-term use or chronic stable use of a prescribed medication in that class. Single positive results on urine screen for alcohol are discussed in Section on Rescreening. 40

43 M Protocol 16. Clinically significant abnormalities, other than HCV infection in a subject post liver transplant, based upon the results of a medical history, physical examination, vital signs, laboratory profile and a 12-lead electrocardiogram (ECG) that make the subject an unsuitable candidate for this study in the opinion of the investigator. 17. During the Screening Period, the subject is being investigated for a fever of unknown etiology or is being treated for an active infection (active or presumed) or is receiving secondary prophylaxis for an infection which occurred in the post transplant period. 18. Previous use of any investigational or commercially available anti-hcv agent other than IFN-based therapy (cifn and/or PegIFN), with or without RBV, including previous exposure to ABT-450, ABT-333 or ABT De novo HCV infection in the post transplant period. 20. History of steroid resistant rejection of the transplanted liver at any time in the post transplant period or a history of rejection (biopsy proven or presumed) treated with high dose steroids within 3 months of Screening. 21. History of uncontrolled seizures, uncontrolled diabetes as defined by a glycated hemoglobin (hemoglobin A1C) level > 8.0% at the Screening Visit, active or suspected malignancy or history of malignancy (other than basal cell skin cancer or cervical carcinoma in situ or hepatocellular carcinoma prior to transplant) in the past 5 years. 22. Any cause of active/prior liver disease other than chronic HCV infection, including but not limited to the following: Hemochromatosis Alpha-1 antitrypsin deficiency Wilson's disease 41

44 M Protocol Autoimmune hepatitis Alcoholic liver disease Nonalcoholic steatohepatitis Drug-related liver disease 23. Screening laboratory analyses showing any of the following abnormal laboratory results: ALT > 5 Upper limit of normal (ULN). AST > 5 ULN. Calculated creatinine clearance (using Cockcroft-Gault method) < 55 ml/min. Subjects with a calculated creatinine clearance 50 and less < 55 ml/min may be eligible. See Rescreening, Section Albumin < 3.3 g/dl. Prothrombin time/international normalized ration (INR) > 1.5. Subjects with a known inherited blood disorder and INR > 1.5 may be enrolled with permission of the AbbVie Study Designated Physician. Hemoglobin LLN. Platelets < 100,000 cells per mm 3. Absolute neutrophil count (ANC) < 1500 cells/μl. Total bilirubin 3.0 mg/dl. 24. Clinically significant abnormal ECG, or ECG with QT interval corrected for heart rate (QTc) using Fridericia's correction formula (QTcF) > 450 msec at Screening or Study Day 1 (prior to dosing). 25. Receipt of any investigational product within a time period equal to 10 half-lives of the product, if known, or a minimum of 2 weeks prior to the Screening Period. 26. Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive ABT-267, ABT-333, ABT-450, ritonavir or RBV. 42

45 M Protocol 27. Current enrollment in another clinical study or previous enrollment in this study. (Subjects who previously participated in trials of investigational anti-hcv agents may be enrolled if they can produce documentation that they received only placebo.) Concurrent participation in a non-interventional, epidemiologic or registry trial may be permitted with approval by the AbbVie Study Designated Physician. Rationale for Exclusion Criteria (1, 6 8, 10, 15 16, 21, 23 24, 26) To ensure safety of the subjects throughout the study. (2 5, 25, 27) To avoid bias for the evaluation of efficacy and safety by concomitant use of other medications. (8, 12 14, 17 20) To avoid bias for the evaluation of efficacy and safety. (9, 11, 22) To exclude subjects with liver diseases other than HCV Prior and Concomitant Therapy Any medication or vaccine (including over-the-counter or prescription medicines, vitamins and/or herbal supplements) that the subject is receiving from the time of signing the consent through the Treatment Period of the study, must be recorded along with the reason for use, date(s) of administration including start and end dates, and dosage information including dose, route and frequency. The investigator should review all concomitant medications for any potential interactions. After thirty days post-dosing, during the PTP, only antiviral therapies related to the treatment of HCV, immunosuppressant medications (i.e., tacrolimus and cyclosporine), and medications prescribed in association with an adverse event (AE) or serious adverse event (SAE) will be recorded in the electronic case report. 43

46 M Protocol The AbbVie study-designated physician should be contacted if there are any questions regarding concomitant or prior therapy(ies) Prior HCV Therapy Individuals may have received cifn and/or PegIFN with or without RBV as HCV therapy at any time prior to liver transplantation. Subjects who received treatment in the post transplant period with cifn or PegIFN, with or without RBV, will not be eligible. Prior or current use of any other investigational drug or commercially available anti-hcv drug such as the DAA's telaprevir or boceprevir, is exclusionary. Subjects who previously participated in trials of investigational anti-hcv agents may be enrolled if documentation can be provided that the subject received only placebo for the duration of the trial Concomitant Therapy Subjects must be able to safely discontinue any prohibited medications or herbal supplements within 2 weeks or within 10 half-lives of the respective medication/supplement, whichever is longer, prior to initial administration of study drugs and up to 2 weeks following discontinuation of study drugs. Subjects must be consented prior to discontinuing any prohibited medications or herbals supplements for the purpose of meeting study inclusion criteria. The investigator should confirm that concomitant medications can be administered with DAAs, ritonavir and RBV. Some medications may require dose adjustments due to potential for drug-drug interactions. During the PTP, investigators should reassess concomitant medications and after 2 weeks in the PTP subjects may resume previously prohibited medications or revert to pre-study doses, if applicable with the exception of tacrolimus and cyclosporine which should be managed as per the Guidelines for Tacrolimus and Cyclosporine Management Document and Section , Management of Cyclosporine or Tacrolimus Dosing. 44

47 M Protocol Use of hematopoietic growth factors will be permitted during the study but usage must be recorded in the ecrf. Management of hematologic growth factor therapy is the responsibility of the investigator; growth factors will not be provided by the Sponsor, and the Sponsor will not reimburse for the expense of growth factors or their use. Investigators should refer to the package inserts for erythropoiesis stimulating agents for additional information regarding their use Management of Tacrolimus or Cyclosporine Dosing Drug-drug interaction studies of ABT-450/r, ABT-267 and ABT-333 coadministered with cyclosporine or tacrolimus have been conducted and detailed information about these studies can be found in the Introduction (Section 3.0). During the study, the dosing of tacrolimus and cyclosporine will be informed by the scheduled blood level testing. Further, tacrolimus and cyclosporine blood level testing may be performed at any time during the study at the investigator's discretion. Treatment Period Tacrolimus: Based on analysis of the preliminary pharmacokinetic data, tacrolimus will be dosed at 0.5 mg/week dose from the time of starting the DAA regimen. It is anticipated that this will maintain the tacrolimus levels within the therapeutic range. Subsequent dosing and dose frequency modifications will be further informed by the individual drug level data. Dosing of tacrolimus in a setting where alternative tacrolimus formulations, e.g., 0.2 mg, are approved and available is discussed in the management guide. Cyclosporine: Based on analysis of the preliminary pharmacokinetic data cyclosporine dose adjustment will be necessary during coadministration of the DAAs. On Study Day 1 when the study drug regimen is started it is recommended that the prestudy total daily cyclosporine dose should be reduced to one-fifth and that this will be taken as a single daily dose concurrently with the study DAA regimen. Consideration of a further reduction in cyclosporine dose at the beginning of Week 2 by approximately half again 45

48 M Protocol may be warranted. Cyclosporine trough levels are anticipated to stabilize at approximately Study Week 3. Given the potential impact of interrupting study drugs on CNI levels, if an interruption in study drugs is anticipated or required by the protocol, the investigator should contact the SDP to ensure that a plan is in place for appropriate CNI dose modification during the interruption. Similarly if study drugs are to be restarted after an interruption the investigator should contact the SDP to ensure that a plan is in place for appropriate CNI dose modification when study drugs are restarted. The study drug regimen should not be interrupted for more than 7 days. If study drugs need to be interrupted for more than 7 days, the Study Designated Physician should be contacted and consideration should be given to discontinue the subject. Post-Treatment Period Tacrolimus Dosing in the Post-Treatment Period: Day 1 of the Post-Treatment Period: On Day 1 of the Post-Treatment Period, it is recommended that tacrolimus should not be taken by the subject. This is because the inhibitory effect of the study drug regimen on tacrolimus metabolism is still relevant to tacrolimus levels on Day 1 of the post-treatment phase. Day 2 of the Post-Treatment Period: On Day 2 of the Post-Treatment Period, the impact of the study drug regimen on tacrolimus metabolism is anticipated to have greatly reduced and it is suggested that the prestudy dose of tacrolimus can be resumed. Further modifications in tacrolimus dosing or dose frequency will be guided by the scheduled tacrolimus trough level testing. Also, at the investigators discretion extra blood draws for tacrolimus level testing may be performed at any time as unscheduled visits. Cyclosporine Dosing in the Post-Treatment Period: Compared to tacrolimus, cyclosporine metabolism is less impacted by the inhibitory effect of DAA's. Therefore on Day 1 of the Post-Treatment Period, it is recommended that the 46

49 M Protocol prestudy dose of cyclosporine can be resumed. Further modifications in cyclosporine dosing or dose frequency will be guided by the scheduled cyclosporine trough level testing. Also, at the investigators discretion extra blood draws for cyclosporine level testing may be performed at any time as unscheduled visits. Further modifications in cyclosporine or tacrolimus dosing or dose frequency will be guided by the scheduled cyclosporine or tacrolimus trough level testing. Also, at the investigator's discretion extra blood draws for cyclosporine or tacrolimus level testing may be performed at any time as unscheduled visits. Details regarding dose recommendations for tacrolimus and cyclosporine and their concentration management during the study are given in the Guidelines for Tacrolimus and Cyclosporine Management Document. Clinical experience suggests some differences may be observed between patients in relation to cyclosporine or tacrolimus dosing and associated trough levels. CNI dosing in the study will be guided by the recommended dose reductions which are based on healthy volunteer data and modeled to achieve troughs appropriate to the post transplant setting. In addition, it will also be guided by the frequent CNI trough level estimates particularly during the first weeks of study drugs and the investigators clinical experience in the management of these drugs in the post transplant setting. Blood Samples for the Management of Tacrolimus or Cyclosporine Blood samples for the management of concomitant medications related to liver transplant rejection (tacrolimus or cyclosporine) will be drawn at the investigative site per local standard practice. At minimum a sample should be drawn to measure the level of tacrolimus or cyclosporine during the Study Treatment Lead-In Period (no more than 14 days and no less than 2 days prior to Study Day 1) and during the study visits outlined in Table 2 and Table 3. At the investigator's discretion, an optional visit may be considered on Study Day 10 for management of immunosuppressant medications. Additional tacrolimus or cyclosporine trough samples may be drawn as unscheduled visits throughout the study as determined appropriate by the investigator. At a minimum, the 47

50 M Protocol site will collect the date, time, and dose of last CNI ingestion as well as the time and date of the blood sample collection. When a sample is drawn for the local lab using the criteria in Section 5.3.2, a parallel sample for the assay of tacrolimus or cyclosporine (and BUN and creatinine) should be drawn and sent to the Central Laboratory. Results from the local laboratory will be used for the medical management of the subject by the investigator. The local laboratory results and any changes in immunosuppressant medication will be entered into the ecrf Prohibited Therapy Medications which are contraindicated with the study regimen are listed in Table 1. Investigators should also refer to the ritonavir and RBV labeling for lists of prohibited medications. In addition to the medications listed in Table 1, use of medications that are known strong inhibitors or inducers of CYP3A, or inhibitors and inducers of CYP2C8 are prohibited within 2 weeks prior to the initial dose of study drugs and until 2 weeks after the subject has completed study drugs in the Treatment Period. HCV medications other than those specified in the protocol will not be allowed during the Treatment Period of the study. 5.3 Efficacy, Pharmacokinetic, Pharmacogenetic and Safety Assessments/Variables Efficacy and Safety Measurements Assessed and Flow Chart 48

51 M Protocol Table 2. Study Activities Treatment Period Activity Screening Study Treatment Lead-In Period ( 14 to 2 Days from Baseline) Day1/ Baseline a Study Day 3 (±1 day) Study Day 7 Optional b Study Day 10 (±2 days) Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24/ EOT/ Premature D/C from Treatment Unscheduled Visit for Management of CNI Meds Informed Consent X Provide RBV Medication Guides and Partner Risk Sheet c X Medical History d X X Physical Exam X X X X X X Vital Signs, Weight and Height X e X X X X X X X X X X X 12-Lead ECG X X X X Chemistry/Hematology/Urinalysis X X X X X X X X X X X X X X X f Sample for Cyclosporine or Tacrolimus Trough (Local and Central Lab) X X X X X X X X X X X X X X X Pharmacokinetic Samples X g X X X X X X X X X X X X X Pregnancy Test serum (s) urine (u) h X (s) X (u, s) X (u) X (u) X (u) X (u) X (u) X (u) FSH (females) i X HBsAg, Anti-HIV Ab and Anti-HCV Ab X 49

52 M Protocol Table 2. Study Activities Treatment Period (Continued) Activity Screening Study Treatment Lead-In Period ( 14 to 2 Days from Baseline) Day1/ Baseline a Study Day 3 (±1 day) Study Day 7 Optional b Study Day 10 (±2 days) Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24/ EOT/ Premature D/C from Treatment Unscheduled Visit for Management of CNI Meds Drug/Alcohol Screen X Coagulation Panel X X X X X X X X X X X Hemoglobin A1C (diabetic patients only) HCV Genotype Liver Biopsy j Concomitant Medication Assessment X X X X X X X X X X X X X X X X X X Adverse Event Assessment X X X X X X X X X X X X X X Enrollment X Patient Reported Outcomes X X X X X Instruments (PROs) k Total Insulin X X X IL28B Pharmacogenetic Sample Optional Pharmacogenetic Sample l X X HCV RNA m X X X X X X X X X X X X X 50

53 M Protocol Table 2. Study Activities Treatment Period (Continued) Activity Screening Study Treatment Lead-In Period ( 14 to 2 Days from Baseline) Day1/ Baseline a Study Day 3 (±1 day) Study Day 7 Optional b Study Day 10 (±2 days) Archive Plasma Sample X X X X X X X X X X X X X HCV Resistance Testing Sample X X X X X X X X X X X X IP 10 Sample X X X Study Drugs Dispensed X X X X X X Medication Event Monitoring System (MEMS) Cap Dispensed Study drugs Collected and Compliance Reviewed MEMS Cap Downloaded and Collected Wk = Week; EOT = End of treatment; D/C = Discontinuation a. All procedures will be performed prior to first dose. X Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24/ EOT/ Premature D/C from Treatment X X X X X X X X X X X X X X b. An Optional Study Day 10 Visit may be done at the investigator's discretion for the management of concomitant immunosuppressant medications. c. Where applicable/locally available. d. Medical history will be updated at the Study Day 1 Visit. This updated medical history will serve as the Baseline for clinical assessment. e. Height will be measured at the Screening Visit only. Unscheduled Visit for Management of CNI Meds f. Unscheduled laboratory tests may be done at the investigator's discretion for the management of CNI and should include BUN and creatinine sent to the central laboratory. g. Intensive Pharmacokinetic Samples to be drawn prior to dosing and at 2 and 4 hours after DAA dosing on Study Day 1. 51

54 M Protocol Table 2. Study Activities Treatment Period (Continued) h. Urine pregnancy testing is not required after the Day 1/Baseline Visit for female subjects with a documented history of bilateral tubal ligation, bilateral oophorectomy or hysterectomy or who are confirmed to be post-menopausal. i. FSH testing will be done as confirmation of post-menopausal status in women. j. For subjects who have not had a qualifying liver biopsy within the previous 3 months. k. Short-Form 36 Version 2 health status survey (SF-36V2), EuroQol 5 Dimensions 5 Levels Health State Instrument (EQ-5D-5L), and Hepatitis C Virus Patient Reported Outcomes Instrument (HCVPRO), should be administered before any study procedures and in the order listed. l. If the optional Pharmacogenetic sample is not collected on Study Day 1, it may be collected at any other visit during the study. m. HCV RNA Samples to be drawn prior to dosing and at 2 and 4 hours after DAA dosing on Study Day 1. 52

55 M Protocol Table 3. Study Activities Post-Treatment Period (PTP) Activity PTP Day 3 (± 1 Day) PTP Day 7 Optional a PTP Day 10 (±2 days) PTP Wk 2 PTP Wk 3 PTP Wk 4 PTP Wk 8 PTP Wk 12 PTP Wk 24 PTP Wk 36 Vital Signs and Weight X X X X X X X X X X X PTP Wk 48 or PT D/C Unscheduled Visit for Management of CNI Meds Chemistry/Hematology/Urinalysis X X X X X X X X Coagulation Panel X X X X X X X Cyclosporine or Tacrolimus trough X X X X X X X Monthly Pregnancy Test (females) b X X (Weeks 12, 16, 20, 24, 28) PRO Instruments c X X X X Concomitant Medication X X X X X X X X X X X X Assessment d Adverse Event Assessment e X X X X X X X X X X X X HCV RNA X X X X X X X X X HCV Resistance Samples X X X X X X X X X Archive Plasma Samples X X X X X X X X X IP-10 Sample X X Wk = Week; PTP D/C = Post-Treatment Period Discontinuation 53

56 M Protocol Table 3. Study Activities Post-Treatment Period (PTP) (Continued) a. An Optional PTP Day 10 Visit may be done at the investigator's discretion for the management of concomitant immunosuppressant medications. b. Urine pregnancy testing is not required after Study Day 1 Visit for female subjects with a documented history of bilateral tubal ligation, hysterectomy, bilateral oophorectomy, or who are confirmed post-menopausal. At PTP Weeks 16, 20 and 28, subjects may have an unscheduled office visit for pregnancy testing or elect to perform the tests at home with test kits provided by the site. Additional testing may be required per local RBV label. c. Short-Form 36 Version 2 health status survey (SF-36V2), EuroQol 5 Dimensions 5 Levels Health State Instrument (EQ-5D-5L), and Hepatitis C Virus Patient Reported Outcomes Instrument (HCVPRO), should be administered before any study procedures and in the order listed. d. Only medications related to the treatment of HCV and medications prescribed in association with an SAE will be collected after 30 days post-dosing. e. Only SAEs will be collected after 30 days post-dosing. Note: Day 1 of the PTP is defined as the day after the last dose of study drugs. 54

57 M Protocol Study Procedures The study procedures outlined in Table 2 and Table 3 are discussed in detail in this section, with the exception of the assessment of concomitant medications (Section ), the management of tacrolimus and cyclosporine dosing (Section ), the collection of the IL28B sample (Section ), the optional sample for pharmacogenetic analysis (Section ), the collection of blood samples for pharmacokinetic analysis (Section 5.3.2), the use of MEMS caps and the monitoring of treatment compliance (Section 5.5.6) and the collection of adverse event information (Section 6.4). Informed Consent and RBV Information Signed study-specific informed consent will be obtained from the subject before any study procedures are performed. Details about how informed consent will be obtained and documented are provided in Section 9.3. Medical History A complete medical history, including date of transplant, type of donor (deceased or living), history of tobacco and alcohol use, will be taken from each subject during the Screening Visit. The subject's medical history will be updated at the Study Day 1 Visit. This updated medical history will serve as the baseline for clinical assessment. Concomitant Medication Assessment Use of medications (prescription or over-the-counter, including vitamins and herbal supplements) from 2 weeks prior to study drug administration through 30 days after last dose of study drug will be recorded in the ecrf at each study visit indicated in Table 2 and Table 3. Only medications associated with HCV treatment or a serious adverse event (SAE) and immunosuppressant medications (i.e., tacrolimus and cyclosporine) will be collected more than 30 days after the last dose of study drugs. 55

58 M Protocol Physical Examination A complete physical examination will be performed at visits specified in Table 2 or upon subject discontinuation. A symptom-directed physical examination may be performed at any other visit, when necessary. The physical examination performed on Study Day 1 will serve as the baseline physical examination for clinical assessment. Any significant physical examination findings after the first dose will be recorded as adverse events. Vital Signs, Weight, Height Body temperature (oral), blood pressure, pulse and body weight will be measured at the visits specified in Table 2 and Table 3. The vital signs performed on Study Day 1 will serve as the baseline for clinical assessment. Blood pressure and pulse rate should be measured after the subject has been sitting for at least 3 minutes. The subject should wear lightweight clothing and no shoes during weighing. Height will only be measured at Screening; the subject will not wear shoes. 12-Lead Electrocardiogram A 12-lead resting ECG will be obtained at the visits specified in Table 2, or upon subject discontinuation (or as clinically needed). The Study Day 1 reading will serve as the baseline assessment. The ECGs will be evaluated by an appropriately trained physician at the site ("local reader"). The local reader from the site will sign, and date all ECG tracings and will provide his/her global interpretation as a written comment on the tracing using the following categories: Normal ECG Abnormal ECG not clinically significant Abnormal ECG clinically significant 56

59 M Protocol Only the local reader's evaluation of the ECG will be collected and documented in the subject's source. The automatic machine reading (i.e., machine-generated measurements and interpretation that are automatically printed on the ECG tracing) will not be collected. The QT interval measurement (corrected by Fridericia formula, QTcF) will be documented in the ecrf only if the local reader's assessment is "prolonged QT." The original ECG tracing will be retained in the subject's records at the study site. Clinical Laboratory Tests Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 4 at the visits specified in Table 2 and Table 3. Blood samples for serum chemistry tests should ideally be collected following a minimum 8-hour fast (with the exception of the Screening Visit, which may be non-fasting). Subjects whose visits occur prior to the morning dose of study drugs should be instructed to fast after midnight. Subjects whose visits occur following the morning dose of study drugs should be instructed to fast after breakfast until the study visit occurs. Blood samples should still be drawn if the subject did not fast for at least 8 hours. Fasting status will be recorded in the source documents and on the laboratory requisition. The baseline laboratory test results for clinical assessment for a particular test will be defined as the last measurement prior to the initial dose of study drugs. Blood samples for tacrolimus or cyclosporine trough level estimation will be submitted for storage to the central laboratory. A second blood sample for tacrolimus and cyclosporine analysis will be sent to the local laboratory. At each blood draw, the date, time, and dosage of the last tacrolimus or cyclosporine dose as well as the date and time of the sample collection will be recorded in the electronic case report form (ecrf). Investigators will use the local laboratory results for management of tacrolimus or cyclosporine related adverse events or dose modifications during the study. Local results will be entered into the EDC system. 57

60 M Protocol A central laboratory will be utilized to process and provide results for the clinical laboratory tests. Sites should refer to the laboratory manual provided by the central laboratory, the Sponsor, or its designee for instructions regarding the collection, processing, and shipping of all laboratory samples to the Central Laboratory. The certified laboratory chosen for this study is Covance. Depending on the location of the study site, samples will be sent to one of the following addresses: Local laboratory samples should be managed per standard medical practice for each institution. Depending on the location of the study site, samples will be sent to one of the following addresses: For sites in the USA: Covance For sites in Spain: Covance 58

61 M Protocol Table 4. Clinical Laboratory Tests Hematology Clinical Chemistry Urinalysis Additional Tests Hematocrit Hemoglobin Red Blood Cell (RBC) count White Blood Cell (WBC) count Neutrophils Bands, if detected Lymphocytes Monocytes Basophils Eosinophils Platelet count (estimate not acceptable) ANC Prothrombin Time/INR Activated partial thromboplastin time (aptt) Reticulocyte count Blood Urea Nitrogen (BUN) a Creatinine a Total bilirubin Direct and indirect bilirubin Serum glutamic-pyruvic transaminase (SGPT/ALT) Serum glutamic-oxaloacetic transaminase (SGOT/AST) Alkaline phosphatase Sodium Potassium Calcium Inorganic phosphorus Uric acid Cholesterol Total protein Glucose Triglycerides Albumin Chloride Bicarbonate Magnesium Gamma-glutamyl transferase (GGT) Creatinine clearance (Cockcroft-Gault and MDRD calculations) Specific gravity Ketones ph Protein Albumin Blood Glucose Urobilinogen Bilirubin Leukocyte esterase Microscopic (reflex) Urine Archive Specimen i HBsAg b Anti-HCV Ab b Anti-HIV Ab b FSH (all females) b Opiates b Barbiturates b Amphetamines b Cocaine b Benzodiazepines b Alcohol b Phencyclidine b Propoxyphene b Methadone b Urine and Serum Human Chorionic Gonadotropin (hcg) (females) c Total insulin d HCV RNA Hemoglobin A1C b,e IP-10 IL28B HCV genotype and subtype b Hepatitis A Antibody, Total f Hepatitis B Panel f Hepatitis E Virus IgG f Hepatitis E Virus IgM f Pharmacogenetic sample (optional) Tacrolimus level g Cyclosporine level h a. In addition to the Study Days outlined in Table 2 and Table 3, this is to be drawn at time of unscheduled visits for the management of CNIs. b. Performed only at Screening. c. Urine pregnancy testing is not required after Day 1 of the Treatment Period for female subjects who are confirmed to be post-menopausal or who have a documented history of prior bilateral tubal ligation, bilateral oophorectomy or hysterectomy. d. Performed on Day 1 (Treatment Period) only. e. Diabetic subjects only. f. May be performed as part of management of transaminase elevations. See Section 6.7.4, Management of Transaminase Elevations for details. g. For subjects taking tacrolimus only. h. For subjects taking cyclosporine only. i. Performed if creatinine clearance level < 50 ml/minute. See Section 6.7.5, Creatinine Clearance for details. 59

62 M Protocol For any laboratory test value outside the reference range that the investigator considers clinically significant: The investigator will repeat the test to verify the out-of-range value. The investigator will follow the out-of-range value to a satisfactory clinical resolution. A laboratory test value that requires a subject to be discontinued from the study or study drugs or requires a subject to receive treatment to manage the laboratory value will be recorded as an adverse event. The management of laboratory abnormalities that may occur during the study are described in Section 6.7. Pregnancy Test A urine pregnancy test will be performed for all female subjects at all the visits specified in Table 2 and Table 3. In addition, a serum pregnancy test will be performed at Screening and Study Day 1 Visits and analyzed by the central laboratory. All urine pregnancy tests will be performed on-site during the study visit if there is a scheduled visit, as specified in Table 2 and Table 3, and monthly for a minimum of 7 months after the discontinuation of RBV, or according to the local RBV label and/or consistent with local treatment guidelines for RBV. Urine pregnancy tests are not required after Study Day 1 for female subjects with a documented history of bilateral tubal ligation, hysterectomy, bilateral oophorectomy, or for subjects who are confirmed to be postmenopausal. Confirmation of postmenopausal status measured by FSH will be obtained at the Screening Visit only. During the PTP where there is not a scheduled study visit, female subjects of childbearing potential may either have pregnancy testing performed at the site as an unscheduled study visit using an unscheduled test kit or a urine pregnancy test may be conducted by the subject at home with a pregnancy test kit provided by the site; site personnel should contact these female study subjects to capture the results of any study-related pregnancy 60

63 M Protocol tests performed at home. The pregnancy test results will only be recorded in the subject's source records. If the subject elects to return to the study site for an unscheduled visit for pregnancy testing, the results of the urine pregnancy test will be recorded in the ecrf, unless serum pregnancy is elected. Serum pregnancy testing will be completed by the central laboratory and loaded into the clinical database. Hepatitis and HIV Screen HBsAg, anti-hcvab and anti-hiv Ab will be performed at Screening. The investigator must discuss any local reporting requirements to local health agencies with the subject. The site will report these results per local regulations, if necessary. The HBV HBsAg results will be reported by the central laboratory to the clinical database. Urine Screens for Drugs of Abuse Urine specimens will be tested at the Screening Visit for the presence of drugs of abuse. The panel for drugs of abuse will minimally include the drugs listed in Table 4. A positive screen is exclusionary, with the exception of a positive screen associated with documented short-term use or chronic stable use of a prescribed medication in that class (excluding methadone or buprenorphine). Subjects who otherwise meet all eligibility criteria, but have a positive urine alcohol screen, may have only the urine drug screen repeated. If the repeat urine drug screen is negative (except for cases in which the screen is positive for a prescribed drug), the subject may be considered eligible. These analyses will be performed by the certified central laboratory chosen for the study. HCV Genotype and Subtype Plasma samples for HCV genotype and subtype will be collected at the Screening Visit. Genotype and subtype will be assessed using the Versant HCV Genotype Inno-LiPA Assay, version 2.0 or higher (LiPA; Siemens Healthcare Diagnostics, Tarrytown, NY). 61

64 M Protocol Liver Biopsy Subjects who have not had a qualifying liver biopsy within the previous 3 months but who otherwise meet all of the inclusion criteria and none of the exclusion criteria will undergo liver biopsy prior to enrollment. The subject will only be eligible if the biopsy performed within the previous 3 months or during the Screening Period shows evidence of evidence of fibrosis F2 (Metavir scale) confirmed by the central pathology reader. HCV RNA Levels Plasma samples for HCV RNA levels will be collected as indicated in Table 2 and Table 3. Plasma HCV RNA levels will be determined for each sample collected by the central laboratory using the Roche COBAS TaqMan real-time reverse transcriptase-pcr (RT-PCR) assay v2.0. The lower limit of detection (LLOD) is 15 IU/mL and results below LLOD are reported as "HCV RNA not detected;" the LLOQ for this assay is 25 IU/mL and results below LLOQ but detectable are reported as "< 25 IU/mL HCV RNA detected." HCV Resistance Testing Sample A plasma sample for HCV resistance testing will be collected at the study visits, indicated in Table 2 and Table 3. Archive Plasma Sample Archive plasma samples will be collected at the study visits, indicated in Table 2 and Table 3. Archive plasma samples are being collected for possible additional analyses, including but not limited to, study drugs or metabolite measurements, viral load, safety/efficacy assessments, HCV gene sequencing, HCV resistance testing, and other possible predictors of response, as determined by the Sponsor. Interferon Gamma-Induced Protein 10 (IP-10) Levels A plasma sample for IP-10 testing will be collected at the study visits indicated in Table 2 and Table 3. 62

65 M Protocol Patient Reported Outcomes (PRO) Instruments (Questionnaires) Subjects will complete the self-administered PRO instruments (where allowed per local regulatory guidelines) on the study days specified in Table 2 and Table 3. Subjects will be instructed to follow the instructions provided with each instrument and to provide the best possible response to each item. Site personnel shall not provide interpretation or assistance to subjects other than encouragement to complete the tasks. Subjects who are functionally unable to read any of the instruments may have site personnel read the questionnaires to them. Site personnel will encourage completion of each instrument at all visits and will ensure that a response is entered for all items. In this study, PRO instruments should be consistently presented so that subjects complete the SF-36V2 instrument first, the EQ-5D-5L, and finally the HCVPRO. PRO instruments should be completed prior to drug administration (on Day 1) and prior to any discussion of adverse events or any review of laboratory findings, including HCV RNA levels. HCV Patient Report Outcomes (HCVPRO) Instrument The HCVPRO has been developed specifically to capture the function and wellbeing impact of HCV conditions and treatment. The instrument has been preliminarily validated and further validation is ongoing. The HCVPRO contains 16 items important to HCV patients; items are totaled to a summary score. Higher HCVPRO score indicates a better state of health. Completion of the HCVPRO should require approximately 5 minutes. EuroQol-5 Dimensions-5 Level (EQ-5D-5L) The EQ-5D-5L is a health state utility instrument that evaluates preference for health status (utility). The 5 items in the EQ-5D-5L comprise 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) each of which are rated on 5 levels of severity. Responses to the 5 items encode a discrete health state which is mapped to a preference (utility) specific for different societies. Subjects also rate their 63

66 M Protocol perception of their overall health on a separate visual analogue scale (VAS). The EQ-5D-5L should require approximately 5 minutes to complete. Short Form 36 Version 2 Health Status Survey The SF-36V2 is a general Health Related Quality of Life (HRQoL) instrument with extensive use in multiple disease states. The SF-36V2 instrument comprises 36 total items (questions) targeting a subject's functional health and wellbeing in 8 dimensions (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Scoring is totaled into a Physical Component Summary and a Mental Component Summary. Higher SF-36V2 scores indicate a better state of health. Completion of the SF-36V2 should require approximately 10 minutes. Enrollment and Assignment of Subject Numbers All screening activities must be completed and reviewed prior to enrollment. Subjects who meet the eligibility criteria will proceed to enrollment via the IRT system on Day 1 (Treatment Period). Subjects will initially be assigned a unique subject number at the Screening Visit. Enrolled subjects will retain this subject number throughout the study. Subject numbers will be 6-digit numbers with the first 3 digits representing the site and the last 3 digits assigned sequentially to the subjects within the site. The first 3 digits will be sequentially assigned to sites, starting with 100. The last 3 digits will be sequential for subjects within a site, starting with 601. So for example, within one site (100), subject numbers will be assigned sequentially as follows: , , , and so forth. Similarly, at a second site (101), subject numbers will be assigned sequentially as follows: , , , and so forth. MEMS Caps At the Day 1 Visit (TP), subjects will be assigned 3 MEMS caps. To ensure that a dosing event is recorded for the first dose of study drug at the site on Study Day 1 of the TP, the 64

67 M Protocol site should place the MEMS cap on the bottles of study drug before dispensing the first dose. Additionally, at each visit, site personnel should download the MEMS dosing history data from the MEMS cap, review, and counsel the patient as appropriate regarding compliance. Additional information regarding Treatment Compliance and MEMS can be found in Section and Section Study Drugs Compliance for Kits Study drugs compliance will be recorded per kit in the IRT system. Study drugs will be collected at each drug dispensation visit after Day 1, as indicated in Table 2. The number of tablets of ABT-450/r/ABT-267, ABT-333, and of RBV remaining in each bottle will be recorded in the source and transferred to the IRT system along with the date of reconciliation Meals and Dietary Requirements All study drugs should be dosed together and administered with food. When cyclosporine or tacrolimus is scheduled to be taken (as per instruction from the investigator), it should be administered with food in combination with the morning dose of study drugs Blood Samples for Pharmacogenetic Analysis IL28B Sample One (required) 4 ml whole blood sample for DNA isolation will be collected from each subject at the Study Day 1 Visit for Interleuken 28B (IL28B) pharmacogenetic analysis. This sample will not be used for any testing other than IL28B genotypes. Results of this testing will be made available to the investigator. Optional Sample for Pharmacogenetic Analysis A separate (optional) 4 ml whole blood sample for DNA isolation will be collected on Day 1 (Treatment Period) or at any time during the TP, from each subject who consents to provide the optional sample for pharmacogenetic analysis. If the optional 65

68 M Protocol pharmacogenetic sample is not collected at Day 1, it may be collected at any other visit during the study. The procedure for obtaining and documenting informed consent is discussed in Section 9.3. Results may not be included in the Clinical Study Report Drug Concentration Measurements Collection of Samples for Analysis Blood samples for assay of ABT-450, possible ABT-450 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ABT-267, possible ABT-267 metabolites, as well as ritonavir and RBV will be collected prior to dosing (0 hr), 2, and 4 hours post morning dose on Study Day 1 and at each subsequent study visit up to 24 weeks (irrespective of study drug dosing time) or upon subject discontinuation as specified in Table 3. The time that each blood sample is collected will be recorded to the nearest minute. A total of 14 blood samples are planned to be collected per subject for cyclosporine or tacrolimus pharmacokinetic analysis. A total of 15 blood samples are planned to be collected per subject for ABT-333, ABT-333 M1, ABT-450, ritonavir and ABT-267. The total number of blood samples planned for pharmacokinetic analysis is 870 for the entire treatment period. In addition, in the Post-Treatment Period, a total of 6 samples are planned to be collected per subject for cyclosporine or tacrolimus pharmacokinetic analysis. The total number of blood samples planned for pharmacokinetic analysis is 180 for the Post-Treatment Period. Also, at the investigators discretion extra blood draws for tacrolimus or cyclosporine level testing may be performed at any time as unscheduled visits during treatment as well as Post-Treatment Period. Blood samples for the assay of cyclosporine and tacrolimus trough level estimation will be collected prior to the morning dose, as indicated in Table 2 and Table 3. This sample will be analyzed by both the analytical and local laboratory. 66

69 M Protocol The date and time that each blood sample is collected and the date, time and dose of the subject's last immunosuppressant dose will be recorded in the ecrf. The samples to be analyzed by the local laboratory will be processed as per the local laboratory's standard practice. The samples which will be analyzed by the analytical laboratory will be processed as indicated in the lab manual provided by the central laboratory Handling/Processing of Samples Specific instructions for collection of blood samples and subsequent preparation and storage of the plasma samples for the pharmacokinetic assays of ABT-450, possible ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ritonavir and RBV will be provided by the central laboratory, the Sponsor, or its designee. Specific instructions for the collection of blood samples and subsequent preparation and storage of blood samples for the analysis of cyclosporine or tacrolimus will be provided in the laboratory manual provided by the central laboratory. Local laboratory analysis of blood samples for cyclosporine and tacrolimus samples will be done as per the investigator's local laboratory policies and procedures Disposition of Samples The frozen plasma samples for the pharmacokinetic assays of ABT-450, possible ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ritonavir, RBV samples will be packed in dry ice sufficient to last during transport, and transferred from the study site to the central laboratory. An inventory of the samples included will accompany the package. 67

70 M Protocol The central laboratory will then ship the samples for the pharmacokinetic assays of ABT-450, ABT-267, ABT-333, ritonavir, and RBV to: Sample Receiving An inventory of the included samples will accompany the package and an electronic copy of the Manifests (including subject number, study day, the time of sample collection and barcode) will be sent to the contact person at The frozen blood samples for cyclosporine and tacrolimus will be packed in dry ice sufficient to last during transport from the study site to the central laboratory. Refer to the laboratory manual for further details. The central laboratory will then ship the samples for pharmacokinetic assay of cyclosporine to: World Wide Clinical Trials 68

71 M Protocol On the day of shipping, an electronic copy of the inventory should be ed to. and the Sponsor. The central laboratory will then ship the samples for pharmacokinetic assay of tacrolimus to: Attn: Sample Controller On the day of shipping, a copy of the inventory sheet should be ed to and the Sponsor Measurement Methods Plasma concentrations of ABT-450, ritonavir, ABT-267, ABT-333, ABT-333 M1 metabolite, and RBV will be determined using validated assay methods under the supervision of the Drug Analysis Department at AbbVie. Plasma concentrations of metabolites of ABT-450 and ABT-267, and other metabolites of ABT-333 may also be determined using non-validated methods. Blood concentrations of cyclosporine and tacrolimus will be determined using validated assays, at the labs indicated in Section , under the supervision of the Drug Analysis Department at AbbVie. 69

72 M Protocol Efficacy Variables Virologic response will be assessed by HCV RNA in IU/mL at various time points from Day 1 through 48 weeks after completion of treatment Primary Variable The primary endpoint is the percentage of subjects with SVR 12 (HCV RNA < LLOQ 12 weeks after the last actual dose of study drugs) Secondary Variables The secondary endpoints are: The percentage of subjects with SVR 24 (HCV RNA < LLOQ 24 weeks after the last actual dose of study drugs); The percentage of subjects with virologic failure during treatment; The percentage of subjects with post-treatment relapse Resistance Variables The following resistance analyses will be performed for subjects who experience virologic failure: the variants at each amino acid position at baseline identified by population nucleotide sequencing will be compared to the appropriate prototypic reference sequence, and the variants at available post-baseline time points will be compared to baseline and the appropriate prototypic reference sequences Safety Variables The following safety evaluations will be performed during the study: adverse event monitoring and vital signs, physical examination, ECG, and laboratory tests assessments. 70

73 M Protocol Pharmacokinetic Variables Individual plasma concentrations of ABT-450, ritonavir, ABT-267, ABT-333, ribavirin and possible metabolites will be tabulated and summarized. Individual blood concentrations of the cyclosporine and tacrolimus will be tabulated and summarized Pharmacogenetic Variables IL28B genotypes are associated with response to PegIFN and RBV and some PegIFN-free regimens. IL28B status in whole blood samples will be determined for each subject and analyzed as a factor contributing to the subject's response to study treatment. These IL28B genotype results may be analyzed as part of a multi-study assessment of IL28B and response to ABT-450, ABT-267, ABT-333, or drugs of these classes. The results may also be used for the development of diagnostic tests related to IL28B and study treatment, or drugs of these classes. The results of additional pharmacogenetic analyses may not be reported with the clinical study report. DNA samples from subjects who separately consent for additional pharmacogenetic analysis may be analyzed for genetic factors contributing to the subject's response to study treatment, in terms of pharmacokinetics, pharmacodynamics, efficacy, tolerability and safety. Such genetic factors may include genes for drug metabolizing enzymes, drug transport proteins, genes within the target pathway, or other genes believed to be related to drug response (including IL28B). Some genes currently insufficiently characterized or unknown may be understood to be important at the time of analysis. Pharmacogenetic analyses will be limited to studying response to HCV therapy; no other analyses will be performed. 71

74 M Protocol 5.4 Removal of Subjects from Therapy or Assessment Discontinuation of Individual Subjects Each subject has the right to withdraw from the study at any time. In addition, the investigator may discontinue a subject from the study at any time if the investigator considers it necessary for any reason, including the occurrence of an adverse event or noncompliance with the protocol. If, during the course of study drugs administration, the subject prematurely discontinues during the TP, the procedures outlined for the Treatment Discontinuation Visit should be completed as defined in Table 2. It is recommended that this visit occur on the day of study drugs discontinuation, but no later than 2 days after their final dose of study drugs and prior to the initiation of any other anti-hcv therapy. However, these procedures should not interfere with the initiation of any new treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's condition. Following discontinuation of study drugs, the subject will be treated in accordance with the investigator's best clinical judgment. The date of the last dose of any study drugs and reason for discontinuation from the Treatment Period will be recorded in the EDC system. The subject should then begin the PTP where the subject will be monitored for 48 weeks for safety, HCV RNA levels, the emergence and persistence of resistant viral variants and PROs. If a subject is discontinued from study drugs (Treatment Period) or the Post-Treatment Period with an on going adverse event or an unresolved laboratory result that is significantly outside of the reference range, the investigator will attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result or adverse even is achieved. If a subject discontinues from the PTP, the subject should return for post-treatment discontinuation procedures as defined in Table 3. The reason for discontinuation will also be recorded in the Study Discontinuation ecrf. 72

75 M Protocol In the event that a positive result is obtained on a pregnancy test for a subject or a subject reports becoming pregnant during the study, the administration of study drugs (including RBV) to that subject must be discontinued immediately. Specific instructions regarding subject pregnancy can be found in Section 6.6. The investigator is also encouraged to report the pregnancy information to the voluntary RBV Pregnancy Registry. Subjects who experience an episode of rejection of the transplanted liver that is histologically confirmed or requires treatment with high dose steroids while receiving study drugs will be required to permanently discontinue study drugs and will enter the Post-Treatment Period. For subjects permanently discontinuing study drugs, investigators should be aware of the potential for consequent alterations in CNI levels and should contact the SDP to ensure that a plan is in place for appropriate CNI dose modification in the PTP. See Section for further information on the management of CNIs Virologic Failure Criteria The following criteria will be considered evidence of virologic failure while the subject is on study drugs: Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV RNA measurements > 1 log 10 IU/mL above nadir) at any time point during treatment; Failure to achieve HCV RNA < LLOQ by Week 6; Confirmed HCV RNA LLOQ (defined as two consecutive HCV RNA measurements LLOQ) at any point during treatment after HCV RNA < LLOQ. Where required, confirmatory testing should be completed as soon as possible. If any of the above criteria are met, the subject will discontinue study treatment (Section 5.4.1). Subjects should remain on study treatment until the virologic failure has been confirmed. 73

76 M Protocol Subjects with HCV RNA < LLOQ at the end of treatment and who a confirmed HCV RNA LLOQ (defined as 2 consecutive HCV RNA measurements LLOQ) at any point in the Post-Treatment Period will be considered to have relapsed. Confirmation of an HCV RNA LLOQ in the Post-Treatment Period should be completed as soon as possible Discontinuation of Entire Study The Sponsor may terminate this study prematurely, either in its entirety or at any study site, for reasonable cause provided that written notice is submitted in advance of the intended termination. The investigator may also terminate the study at his/her site for reasonable cause, after providing written notice to the Sponsor in advance of the intended termination. Advance notice is not required by either party if the study is stopped due to safety concerns. If the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the investigator and subsequently provide written instructions for study termination. 5.5 Treatments Treatments Administered Each dose of open-label DAA study drugs (ABT-450/r/ABT-267 and ABT-333) and open-label ribavirin will be dispensed in the form of tablets. Study drugs will be dispensed at the visits listed in Table 2. ABT-450/r/ABT-267 will be provided by the Sponsor as 75 mg/50 mg/12.5 mg tablets. ABT-450/r/ABT-267 will be taken orally as 2 tablets every morning which corresponds to a 150 mg ABT-450/100 mg ritonavir/25 mg ABT-267 dose QD. ABT-333 will be provided by the Sponsor as 250 mg tablets. ABT-333 will be taken orally as 1 tablet twice daily, which corresponds to a 250 mg dose BID. 74

77 M Protocol RBV will also be provided to the investigator by the Sponsor for use in this study. RBV will be provided as 200 mg tablets during the Treatment Period. RBV has weight-based dosing of 1000 mg to 1200 mg divided twice daily per local label. (For example, for subjects weighing less than 75 kg, RBV may be taken orally as 2 tablets in the morning and 3 tablets in the evening which corresponds to a 1000 mg total daily dose. Or for subjects weighing 75 kg or more, RBV may be taken orally as 3 tablets in the morning and 3 tablets in the evening which corresponds to a 1200 mg total daily dose.). However, in this special population with an increased risk of RBV associated anemia RBV dosing may be managed at the investigator's discretion for the treatment of HCV in liver transplant recipients. Subjects will be instructed to take study medication at the same time(s) every day. All cyclosporine or tacrolimus doses will be taken with the morning doses of study drugs and with food. All compounds including cyclosporine or tacrolimus should be taken together with food. This is important as taking the DAAs in combination with the CNIs at different times can significantly alter the level of the immunosuppressants. On the morning of Study Day 1, at the site, subjects will be administered study drugs by the study site personnel and receive instructions for self administration of all study drugs from Study Day 2 through Study Week 24 of the TP. The date and time of administration of the first dose of each drug will be recorded in the ecrf. Investigators should inform subjects not to take their morning CNI dose prior to the site visit on Study Day 1. Subjects should take the first study-appropriate dose of their CNI concurrently with the first dose of study drug at the site on the morning of Study Day 1. Following enrollment, the site will use the IRT system to obtain the study drugs kit numbers to dispense at the study visits specified in Table 2. Study drugs must not be dispensed without contacting the IRT system, and only for subjects enrolled in the study through the IRT system. At the end of the TP or at the TP D/C Visit, the site will contact the IRT system to provide visit date information and study drugs return information for each kit (Section ). 75

78 M Protocol All subjects who receive at least one dose of study drugs who fail to achieve virologic suppression, or who experience virologic breakthrough on DAA therapy will be discontinued from treatment. These subjects and those who relapse post DAA therapy may be offered another AbbVie-sponsored treatment study comprising ABT-450/r + ABT PegIFN + RBV. Alternatively, the investigator can prescribe another regimen which will not be provided or reimbursed by AbbVie Identity of Investigational Products Information about the study drugs to be used in this study is presented in Table 5. Table 5. Identity of Investigational Products Investigational Product Manufacturer Mode of Administration Dosage Form Strength ABT-450/Ritonavir/ABT-267 AbbVie/Abbott Oral Tablet 75 mg/50 mg/ 12.5 mg ABT-333 AbbVie/Abbott Oral Tablet 250 mg Ribavirin Roche or Generic Manufacturer Oral Tablet 200 mg Packaging and Labeling ABT-450/r/ABT-267 will be supplied in bottles containing 64 tablets. ABT-333 will be supplied in bottles containing 64 tablets. RBV will be supplied in bottles containing 168 tablets each. Each bottle will be labeled as required per country requirements. The labels must remain affixed to the bottles. All blank spaces should be completed by site staff prior to dispensing to subject. 76

79 M Protocol Storage and Disposition of Study Drugs Study Drugs ABT-450/Ritonavir/ABT-267 bottles ABT-333 bottles Ribavirin bottles Storage Conditions 15 to 25 C (59 to 77 F) 15 to 25 C (59 to 77 F) 15 to 25 C (59 to 77 F) The investigational products are for investigational use only and are to be used only within the context of this study. The study drugs supplied for this study must be maintained under adequate security and stored under the conditions specified on the label until dispensed for subject use or returned to the Sponsor. Upon receipt of study drugs, the site will acknowledge receipt within the IRT system Assigning to Treatment Groups At the Screening Visit, all subjects will be assigned a unique subject number through the use of IRT. For subjects who do not meet the study selection criteria, the site personnel must contact the IRT system and identify the subject as a screen failure. Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be enrolled into the study on Study Day 1. Subjects who are enrolled will retain their subject number, assigned at the Screening Visit, throughout the study. For enrollment of eligible subjects into the study, the site will utilize the IRT system in order to receive unique study drugs kit numbers. The study drugs kit numbers will be assigned according to schedules computer-generated before the start of the study by the AbbVie Statistics Department. Contact information and user guidelines for IRT use will be provided to each site. Upon receipt of study drugs, the site will acknowledge receipt in the IRT system Selection and Timing of Dose for Each Subject Study drugs dosing will be initiated at the Study Day 1 Visit. ABT-450/r/ABT-267 will be dosed every morning, and ABT-333 and RBV will be dosed BID. Study drugs and cyclosporine or tacrolimus should be taken together with food at approximately the same 77

80 M Protocol times in the morning every day. This is important as taking the DAAs in combination with the immunosuppressants at different times can significantly alter the level of the immunosuppressants Blinding This is an open-label study Data Monitoring Committee (DMC) An independent DMC will review safety data from this study and provide recommendations to the AbbVie Study Designated Physician as per the DMC charter. The charter also describes DMC membership, which will include individuals with experience in the management of patients with chronic HCV infection, and member responsibilities. The DMC will receive interim summaries of safety data according to a schedule and format specified in the charter. After each review, the DMC will communicate its recommendations to the Sponsor. The Sponsor will retain sole responsibility for study management, communication with study sites and regulatory authorities Treatment Compliance The investigator or his/her designated and qualified representatives will administer/dispense study drugs only to subjects enrolled in the study in accordance with the protocol. The study drugs must not be used for reasons other than that described in the protocol. All study drugs will be dispensed to subjects by study-site personnel under the direction of the investigator. At the start of the study, each subject should receive counseling regarding the importance of dosing adherence with the treatment regimen with regards to virologic response and potential development of resistance. Subjects will be administered study drugs at the site at the Study Day 1 Visit. The start and stop dates of all study drugs will be recorded in the source documents and ecrfs. 78

81 M Protocol Subjects will be instructed to return all bottles of study drugs (full, partial, or empty) to the study site at each drug dispensation visit indicated in Table 2. Study site personnel will inspect the contents of the bottles and record the status of each one as well as the exact number of remaining tablets of ABT-450/r/ABT-267, ABT-333, and RBV and the date of reconciliation in the IRT system. Reconciliation should occur when the bottle is returned at each visit indicated in Table 2. If poor adherence is noted, the subject should be counseled and this should be documented in the subject's source. Study drugs should not be interrupted for toxicity management or any other reason for more than 7 days consecutively. If study drugs need to be interrupted for more than 7 days consecutively, the Study Designated Physician should be contacted and consideration should be given to discontinue the subject. The date and time of administration of the first dose of each drug will be recorded in the source documents and the ecrf. A single date of last dose of all study drugs will be recorded in the source documents and the ecrf MEMS Caps All subjects will utilize a MEMS monitor (cap), manufactured by Advanced Analytical Research on Drug Exposure (AARDEX) on the bottles for study drug. The MEMS cap will be used to obtain daily dosing histories for study drugs for all subjects. In addition, MEMS data will be provided to the investigator to guide treatment compliance discussions and will be the primary data used to assess PK time relative to dose. The MEMS cap is a threaded cap containing an internal electronic clock, with an integrated electronically erasable programmable read-only memory, a special micro-switch and battery. Once fastened onto the medication bottle, the MEMS cap silently records the date and time of all dosing events (event = opening + closing). This electronic monitor provides a means of objectively measuring a subject's adherence with the study medication. 79

82 M Protocol At the Study Day 1 Visit of the TP, subjects will be assigned the MEMs caps that will be placed on the bottles of study drugs in place of the original cap. The original cap should be saved so it can be placed back on the bottle upon return by the subject in order to store returned study drug. The MEMS cap must only be used by the subject to whom it was assigned. Each MEMS cap has a unique serial number that must be recorded in the subject's source documentation. It is suggested that the subject's subject number be written on his or her MEMS cap in permanent ink. The subjects will be instructed to open the bottle when it is time to take the medicine, to remove the proper amount of medication and promptly close the bottle, then ingest the prescribed dose. The subject should be instructed to transfer the MEMS cap to the next full bottle of study drug at the same time that they take their last dose from the current in-use bottle. The MEMS cap will be collected from the subject at the completion of study drugs as applicable. If MEMS caps cannot be imported into a participating study country or if other issues preclude the use of MEMS cap at a site(s), dosing histories will not be obtained for subjects enrolled at that site(s). Additional instructions for the subject on how to use the MEMS cap will be provided by the Sponsor Drug Accountability The investigator or his/her representative will verify that study drugs supplies are received intact and in the correct amounts. This will be documented by signing and dating the Proof of Receipt (POR) or similar document and via recording in the IRT system. A current (running) and accurate inventory of study drugs will be kept by the investigator and will include lot number, POR number, number of tablets dispensed, subject number, initials of person who dispensed study drugs and date dispensed for each subject. An overall accountability of the study drugs will be performed and verified by the Sponsor 80

83 M Protocol monitor throughout the Treatment Period. Final accountability will be performed by the monitor at the end of study drugs treatment at the site. During the study, should an enrolled subject misplace or damage a study drugs bottle, the site must contact the IRT system to report the misplaced or damaged study drugs. If the bottles are damaged, the subject will be requested to return the remaining study drugs to the site. Replacement study drugs may only be dispensed to the subject by contacting the IRT system. Study drugs replacement and an explanation of the reason for the misplaced or damaged study drugs will be documented within the IRT system. Study drugs start dates and times for each drug and the date of the last dose of the regimen will be documented in the subject's source documents and recorded on the appropriate ecrf. The status of each bottle, number of each type of tablets remaining in each one returned, and the date of reconciliation will be documented in the IRT system. The monitor will review study drugs accountability on an ongoing basis. Upon completion of or discontinuation from the Treatment Period, all original bottles (containing unused study drugs) will be returned to the Sponsor (or designee) according to instructions from the Sponsor and according to local regulations following completion of drug accountability procedures. The number of tablets of each type of study drug returned will be noted on the drug accountability log and the IRT system (if not previously recorded) and appropriate drug return forms. Labels must remain attached to the containers. 5.6 Discussion and Justification of Study Design Discussion of Study Design and Choice of Control Groups The 3 DAA regimen of ABT-450/r/ABT ABT-333 with RBV is being evaluated in the current study based on data from Phase 2b Study M Available data from Study M indicate that, when dosed in treatment-naïve subjects for 12 weeks, the 3 DAA regimen of ABT-450/r +ABT ABT RBV shows higher SVR 12 results (77 of 79 subjects, 97.5%) as compared to the 2 DAA arms of ABT-450/r + ABT

84 M Protocol RBV (71 of 79 subjects, 90%) or ABT-450/r + ABT RBV (35 of 41 subjects, 85%). The 3 DAA regimen without ribavirin showed high SVR 12 rates ((24 of 25 subjects, 96%) in genotype 1b subjects; genotype 1a subjects showed a lower SVR 12 rate (43 of 52 subjects, 83%) as compared to the 3DAA + RBV regimen (52 of 54 subjects, 96%). Thus, the 3 DAA + RBV regimen dosed for 12 weeks provides the highest possibility of achieving SVR in treatment-naïve genotype 1 subjects. Based upon the results of high SVR rates in three Phase 2 studies, including the largest study, Study M (discussed in detail in Section 3.0), AbbVie plans to evaluate ABT-450/r/ABT-267 and ABT-333 coadministered with RBV in adult liver transplant recipients with chronic HCV genotype 1 infection in a multicenter, open-label, Phase 2 study. A placebo-controlled trial was not considered to be appropriate in post liver transplant subjects due to the interim risk of hepatic progression during the study for placebo recipients. The use of an active comparator arm was considered in the study design. The approved direct acting antiviral agents telaprevir and boceprevir, in combination with PegIFN and ribavirin result in improved treatment outcomes for those with HCV. However, there is a paucity of data describing efficacy and safety in liver transplant recipients and these agents are not currently indicated for use in this patient population. Given the not inconsiderable toxicities, low SVR rates and high discontinuation rates with PegIFN/RBV, as well as the potential for dropout among those who would not receive the DAA/RBV therapy in a comparator study and due to the overall expected higher efficacy and lower toxicities rates with the DAA/RBV therapy it was decided not to add a PegIFN/RBV comparator arm to this Phase 2 study. ABT-450/r with ABT-267 and ABT-333 combined with RBV have been well-tolerated for up to 24 weeks in HCV infected subjects in Study M Available data suggest that 12 weeks of treatment with DAAs and RBV is sufficient for subjects with HCV, as illustrated by available clinical data in Study M However, the duration of therapy required to cure HCV in the post transplant setting has not yet been defined. The 82

85 M Protocol observed overall lower responses to PegIFN-RBV suggest that this is a difficult to population. Consequently, the duration of treatment for this population will be 24 weeks. Given the above considerations, it is anticipated that the study design will maximize the probability of success in this harder-to-cure population while avoiding the side-effects of pegylated interferon. It is anticipated that SVR rates with this regimen will exceed those of the current standard of care, PegIFN-RBV. Also, DMC oversight will further ensure the safety of all subjects Appropriateness of Measurements Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized in this study. HCV RNA assays are standard and validated. Clonal and population sequencing methods are experimental. SF-36V2 and EQ-5D-5L PRO instruments are standards in the literature and thoroughly validated; the HCVPRO is preliminarily validated Suitability of Subject Population The selection of subjects infected with HCV genotype 1 virus will allow for the assessment of safety, pharmacokinetics and antiviral activity of ABT-450/r, ABT-267, ABT-333 and RBV dosed in combination. This study will restrict enrollment to HCV genotype 1-infected liver transplant recipients who are either treatment-naïve or treatment-experienced prior to liver transplant with cifn or PegIFN (with or without RBV) and who have no evidence of advanced liver disease, thereby limiting risk of unanticipated pharmacokinetic or other adverse effects not observed in prior dosing in healthy volunteers or HCV-infected subjects. HCV-infected subjects with transaminase levels up to 5 times the ULN will be allowed to enroll, as many patients with chronic HCV infection who are otherwise healthy, have stable elevations of AST and ALT levels ( 5 ULN) and are considered representative of the population who will receive ABT-450/r, ABT-267, and ABT-333. A portion of the HCV-infected liver transplant recipients have a relatively high BMI. Because of the acceptable safety and 83

86 M Protocol pharmacokinetic profiles of ABT-450/r, ABT-267 and ABT-333 in Phase 1 and Phase 2 studies, this protocol will enroll subjects with a BMI up to 38 kg/m 2. Since DAA interaction studies have only been conducted with cyclosporine and tacrolimus, the study will only enroll subjects who are on stable doses of either of these two widely used drugs. Individuals who are clinically stable at 12 or more months after an uncomplicated transplant are anticipated to have discontinued corticosteroids or at least may only be on low maintenance corticosteroid doses. The requirements for HbA1C ( 8%) and calculated creatinine clearance ( 55mL/min) are to limit the impact of prior CNI toxicity or diabetes on renal function in this population. The inclusion of subjects who could use PegIFN in the post transplant setting is to ensure that should study drug treatment failure occur subjects will have the option to use PegIFN in a subsequent treatment regimen Selection of Doses in the Study Doses of the three DAAs to be used in this study have shown significant antiviral activity both as monotherapy, in combination with PegIFN + RBV, and in combination with each other and RBV. Doses comparable to, and higher than the DAA doses to be administered in this study have been studied in single- and multiple-dose healthy volunteer studies and administered to HCV-infected subjects as monotherapy or in combination with PegIFN RBV and found to be generally safe and well-tolerated. Of note, coadministration of ABT-450/r, ABT-267 and ABT-333 at the doses planned for use in this study do not clinically significantly impact plasma exposures compared to administration as single agents thus dose adjustments based on drug interactions are not required. The DAAs to be administered in this study have been evaluated in approximately 570 subjects in Study M Of these, approximately 240 subjects received the specific combination of ABT-450/r (dosed 100/100 or 150/100 mg QD) + ABT-267 (25 mg QD) + ABT-333 (400 mg BID) + RBV (weight based dosing). As noted in Section 3.0, overall the regimen was associated with high SVR 12 rates and was well-tolerated. 84

87 M Protocol ABT-450/r Monotherapy data for ABT-450/r indicated that despite comparable decrease in viral load from baseline following 3 days of monotherapy, higher doses resulted in selection of fewer resistant variants. Thus the 200 mg dose had a better resistance profile than the 100 mg dose or the 50 mg dose. In combination with PegIFN/RBV, the 100 and 200 mg doses showed comparable SVR (88%). Data from the on-going Phase 2 study, Study M indicated that the combination of 3 DAAs with RBV in treatment-experienced subjects showed higher SVR 12 and lower rebound at the 150 mg dose as compared to the 100 mg dose. Higher doses of ABT-450 (200 and 250 mg) might provide a more favorable resistance profile but were associated with more frequent Grade 3 ALT elevations. The ABT-450 formulation planned for this study has a ~50% higher exposure as compared to the formulation used in Study M but provides exposure ~60% lower than that from the 200 mg dose used in Study M This increase in exposure is not expected to adversely affect safety. Hence the 150 mg dose of ABT-450 when dosed in combination is the optimal dose based on safety, efficacy and resistance profile and will be used in this study. The maximum dose of ABT-450/r/ABT mg/50 mg/12.5 mg tablets will not exceed 150 mg/100 mg/25 mg per day for 24 weeks. ABT-267 Following 3 days of ABT-267 monotherapy at doses of 1.5 mg to 200 mg QD, the 25 mg dose of ABT-267 showed viral load decline comparable to higher doses (Study M and Study M13-386). Preliminary resistance analysis from the Phase 1b Study M12-116, suggests that ABT-267 doses > 25 to 50 mg QD do not confer an advantage in suppression of commonly selected resistant variants. On the contrary higher ABT-267 doses have been associated with decrease in ABT-450 exposures; a 200 mg ABT-267 dose resulted in ~80% lower ABT-450 exposures (250 mg dosed with 100 mg ritonavir). Modeling and simulation to predict SVR rates suggest that an ABT mg dose is optimal when combined with ABT-450/r with or without ABT-333. Higher doses are not 85

88 M Protocol predicted to increase SVR rates or permit a decrease in duration. The maximum ABT-267 dose administered in this study will not exceed 25 mg daily for 24 weeks. The maximum dose of ABT-450/r/ABT mg/50 mg/12.5 mg tablets will not exceed 150 mg/100 mg/25mg per day for 24 weeks. ABT-333 Following 2 to 3 days of monotherapy with ABT-333 in Phase 2 studies (Study M and Study M11-602), viral load declines were similar (approximately 1 log 10 IU/mL) for doses of 300 mg BID, 400 mg BID, 600 mg BID, 800 mg BID and 1200 mg QD. In contrast, a dose of 100 mg BID appeared to show less antiviral activity when administered as monotherapy in the Phase 1b Study M When combined with PegIFN/RBV for 12 weeks followed by 36 weeks of PegIFN/RBV both the 400 mg and 800 mg BID doses showed similar SVR rates (63%). While both the 400 mg BID and 800 mg BID doses of ABT-333 in Study M were well-tolerated by HCV-infected subjects for 12 weeks in combination with PegIFN/RBV, the 800 mg BID dose was associated with a greater mean hemoglobin reduction compared to 400 mg BID and compared to placebo plus PegIFN/RBV. Thus, the 400 mg BID dose appears to show similar efficacy and a superior safety profile to the 800 mg BID dose. The clinical data, dose response plot and hemoglobin data indicates that total daily dose of ~600 mg (300 mg BID capsule) is the optimal ABT-333 dose, and that doses of 100 mg BID are subtherapeutic. The exposures from the 300 mg BID capsule were however comparable to the 400 mg BID tablet doses in Study M The 400 mg tablet was also used in Study M For the current study, a new higher bioavailability formulation will be used. The relative bioavailability of a 250 mg dose of this formulation is expected to be comparable to the 400 mg tablet formulation used in Study M Hence, the ABT-333 dose selected for this study is 250 mg dosed BID. The maximum dose of ABT mg tablets administered in this study will not exceed 500 mg per day for 24 weeks. 86

89 M Protocol Ribavirin The recommended daily dose of RBV in this study is 1000 to 1200 mg, divided twice daily, and based on subject weight. This dose is approved for treatment of adult patients with chronic hepatitis C infection in combination with PegIFN. The same dose is selected for this study because its safety profile has been well characterized when administered with PegIFN, including the incidence of hemolytic anemia, and there are well-defined dose reduction criteria in the event of RBV-induced anemia. In addition, this dose was studied in the absence of PegIFN in approximately 61 subjects with chronic HCV infection in Study M and Study M12-746, and was found to be generally safe and well-tolerated. The maximum RBV dose administered in this study will not exceed 1200 mg, divided twice daily for 24 weeks. However, in this special population with an increased risk of RBV associated anemia RBV dosing may be managed by the investigator consistent with local practice for the treatment of HCV in liver transplant recipients such that total doses of RBV doses less than 1200 mg per day may be preferred. 6.0 Adverse Events The investigator will monitor each subject for clinical and laboratory evidence of adverse events on a routine basis throughout the study. The investigator will assess and record any adverse event in detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the adverse event to study drugs (DAAs or RBV), and any action(s) taken. For serious adverse events considered as having "no reasonable possibility" of being associated with study drugs, the investigator will provide an "Other" cause of the event. For adverse events to be considered intermittent, the events must be of similar nature and severity. Adverse events, whether in response to a query, observed by site personnel, or reported spontaneously by the subject will be recorded. All adverse events will be followed to a satisfactory conclusion. 87

90 M Protocol 6.1 Definitions Adverse Event An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not the event is considered causally related to the use of the product. Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from accidental or intentional overdose, drug abuse, or drug withdrawal. Any worsening of a pre-existing condition or illness is considered an adverse event. Worsening in severity of a reported adverse event should be reported as a new adverse event. Laboratory abnormalities and changes in vital signs are considered to be adverse events only if they result in discontinuation from the study, necessitate therapeutic medical intervention, meets protocol specific criteria (see Section 6.7 regarding toxicity management) and/or if the investigator considers them to be adverse events. An elective surgery/procedure scheduled to occur during a study will not be considered an adverse event if the surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been pre-planned prior to study entry. However, if the pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition for which the elective surgery/procedure is being done will be considered an adverse event Serious Adverse Events If an adverse event meets any of the following criteria, it is to be reported to the Sponsor as a serious adverse event (SAE) within 24 hours of the site being made aware of the serious adverse event. 88

91 M Protocol Death of Subject Life-Threatening Hospitalization or Prolongation of Hospitalization An event that results in the death of a subject. An event that, in the opinion of the investigator, would have resulted in immediate fatality if medical intervention had not been taken. This does not include an event that would have been fatal if it had occurred in a more severe form. An event that results in an admission to the hospital for any length of time or prolongs the subject's hospital stay. This does not include an emergency room visit or admission to an outpatient facility. Congenital Anomaly Persistent or Significant Disability/Incapacity Important Medical Event Requiring Medical or Surgical Intervention to Prevent Serious Outcome An anomaly detected at or after birth, or any anomaly that results in fetal loss. An event that results in a condition that substantially interferes with the activities of daily living of a study subject. Disability is not intended to include experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle). An important medical event that may not be immediately life-threatening or result in death or hospitalization, but based on medical judgment may jeopardize the subject and may require medical or surgical intervention to prevent any of the outcomes listed above (i.e., death of subject, life-threatening, hospitalization, prolongation of hospitalization, congenital anomaly, or persistent or significant disability/incapacity). Additionally, any elective or spontaneous abortion or stillbirth is considered an important medical event. Examples of such events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. For serious adverse events with the outcome of death, the date and cause of death will be recorded on the appropriate case report form. 89

92 M Protocol 6.2 Adverse Event Severity The investigator will use the following definitions to rate the severity of each adverse event: Mild Moderate Severe The adverse event is transient and easily tolerated by the subject. The adverse event causes the subject discomfort and interrupts the subject's usual activities. The adverse event causes considerable interference with the subject's usual activities and may be incapacitating or life-threatening. 6.3 Relationship to Study drugs The investigator will use the following definitions to assess the relationship of the adverse event to the use of study drugs. Assessment of relatedness will be made with respect to the DAAs (ABT-450/r/ABT-267 and ABT-333) and with respect to RBV: Reasonable Possibility No Reasonable Possibility An adverse event where there is evidence to suggest a causal relationship between the study drugs and the adverse event. An adverse event where there is no evidence to suggest a causal relationship between the study drugs and the adverse event. For causality assessments, events assessed as having a reasonable possibility of being related to the study drugs will be considered "associated." Events assessed as having no reasonable possibility of being related to study drugs will be considered "not associated." In addition, when the investigator has not reported a causality or deemed it not assessable, the Sponsor will consider the event associated. If an investigator's opinion of no reasonable possibility of being related to study drugs is given for a serious adverse event, then another cause of event must be provided by the investigator. 90

93 M Protocol 6.4 Adverse Event Collection Period All adverse events reported from the time of study drug administration until 30 days following discontinuation of study drug administration have elapsed will be collected, whether solicited or spontaneously reported by the subject. In addition, serious adverse events will be collected from the time the subject signed the study-specific informed consent until the end of their participation in the study. Adverse event information will be collected as shown in Figure 3. Figure 3. Adverse Event Collection SAEs SAEs and Non-Serious AEs Elicited and/or Spontaneously Reported SAEs Consent Signed Study drug Start Study Drug Stopped 30 Days or After Study Drug Stopped End of Study 6.5 Adverse Event Reporting In the event of a serious adverse event, whether associated with study drugs or not, the investigator will notify the Antiviral Safety Management Team within 24 hours of the site being made aware of the serious adverse event by entering the serious adverse event data into the EDC system. Serious adverse events that occur prior to the site having access to the RAVE system or if RAVE is not operable should be faxed to the Antiviral Safety Management Team within 24 hours of being made aware of the serious adverse event. FAX to: For serious adverse event concerns, contact the Antiviral Safety Team at: 91

94 M Protocol Antiviral Safety Team For any subject safety concerns, please contact the physician listed below: Primary Study-Designated Physician: Eoin Coakley, MD Telephone Contact Information: The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with Directive 2001/20/EC. The reference document used for SUSAR reporting in the EU countries will be the most current versions of the Investigator's Brochure or label. 6.6 Pregnancy Subjects and their partners should avoid pregnancy and males should avoid sperm donation throughout the course of the study, starting with Study Day 1 and for 7 months 92

95 M Protocol after the last dose of RBV (or per local RBV label) and/or consistent with local treatment guidelines for RBV. Pregnancy in a study subject must be reported to the Sponsor within 1 working day of the site becoming aware of the pregnancy. Subjects who report a positive pregnancy test during the Treatment Period must be notified to stop all study medication (Section 5.4.1) and be discontinued. The site must complete and fax to the Sponsor the appropriate pregnancy-specific forms that will require the collection of maternal information and fetal outcome information. The investigator is also encouraged to report the pregnancy information to the voluntary RBV Pregnancy Registry. Pregnancy in a study subject is not considered an adverse event. However, the medical outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is considered a serious adverse event and must be reported to the Sponsor within 24 hours of the site becoming aware of the event. 6.7 Toxicity Management For the purpose of medical management, all adverse events and laboratory abnormalities that occur during the study must be evaluated by the investigator. A table of Clinical Toxicity Grades for evaluating laboratory abnormalities is provided in Appendix C. This table should be used in determination of the appropriate toxicity management as discussed in Section and Section A drug-related toxicity is an adverse event or laboratory value outside of the reference range that is judged by the investigator or the Sponsor as having a "reasonable possibility" of being related to the study drugs (Section 6.3). A toxicity is deemed "clinically significant" based on the medical judgment of the investigator. Laboratory abnormalities will be managed as deemed clinically appropriate by the investigator until resolved. Study drugs should not be interrupted for toxicity management for more than 7 consecutive days. If study drugs need to be interrupted for more than 7 consecutive 93

96 M Protocol days, consideration should be given to discontinue the subject and the Study Designated Physician should be contacted. During the study, timeliness of EDC data entry to reflect study drugs interruptions and/or RBV dose modifications and consequent required adverse events ensures that the AbbVie Safety Team (medical monitor, safety monitor, DMC) have the data necessary for signal detection at safety data review and DMC meetings. The investigator should ensure that any study drugs interruptions or RBV dose modifications and consequent required adverse events are entered into the appropriate ecrfs. Safety surveillance, via regular review of safety labs will be performed by AbbVie personnel and/or its designee. If during these reviews, an issue is identified which warrants discontinuation of study drugs by a subject, the investigator will be notified. The toxicity management guidelines below should be followed. Because of the potential impact of interruption/discontinuation of DAAs/RBV on CNI levels, investigators should contact the SDP when an interruption/discontinuation is anticipated or required by protocol to ensure that a plan for appropriate CNI dose modification is in place. Similarly for those recommencing DAA's/RBV after an interruption the investigator should contact the SDP to ensure that a plan for appropriate CNI dose adjustment is in place. Where an interruption is required the study drugs should not be interrupted for more than 7 days. If study drugs need to be interrupted for more than 7 days, the Study Designated Physician should be contacted and consideration should be given to discontinue the subject Grades 1 or 2 Laboratory Abnormalities and Mild or Moderate Adverse Events Subjects who develop a study drug-related (reasonable possibility) mild or moderate adverse event or Grades 1 or 2 laboratory abnormality (other than those discussed separately in Toxicity Management sections for hemoglobin parameters [Section 6.7.3], total bilirubin and hepatic transaminase parameters [Section 6.7.4] and creatinine 94

97 M Protocol clearance parameters [Section 6.7.5]) may continue study drugs with follow-up per study protocol. If the adverse event or laboratory parameter does not improve or normalize within 2 scheduled study visits and an etiology other than study drugs has not been determined, then the SDP can be contacted to further discuss subject management. Subjects may continue study drugs; study drug interruption is not required Grades 3 or 4 Laboratory Abnormalities and Severe or Serious Adverse Events Grades 3 4 Laboratory Abnormalities With the exception of Grade 3 or greater elevations in uric acid, total cholesterol or triglycerides, if a subject experiences a Grade 3 or greater laboratory parameter during the study (other than those discussed in the toxicity management Sections through below), the abnormal laboratory test should be repeated. If the Grade 3 or greater abnormality is confirmed, the study drugs should be interrupted and the laboratory parameter followed until it reaches Grade 1. The study drugs can be restarted if the laboratory parameter reaches Grade 1 within 7 days of study drug interruption. If study drugs are interrupted and restarted and abnormality recurs, then all study drugs should be permanently discontinued. If the abnormality does not improve to Grade 1 or less within 7 days of interruption, the study drugs should be permanently discontinued. If the investigator believes that the confirmed Grade 3 or greater laboratory abnormality can be managed medically without interruption, then the AbbVie Study Designated Physician should be contacted to discuss continued study drug administration with medical management. If the laboratory abnormality does not improve with medical management within 2 scheduled study visits, then study drugs should be interrupted and the laboratory abnormality followed. If the laboratory abnormality improves within 7 days of study drug interruption, study drugs may be restarted. If the laboratory abnormality recurs upon restart, then study drugs should be permanently discontinued. If the laboratory abnormality does not improve within 7 days, then study drugs should be 95

98 M Protocol permanently discontinued. Immunosuppressant levels should be monitored at the investigator's discretion during periods of interruption and reinitiation of study drugs. Severe Adverse Event If a subject experiences a severe drug-related (reasonable possibility) adverse event (other than those based on abnormal lab parameters discussed in Sections through 6.7.5) during the study, the study drugs should be interrupted. Study drugs may be restarted if the adverse event improves or resolves within 7 days of the interruption. If study drugs are interrupted and restarted and adverse event recurs, then study drugs should be permanently discontinued. If the adverse event does not improve or resolve within 7 days of the interruption the study drugs should be permanently discontinued. If the investigator believes that the severe drug-related (reasonable possibility) adverse event can be managed medically without interruption, then the Study Designated Physician should be contacted to discuss continued study drugs administration with medical management. If the severe adverse event does not improve with medical management within 2 scheduled study visits, then study drugs should be interrupted. If the severe adverse event improves within 7 days of the interruption, then study drugs may be restarted. If the severe adverse event recurs upon restart, then study drugs should be permanently discontinued. If the severe adverse event does not improve within 7 days of the interruption, then study drugs should be permanently discontinued. If a subject experiences a severe adverse event which in the opinion of the investigator is considered unrelated to study drugs (no reasonable possibility) and which can be managed medically without interruption of study drugs, then the SDP should be contact to discuss continued study drug administration with medical management. A severe adverse event and any associated dose interruptions (or discontinuations) should be entered into the appropriate ecrfs. Immunosuppressant levels should be monitored at the investigator's discretion during periods of interruption and reinitiation of study drugs. 96

99 M Protocol Serious Adverse Event If a subject experiences a serious drug-related (reasonable possibility) adverse event (other than those based on abnormal lab parameters discussed in Sections through 6.7.5) during the study, the study drugs should be permanently discontinued. If the investigator believes that the severe drug-related (reasonable possibility) adverse event can be managed medically without interruption, then the AbbVie Study Designated Physician should be contacted to discuss continued study drug administration with medical management. If the severe adverse event does not improve with medical management within 2 scheduled study visits, then study drugs should be interrupted. If the severe adverse event improves within 7 days of the interruption, then study drugs may be restarted. If the severe adverse event recurs upon restart, then study drugs should be permanently discontinued. If the severe adverse event does not improve within 7 days of the interruption, then study drugs should be permanently discontinued. If a subject experiences a serious adverse event considered unrelated (no reasonable possibility) to study drugs the study drugs may be continued. If the study drugs are interrupted because it is deemed necessary for clinical management, the interruption should not exceed 7 days. Because of the potential impact of interruption/discontinuation of study drugs on CNI levels, investigators should contact the SDP when an interruption/discontinuation is anticipated or required by protocol to ensure that a plan for appropriate CNI dose modification is in place. Similarly, for those recommencing study drugs after an interruption the investigator should contact the SDP to ensure that a plan for appropriate CNI dose adjustment is in place. The investigator should ensure that all serious adverse events are reported to AbbVie Safety within 24 hours of awareness. Serious adverse event follow-up information, including associated dose interruptions (or discontinuations), also needs to be reported to the Sponsor within 24 hours of awareness by entering updated SAE information into the appropriate ecrfs. 97

100 M Protocol Management of Decreases in Hemoglobin Reductions in hemoglobin are a well characterized side effect of RBV exposure. Hemoglobin abnormalities should be managed according to Table 6. Management will be different for subjects without a history of known cardiac disease and subjects with known cardiac disease. If a subject experiences a hemoglobin decrease (as outlined in Table 6), a confirmatory test should be performed. If the hemoglobin decrease is confirmed, the management guidelines in Table 6 should be followed. Use of hematologic growth factors such as erythropoietin, filgrastim or blood transfusions are permitted. Management of hematologic growth factor therapy is the responsibility of the investigator, and growth factors will not be provided by the Sponsor. Alternate management of hemoglobin decreases requires approval of the Study Designated Physician. Use of hematologic growth factors or blood transfusion should be recorded in the ecrf. 98

101 M Protocol Table 6. Management of Hemoglobin Decreases Hemoglobin < 10.0 g/dl but 8.5g/dL Hemoglobin < 8.5 g/dl Hemoglobin decrease of 2 g/dl during a 4-week treatment period (Hb 10 g/dl) without symptoms and/or signs of cardiac disease Hemoglobin decrease of 2 g/dl during a 4-week treatment period (Hb 10 g/dl) with symptoms and/or signs of cardiac disease Hemoglobin < 10 g/dl Hemoglobin in Patients with No Cardiac Disease Study drugs may be continued; Consider RBV dose reduction. Continue to monitor hemoglobin per protocol. If hemoglobin increases to 10 g/dl, may increase RBV; with gradual dose increases towards original dose. If Hb decreases to < 8.5 g/dl, see appropriate row below. Contact SDP for discussion regarding work up, management of subject and study drugs. Enter into appropriate ecrfs and create corresponding adverse event (AE) if subject is discontinued or requires medical intervention. Hemoglobin in Patients with History of Stable Cardiac Disease Study drugs may be continued. Consider RBV dose reduction. Continue to monitor hemoglobin levels per protocol. If a subsequent hemoglobin result is greater than the level that triggered the dose reduction the investigator may elect to increase RBV; with gradual dose increases towards original dose. If hemoglobin does not increase; investigator may work up subject and manage as medically appropriate. If hemoglobin decreases to < 10 g/dl see appropriate row below. If the subject has symptoms consistent with their cardiac disease; work up and manage subject as medically appropriate; manage RBV per the rows above; AbbVie Study Designated Physician may be contacted to further discuss subject's management. Study drugs may be continued. Contact SDP for discussion regarding work up, management of the subject and study drugs. Enter into appropriate ecrfs and create corresponding adverse event (AE) Management of Transaminase Elevations In the setting of elevations in ALT investigators will follow the management described in Table 7. If at any time a investigator suspects rejection of the transplanted liver while the subject is receiving study drug, then dose adjustment of tacrolimus or cyclosporine may 99

102 M Protocol be performed per the investigator's usual practice and the event captured on ecrf. If the abnormality is non-responsive to CNI adjustment or if the investigator wishes to empirically augment the immunosuppressive regimen, e.g., commencement of high dose steroids or the addition of other immunosuppressants but without the availability of a liver biopsy confirming rejection, then study drugs should be discontinued. If the investigator wishes to continue study drugs, then the study designated physician should be contacted to obtain permission. If a liver biopsy is performed as part of the evaluation of rejection and the histologic findings are consistent with rejection as determined by the local and/or central pathologist, the investigator should follow the usual management of rejection and study drugs should be discontinued. If the investigator wishes to continue study drugs in the setting of histologically confirmed rejection, then the study designated physician should be contacted in obtain permission. Because of the potential impact of interruption/discontinuation of study drugs on CNI levels investigators should contact the SDP when an interruption/discontinuation is anticipated or required by protocol to ensure that a plan for appropriate CNI dose modification is in place. If the findings of the liver biopsy are not consistent with rejection or if the clinical suspicion of rejection is low or the liver biopsy results are pending and the subject experiences an ALT level 5 ULN that is 2 Baseline, confirmatory testing should be performed. If the ALT level is confirmed 5 ULN and 2 Baseline and the HCV RNA is declining or is undetectable, then management should be per Table 7. If liver biopsy has not been performed, consideration should be made to performing a liver biopsy. If the investigator wishes to pursue alternative management of study drugs in the setting of ALT increases approval of the Study Designated Physician must first be obtained. 100

103 M Protocol Table 7. Management of Confirmed ALT Levels Greater than or Equal to 5 ULN and Greater than or Equal to 2 Baseline ALT 10 ULN or with symptoms and signs of hepatitis present ALT 5 ULN but < 10 ULN without symptoms or signs of hepatitis Note: Discontinue study drugs. If rejection has been ruled out or liver biopsy results are pending. Fill in hepatic questionnaire, update concomitant medications ecrf and obtain appropriate additional testing (e.g., liver biopsy, serology for hepatitis A, B, and E, urine for drug screen). Evaluation and management as medically appropriate. Continue study drugs if rejection is not suspected and repeat LFTs and INR within 3 days and as clinically indicated until resolution. If ALT values during follow-up are increased from the prior values or there is increasing INR, or symptoms/signs of hepatitis then interrupt study drugs and manage as appropriate. SDP approval is required to restart subject on study drugs. If results of the liver biopsy become available and are consistent with rejection, study drugs should be discontinued and appropriate management and monitoring per usual practice should be performed. Fill in hepatic questionnaire, update concomitant medications ecrf, and as appropriate consider obtaining additional testing (e.g., liver biopsy, serology for hepatitis A, B, and E, urine for drug screen) Creatinine Clearance Creatinine clearance (CrCl) will be calculated throughout the study using Cockcroft-Gault method. CrCl values will be provided to the investigators. For a confirmed CrCl < 50mL/min the following should be performed if indicated: (1) Obtain a urine sample for urinalysis and urine for albumin, and another urine specimen for archive. (2) Creatinine and chemistries should be repeated within 7 days and as clinically indicated until resolution. 101

104 M Protocol (3) Ribavirin dose should be adjusted per local label. Alternative management of RBV dose in the setting of reduced renal function will require approval of the AbbVie Study Designated Physician. (4) Concomitant medication dose reduction or discontinuation based on CrCL should be done, if applicable. (5) The Study Designated Physician should be contacted to discuss whether dose modification or drug substitution may be required for concomitant medications which may be impacted by the DAA regimen. If anti-hypertensive medications are adjusted, vital signs may be monitored to ensure appropriate blood pressure control. In addition, dose adjustment of cyclosporine or tacrolimus per the investigator's usual practice may be required. If CrCl does not improve by 2 scheduled study visits (2 CrCl values still < 50 ml/min) the SDP should be contacted to discuss further medical management, including management of study drugs. If the calculated CrCL is confirmed to be <40 ml/minute then study drugs should be discontinued and Study Designated Physician notified as well as capturing the event on an ecrf. If CrCl improves, consideration should be given to the readjustment of any dose modifications that have been made. The investigator should ensure that any concomitant medication changes, RBV dose reductions, and study drugs discontinuations, as well as consequent related adverse events are captured on an ecrf. 102

105 M Protocol 7.0 Protocol Deviations The investigator should not implement any deviation from the protocol without prior review and agreement by the Sponsor and in accordance with the Independent Ethics Committee (IEC)/Independent Review Board (IRB) and local regulations, except when necessary to eliminate an immediate hazard to study subjects. When a deviation from the protocol is deemed necessary for an individual subject, the investigator must contact the following AbbVie personnel: Primary Contact: Such contact must be made as soon as possible to permit a review by the Sponsor to determine the impact of the deviation on the subject and/or the study. Any significant protocol deviations affecting subject eligibility and/or safety must be reviewed and/or approved by the IEC/IRB and regulatory authorities, as applicable, prior to implementation. 8.0 Statistical Methods and Determination of Sample Size 8.1 Statistical and Analytical Plans There will be interim analyses after all subjects have completed treatment or prematurely discontinued study drugs, and after the last subject has reached Post-Treatment Week 12 or prematurely discontinued study. For each of these interim analyses, appropriate 103

106 M Protocol database clean up procedures will be performed. There will be no statistical adjustment employed due to these analyses as this is a single arm, open-label trial and no changes to the trial design will be made as a result of these analyses. SAS (SAS Institute, Inc., Cary, NC) for the UNIX operating system will be used for all analyses. All confidence intervals will be 2-sided with an α level of Descriptive statistics will be provided, such as the number of observations (N), mean, and standard deviation (SD) for continuous variables and counts and percentages for discrete variables. Efficacy, safety, and demographic analyses will be performed on the intent-to-treat (ITT) population defined as all enrolled subjects who receive at least one dose study drugs. No data will be imputed for any efficacy or safety analysis except for the PRO questionnaires and for analyses of the HCV RNA endpoints of RVR, EOTR, and all SVR endpoints. If a respondent answers at least 50% of the items in a multi-item scale of the SF-36v2, the missing items will be imputed with the average score of the answered items in the same scale. In cases where the respondent did not answer at least 50% of the items, the score for that domain will be considered missing. The Mental and Physical Component Summary measures will not be computed if any domain is missing. For the HCVPRO total score, if a respondent answers at least 12 of the 16 items, the missing items will be imputed with the average score of the answered items. In cases where the respondent did not answer five or more items, the total score will be considered missing. For EQ-5D-5L index and VAS scores, no imputation will be performed for missing items. HCV RNA values will be selected for the analyses of HCV RNA endpoints of RVR, EOTR, and all SVR endpoints based on the defined visit windows. When there is no HCV RNA value in a visit window based on defined visit windows, the closest values before and after the window, regardless of the value chosen for the subsequent and preceding window, will be used for the flanking imputation described below. For flanking imputation, if a subject has a missing HCV RNA value at a Post-Baseline Visit but with undetectable or unquantifiable HCV RNA levels at both the preceding 104

107 M Protocol value and succeeding value, the HCV RNA level will be considered undetectable or unquantifiable, respectively, at this visit for this subject. Subsequent to this flanking imputation, if a subject is missing a value for the visit window associated with the analysis, the subject will be imputed as a visit failure (i.e., not undetectable or unquantifiable) for analyses of RVR and EOTR. Following flanking imputation for SVR analyses (e.g., SVR 12, SVR 24 ), if there is no value in the appropriate window but there is an HCV RNA value after the window, then it will be imputed into the SVR window. Subsequent to this imputation, if a subject is missing a value for the window associated with the SVR analysis, the subject will be imputed as a failure (i.e., not undetectable or unquantifiable). Relapse is defined as confirmed HCV RNA LLOQ in the PTP for subjects with HCV RNA < LLOQ at Final Treatment Visit who complete treatment. If the last available post-treatment value is LLOQ, then the subject will be considered a relapse and will not require confirmation. Virologic failure during treatment includes subjects who fail to suppress at the end of treatment (HCV RNA LLOQ at Final Treatment Visit) or experience virologic breakthrough which is defined as confirmed HCV RNA LLOQ (defined as two consecutive HCV RNA measurements LLOQ) at any point during treatment after HCV RNA < LLOQ Demographics Demographics and baseline characteristics will be summarized for the ITT population. Demographics include age, weight, and BMI, and the frequency of gender, race and ethnicity. Baseline characteristics will include HCV genotype 1 subtype (1a, 1b, or other), IL28B genotype ([CC, CT, or TT] and [CC or non-cc]), baseline HCV RNA levels ([continuous] and [< 800,000 IU/mL or 800,000 IU/mL]), baseline IP-10 ([continuous] and [< 600 pg/ml or 600 pg/ml]), baseline HOMA-IR (< 3 mu mmol/l2 or 3 mu mmol/l2), and tobacco (user, ex-user, or non-user) 105

108 M Protocol and alcohol use (drinker, ex-drinker, or non-drinker) status. Summary statistics (N, mean, median, SD, and range) will be generated for continuous variables (e.g., age and BMI). The number and percentage of subjects will be presented for categorical variables (e.g., gender and race) Efficacy All efficacy analyses will be performed on the intent-to-treat (ITT) population, defined as all subjects who were enrolled and received at least one dose of study drugs Primary Efficacy Endpoint The primary efficacy endpoint is the percentage of subjects with SVR 12 (HCV RNA < LLOQ 12 weeks after the last actual dose of study drugs). The simple percentage of subjects with SVR 12 will be calculated and a 2-sided 95% confidence interval will be calculated using the normal approximation to the binomial Secondary Efficacy Endpoints The secondary efficacy endpoints are: 1) SVR 24 (HCV RNA < LLOQ 24 weeks after the last actual dose of study drugs), 2) virologic failure during treatment (defined as confirmed HCV RNA LLOQ after HCV RNA < LLOQ during treatment or HCV RNA LLOQ at the end of treatment) and 3) post-treatment relapse (defined as confirmed HCV RNA LLOQ between end of treatment and 12 weeks after the last dose of study drugs among subjects completing treatment and with HCV RNA < LLOQ at the end of treatment). The simple percentage of subjects with SVR 24, the simple percentage of subjects with virologic failure and the simple percentage of subjects with post-treatment relapse will be calculated and a corresponding 2-sided 95% confidence interval will be calculated using the normal approximation to the binomial. 106

109 M Protocol Subgroup Analysis The percentage (and 2-sided confidence intervals) of subjects with SVR 12 will be presented by the following subgroups: IL28B genotype (CC or non-cc), (CC, CT, or TT); HCV genotype 1 subtype (1a, 1b, other); Baseline HCV RNA level (< 800,000 IU/mL or 800,000 IU/mL); Baseline IP-10 (< 600 ng/ml or 600 ng/ml); Sex (Male versus female); Age (< 65 versus 65 years); Race (black versus non-black); Ethnicity (Hispanic versus none); Geographic Region (North America or Spain); BMI (< 30 or 30 kg/m 2 ); History of Diabetes (yes/no) Additional Efficacy Endpoints The following additional efficacy endpoints will be summarized and analyzed as specified. the percentage of subjects with RVR (HCV RNA < LLOQ at Week 4) the percentage of subjects with EOTR (HCV RNA < LLOQ at Week 24) the percentage of subjects with unquantifiable HCV RNA at each Post-Baseline Visit throughout the Treatment Period using only subjects with data in each visit window (i.e., no imputation for missing data); the percentage of subjects meeting each and any virologic failure criteria during treatment; 107

110 M Protocol the percentage of subjects with HCV RNA < LLOQ 4 weeks after the last actual dose of study drugs (SVR 4 ); the percentage of subjects with HCV RNA < LLOQ 12 weeks after the last planned dose of study drugs (SVR 12planned ); the percentage of subjects with HCV RNA < LLOQ 24 weeks after the last planned dose of study drugs (SVR 24planned ); the percentage of subjects who completed study drugs with HCV RNA < LLOQ at the Final Treatment Visit who subsequently relapse at any time post-treatment; time to suppression of HCV RNA during the Treatment Period; time to relapse at anytime post-treatment. The percentage of subjects with RVR, EOTR, SVR 4, SVR 12planned, and SVR 24planned, and relapse will be calculated as a simple percentage and 2-sided 95% confidence intervals will be calculated using the normal approximation to the binomial; missing data will be imputed as described in Section 8.1. All other endpoints will be presented using data as observed, i.e., not performing any missing data imputations. From HCV RNA levels, the time to suppression on treatment and time to relapse post-treatment will be calculated for each subject, and the median time will be estimated using Kaplan-Meier methodology for right censored observations Patient Reported Outcomes The following exploratory analyses of patient reported outcomes (PROs) will be performed: mean change from baseline in HCVPRO total score to each applicable post-baseline time point; mean change from baseline in EQ-5D-5L health index score and VAS score to each applicable post-baseline time point; 108

111 M Protocol mean change from baseline in the SF-36V2 Mental Component Summary (MCS) and Physical Component Summary (PCS) scores to each applicable post-baseline time point the percentage of subjects with no decrease from baseline in SF-36 MCS and PCS greater than or equal to the minimal clinically important difference (MCID); the percentage of subjects with no decrease from baseline in HCVPRO total score greater than or equal to the MCID; the percentage of subjects with no decrease from baseline in EQ-5D-5L health index score greater than or equal to the MCID. Summary statistics (n, mean, SD, median, minimum and maximum) at each visit and for change from baseline to each visit will be provided for the HCVPRO total score, the EQ-5D-5L health index and VAS scores, and the SF-36V2 PCS and MCS scores. For HCVPRO total score, a continuous plot will be provided with percent change from baseline to Final Treatment Visit on the horizontal axis and the cumulative percent of subjects experiencing up to that change on the vertical axis. In addition, the MCID for the SF-36V2 will be a decrease of 5 points from baseline to the Final Treatment Visit for both the MCS and PCS scores. The MCID during treatment will be calculated for the HCVPRO total score and the EQ-5D-5L health index using Receiver Operating Characteristic (ROC) curves with a change from Baseline to Final Treatment Visit of 5 points in the SF-36V2 PCS and MCS summary measures as anchors. The percentage of subjects with a change from Baseline to Final Treatment Visit in each of these measures > the appropriate MCID will be calculated. Additional analyses of PROs will be performed as useful and appropriate. 109

112 M Protocol Resistance Analyses The genes of interest for sequencing in this study are those encoding NS3 protease domain (amino acids 1 181), NS5A domain 1 (amino acids 1 215), and NS5B amino acids Only samples with an HCV RNA level of 1000 IU/mL will undergo sequence analysis in order to allow accurate assessment of products of amplification. Therefore, if the HCV RNA level at the time of virologic failure is < 1000 IU/mL, the sample closest in time after the failure with an HCV RNA level 1000 IU/mL will be used. The following resistance variables will be summarized for all subjects who experience virologic failure and who have resistance data available: The variants at each amino acid position (1) by nucleotide population sequencing at baseline compared to the prototypic reference sequence, and (2) by nucleotide population and/or clonal sequencing for each post-baseline time point that is analyzed compared to baseline and prototypic reference sequences. For those subjects with virologic failure, their baseline HCV amino acid sequence as determined by population nucleotide sequencing will be compared to the appropriate prototypic reference amino acid sequence for each target. A listing by subject of all variants at baseline relative to the prototypic reference amino acid sequence will be provided for each DAA target (NS3, NS5A, and NS5B). For those subjects with virologic failure, the HCV amino acid sequence at each timepoint as determined by population sequencing will be compared with the baseline and appropriate prototypic reference amino acid sequences. A listing by subject of all variants relative to the baseline and appropriate prototypic reference amino acid sequence will be provided for each DAA target (NS3, NS5A, and NS5B). For each DAA target, resistance-associated signature amino acid variants will be identified by AbbVie Clinical Virology. 110

113 M Protocol Clonal sequencing will be performed at the time of virologic failure only if no variants are detected at signature resistance-associated amino acid positions by population sequencing. For the subset of these subjects for whom clonal sequencing is performed, the amino acid variants determined by clonal sequencing will be summarized by counting the number of clones whose amino acid sequence does not match that of the population baseline sequence at each visit and amino acid position, out of the total number of clones analyzed. For subjects who experience virologic failure, signature resistance-associated amino acid variants determined by population and/or clonal sequencing will be summarized for each drug target and subject. Two additional summaries (and accompanying listings) will be created for all subjects who experience virologic failure to assess the effects of amino acid substitutions based on population sequencing for each target gene on failure: 1) a summary of subjects who failed due to on-treatment virologic failure by treatment-emerged variants (single or double) at signature amino acid positions compared to baseline, 2) a summary of those who failed due to relapse by post-treatment emerged variants (single or double) at signature amino acid positions compared to baseline, and 3) the persistence of resistance-associated amino acid variants by a summary of subjects who failed by the substitutions at the time of failure and PT Week 24 and Week 48. A subject who experiences virologic failure will be considered to have emerged/enriched variants if at any time point after baseline a variant (that was not detected at baseline) is detectable by population sequencing, or alternatively if at any time point after baseline the increase from baseline in percentage of clones of any variant by clonal sequencing is greater than 20%. If there are at least 2 subjects with an emerged/enriched variant meeting this definition, then the number and percentage of subjects with emerged/enriched variants from baseline will be summarized by amino acid variant. A separate listing of all these subjects and the emerged variants will be provided Safety All subjects who receive at least one dose of study drugs will be included in the safety analyses. 111

114 M Protocol Adverse Events Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 16 Treatment-emergent events are defined as any event that begins or worsens in severity after initiation of study drugs through the last dose of study drugs. The number and percentage of subjects with treatment-emergent adverse events will be tabulated by primary MedDRA System Organ Class (SOC) and preferred term. The tabulation of the number of subjects with treatment-emergent adverse events also will be provided with further breakdown by severity rating and relationship to study drugs. Subjects reporting more than one adverse event for a given MedDRA preferred term will be counted only once for that term using the most severe incident for the severity rating table and the most related for the relationship to study drugs table. Subjects reporting more than one type of event within a SOC will be counted only once for that SOC. Additional analyses will be performed if useful and appropriate Clinical Laboratory Data Clinical laboratory tests will be summarized at each visit during the Treatment Period. The baseline value will be the last measurement prior to the initial dose of study drugs. Mean changes from Baseline to each treatment and post-treatment visit will be summarized. Laboratory data values will be categorized as low, normal, or high based on reference ranges of the laboratory used in this study. The number and percent of subjects who experience post-baseline shifts in clinical laboratory values from low/normal to high and high/normal to low based on the normal range will be summarized. In addition, the number and percentage of subjects with post-baseline values meeting pre-specified criteria for Potentially Clinically Significant (PCS) laboratory values will be summarized. 112

115 M Protocol Additional analyses will be performed if useful and appropriate Vital Signs Data Vital sign measurements will be summarized at each visit during the TP, mean changes in temperature, systolic and diastolic blood pressure, pulse, and weight from Baseline to each treatment and post-treatment visit will be summarized descriptively. The baseline value will be the last measurement prior to the initial dose of study drugs. Frequencies and percentages of subjects with post-baseline values meeting pre-defined criteria for PCS vital sign values will also be summarized Pharmacokinetic and Exposure-Response Analyses Plasma concentrations of ABT-450, possible ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ritonavir and ribavirin will be tabulated for each subject and group. Blood concentrations of cyclosporine and tacrolimus will be tabulated for each subject and group. Summary statistics will be computed for each time and visit. Plasma concentration data from this study may be combined with data from other studies and analyzed using the following general methodology. Population pharmacokinetic analyses will be performed using the actual sampling time relative to dosing. Pharmacokinetic models will be built using a non-linear mixed-effect modeling approach with the NONMEM software (version VI, or higher version). The structure of the starting pharmacokinetic model will be based on the pharmacokinetic analysis of data from previous studies. Apparent oral clearance (CL/F) and apparent volume of distribution (V/F) of the PK analytes will be the pharmacokinetic parameters of major interest in the NONMEM analyses. If necessary, other parameters, including the parameters describing absorption characteristics, may be fixed if useful in the analysis. The evaluation criteria described below will be used to examine the performance of different models. 113

116 M Protocol The objective function of the best model is significantly smaller than the alternative model(s). The observed and predicted concentrations from the preferred model are more randomly distributed across the line of unity (a straight line with zero intercept and a slope of one) than the alternative model(s). Visual inspection of model fits standard errors of model parameters and change in inter-subject and intra-subject error. Once an appropriate base pharmacokinetic model (including inter- and intra-subject error structure) is developed, empirical Bayesian estimates of individual model parameters will be calculated by the posterior conditional estimation technique using NONMEM. The relationship between these conditional estimates CL/F and V/F values with only potentially physiologically relevant or clinically meaningful covariates (such as subject age, sex, body weight, concomitant medications, laboratory markers of hepatic or renal function, etc.) will be explored using either stepwise forward selection method, or generalized additive method (GAM) or another suitable regression/smoothing method at a significance level of After identification of all relevant covariates, a stepwise backward elimination of covariates from the full model will be employed to evaluate the significance (at P < 0.005, corresponding to an increase in objective function > 7.88 for one degree of freedom) of each covariate in the full model. In general, all continuous covariates will be entered in the model, initially in a linear fashion, with continuous covariates centered around the median value. Linear or non-linear relationships of primary pharmacokinetic parameters with various covariates may also be explored. For example: TVCLi = + Theta(2) (Comedication [1,2, ] + Theta(3) (WTi-median value) + Theta(4) (AGEi - median value). Where TVCLi = Typical value of clearance for an individual i1, Theta(1) is the intercept and Theta(2) - (4) are regression parameters relating the fixed effects (weight and age centered on the median value) to clearance. 114

117 M Protocol Relationship between exposure and clinical observations (antiviral activity) will be explored. Exposure-response relationships for primary and secondary efficacy variables and/or some safety measures of interest may also be explored. The relationship between exposure (e.g., population pharmacokinetic model predicted concentrations over time or average concentrations or AUC or trough concentrations of the individual model-predicted pharmacokinetic profiles, or some other appropriate measure of exposure) and antiviral activity will be explored. Exposure response relationships will be explored using a semi-mechanistic viral dynamic model and/or logistic regression analyses. The viral dynamic model will account for target cell growth and death, infection of target cells, infected cell infection and death rate, production of virus by infected cells, and inhibition of production of virus by the various DAAs. Effect of ribavirin will be explored on infection of target cells by virus. Models will explore mutation of the wild type to single and/or double mutant species depending on the available clinical resistance data. Additional adjustments to the structural and error models will be made during model development as appropriate. Logistic regression analyses will explore the relationship between exposure and one or more virologic endpoints (e.g., RVR, EVR, SVR 4, SVR 12, relapse following end of treatment and breakthrough on treatment). Additionally, relationship between exposure and safety endpoints of interest may also be explored. 8.2 Determination of Sample Size It is planned to enroll 30 subjects to this study. With a sample size of 30 subjects and an observed SVR 12 rate of 80%, the 2-sided 95% confidence interval, using the normal approximation to the binomial, will be (65.7%, 94.3%) with a width of 28.6%. Subjects who do not have data at PTP Week 12 (after performing the described imputation) count 115

118 M Protocol as failures for SVR 12 so no adjustment for dropout is applicable. The 2-sided 95% confidence intervals using the normal approximation to the binomial for various SVR 12 rates, given a sample size of 30 are presented in Table 8. Table 8. 2-Sided 95% Confidence Intervals Using the Normal Approximation to the Binomial for SVR 12 Rates Observed SVR 12 Rate 2-Sided 95% CI N = 30 60% (42.5%, 77.5%) 70% (53.6%, 86.4%) 80% (65.7%, 94.3%) From the perspective of safety assessment, the probability that a given adverse event would not be observed in a group of 30 subjects is shown in the second column of Table 9 for various true population incidence rates. With 30 subjects, the probability is at least 96% to observe an adverse event with an incidence rate of 10% or higher. Table 9. Probability of Not Observing an Adverse Event or Lab Abnormality for Various True Incidence Rates True Incidence Rate Probability of Not Observing < < < Randomization Methods There is no randomization in this study. All enrolled subjects will receive ABT-450/r/ABT ABT-333 coadministered with RBV for 24 weeks. 116

119 M Protocol 9.0 Ethics 9.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, the Investigator's Brochure, the informed consent and all other forms of subject information related to the study (e.g., advertisements used to recruit subjects) and any other necessary documents be reviewed by an IEC/IRB. The IEC/IRB will review the ethical, scientific and medical appropriateness of the study before it is conducted. IEC/IRB approval of the protocol, informed consent and subject information and/or advertising, as relevant, will be obtained prior to the authorization of drug shipment to a study site. Any amendments to the protocol will require IEC/IRB approval prior to implementation of any changes made to the study design. The investigator will be required to submit, maintain and archive study essential documents according to International Conference on Harmonization (ICH) GCP. Any serious adverse events that meet the reporting criteria, as dictated by local regulations, will be reported to both responsible Ethics Committees and Regulatory Agencies, as required by local regulations. During the conduct of the study, the investigator should promptly provide written reports (e.g., ICH Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB of any changes that affect the conduct of the study and/or increase the risk to subjects. Written documentation of the submission to the IEC/IRB should also be provided to the Sponsor. 9.2 Ethical Conduct of the Study The study will be conducted in accordance with the protocol, ICH guidelines, applicable regulations and guidelines governing clinical study conduct and the ethical principles that have their origin in the Declaration of Helsinki. Responsibilities of the clinical investigator are specified in Appendix A. 117

120 M Protocol 9.3 Subject Information and Consent The investigator or his/her representative will explain the nature of the study to the subject, and answer all questions regarding this study. Prior to any study-related screening procedures being performed on the subject, the informed consent statement will be reviewed and signed and dated by the subject, the person who administered the informed consent, and any other signatories according to local requirements. A copy of the informed consent form will be given to the subject and the original will be placed in the subject's medical record. An entry must also be made in the subject's dated source documents to confirm that informed consent was obtained prior to any study-related procedures and that the subject received a signed copy. IL28B genotypes will be determined for each subject. Consent for determination of IL28B status will be included in the study informed consent. Additional pharmacogenetic analysis, other than IL28B analysis will only be performed if the subject has voluntarily signed and dated the IEC/IRB approved pharmacogenetic and informed consents, after the nature of the testing has been explained and the subject has had the opportunity to ask questions. The subject must provide consent specific to pharmacogenetic before the pharmacogenetic testing is performed. If the subject does not consent to the additional pharmacogenetic testing it will not impact the subject's participation in the study Source Documents and Case Report Form Completion 10.1 Source Documents Source documents are defined as original documents, data and records. This may include hospital records, clinical and office charts, laboratory data/information, subjects' diaries or evaluation checklists, pharmacy dispensing and other records, recorded data from automated instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays. Data collected during this study must be recorded on the appropriate source documents. 118

121 M Protocol The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB review, and regulatory inspection(s), providing direct access to source data documents Case Report Forms Case report forms (CRF) must be completed for each subject screened/enrolled in this study. These forms will be used to transmit information collected during the study to the Sponsor and regulatory authorities, as applicable. The CRF data for this study are being collected with an EDC system called Rave provided by the technology vendor Medidata Solutions Incorporated, NY, USA. The EDC system and the study-specific electronic case report forms (ecrfs) will comply with Title 21 CFR Part 11. The documentation related to the validation of the EDC system is available through the vendor, Medidata, while the validation of the study-specific ecrfs will be conducted by the Sponsor and will be maintained in the Trial Master File at the Sponsor. The investigator will document subject data in his/her own subject files. These subject files will serve as source data for the study. All ecrf data required by this protocol will be recorded by investigative site personnel in the EDC system. All data entered into the ecrf will be supported by source documentation. The investigator or an authorized member of the investigator's staff will make any necessary corrections to the ecrf. All change information, including the date and person performing the corrections, will be available via the audit trail, which is part of the EDC system. For any correction, a reason for the alteration will be provided. The ecrfs will be reviewed periodically for completeness, legibility, and acceptability by the Sponsor personnel (or their representatives). The Sponsor (or their representatives) will also be allowed access to all source documents pertinent to the study in order to verify ecrf entries. The principal investigator will review the ecrfs for completeness and accuracy and provide his or her electronic signature and date to ecrfs as evidence thereof. Medidata will provide access to the EDC system for the duration of the trial through a password-protected method of internet access. Such access will be removed from 119

122 M Protocol investigator sites at the end of the site's participation in the study. Data from the EDC system will be archived on appropriate data media (CD-ROM, etc.) and provided to the investigator at that time as a durable record of the site's ecrf data. It will be possible for the investigator to make paper printouts from that media Data Quality Assurance Computer logic and manual checks will be created to identify items such as inconsistent study dates. Any necessary corrections will be made to the ecrf Use of Information Any pharmacogenetic research that may be done using DNA samples from this study will be experimental in nature and the results will not be suitable for clinical decision making or patient management. Hence, neither the investigator, the subject, nor the subject's physician (if different from the investigator) will be informed of individual subject pharmacogenetic results, should analyses be performed, nor will anyone not directly involved in this research. Correspondingly, genetic researchers will have no access to subject identifiers. Individual results will not be reported to anyone not directly involved in this research other than for regulatory purposes. Aggregate pharmacogenetic information from this study may be used in scientific publications or presented at medical conventions. Pharmacogenetic information will be published or presented only in a way that does not identify any individual subject Completion of the Study The investigator will conduct the study in compliance with the protocol and complete the study within the timeframe specified in the contract between the investigator and the Sponsor. Continuation of this study beyond this date must be mutually agreed upon in writing by both the investigator and the Sponsor. The investigator will provide a final report to the IEC/IRB following conclusion of the study, and will forward a copy of this report to the Sponsor or their representative. 120

123 M Protocol The investigator must retain any records related to the study according to local requirements. If the investigator is not able to retain the records, he/she must notify the Sponsor to arrange alternative archiving options. The Sponsor will select the signatory investigator from the investigators who participate in the study. Selection criteria for this investigator will include level of participation as well as significant knowledge of the clinical research, investigational drug and study protocol. The signatory investigator for the study will review and sign the final study report in accordance with the European Medicines Agency (EMA) Guidance on Investigator's Signature for Study Reports. The end-of-study is defined as the date of the last subject's last visit. 121

124 M Protocol 14.0 Investigator's Agreement 1. I have received and reviewed the investigator's Brochure for ABT-450, ABT-267, ABT-333 and the product labeling for ritonavir and RBV. 2. I have read this protocol and agree that the study is ethical. 3. I agree to conduct the study as outlined and in accordance with all applicable regulations and guidelines. 4. I agree to maintain the confidentiality of all information received or developed in connection with this protocol. 5. I agree that all electronic signatures will be considered the equivalent of a handwritten signature and will be legally binding. Protocol Title: Open-label, Single Arm, Phase 2 Study to Evaluate the Safety and Efficacy of the Combination of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered with Ribavirin (RBV) in Adult Liver Transplant Recipients with Genotype 1 Hepatitis C Virus (HCV) Infection Protocol Date: 12 November 2012 Signature of Principal Investigator Date Name of Principal Investigator (printed or typed) 122

125 M Protocol 15.0 Reference List 1. Wiesner RH, Sorrell M, Villamil F; International Liver Transplantation Society Expert Panel. Report of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C. Liver Transpl. 2003;9(11):S Berenguer M, Palau A, Aguilera V, et al. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation. Am J Transplant. 2008;8(3): Gane EJ, Roberts SK, Stedman CAM, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo controlled, dose-escalation trial. The Lancet. 2010;376 (9751a): Zeuzem S, Asselah T, Angus PW, et al. Strong antiviral activity and safety of IFN sparing treatment with the protease inhibitor BI , the HCV polymerase inhibitor BI and ribavirin in patients with chronic hepatitis C. Hepatology. 2010;52 (Suppl.):876A. 5. Lok AS, Gardiner DF, Lawitz E, et al. Combination therapy with BMS and BMS alone or with PegIFN and RBV results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders [Abstract]. Hepatology. 2010;52 (Suppl.):877A. 6. Gane EJ, Stedman CA, Hyland RH, et al. Once Daily PSI-7977 plus RBV: Pegylated interferon-alfa not required for Complete Rapid viral response in Treatment-naive Patients with HCV GT2 or GT3. 62 nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4 8, Abstract

126 M Protocol 7. Chayama K, Takahashi S, Kawakami Y, et al. Dual Oral Combination Therapy with the NS5A Inhibitor BMS and the NS3 Protease Inhibitor BMS Achieved 90% Sustained Virologic Response (SVR 12 ) in HCV Genotype 1b-Infected Null Responders. 62 nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4 8, Abstract LB INCIVEK (telaprevir) [package insert]. Vertex Pharmaceuticals Incorporated; Cambridge, MA. 9. Victrelis (boceprevir) [package insert]. Schering Corporation, a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 10. Kwo PY, Ghabril M, Lacerda M, et al. Use of telaprevir plus peg interferon/ribavirin for null responders post OLT with advanced fibrosis/cholestatic hepatitis C. Abstract 845 DDW May 19 22, 2012; San Diego, California. 11. Coilly A, Roche B, Botta-Fridlund D, et al. Efficacy and safety of protease inhibitors for severe hepatitis c recurrence after liver transplantation: a first multicentric experience. J Hepatol. 2012;vol. 56:S Coilly A, Furlan V, Roche B, et al. Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence. Antimicrob Agents Chemother. 2012;56(11): doi: /AAC Abbott. ABT-450 Investigator's Brochure Edition Abbott. ABT-267 Investigator's Brochure Edition Abbott. ABT-333 Investigator's Brochure Edition Medical Dictionary for Regulatory Activities (MedDRA), version

127 M Protocol Appendix A. Responsibilities of the Clinical Investigator Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site location. In signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is agreeing to the following: 1. Conducting the study in accordance with the relevant, current protocol, making changes in a protocol only after notifying AbbVie, except when necessary to protect the safety, rights or welfare of subjects. 2. Personally conducting or supervising the described investigation(s). 3. Informing all subjects, or persons used as controls, that the drugs are being used for investigational purposes and complying with the requirements relating to informed consent and ethics committees [e.g., independent ethics committee (IEC) or institutional review board (IRB)] review and approval of the protocol and amendments. 4. Reporting adverse experiences that occur in the course of the investigation(s) to AbbVie and the site director. 5. Reading the information in the Investigator's Brochure/safety material provided, including the instructions for use and the potential risks and side effects of the investigational product(s). 6. Informing all associates, colleagues, and employees assisting in the conduct of the study about their obligations in meeting the above commitments. 125

128 M Protocol 7. Maintaining adequate and accurate records of the conduct of the study, making those records available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, and retaining all study-related documents until notification from AbbVie. 8. Maintaining records demonstrating that an ethics committee reviewed and approved the initial clinical investigation and all amendments. 9. Reporting promptly, all changes in the research activity and all unanticipated problems involving risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, institution director) and/or directly to the ethics committees and AbbVie. 10. Following the protocol and not make any changes in the research without ethics committee approval, except where necessary to eliminate apparent immediate hazards to human subjects. 126

129 M Protocol Appendix B. List of Protocol Signatories Name Title Functional Area 127

130 M Protocol Appendix C. Clinical Toxicity Grades Clinical Toxicity Grades for HCV Studies 1,2 GRADE 1 TOXICITY GRADE 2 TOXICITY GRADE 3 TOXICITY GRADE 4 TOXICITY HEMATOLOGY ABSOLUTE NEUTROPHIL COUNT DECREASED < LLN 1500/mm 3 < LLN /L < /mm 3 < /L < /mm 3 < /L < 500/mm 3 < /L EOSINOPHIL COUNT INCREASED cells/mm cells/mm 3 > 5000 cells/mm 3 Hypereosinophilic HEMOGLOBIN DECREASED < LLN 10.0 g/dl < LLN 6.2 mmol/l < LLN 100 g/l < g/dl < mmol/l < g/L < g/dl < mmol/l < g/l < 6.5 g/dl < 4.0 mmol/l < 65 g/l INTERNATIONAL NORMALIZED RATIO (INR), INCREASED LYMPHOCYTE COUNT DECREASED PLATELETS DECREASED > ULN > ULN > 2 ULN < LLN 800/mm 3 < /mm 3 < mm 3 < LLN /L < /L < /L < LLN 75,000/mm 3 < 75,000 50,000/mm 3 < 50,000 < LLN /L < /L 25,000/mm 3 < /L < 200/mm 3 < /L < 25,000/mm 3 < /L PTT > ULN > ULN > 2 ULN WHITE BLOOD CELL < LLN 3000/mm 3 < /mm 3 < /mm 3 COUNT DECREASED < LLN /L < /L < /L < 1000/mm 3 < /L WHITE BLOOD CELL COUNT INCREASED 10,800 15,000 > 15,000 20,000 > 20,000 25,000 > 25,000 cells/mm 3 cells/mm 3 cells/mm 3 cells/mm 3 CHEMISTRIES ALBUMIN, SERUM, LOW < LLN 3 g/dl < LLN 30 g/l < 3 2 g/dl < g/l < 2 g/dl < 20 g/l BILIRUBIN, HIGH > ULN 1.5 ULN > ULN > ULN > 10.0 ULN BUN ULN > ULN > ULN > 10 ULN CALCIUM, SERUM LOW < LLN 8.0 mg/dl < LLN 2.0 mmol/l < mg/dl < mmol/l < mg/dl < mmol/l < 6.0 mg/dl < 1.5 mmol/l CALCIUM, SERUM HIGH > ULN 11.5 mg/dl > ULN 2.9 mmol/l > mg/dl > mmol/l > mg/dl > mmol/l > 13.5 mg/dl > 3.4 mmol/l 128

131 M Protocol CHEMISTRIES (continued) CALIUM, IONIZED, LOW CALCIUM, IONIZED, HIGH CHOLESTEROL HIGH Clinical Toxicity Grades for HCV Studies 1,2 GRADE 1 TOXICITY GRADE 2 TOXICITY GRADE 3 TOXICITY GRADE 4 TOXICITY < LLN 1.0 mmol/l < mmol/l < mmol/l < 0.8 mmol/l > ULN 1.5 mmol/l > mmol/l > mmol/l > 1.8 mmol/l > ULN 300 mg/dl > ULN 7.75 mmol/l > mg/dl > mmol/l > mg/dl > mmol/l > 500 mg/dl > mmol/l CREATININE mg/dl mg/dl mg/dl > 2.5 mg/dl or requires dialysis GLUCOSE, SERUM, LOW GLUCOSE, SERUM, HIGH (Fasting) MAGNESIUM, SERUM, LOW MAGNESIUM, SERUM, HIGH PHOSPHATE, SERUM, LOW POTASSIUM, SERUM, LOW POTASSIUM, SERUM, HIGH PROTEIN, SERUM, LOW SODIUM, SERUM, LOW SODIUM, SERUM, HIGH TRIGLYCERIDES HIGH (Fasting) < LLN 55 mg/dl < LLN 3.0 mmol/l > ULN 160 mg/dl > ULN 8.9 mmol/l < LLN 1.2 mg/dl < LLN 0.5 mmol/l > ULN 3.0 mg/dl > ULN 1.23 mmol/l < LLN 2.5 mg/dl < LLN 0.8 mmol/l < mg/dl < mmol/l > mg/dl > mmol/l < mg/dl < mmol/l < mg/dl < mmol/l < mg/dl < mmol/l > mg/dl > mmol/l < mg/dl < mmol/l > mg/dl > mmol/l < mg/dl < mmol/l < 30 mg/dl < 1.7 mmol/l > 500 mg/dl > 27.8 mmol/l or acidosis < 0.7 mg/dl < 0.3 mmol/l > 8.0 mg/dl > 3.30 mmol/l < 1.0 mg/dl < 0.3 mmol/l < LLN 3.0 mmol/l < mmol/l < 2.5 mmol/l > ULN 5.5 mmol/l > mmol/l > mmol/l > 7.0 mmol/l g/dl < g/dl < 5.0 g/dl < LLN 130 mmol/l < mmol/l < 120 mmol/l > ULN 150 mmol/l > mmol/l > mmol/l mg/dl; mmol/l > mg/dl; > mmol/l Hospitalization may be indicated > mg/dl; > mmol/l > 160 mmol/l > 1000 mg/dl; > 11.4 mmol/l 129

132 M Protocol CHEMISTRIES (continued) URIC ACID, SERUM, HIGH ENZYMES Clinical Toxicity Grades for HCV Studies 1,2 GRADE 1 TOXICITY GRADE 2 TOXICITY GRADE 3 TOXICITY GRADE 4 TOXICITY mg/dl mg/dl mg/dl > 15.0 mg/dl ALT/SGPT > ULN 3.0 ULN > ULN; > ULN > 20.0 ULN AST/SGOT > ULN 3.0 ULN > ULN; > ULN > 20.0 ULN ALKALINE PHOSPHATASE > ULN 2.5 ULN > ULN > ULN > 20.0 ULN AMYLASE > ULN 1.5 ULN ULN > ULN > 5.0 ULN LIPASE > ULN 1.5 ULN > ULN > ULN > 5.0 ULN 1. Adapted from the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.0 (CTCAE). 2. Used for all HCV development compounds. 130

133 Document Approval Study M Open-label, Single Arm, Phase 2 Study to Evaluate the Safety and Efficacy of the Combination of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered with Ribavirin (RBV) in Adult Liver Transplant Recipients with Genotype 1 Hepatitis C Virus (HCV) Infection - EudraCT Nov2012 Version: 1.0 Date: 13-Nov :13:44 PM Abbott ID: F9F68028C85A en Signed by: Date: Meaning Of Signature:

134 M Protocol Amendment Title Page Clinical Study Protocol M Open-label, Single Arm, Phase 2 Study to Evaluate the Safety and Efficacy of the Combination of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered with Ribavirin (RBV) in Adult Liver Transplant Recipients with Genotype 1 Hepatitis C Virus (HCV) Infection AbbVie Investigational Product: Incorporating Amendments 1 and 2 Date: 08 April 2013 Development Phase: 2 Study Design: EudraCT Number: Investigator: Sponsor: Sponsor/Emergency Contact: ABT-450/Ritonavir/ABT-267, ABT-333 This is an open-label, single arm, combination drug study. Multicenter. Investigator information is on file at AbbVie. AbbVie* Eoin Coakley, MD Associate Medical Director Phone: Fax: Mobile: ( This study will be conducted in compliance with the protocol, Good Clinical Practice and all other applicable regulatory requirements, including the archiving of essential documents. *The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial Application with the Competent Authority. Confidential Information No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie. 1

135 M Protocol Amendment Protocol Amendment: Summary of Changes The purpose of this amendment is to: Prohibit the use of hormonal contraceptives during study drug administration. Rationale: Hormonal contraceptives are not expected to be effective when dosed with the DAA regimen and may be associated with an increased risk for ALT elevation. An itemized list of all changes to the protocol under this amendment can be found in Appendix D. 2

136 M Protocol Amendment Synopsis AbbVie Protocol Number: M Name of Study Drug: ABT-450, ritonavir, ABT-267, ABT-333 Name of Active Ingredient: ABT-450: (2R,6S,12Z,13aS,14aR,16aS)-N- (cyclopropylsulfonyl)-6-{[(5-methylpyrazin-2-yl) carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6- yloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16 atetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4] diazacyclopentadecine-14a(5h)-carboxamide hydrate ritonavir: [5S-(5R*,8R*,10R*,11R*)]-10- Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1- methylethyl)-4-thiazolyl]-3,6-dioxo-8,11- bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester ABT-267: Dimethyl ([(2S,5S)-1-(4- tertbutylphenyl)pyrrolidine-2,5-diyl]bis{benzene- 4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3- methyl-1-oxobutane-1,2-diyl]})biscarbamate hydrate ABT-333: (sodium N-{6-[3-tert-butyl-5-(2,4-dioxo- 3,4 dihydropyrimidin-1(2h)-yl)-2- methoxyphenyl]naphthalen-2-yl} methanesulfonamide hydrate) Protocol Title: Phase of Development: 2 Date of Protocol Synopsis: 08 April 2013 Open-label, Single Arm, Phase 2 Study to Evaluate the Safety and Efficacy of the Combination of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered with Ribavirin (RBV) in Adult Liver Transplant Recipients with Genotype 1 Hepatitis C Virus (HCV) Infection Objectives: The primary objectives of this study are to assess the safety and efficacy (the percentage of subjects achieving a 12-week sustained virologic response, SVR 12 (HCV ribonucleic acid (RNA) < lower limit of quantification (LLOQ) 12 weeks following treatment) of coformulated ABT-450 with ritonavir (r) and ABT-267 (ABT-450/r/ABT-267) and ABT-333 coadministered with ribavirin (RBV) for 24 weeks in HCV genotype 1 infected adult liver transplant recipients with recurrent HCV genotype 1 infection. The secondary objectives of this study are to assess the percentage of subjects with virologic failure during treatment, and the percentage of subjects achieving a 24-week sustained virologic response, SVR 24 (HCV RNA < LLOQ 24 weeks following treatment), the percentage of subjects with relapse post-treatment. 3

137 M Protocol Amendment 2 Investigators: Multicenter trial: investigator information is on file at AbbVie. Study Sites: Approximately 10 sites. Study Population: Adults between the ages of 18 to 70 years of age, inclusive who are liver transplant recipients with recurrent HCV genotype 1 infection. Number of Subjects to be Enrolled: Approximately 30. Methodology: This is a Phase 2, multicenter study evaluating the safety and efficacy of the combination of direct acting antivirals (DAA) ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks in adult liver transplant recipients with recurrent HCV genotype 1 infection. Approximately 30 HCV genotype 1-infected treatment naïve or treatment experienced (conventional IFN or PegIFN with or without RBV prior to transplant) liver transplant recipients will enroll in this trial. Subjects will be enrolled into the study for a total of 72 weeks not including a 35-day Screening Period and a Study Treatment Lead-In Period up to 14 days prior to enrollment into the study. This study will consist of two periods, the Treatment Period (TP) and the Post-Treatment Period (PTP). After the Screening Period, subjects who meet the eligibility criteria will undergo a Study Treatment Lead-In Period which will occur up to 14 days but no less than 2 days prior to enrollment into the TP. During the Study Treatment Lead-In Period, subjects who have met enrollment criteria will return to the site for laboratory tests to measure the CNI trough level. This trough level will serve to confirm that the CNI dose is appropriate before commencing study drugs and will form the basis for CNI dose adjustment when the subject commences the DAA-RBV therapy. During the TP, patients will receive 24 weeks of ABT-450/r/ABT-267, ABT-333 and RBV. Visits will occur during the Treatment Period at Study Day 1, 3, 7, 10 (optional), and Weeks 2, 3, 4, 6, 8, 12, 16, 20, and 24. During PTP, visits will occur at Study Day 3, 7, 10 (optional), and Weeks 2, 3, 4, 8, 12, 24, 36 and 48. The safety data will be reviewed by the sponsor, as this is an open-label study and by an independent Data Monitoring Committee during the Treatment Period of the study. The following criteria will be considered evidence of virologic failure while the subject is on study drugs and these subjects will be discontinued from direct-acting antiviral agent (DAA) therapy: Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV RNA measurements of > 1 log 10 IU/mL above nadir) at any time point during treatment, Failure to achieve HCV RNA < LLOQ by Week 6; or Confirmed HCV RNA LLOQ (defined as 2 consecutive HCV RNA measurements LLOQ) at any point during treatment after HCV RNA < LLOQ. All subjects who receive at least one dose of DAAs will be monitored for up to 48 weeks following the last dose of DAA to monitor for the durability of viral response, safety and for the emergence and persistence of resistant viral variants in the Post-Treatment Period. 4

138 M Protocol Amendment 2 Diagnosis and Main Criteria for Inclusion/Exclusion: Main Inclusion: 1. Male or female between the ages of 18 and 70 years, inclusive, at time of enrollment. 2. Liver transplantation as a consequence of HCV infection no less than 12 months before the Screening Visit. 3. Must have a liver biopsy which shows evidence of fibrosis F2 (Metavir scale) and which is obtained within the 6 months prior to the screening period but not less than 9 months post transplant or during the Screening Period. 4. Screening laboratory result indicating HCV genotype 1 infection. 5. Currently taking an immunosuppressant regimen based on either tacrolimus or cyclosporine where doses of immunosuppressant drugs have not been increased over the 2 months prior to Screening and no new drugs have been added for at least 2 months before Screening. Corticosteroids such as prednisone or prednisolone are permitted as components of the immunosuppressant regimen providing the dose is not more than 5 mg/day. Main Exclusion: 1. Positive test result for Hepatitis B surface antigen (HBsAg) or anti-human Immunodeficiency virus antibody (HIV Ab). 2. Use of any medications listed below as well as those that are contraindicated for use with either ritonavir or RBV within 2 weeks prior to study drugs administration or 10 half-lives, whichever is longer, including but not limited to: Alfuzosin Amiodarone Astemizole Bepridil Bosentan Buprenorphine Clarithromycin Carbamazepine Cisapride Conivaptan Dronedarone Efavirenz Eleptriptan Eplerenone Ergot derivatives Fusidic Acid Gemfibrozil Itraconazole Ketoconazole Lovastatin Methadone Midazolam (oral) Mifepristone Modafinil Montelukast Nefazodone Phenobarbital Phenytoin Pimozide Pioglitazone Propafenone Quercetin * Use of hormonal contraceptives requires SDP approval. Quinidine Rivaroxaban Rifabutin Rifampin Rosiglitazone Salmeterol Simvastatin St. John's Wort Telithromycin Terfenadine Triazolam Trimethoprim Troglitazone Troleandomycin Voriconazole Hormonal contraceptives* 5

139 M Protocol Amendment 2 Diagnosis and Main Criteria for Inclusion/Exclusion (Continued): Main Exclusion (Continued): 3. Clinically significant abnormalities, other than HCV infection in a subject post transplant, based upon the results of a medical history, physical examination, vital signs, laboratory profile and a 12-lead electrocardiogram (ECG) that make the subject an unsuitable candidate for this study in the opinion of the investigator. 4. Recent (within 6 months prior to study drugs administration) history of drug or alcohol abuse that, in the opinion of the investigator, could preclude adherence to the protocol. 5. Previous use of any investigational or commercially available anti-hcv agent other than IFN-based therapy, i.e., conventional (c)ifn and/or pegylated (Peg) IFN, with or without RBV, including previous exposure to ABT-450, ABT-333 or ABT-267. Investigational Products: Doses: Mode of Administration: Duration of Treatment: ABT-450/r/ABT-267: coformulated 75 mg/50 mg/12.5 mg tablet ABT-333: 250 mg tablet Ribavirin: 200 mg tablet ABT-450/r/ABT-267: 150 mg/100 mg/25 mg QD ABT mg BID Ribavirin Per local label or Investigator Practice Oral Subjects will receive ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks. Criteria for Evaluation: Patient Reported Outcomes (PROs): The change in non-disease specific Health Related Quality of Life (HRQoL), HCV-specific function and wellbeing, and Health State Utility will be assessed using the short form 36 version 2 (SF-36 V2), the HCV Patient Reported Outcomes (HCVPRO) instrument, and the EuroQol EQ-5D-5L instrument including the integral visual analogue scale (VAS), respectively. Efficacy: Plasma HCV RNA (IU/mL) will be assessed at each Treatment and Post-Treatment Visit. Resistance: The following resistance information will be tabulated and summarized for subjects who experience virologic failure: the variants at each amino acid position at baseline identified by population nucleotide sequencing will be compared to the appropriate prototypic reference sequence, and the variants at the available post-baseline time points identified by population and/or clonal nucleotide sequencing will be compared to baseline and the appropriate prototypic reference sequences. 6

140 M Protocol Amendment 2 Criteria for Evaluation (Continued): Pharmacokinetic: Individual plasma concentrations of ABT-450, possible ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ritonavir and ribavirin will be tabulated and summarized. Individual blood concentrations of immunosuppressants, cyclosporine and tacrolimus will also be tabulated and summarized. Safety: Safety and tolerability will be assessed by monitoring adverse events, physical examinations, clinical laboratory tests, 12-Lead ECGs and vital signs. Statistical Methods: Efficacy: The primary endpoint is the percentage of subjects with SVR 12 (HCV RNA < LLOQ 12 weeks after the last actual dose of study drugs). The secondary objectives of this study are to assess is the percentage of subjects with SVR 24 (HCV RNA < LLOQ 24 weeks after the last actual dose of study drugs), the percentage of subjects with virologic failure during treatment, and the percentage of subjects with relapse post-treatment. For the primary and secondary endpoints, the simple percentage of subjects meeting the endpoint will be calculated and a 2-sided 95% binomial confidence interval using the normal approximation to the binomial will be computed. PROs: Exploratory analyses of the change in non-disease-specific HRQoL, HCV-specific function and wellbeing, and health state utility will be measured using the SF-36V2, HCVPRO, and EQ-5D-5L instruments, respectively. SF-36V2 and HCVPRO will be analyzed by their total/component scores, as appropriate. The EQ-5D-5L will be analyzed by utility score and by visual analogue scale (VAS) response. Change from baseline in the patient reported outcome (PRO) summary measures will be assessed. Resistance: For all subjects receiving study drug, the variants at each amino acid position at baseline identified by population nucleotide sequencing will be compared to the appropriate prototypic reference sequence. For subjects who experience virologic failure, the variants at available post-baseline time points identified by population and/or clonal nucleotide sequencing will be compared to baseline and the appropriate prototypic reference standard sequences. The most prevalent amino acid variants found by population sequencing and amino acid variants that emerge or become enriched in isolates from at least 2 subjects will be summarized and the persistence of viral resistance will be summarized. Pharmacokinetic: Plasma concentrations of ABT-450, possible ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ritonavir and ribavirin will be tabulated for each subject and group. Blood concentrations of cyclosporine and tacrolimus will be tabulated for each subject and group. Summary statistics will be computed for each time and visit. 7

141 M Protocol Amendment 2 Statistical Methods (Continued): Safety: The number and percentage of subjects reporting treatment-emergent adverse events will be tabulated by Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. Tabulations will also be provided in which the number of subjects reporting an adverse event (MedDRA preferred term) is presented by severity (mild, moderate, or severe) and relationship to study drugs. Change from baseline in laboratory tests and vital sign measurements to each time point of collection will be summarized. Laboratory test and vital sign values that are potentially clinically significant, according to predefined criteria, will be identified and the number and percentage of subjects with potentially clinically significant values will be calculated. Sample Size: It is planned to enroll 30 subjects to this study. With a sample size of 30 subjects and an observed SVR 12 rate of 80%, the 2-sided 95% confidence interval, using the normal approximation to the binomial, will be (65.7%, 94.3%) with a width of 28.6%. Subjects who do not have data at PTP Week 12 (after performing the described imputation) count as failures for SVR 12 so no adjustment for dropout is applicable. With 30 subjects, the probability is at least 96% to observe an adverse event with an incidence rate of 10% or higher. 8

142 M Protocol Amendment List of Abbreviations and Definition of Terms Abbreviations ABT-450/r/ABT-267 AE ALT ANC APRI aptt AARDEX AST BID BMI BUN CNI CRF CYP2C8 CYP3A DAA DNA EC ECG ecrf EDC EDTA EOT EOTR EU EQ-5D-5L FDA FSH GAM GCP GCSF ABT-450 with ritonavir and ABT-267 Adverse event Alanine aminotransferase Absolute neutrophil count Aspartate aminotransferase-to-platelet Ratio Index Activated partial thromboplastin time Advanced Analytical Research on Drug Exposure Aspartate aminotransferase Twice Daily Body mass index Blood urea nitrogen Calcineurin inhibitor Case report form Cytochrome P450 2C8 Cytochrome P450 3A Direct-acting antiviral agent Deoxyribonucleic acid Ethics Committee Electrocardiogram Electronic case report form Electronic data capture Edetic acid (ethylenediaminetetraacetic acid) End of treatment End of treatment response European Union EuroQol 5 Dimensions 5 Levels Health State Instrument US Food and Drug Administration Follicle stimulating hormone Generalized additive method Good Clinical Practice granulocyte colony stimulating factor 9

143 M Protocol Amendment 2 GGT Gamma-glutamyl transferase GLP Good Laboratory Practice HBsAg Hepatitis B surface antigen hcg Human Chorionic Gonadotropin HCV Hepatitis C virus HCV Ab Hepatitis C virus antibody HCVPRO Hepatitis C Virus Patient Reported Outcomes Instrument HEOR Health Economics and Outcomes Research Hemoglobin A1c Glycated hemoglobin HIV Ab Human immunodeficiency virus antibody HRQoL Health Related Quality of Life ICH International Conference on Harmonization IEC Independent ethics committee IFN Interferon IL28B Interleukin 28B IMP Investigational Medical Product INR International normalized ratio IP-10 Interferon gamma-induced protein 10 IRB Institutional Review Board IRT Interactive Response Technology IU International units LLN Lower limit of normal LLOD Lower limit of detection LLOQ Lower limit of quantification MID Minimal important difference MDRD Modification of Diet in Renal Disease MedDRA Medical Dictionary for Regulatory Activities MEMS Medication Event Monitoring System NS3A Nonstructural viral protein 3A NS4A Nonstructural viral protein 4A NS5A Nonstructural viral protein 5A NS5B Nonstructural viral protein 5B OATP1B1 Organic anion transporting polypeptide 1B1 OL Open-label 10

144 M Protocol Amendment 2 PCS PegIFN PG POR PRO PTP QD QTc QTcF r RBC RBV RNA RT-PCR RVR SAE SAS SDP SF-36V2 SGOT SGPT SUSAR SVR SVR 4 SVR 12 SVR 24 TP ULN VAS WBC Potentially clinically significant Pegylated-interferon alpha-2a or alpha-2b Pharmacogenetic Proof of Receipt Patient Reported Outcomes Post-Treatment Period Once daily QT interval corrected for heart rate QTc using Fridericia's correction formula Ritonavir Red blood cells Ribavirin Ribonucleic acid Reverse transcriptase PCR Rapid virologic response Serious adverse event Statistical Analysis System Study Designated Physician Short-Form 36 Version 2 health status survey Serum glutamic oxaloacetic transaminase Serum glutamic pyruvic transaminase Suspected Unexpected Serious Adverse Reaction Sustained virologic response Sustained virologic response 4 weeks post-dosing Sustained virologic response 12 weeks post-dosing Sustained virologic response 24 weeks post-dosing Treatment Period Upper limit of normal Visual analogue scale White blood cells 11

145 M Protocol Amendment 2 Definition of Terms Study Drugs Study Treatment Lead-In Period Study Day 1 Treatment Period (TP) Post-Treatment Period (PTP) ABT-450/r/ABT-267, ABT-333, RBV Maximum of 14 days and minimum of 2 days prior to Study Day 1 First day a subject takes study drugs Baseline/Study Day 1 through last dose of study drugs Day after the last dose of study drugs through Post-Treatment Week 48 or Post-Treatment Discontinuation Pharmacokinetic and Statistical Abbreviations AUC AUC 24 C max C trough t 1/2 T max Area under the plasma concentration-time curve Area under the plasma concentration-time curve from time zero to 24 hours Maximum observed plasma concentration Pre-dose trough plasma concentration Terminal phase elimination half-life Time to maximum observed plasma concentration 12

146 M Protocol Amendment Table of Contents 1.0 Title Page Protocol Amendment: Summary of Changes Synopsis List of Abbreviations and Definition of Terms Table of Contents Introduction Differences Statement Benefits and Risks Study Objectives Primary Objective Secondary Objectives Investigational Plan Overall Study Design and Plan: Description Screening Rescreening Study Treatment Lead-In Period Study Treatment Period (TP) Post-Treatment Period (PTP) Selection of Study Population Inclusion Criteria Exclusion Criteria Prior and Concomitant Therapy Prior HCV Therapy Concomitant Therapy Management of Tacrolimus or Cyclosporine Dosing Prohibited Therapy

147 M Protocol Amendment Efficacy, Pharmacokinetic, Pharmacogenetic and Safety Assessments/Variables Efficacy and Safety Measurements Assessed and Flow Chart Study Procedures Meals and Dietary Requirements Blood Samples for Pharmacogenetic Analysis Drug Concentration Measurements Collection of Samples for Analysis Handling/Processing of Samples Disposition of Samples Measurement Methods Efficacy Variables Primary Variable Secondary Variables Resistance Variables Safety Variables Pharmacokinetic Variables Pharmacogenetic Variables Removal of Subjects from Therapy or Assessment Discontinuation of Individual Subjects Virologic Failure Criteria Discontinuation of Entire Study Treatments Treatments Administered Identity of Investigational Products Packaging and Labeling Storage and Disposition of Study Drugs Assigning to Treatment Groups

148 M Protocol Amendment Selection and Timing of Dose for Each Subject Blinding Data Monitoring Committee (DMC) Treatment Compliance MEMS Caps Drug Accountability Discussion and Justification of Study Design Discussion of Study Design and Choice of Control Groups Appropriateness of Measurements Suitability of Subject Population Selection of Doses in the Study Adverse Events Definitions Adverse Event Serious Adverse Events Adverse Event Severity Relationship to Study drugs Adverse Event Collection Period Adverse Event Reporting Pregnancy Toxicity Management Grades 1 or 2 Laboratory Abnormalities and Mild or Moderate Adverse Events Grades 3 or 4 Laboratory Abnormalities and Severe or Serious Adverse Events Management of Decreases in Hemoglobin Management of Transaminase Elevations Creatinine Clearance

149 M Protocol Amendment Protocol Deviations Statistical Methods and Determination of Sample Size Statistical and Analytical Plans Demographics Efficacy Primary Efficacy Endpoint Secondary Efficacy Endpoints Subgroup Analysis Additional Efficacy Endpoints Patient Reported Outcomes Resistance Analyses Safety Adverse Events Clinical Laboratory Data Vital Signs Data Pharmacokinetic and Exposure-Response Analyses Determination of Sample Size Randomization Methods Ethics Independent Ethics Committee (IEC) or Institutional Review Board (IRB) Ethical Conduct of the Study Subject Information and Consent Source Documents and Case Report Form Completion Source Documents Case Report Forms Data Quality Assurance

150 M Protocol Amendment Use of Information Completion of the Study Investigator's Agreement Reference List List of Tables Table 1. Table 2. Medications Contraindicated for Use with the Study Regimen...41 Study Activities Treatment Period...52 Table 3. Study Activities Post-Treatment Period (PTP)...56 Table 4. Clinical Laboratory Tests...62 Table 5. Identity of Investigational Products...79 Table 6. Management of Hemoglobin Decreases Table 7. Table 8. Table 9. Management of Confirmed ALT Levels Greater than or Equal to 5 ULN and Greater than or Equal to 2 Baseline Sided 95% Confidence Intervals Using the Normal Approximation to the Binomial for SVR 12 Rates Probability of Not Observing an Adverse Event or Lab Abnormality for Various True Incidence Rates List of Figures Figure 1. Study Schematic...30 Figure 2. Schematic of Study Treatment Lead-In Period...34 Figure 3. Adverse Event Collection

151 M Protocol Amendment 2 List of Appendices Appendix A. Responsibilities of the Clinical Investigator Appendix B. List of Protocol Signatories Appendix C. Clinical Toxicity Grades Appendix D. Protocol Amendment: List of Changes

152 M Protocol Amendment Introduction End-stage liver disease secondary to chronic hepatitis C virus (HCV) is one of the most common indications for liver transplantation worldwide. 1 However HCV infection of the new graft occurs in almost all recipients, typically pursuing a more aggressive disease course than in other HCV infected populations. Graft cirrhosis occurs in 10% to 20% of recipients in as little as 5 years. In addition, more than 40% of those with cirrhosis develop complications within 1 year with less than 50% surviving a year after decompensation. The options for those with advancing disease of the transplanted liver may be limited and re-transplantation may not be an option for all patients. Several factors have been associated with the accelerated disease of the transplanted liver including being a female organ recipient, the presence of HCV subtype 1b, higher levels of fibrosis in the explanted liver, treatment of rejection with high dose steroids and the presence of IL28b ( ) non-cc genotype in both host and graft. Nonetheless, treatment induced clearance of HCV in the post transplant setting has been associated with improved 5-year survival and lower rates of progression to cirrhosis and graft decompensation. 2 When considering treatment of HCV post liver transplant there is a consensus that those with evidence of chronic HCV on a liver biopsy as evidenced by inflammation and/or fibrosis may be considered for a trial of pegylated interferon (pegifn) and ribavirin (RBV) therapy and those with fibrosis levels of F2 (Metavir) merit a trial of PegIFN-RBV therapy. However, treatment outcomes in the post transplant setting are not optimal. A pooled analysis of over 40 trials of RBV combined with either conventional (c)ifn or pegylated (Peg)IFN noted low sustained virologic response 24 weeks (SVR 24 ) rates (24% to 27%) and high discontinuation rates (24% to 26%). The overall low SVR rate in transplant recipients is in part because exposure to PegIFN/RBV is typically associated with significant treatment limiting toxicities, particularly anemia and other cytopenias. The high frequency of anemia is in part attributed to greater RBV exposures in this patient population. The calcineurin inhibitors 19

153 M Protocol Amendment 2 (CNIs) tacrolimus or cyclosporine, are widely used as immunosuppressants in liver transplant recipients but are typically associated with some degree of renal impairment. Such renal impairment may augment RBV exposures, potentiating the risk for anemia. Because of the high frequency of anemia with PegIFN/RBV therapy lower doses of RBV are typically used at the outset of therapy and the use of erythropoiesis stimulating agents and even transfusion to manage anemia are relatively common in liver transplant recipients. A recent advance in the treatment of those with HCV genotype 1 has been the availability of the HCV protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC). These direct-acting antiviral agents (DAA) must be used in combination with PegIFN with RBV for up to 48 weeks. However, they are not approved for use in the post transplant setting. Ultimately, it is anticipated that regimens combining multiple DAAs may be curative without the need for PegIFN/RBV. Exploratory studies in otherwise healthy individuals with HCV using such PegIFN/ RBV sparing combination regimens have been initiated, and promising short-term antiviral efficacy has been reported from IFN-free combinations (either with or without RBV) of an HCV protease inhibitor with a nucleoside polymerase inhibitor, 3 a nonnucleoside polymerase inhibitor, 4 and a nonstructural viral protein 5A (NS5A) inhibitor. 5 Additionally, studies evaluating the combination of a nonstructural protein 5B (NS5B) nucleotide polymerase inhibitor and RBV have been initiated. Sustained virologic response 12 weeks post-dosing (SVR 12 ) rates as high as 90% (9/10 subjects) have been observed in genotype 1b infection with an NS5A plus protease inhibitor combination and 100% (10/10 subjects) in genotype 2 or 3 infection with a nucleotide polymerase inhibitor plus RBV. 6,7 In the post transplant setting, the potential to add the DAA's TVR or BOC to PegIFN/RBV therapy is complicated by the potential for interaction with the CNIs, e.g., tacrolimus or cyclosporine. Tacrolimus and cyclosporine have their exposures considerably increased by these DAA's. Tacrolimus dose normalized exposures are increased by 70- and 17-fold, for TVR and BOC, respectively. 8,9 Cyclosporine dose 20

154 M Protocol Amendment 2 normalized exposures are increased by 4.6- and 2.7-fold, for TVR and BOC, respectively. 8,9 This interaction may be managed by monitoring CNI levels, which is the standard of care in this setting and provides a means of monitoring changes in CNI exposure in order to make appropriate dose adjustments. Currently, there are only limited preliminary data from small observational studies describing outcomes with the addition of one of the newly approved DAA's TVR or BOC to PegIFN-RBV therapy in liver transplant recipients Preliminary data presented by Kwo et al evaluated 7 subjects a median of 3.5 years post liver transplant. Each subject had a prior null response to PegIFN/RBV in the post transplant setting and had histologic fibrosis levels ranging 3 4 (Metavir). Subjects were scheduled to receive 48 weeks of PegIFN/RBV with 12 weeks of TVR. RBV doses at the start of therapy ranged 800 to 1000 mg/day. At the end of TVR dosing 5/7 subjects had HCV RNA < LOQ. All subjects also required further RBV dose reduction on study and transfusion and EPO use were common. All of these subjects were taking cyclosporine with mean dose reductions from 193 mg/kg at baseline to 68 mg/kg to the end of TVR dosing consistent with the observed interactions described above. AbbVie currently has a number of DAA compounds in clinical development: ABT-450 is a nonstructural protein 3/nonstructural protein 4A (NS3/NS4A) protease inhibitor, ABT-267 is a nonstructural viral protein 5A (NS5A) inhibitor and ABT-333 is a nonstructural viral protein 5b (NS5B) non-nucleoside polymerase inhibitor. These agents have the potential for coadministration in the treatment of HCV infection. This study is intended to examine the efficacy and safety of 24 weeks of treatment with ABT-450/r/ABT-267 with ABT-333 coadministered with RBV in treatment-naïve or treatment-experienced (standard IFN or PegIFN with or without RBV prior to transplant) adult liver transplant recipients with recurrent HCV genotype 1 infection. ABT-450 ABT-450, (2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-{[(5-methylpyrazin- 2-yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-yloxy)- 21

155 M Protocol Amendment 2 1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2- a][1,4]diazacyclopentadecine-14a(5h)-carboxamide hydrate, is a NS3 protease inhibitor with nanomolar potency against genotype 1 HCV in vitro. ABT-450 is metabolized primarily by cytochrome P450 3A4 (CYP3A) and thus is dosed with ritonavir, (the combination is denoted as ABT-450/r) a potent CYP3A inhibitor, in order to enhance exposures. ABT-450/r has a favorable safety, tolerability, and pharmacokinetic profile at doses administered to date and has shown potent antiviral activity at doses of 50/100 mg QD and greater in HCV genotype 1-infected subjects. Additional detailed information about preclinical toxicology, metabolism, pharmacology and clinical data can be found in the Investigator's Brochure for ABT ABT-267 ABT-267, dimethyl ([(2S,5S)-1-(4-tert-butylphenyl) pyrrolidine-2,5-diyl]bis{benzene4,1- diylcarbamoyl(2s)pyrrolidine-2,1-diyl[(2s)-3-methyl-1-oxobutane-1,2- diyl]})biscarbamate hydrate, is a novel NS5A inhibitor, with inhibitory concentrations in the picomolar range against genotypes 1a and 1b in subgenomic replicon systems. ABT-267 has a favorable safety, tolerability, and pharmacokinetic profile at all doses administered to date, and has shown substantial antiviral activity during 3 days of monotherapy in HCV genotype 1-infected subjects. Additional detailed information about preclinical toxicology, metabolism, pharmacology, and clinical data can be found in the Investigator's Brochure for ABT ABT-333 ABT-333, (sodium N-{6-[3-tert-butyl-5-(2,4-dioxo-3,4 dihydropyrimidin-1(2h)-yl)-2- methoxyphenyl]naphthalen-2-yl}methanesulfonamide), is a non-nucleoside NS5B polymerase inhibitor with inhibitory concentrations in the nanomolar range against genotypes 1a and 1b NS5B in subgenomic replicon systems. ABT-333 has been welltolerated in single and multiple dose studies in healthy volunteers, and when administered 22

156 M Protocol Amendment 2 to HCV-infected subjects at doses up to 800 mg twice daily (BID) for up to 12 weeks. The mean t 1/2 in healthy volunteers ranged from approximately 5 to 8 hours. ABT-333 has a favorable safety, tolerability, and pharmacokinetic profile at doses administered to date and has shown antiviral activity in HCV genotype 1-infected subjects at doses greater than 100 mg BID. Additional detailed information about preclinical toxicology, metabolism, pharmacology and clinical data can be found in the Investigator's Brochure for ABT Combination Dosing in HCV-Infected Subjects in Study M Study M is an ongoing multicenter, open-label Phase 2b study evaluating the antiviral activity, safety and pharmacokinetics of multiple ABT-450/r-based DAA combination regimens in HCV genotype 1-infected adults who are either treatment-naïve or are previous null responders to PegIFN and RBV. This study consists of 14 arms: 9 arms with planned enrollment of 440 treatment-naïve subjects and 5 arms with planned enrollment of 120 null responders. The primary and secondary efficacy endpoints compare the percentage of treatment-naïve subjects achieving a sustained virologic response at 24 weeks post-dosing (SVR 24 ) across the various regimens. Preliminary efficacy data suggest that all regimens demonstrate rapid suppression of HCV-1 RNA levels. All subjects in all 8- and 12-week treatment arms have completed study treatment and are in post-treatment follow-up. Among the treatment-naïve subjects, the SVR 12 rate in those treated with 4 drugs (ABT-450/r + ABT ABT-333 with RBV) for 12 weeks is 97.5% (77/79 subjects). The SVR 12 rates, although still high, are numerically lowest in the 8-week treatment group and the ABT-450/r + ABT-333 +RBV group at 88% (70/80) and 85% (35/41), respectively. The SVR 12 rates in the 12-week groups without ABT-333 and without RBV are 90% to 87%, respectively. Preliminary resistance testing in Study M suggests that in the majority of subjects who experienced virologic failure, viral mutations were selected in the target regions corresponding to the DAAs each subject was receiving with the exception of those treated 23

157 M Protocol Amendment 2 for 8 weeks, among whom most had populations at the time of relapse that were identical to their baseline sample. Preliminary safety analysis showed that all study drugs regimens were well-tolerated for up to 24 weeks in treatment-naïve and prior null responder subjects. Approximately 1.2% discontinued study drugs treatment due to adverse events. The majority of adverse events reported have been mild or moderate in severity, the most frequent including nausea, headache, fatigue, insomnia and diarrhea. Laboratory abnormalities included decreases in hemoglobin, most likely related to RBV, since mean decreases in hemoglobin from baseline to the end of treatment were greater in arms with RBV than in the arm without RBV ( g/dl versus 0.7 g/dl). Grade 3 (or higher) elevations of alanine aminotransferase (ALT) occurred in 5 subjects (all without bilirubin elevation) all of whom were asymptomatic; some of these elevations were seen in subjects taking concomitant hormonal contraceptives. In all 5 cases ALT normalized without intervention or study drugs modification or interruption. Four of these subjects were receiving ABT-450/r at a dosage of 200/100 mg which is greater than the planned ABT-450/r dose in the current study. The highest ALT level in Study M was 408 U/L. To date, the majority of subjects randomized to 24 weeks of treatment in Study M are still receiving study treatment. However, preliminary assessment of safety and efficacy suggest that these treatment regimens are comparable to the corresponding 12-week treatment regimens. Combination Dosing of DAAs with Immunosuppressive Agents Commonly Used in Liver Transplant Patients Phase 1, drug-drug interaction studies of AbbVie DAA combinations with immunosuppressive agents in healthy volunteers are currently ongoing. Available preliminary pharmacokinetic and safety data, to date, from these studies are summarized below. 24

158 M Protocol Amendment 2 Cyclosporine: The pharmacokinetics of a single 30 mg dose of cyclosporine in combination with ABT-450/r, ABT-267 and ABT-333, dosed to steady-state was compared to a single dose of 100 mg cyclosporine dosed alone in healthy individuals in the Study M Effect of ABT-450/r + ABT ABT-267 on Cyclosporine: Cyclosporine C max was not affected by DAA coadministration as dose normalized cyclosporine C max with and without DAAs were comparable. The dose-normalized AUC of cyclosporine, when coadministered with DAAs, was 5.8-fold of cyclosporine exposures when administered alone. Dose normalized C24 of cyclosporine, when coadministered with DAAs at steady-state, was 15.8-fold of the C24 of cyclosporine when administered alone. Cyclosporine T max was delayed by 3 to 4 hours when coadministered with DAAs and t 1/2 increased from 8 to 25 hours. Effect of Cyclosporine on ABT-450/r, ABT-333 and ABT-267: Single dose of cyclosporine did not affect steady state exposures (C max and AUC) of ritonavir and ABT-267; however, ABT-333 and ABT-333 M1 exposures slightly decreased ( 35%) and ABT-450 exposures increased by approximately 44% to 72%. On starting the study regimen the total daily cyclosporine dose should be reduced to one-fifth of the prestudy dose to achieve a C 24 (trough) equivalent to prestudy levels over the first week of the study. The adjusted cyclosporine dosing should be administered with food and with the morning dose of the study DAA-RBV regimen. Subsequent dose modifications will be further informed by the individual drug level data. At the beginning of Week 2 (Study Day 8), it is anticipated that a further dose reduction (by approximately half) may be needed. Thus, the total daily cyclosporine dose at the beginning of Week 2 may need to be reduced to half of the dose administered in Week 1. Cyclosporine trough levels are expected to stabilize from approximately Study Week 3 (Day 15 onwards). For the subjects whose cyclosporine trough levels do not stabilize after week 2, modifications in cyclosporine dosing or dose frequency while on DAAs will be guided by the scheduled 25

159 M Protocol Amendment 2 cyclosporine trough level testing. Also, at the investigators discretion extra blood draws for cyclosporine level testing may be performed at any time as unscheduled visits. Details of dose recommendation for cyclosporine and its concentration management when administered with DAAs are given in the Guidelines for Tacrolimus and Cyclosporine Management Document. Tacrolimus: The pharmacokinetics of a single dose of 0.5 mg tacrolimus co-dosed with 3 DAA combination, ABT-450/r + ABT ABT-267, each at steady-state was compared to a single 2 mg tacrolimus dosed alone in healthy subjects in Study M Below is the summary of the preliminary results from this drug-drug interaction study Effect of ABT-450/r + ABT ABT-333 on Tacrolimus: Dose normalized C max, AUC and C24 of tacrolimus, when coadministered with 3 DAAs (ABT-450/r + ABT ABT-267), was 3.9-fold, 57-fold and 16-fold that of tacrolimus exposures when administered alone, respectively. Tacrolimus T max was delayed by 3 hours and mean terminal phase elimination half-life (t 1/2 ) increased from 32 to 232 hours when coadministered with 3 DAAs. Effect of Tacrolimus on ABT-450/r + ABT ABT-333: A single dose of tacrolimus had minimal effect on DAA steady state exposures. ABT-267, ritonavir, ABT-333 and ABT-333 M1 exposures (C max, AUC and C trough ) were minimally affected when coadministered with tacrolimus ( 24% decrease). ABT-450 exposures (C max, AUC and C trough ) decreased by 27 to 43% when co-administered with tacrolimus. Based on the preliminary pharmacokinetic data from this study, an initial tacrolimus dose of 0.5 mg/week is recommended when coadministered with the study drugs under nonfasting conditions. It is anticipated that this will maintain the tacrolimus levels in the therapeutic range. Subsequent dosing and dose frequency modifications will be further informed by the individual drug level data. Also, at the investigators discretion extra blood draws for cyclosporine level testing may be performed at any time as 26

160 M Protocol Amendment 2 unscheduled visits. Details of dose recommendations for tacrolimus and its concentration management when administered with DAAs are given in the Guidelines for Tacrolimus and Cyclosporine Management Document and include recommendations for the use of tacrolimus in a setting where a lower dose formulation, i.e., 0.2 mg, is approved and available. For liver transplantation recipients with recurrent HCV, the low cure rates and high frequency of treatment limiting toxicities with PegIFN/RBV highlight the need for more efficacious, better tolerated therapies. This study proposes to explore the efficacy and safety of an IFN-free regimen of ABT-450/r/ABT-267 and ABT-333 combined with RBV for 24 weeks in those subjects at least 12 months post liver transplant on a stable cyclosporine or tacrolimus regimen. It is anticipated that this regimen will yield higher SVR rates than have been observed to date, with a lower frequency of adverse events. The study will be conducted with consideration for events of special interest in this unique patient population including the potential for alterations in tacrolimus or cyclosporine levels, RBV associated anemia, and tacrolimus or cyclosporine associated renal impairment as well as other standard safety assessments. Additional discussion and justification of study design may be found in Section Differences Statement The regimen planned for this study was evaluated in the Study M11-652, which is currently active and in which ABT-450/r, ABT-267 and ABT-333 are coadministered with RBV for as long as 24 weeks in treatment-naive and treatment-experienced subjects without cirrhosis. The proposed study, Study M12-999, will be the first study in which ABT-450/r/ABT-267 and ABT-333 coadministered with RBV will be evaluated in HCV infected adult liver transplant recipients. The DAA formulations used in this study also differ from those used in Study M11-652, see Section

161 M Protocol Amendment Benefits and Risks Study M is a single arm study in which an IFN-free regimen of three DAAs and RBV are coadministered for a period of 24 weeks. AbbVie is conducting several trials, which incorporate IFN-free regimens for up to 24 weeks treatment duration. In the largest of these trials, Study M11-652, which is ongoing, after 12 weeks of ABT-450/r, ABT-333, and ABT-267 coadministered with RBV in treatment-naïve noncirrhotic subjects, the SVR 12 rate was 97.5% (77/79 subjects). The treatment regimen in Study M was well-tolerated with few treatment discontinuations or adverse events. Details about the safety of the DAAs, including data from Study M are provided in the Investigator's Brochures for the individual DAAs. Adverse events that are known, and those not previously described, may occur with the DAAs or RBV as detailed in the ICF for this study. In addition, subjects may experience inconvenience or discomfort related to the study visits or study procedures. In the post liver transplant population the risks associated with ABT-450/r/ABT-267 and ABT-333 coadministered with RBV, including the risks of toxicity and virologic failure, are anticipated to be limited and manageable based on the results of ongoing trials. The potential for alterations in exposure to the CNIs, tacrolimus and cyclosporine, when DAA's are started during the Treatment Period and when study drugs are stopped will be mitigated by guided CNI dose reductions and frequent estimates for CNI levels throughout the study particularly within the first weeks of DAA exposure. A similar approach will be followed when DAAs are discontinued or interrupted. Given the potential high rate of cure in this population of HCV-infected subjects, the risk-benefit comparison is favorable. 28

162 M Protocol Amendment Study Objectives 4.1 Primary Objective The primary objectives of this study are to assess safety and efficacy (the percentage of subjects achieving a 12-week sustained virologic response, SVR 12 (HCV ribonucleic acid [RNA] < lower limit of quantification [LLOQ] 12 weeks following treatment) of coformulated ABT-450/r and ABT-267 (ABT-450/r/ABT-267) and ABT-333 coadministered with RBV for 24 weeks in HCV genotype 1-infected adult liver transplant recipients. 4.2 Secondary Objectives The secondary objectives of this study are to assess is the percentage of subjects with SVR 24 (HCV RNA < LLOQ 24 weeks after the last actual dose of study drugs), the percentage of subjects with virologic failure during treatment, and the percentage of subjects with relapse post-treatment. 5.0 Investigational Plan 5.1 Overall Study Design and Plan: Description This is a Phase 2, open-label, multi-center study evaluating the safety and efficacy of ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks in adult liver transplant recipients with recurrent HCV genotype 1 infection. Approximately 30 HCV genotype 1 infected treatment-naïve or treatment-experienced adults (standard IFN or PegIFN) with or without RBV prior to transplant) will be enrolled into the study at approximately 10 sites. The duration of the study for an individual subject will be up to 72 weeks (not including a screening period of up to 35 days duration and a Study Treatment Lead-In Period of up to 14 days duration). This study will consist of two parts: a 24-week Treatment Period (TP) and a 48-week Post-Treatment Period (PTP). During 29

163 M Protocol Amendment 2 the Screening Period, subjects will be evaluated for entrance criteria. If all entrance criteria are met, the subject may enter a Study Treatment Lead-In Period. Figure 1. Study Schematic During the Study Treatment Lead-In Period, subjects who have met enrollment criteria will return to the site for laboratory tests to measure the CNI trough level. This trough level will serve to confirm that in the investigators opinion the CNI dose is appropriate before commencing study drugs and will form the basis for CNI dose adjustment when the subject commences the DAA-RBV therapy. If the investigator considers that the CNI trough level is not within the appropriate range, then the investigator will adjust the CNI dose and if the subsequent CNI trough level, drawn at steady-state, is within the appropriate range the subject may enter the study. Further information regarding the Study Treatment Lead-In Period can be found in Section and is depicted in Figure 2. During the 24-week TP, all enrolled subjects will receive ABT-450/r/ABT /100/25 mg QD + ABT mg BID coadministered with RBV. RBV dosing will be weight based; however, in this special population with an increased risk of RBV associated anemia, RBV dosing may be managed at the discretion of the investigator. Upon completing the TP or at premature discontinuation of the TP, subjects will enter the 48-week PTP and be followed for safety, durability of viral response and emergence or persistence of resistance to DAAs. 30

164 M Protocol Amendment 2 Safety and efficacy evaluations will occur throughout the study. The safety data will be reviewed by the Sponsor, as this is an open-label study, and by an independent Data Monitoring Committee (DMC) during the Treatment Period of the study; see Section Virologic failure criteria, as detailed in Section , will be evaluated and applied by the investigator Screening At the Screening Visit, subjects who provide written (signed and dated) informed consent prior to any study specific procedures, will receive a unique subject number via Interactive Response Technology (IRT) system and will undergo the study procedures identified in Section associated with the Screening Visit. The investigator will evaluate whether the subject meets all of the eligibility criteria specified in Section and Section and record the details of the informed consent process and the results of the screening assessment and the details of the informed consent process in the subject's medical records. Eligible subjects have up to 35 days following the Screening Visit to enter the Study Treatment Lead-In Period. The study is designed to enroll 30 subjects to meet scientific and regulatory objectives without enrolling an undue number of subjects in alignment with ethical considerations. Therefore, if the target number of subjects has been enrolled, there is a possibility that additional subjects in screening will not be enrolled Rescreening Subjects may be rescreened only once as follows: Subjects who meet all eligibility criteria with the exception of one exclusionary laboratory parameter may rescreen once without prior AbbVie approval with the exception of an exclusionary genotype, a positive drug screen (without prescription for the positive drug or as noted below), or a positive HIV, HBV or a positive (not borderline) pregnancy test Subjects who 31

165 M Protocol Amendment 2 test positive at Screening for any of these parameters are not eligible to rescreen. Subjects who otherwise meet all eligibility criteria, but have a positive urine alcohol screen, may have only the urine drug screen repeated. If the repeat urine drug screen is negative (except for cases in which the screen is positive for a prescribed drug), the subject may be considered eligible. Subjects who otherwise meet all eligibility criteria, but have a creatinine clearance < 55 ml/min but 50mL/min (by Cockcroft-Gault) must have a repeat creatinine clearance 55mL/min on repeat to be eligible for enrollment. Subjects who have multiple exclusionary laboratory results require approval from the AbbVie Study Designated Physician prior to rescreening the subject. Subjects being rescreened because of an exclusionary laboratory parameter must be rescreened for all laboratory (excepting the tests listed above) and eligibility criteria, not just those that were exclusionary at the first screening attempt (with the exception of HCV genotype, HIV test and liver biopsy which do not need to be repeated). Subjects being rescreened because of a failure to establish appropriate CNI levels during the Lead-In Period (Lead-In Period failure) must be rescreened for all laboratory and eligibility criteria, not just those that were exclusionary at first screening attempt (with the exception of HCV genotype, HIV test and liver biopsy which do not need to be repeated). Screening liver biopsies will be read by a central pathologist. Subjects with biopsies determined to have a level of fibrosis > F2 by Metavir score will be excluded and may not rescreen. For subjects who do not meet the study eligibility criteria, the site personnel must register the subject as a screen failure in both the IRT and EDC systems. 32

166 M Protocol Amendment Study Treatment Lead-In Period Subjects who meet the study eligibility criteria will be able to enter the Study Treatment Lead-In Period which will last not more than 14 days before Study Day 1. On Study Day 14, subjects will have a tacrolimus or cyclosporine level measured. The blood sample will be drawn as a trough level, i.e., before the subject's next scheduled CNI dose. The date, time and dosage of the last CNI dose and the date and time of the sample collection will be recorded in the electronic case report form (ecrf). From this blood draw, samples will be submitted to both the central and local laboratories. The local laboratory CNI trough level will serve to confirm that the CNI dose is appropriate in the investigator's opinion prior to commencing study drugs and will form the basis for CNI dose adjustment when the subject commences study drugs. Subjects with a CNI trough level drawn at Study Day 14 that is considered by the investigator to be within the appropriate range may proceed directly to Study Day 1 of the TP. If the investigator considers that the CNI trough level is not within the appropriate range, then the investigator will adjust the CNI dose and a second CNI trough level will be drawn at steady-state, 7 days later for tacrolimus and 3 days later for cyclosporine, as shown in Figure 2. Subjects with a repeat CNI trough level drawn no later than 2 days before study entry (Study Day 2) which is considered by the investigator to be within the therapeutic range may proceed to Study Day 1 of the TP. If in the investigator's opinion the subject's repeat trough level at steady-state is not within an acceptable therapeutic range, the subject will be considered a lead-in failure and may not enter the study. Study treatment lead-in failures will be allowed to rescreen once using the procedure as outlined for rescreening subjects who had one exclusionary lab as outlined in Section , Rescreening. Refer to Figure 2 for more information. 33

167 M Protocol Amendment 2 Figure 2. Schematic of Study Treatment Lead-In Period Study Treatment Period (TP) Subjects with HCV genotype 1 who meet the eligibility criteria and who successfully complete the Study Treatment Lead-In Period will be enrolled via IRT into the study. The TP of the study consists of 24 weeks of open-label treatment with ABT-450/r/ABT ABT-333 coadministered with RBV. It is anticipated that each subject will begin the study appropriate dose of the CNI medication on Study Day 1 when the Study drug regimen is commenced at the site. However, at the investigator's discretion a subject may forego CNI dosing on Study Day 1 and/or the day preceding Study Day 1. If the investigator plans to start the adjusted CNI dose on Study Day1, i.e., when the first doses of the study drugs are to be taken, then the investigator should confirm that the subject has not already taken his/her regular (unadjusted) CNI dose that day. If the subject has taken his/her regular (unadjusted) CNI dose on Study Day 1 prior to receiving the first doses study drugs then the investigator should contact the study designated physician as the Day 1 dosing may need to be rescheduled. 34

168 M Protocol Amendment 2 The adjusted CNI dosing will begin on a day selected by the investigator when it should be administered with food and with the morning dose of the study DAA-RBV regimen. If the adjusted CNI dose is to start on Study Day 1 then consideration should be given to having the subject bring the study appropriate CNI dose to the site on Study Day 1. Any modifications in tacrolimus dose and/or dosing schedule during the study should be recorded on the ecrf. Subjects will receive instructions about the study drugs and the dosing schedule at the Day 1 Visit. The study drugs (ABT-450/r/ABT ABT-333 coadministered with RBV) will be dispensed during the TP as indicated in Table 2 during the study visits; sites should ensure that subjects adhere to the study visits. Subjects who cannot complete their study visit per the visit schedule should ensure they do not run out of study drugs prior to their next study visit. Compliance is critical to ensure adequate drug exposure. Investigators can choose to do additional unscheduled visits at any time for the management of CNI medications as described in Table 2 (refer to the Guidance for Tacrolimus and Cyclosporine Management Document and Section for CNI management). Following completion or discontinuation of study drug therapy, all subjects will enter the PTP Period consisting of 48 weeks of post-treatment follow-up. Subjects who prematurely discontinue from the TP should return for a Treatment Discontinuation Visit and undergo the study procedures as defined in Table 2 and as described in Section Ideally, this should occur on the day of study drug discontinuation, but is recommended to be no later than 2 days after their final dose of study drugs and prior to the initiation of any other anti-hcv therapy. The PTP will begin the first day after the last day of study drug dosing. Because of the potential impact of interruption/discontinuation of study drugs on CNI levels, investigators should contact the Study Designated Physician (SDP) when an interruption/discontinuation is anticipated or required by the protocol to ensure that a plan for appropriate CNI dose modification is in place. Similarly for those subjects 35

169 M Protocol Amendment 2 recommencing DAA's after an interruption the investigator should contact the SDP to ensure that a plan for appropriate CNI dose adjustment is in place. Refer to the Guidance for Tacrolimus and Cyclosporine Management Document and Section on the management of CNIs Post-Treatment Period (PTP) All subjects who receive at least one dose of study drugs will be monitored for HCV RNA, safety, PRO's and for the emergence and/or persistence of resistance-associated viral variants for an additional 48 weeks following the last dose of study drugs. Subjects will return to the study site as outlined in Table 3 for PTP procedures. The PTP will begin the day after the last dose of study drugs. Subjects who prematurely discontinue the PTP should return to the site for a PTP Discontinuation Visit as outlined in Table 3. Refer to the Guidelines for Tacrolimus and Cyclosporine Management Document and Section for further details on management of CNIs. Subjects who receive at least one dose of study drug and who do not achieve and maintain virologic suppression (HCV RNA < LLOQ), or who relapse post DAA therapy, may be offered another AbbVie-sponsored study. Subjects may also be offered another non-abbvie treatment as determined appropriate by the investigator. 5.2 Selection of Study Population HCV genotype 1-infected adult liver transplant recipients who are treatment-naïve, or treatment-experienced with conventional (c) IFN and/or PegIFN, with and without RBV treatment at any time prior to transplant, and who meet the inclusion criteria and who do not meet any of the exclusion criteria will be eligible for enrollment into the study upon successfully completing the Study Treatment Lead-In Period Inclusion Criteria 1. Male or female between 18 and 70 years of age, inclusive, at time of enrollment. 36

170 M Protocol Amendment 2 2. The subject is a recipient of a cadaveric or living donor liver transplant. 3. Liver transplantation as a consequence of HCV infection no less than 12 months before the Screening Visit. 4. Female who is: practicing total abstinence from sexual intercourse (minimum 1 complete menstrual cycle) sexually active with female partners only not of childbearing potential, defined as: postmenopausal for at least 2 years prior to screening (defined as amenorrheic for longer than 2 years, age appropriate, and confirmed by a follicle-stimulating hormone [FSH] level indicating a postmenopausal state), or surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy or hysterectomy) or has a vasectomized partner(s); of childbearing potential and sexually active with male partner(s): currently using at least one effective method of birth control at the time of screening and two effective methods of birth control while receiving study drugs (as outlined in the subject information and consent form or other subject information documents), starting with Study Day 1 and for 7 months after stopping study drug as directed by the local ribavirin label. (Note: Hormonal contraceptives, including oral, topical, injectable or implantable varieties, may not be used while receiving study drug treatment.) 5. Females must have negative results for pregnancy (hcg) tests (except for the circumstances outlined below regarding borderline pregnancy tests): at Screening by serum specimen obtained within 49 days prior to initial study drug administration, and at Baseline (prior to dosing) by urine specimen. 37

171 M Protocol Amendment 2 Female subjects with a borderline hcg at Screening and/or Day 1 may enroll into the study if they either: have a documented history of bilateral tubal ligation, hysterectomy, bilateral oophorectomy; or are confirmed to be postmenopausal defined as amenorrheic for longer than 2 years, age appropriate, and confirmed by a follicle-stimulating hormone [FSH] level indicating a postmenopausal state at Screening. 6. Sexually active males must be surgically sterile or have male partners only or if sexually active with female partner(s) of childbearing potential must agree to practice two effective forms of birth control as outlined in the subject information and consent form or other subject information documents throughout the course of the study, starting with Study Day 1 and for 7 months after stopping study drug or as directed by the local ribavirin label. (Note: Contraceptives containing ethinyl estradiol or depo-progesterone are considered effective if used by the female partners of male study subjects.) 7. Currently taking an immunosuppressant regimen based on either tacrolimus or cyclosporine where doses of immunosuppressant drugs have not been increased for at least 2 months before Screening and no new immunosuppressant drugs have been added for at least 2 months before Screening. Corticosteroids such as prednisone or prednisolone are permitted as components of the immunosuppressant regimen providing the dose is no more than 5 mg/day. 8. Subjects with liver transplantation as a consequence of hepatocellular carcinoma (HCC) in the setting of chronic HCV may be eligible if a. Prior to transplantation the HCC is not known to have ever exceeded the Milan Criteria including on the pathologic examination of the explanted liver (Milan Criteria defined as either a single HCC lesion 5 cm or up to three separate HCC lesions none larger than 3 cm, and with no evidence of gross vascular invasion, and no regional nodal or distant metastases) 38

172 M Protocol Amendment 2 and b. Post transplantation there is no evidence of recurrence of HCC 9. Screening laboratory result indicating HCV genotype 1 infection. 10. Subjects must be able to understand and adhere to the study visit schedule and all other protocol requirements. 11. Body Mass Index (BMI) is from 18 to < 38 kg/m 2 at the time of Screening. BMI is calculated as weight measured in kilograms (kg) divided by the square of height measured in meters (m). 12. Must voluntarily sign and date an informed consent form, approved by an Institutional Review Board/Ethics Committee (IRB/EC), prior to the initiation of any screening or study specific procedures. 13. Must have a liver biopsy which shows evidence of fibrosis F2 (Metavir scale) and which is obtained within the 6 months prior to the screening period but not less than 9 months post transplant or during the Screening Period. 14. Subject has plasma HCV RNA level > 10,000 IU/mL at Screening. 15. Subject has either never received treatment for HCV or if the subject has received treatment (s), it was limited to standard IFN and/or PegIFN with or without RBV at any time prior to liver transplantation. Rationale for Inclusion Criteria (1 3, 7 9, 11, 13 15) To select the appropriate subject population with sufficient disease severity for evaluation. (10) For the safety of study subjects. (4 6) RBV has known teratogenic effects. 39

173 M Protocol Amendment 2 (12) In accordance with harmonized Good Clinical Practice (GCP) Exclusion Criteria 1. History of severe, life-threatening or other significant sensitivity to any drug. 2. Use of any herbal supplements (including milk thistle) within the 2-week period prior to the first dose of study drugs. 3. Use of everolimus, sirolimus or azathioprine as part of the stable immunosuppressive regimen within three months of Screening. 4. Use of any medications listed in Table 1 as well as any other medications that are contraindicated for use with either ritonavir or RBV within 2 weeks prior to study drugs administration or 10 half-lives, whichever is longer, including but not limited to those medications listed in Table 1: 40

174 M Protocol Amendment 2 Table 1. Medications Contraindicated for Use with the Study Regimen Alfuzosin Gemfibrozil Amiodarone Itraconazole Astemizole Ketoconazole Bepridil Lovastatin Bosentan Methadone Buprenorphine Midazolam (oral) Clarithromycin Mifepristone Carbamazepine Modafinil Cisapride Montelukast Conivaptan Nefazodone Dronedarone Phenobarbital Efavirenz Phenytoin Eleptriptan Pimozide Eplerenone Pioglitazone Ergot derivatives Propafenone Fusidic Acid Quercetin * Use of hormonal contraceptives requires SDP approval. Quinidine Rivaroxaban Rifabutin Rifampin Rosiglitazone Salmeterol Simvastatin St. John's Wort Telithromycin Terfenadine Triazolam Trimethoprim Troglitazone Troleandomycin Voriconazole Hormonal contraceptives* Not all medications contraindicated with ritonavir or ribavirin are listed above. Refer to the most current package inserts or product labeling of ritonavir and ribavirin for a complete list of contraindicated medications. 5. Use of known strong inhibitors of cytochrome P450 3A (CYP3A), inhibitors of P450 2C8 (CYP2C8) cytochrome (e.g., gemfibrozil, montelukast) or inducers of CYP2C8 or CYP3A (e.g., phenobarbital, rifampin, carbamazepine, St. John's Wort) within 2 weeks prior to study drugs administration. 6. Females who are pregnant or plan to become pregnant, or breastfeeding, or males whose partners are pregnant or planning to become pregnant within 7 months (or per local RBV label) after their last dose of study drugs. 41

175 M Protocol Amendment 2 7. Recent (within 6 months prior to study drug administration) history of drug or alcohol abuse that, in the opinion of the investigator, could preclude adherence to the protocol. 8. Positive test result at screening for Hepatitis B surface antigen (HBsAg) or anti-human immunodeficiency virus antibody (HIV Ab). 9. History of re-transplantation of the liver or history of any other organ transplant in addition to transplantation of the liver. 10. Recipient of a liver transplant from a donor with known HIV infection, HBV surface antigen-positive and/or HCV antibody-positive test results. 11. Documented history of post transplant complications directly involving the hepatic vasculature, e.g., thrombosis of the portal vein, the hepatic artery and/or hepatic vein, which in the opinion of the investigator has not resolved at the time of Screening. 12. Documentation of gastro-esophageal varices, ascites and/or hepatic encephalopathy following liver transplantation. 13. HCV genotype performed during screening which indicates a mixed genotypic infection. 14. Positive result of a urine drug screen at the Screening Visit for opiates, methadone, barbiturates, amphetamines, cocaine, benzodiazepines, phencyclidine, propoxyphene, or alcohol, with the exception of a positive result associated with documented short-term use or chronic stable use of a prescribed medication in that class. Single positive results on urine screen for alcohol are discussed in Section on Rescreening. 42

176 M Protocol Amendment 2 Subjects with dietary habits that include food substances such as poppy seeds that may yield a positive test for opiates in urine should be advised to forego these foodstuffs for at least 3 days prior to screening since a positive test for opiates in the absence of relevant prescribed medication would be considered exclusionary. 15. Clinically significant abnormalities, other than HCV infection in a subject post liver transplant, based upon the results of a medical history, physical examination, vital signs, laboratory profile and a 12-lead electrocardiogram (ECG) that make the subject an unsuitable candidate for this study in the opinion of the investigator. 16. During the Screening Period, the subject is being investigated for a fever of unknown etiology or is being treated for an active infection (active or presumed) or is receiving secondary prophylaxis for an infection which occurred in the post transplant period. 17. Previous use of any investigational or commercially available anti-hcv agent other than IFN-based therapy (standard IFN and/or PegIFN), with or without RBV, including previous exposure to ABT-450, ABT-333 or ABT De novo HCV infection in the post transplant period. 19. History of steroid resistant rejection of the transplanted liver at any time in the post transplant period or a history of rejection (biopsy proven or presumed) treated with high dose steroids within 3 months of Screening. 20. History of uncontrolled seizures, uncontrolled diabetes as defined by a glycated hemoglobin (hemoglobin A1C) level > 8.0% at the Screening Visit, active or suspected malignancy or history of malignancy (other than basal cell skin cancer or cervical carcinoma in situ or hepatocellular carcinoma prior to transplant) in the past 5 years. 43

177 M Protocol Amendment Any cause of active liver disease in the post transplant period other than chronic HCV infection, nonalcoholic steatohepatitis and/or steatosis but including following: Hemochromatosis Alpha-1 antitrypsin deficiency Wilson's disease Autoimmune hepatitis Alcoholic liver disease Drug-related liver disease 22. Screening laboratory analyses showing any of the following abnormal laboratory results: ALT > 5 Upper limit of normal (ULN). AST > 5 ULN. Calculated creatinine clearance (using Cockcroft-Gault method) < 55 ml/min. Subjects with a calculated creatinine clearance 50 and less < 55 ml/min may be eligible. See Rescreening, Section Albumin < 3.3 g/dl. Prothrombin time/international normalized ration (INR) > 1.5. Subjects with a known inherited blood disorder and INR > 1.5 may be enrolled with permission of the AbbVie Study Designated Physician. Hemoglobin LLN. Platelets < 75,000 cells per mm 3. Absolute neutrophil count (ANC) < 1500 cells/µl or < 1200 cells/µl for subjects of African descent who are black. Total bilirubin 3.0 mg/dl. 44

178 M Protocol Amendment Clinically significant abnormal ECG, or ECG with QT interval corrected for heart rate (QTc) using Fridericia's correction formula (QTcF) > 460 msec at Screening or Study Day 1 (prior to dosing). 24. Receipt of any investigational product within a time period equal to 10 half-lives of the product, if known, or a minimum of 2 weeks prior to the Screening Period. 25. Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive ABT-267, ABT-333, ABT-450, ritonavir or RBV. 26. Current enrollment in another clinical study or previous enrollment in this study. (Subjects who previously participated in trials of investigational anti-hcv agents may be enrolled if they can produce documentation that they received only placebo.) Concurrent participation in a non-interventional, epidemiologic or registry trial may be permitted with approval by the AbbVie Study Designated Physician. Rationale for Exclusion Criteria (1, 6 7, 9, 14 15, 20, 22 23, 25) To ensure safety of the subjects throughout the study. (2 5, 24, 26) To avoid bias for the evaluation of efficacy and safety by concomitant use of other medications. (7, 11 13, 16 19) To avoid bias for the evaluation of efficacy and safety. (8, 10, 21) To exclude subjects with liver diseases other than HCV Prior and Concomitant Therapy Any medication or vaccine (including over-the-counter or prescription medicines, vitamins and/or herbal supplements) that the subject is receiving from the time of signing the consent through the Treatment Period of the study, must be recorded along with the reason for use, date(s) of administration including start and end dates, and dosage 45

179 M Protocol Amendment 2 information including dose, route and frequency. The investigator should review all concomitant medications for any potential interactions. After thirty days post-dosing, during the PTP, only antiviral therapies related to the treatment of HCV, immunosuppressant medications (i.e., tacrolimus and cyclosporine), and medications prescribed in association with an adverse event (AE) or serious adverse event (SAE) will be recorded in the electronic case report. The AbbVie study-designated physician should be contacted if there are any questions regarding concomitant or prior therapy(ies) Prior HCV Therapy Individuals may have received standard IFN and/or PegIFN with or without RBV as HCV therapy at any time prior to liver transplantation. Subjects who received treatment in the post transplant period with standard IFN or PegIFN, with or without RBV, will not be eligible. Prior or current use of any other investigational drug or commercially available anti-hcv drug such as the DAA's telaprevir or boceprevir, is exclusionary. Subjects who previously participated in trials of investigational anti-hcv agents may be enrolled if documentation can be provided that the subject received only placebo for the duration of the trial Concomitant Therapy Subjects must be able to safely discontinue any prohibited medications or herbal supplements within 2 weeks or within 10 half-lives of the respective medication/supplement, whichever is longer, prior to initial administration of study drugs and up to 2 weeks following discontinuation of study drugs. Subjects must be consented prior to discontinuing any prohibited medications or herbals supplements for the purpose of meeting study inclusion criteria. 46

180 M Protocol Amendment 2 The investigator should confirm that concomitant medications can be administered with DAAs, ritonavir and RBV. Some medications may require dose adjustments due to potential for drug-drug interactions. During the PTP, investigators should reassess concomitant medications and after 2 weeks in the PTP subjects may resume previously prohibited medications or revert to pre-study doses, if applicable with the exception of tacrolimus and cyclosporine which should be managed as per the Guidelines for Tacrolimus and Cyclosporine Management Document and Section , Management of Cyclosporine or Tacrolimus Dosing. Use of hematopoietic growth factors will be permitted during the study but usage must be recorded in the ecrf. Management of hematologic growth factor therapy is the responsibility of the investigator; growth factors will not be provided by the Sponsor, and the Sponsor will not reimburse for the expense of growth factors or their use. Investigators should refer to the package inserts for erythropoiesis stimulating agents for additional information regarding their use Management of Tacrolimus or Cyclosporine Dosing Drug-drug interaction studies of ABT-450/r, ABT-267 and ABT-333 coadministered with cyclosporine or tacrolimus have been conducted and detailed information about these studies can be found in the Introduction (Section 3.0). During the study, the dosing of tacrolimus and cyclosporine will be informed by the scheduled blood level testing. Further, tacrolimus and cyclosporine blood level testing may be performed at any time during the study at the investigator's discretion. Treatment Period Tacrolimus: Based on analysis of the preliminary pharmacokinetic data, tacrolimus dose adjustment will be necessary during coadministration of the DAAs. An initial tacrolimus dose of 0.5 mg/week is recommended from the time of starting the DAA regimen under nonfasting conditions. It is anticipated that this will maintain the tacrolimus levels within 47

181 M Protocol Amendment 2 the therapeutic range. Subsequent dosing and dose frequency modifications will be further informed by the individual drug level data. Dosing of tacrolimus in a setting where alternative tacrolimus formulations, e.g., 0.2 mg, are approved and available is discussed in the management guide. Cyclosporine: Based on analysis of the preliminary pharmacokinetic data cyclosporine dose adjustment will be necessary during coadministration of the DAAs. On Study Day 1 when the study drug regimen is started, it is recommended that the prestudy total daily cyclosporine dose should be reduced to one-fifth and that this will be taken as a single daily dose concurrently with the study DAA regimen and food. Consideration of a further reduction in cyclosporine dose at the beginning of Week 2 by approximately half again may be needed. Subsequent dosing and dose frequency modifications will be further informed by the individual drug level data. Cyclosporine trough levels are anticipated to stabilize at approximately Study Week 3 (Day 15 onwards). For subjects whose cyclosporine levels do not stabilize after week 2, modifications in cyclosporine dosing or dose frequency will be guided by the scheduled cyclosporine trough level testing and levels drawn at the investigators discretion. Given the potential impact of interrupting study drugs on CNI levels, if an interruption in study drugs is anticipated or required by the protocol, the investigator should contact the SDP to ensure that a plan is in place for appropriate CNI dose modification during the interruption. Similarly if study drugs are to be restarted after an interruption the investigator should contact the SDP to ensure that a plan is in place for appropriate CNI dose modification when study drugs are restarted. The study drug regimen should not be interrupted for more than 7 days. If study drugs need to be interrupted for more than 7 days, the Study Designated Physician should be contacted and consideration should be given to discontinue the subject. 48

182 M Protocol Amendment 2 Post-Treatment Period Tacrolimus Dosing in the Post-Treatment Period: Day 1 of the Post-Treatment Period: On Day 1 of the Post-Treatment Period, it is recommended that tacrolimus should not be taken by the subject. This is because the inhibitory effect of the study drug regimen on tacrolimus metabolism is still relevant to tacrolimus levels on Day 1 of the post-treatment phase. Day 2 of the Post-Treatment Period: On Day 2 of the Post-Treatment Period, the impact of the study drug regimen on tacrolimus metabolism is anticipated to have greatly reduced and it is suggested that the prestudy dose of tacrolimus can be resumed based on the trough levels. Further modifications in tacrolimus dosing or dose frequency will be guided by the scheduled tacrolimus trough level testing. Also, at the investigators discretion extra blood draws for tacrolimus level testing may be performed at any time as unscheduled visits. Cyclosporine Dosing in the Post-Treatment Period: Compared to tacrolimus, cyclosporine metabolism is less impacted by the inhibitory effect of DAA's. Therefore on Day 1 of the Post-Treatment Period, it is recommended that the prestudy dose of cyclosporine can be resumed. Further modifications in cyclosporine dosing or dose frequency will be guided by the scheduled cyclosporine trough level testing. Also, at the investigators discretion extra blood draws for cyclosporine level testing may be performed at any time as unscheduled visits. Further modifications in cyclosporine or tacrolimus dosing or dose frequency will be guided by the scheduled cyclosporine or tacrolimus trough level testing. Also, at the investigator's discretion extra blood draws for cyclosporine or tacrolimus level testing may be performed at any time as unscheduled visits. Details regarding dose recommendations for tacrolimus and cyclosporine and their concentration management during the study are given in the Guidelines for Tacrolimus 49

183 M Protocol Amendment 2 and Cyclosporine Management Document. Clinical experience suggests some differences may be observed between patients in relation to cyclosporine or tacrolimus dosing and associated trough levels. CNI dosing in the study will be guided by the recommended dose reductions which are based on healthy volunteer data and modeled to achieve troughs appropriate to the post transplant setting. In addition, it will also be guided by the frequent CNI trough level estimates particularly during the first weeks of study drugs and the investigators clinical experience in the management of these drugs in the post transplant setting. Blood Samples for the Management of Tacrolimus or Cyclosporine Blood samples for the management of concomitant medications related to liver transplant rejection (tacrolimus or cyclosporine) will be drawn at the investigative site per local standard practice. At minimum a sample should be drawn to measure the level of tacrolimus or cyclosporine during the Study Treatment Lead-In Period (no more than 14 days and no less than 2 days prior to Study Day 1) and during the study visits outlined in Table 2 and Table 3. At the investigator's discretion, an optional visit may be considered on Study Day 10 for management of immunosuppressant medications. Additional tacrolimus or cyclosporine trough samples may be drawn as unscheduled visits throughout the study as determined appropriate by the investigator. At a minimum, the site will collect the date, time, and dose of last CNI ingestion as well as the time and date of the blood sample collection. When a sample is drawn for the local lab using the criteria in Section 5.3.2, a parallel sample for the assay of tacrolimus or cyclosporine (and BUN and creatinine) should be drawn and sent to the Central Laboratory. Results from the local laboratory will be used for the medical management of the subject by the investigator. The local laboratory results and any changes in immunosuppressant medication will be entered into the ecrf. 50

184 M Protocol Amendment Prohibited Therapy Medications which are contraindicated with the study regimen are listed in Table 1. Investigators should also refer to the ritonavir and RBV labeling for lists of prohibited medications. In addition to the medications listed in Table 1, use of medications that are known strong inhibitors or inducers of CYP3A, or inhibitors and inducers of CYP2C8 are prohibited within 2 weeks prior to the initial dose of study drugs and until 2 weeks after the subject has completed study drugs in the Treatment Period. Hormonal contraceptives (including oral, topical, injectable or implantable varieties) may not be used from 2 weeks prior to the first dose of study drug until 2 weeks after the end of study drug dosing unless approved by the Study Designated Physician. Post-menopausal hormone replacement therapy may be used at the discretion of the Investigator. HCV medications other than those specified in the protocol will not be allowed during the Treatment Period of the study. 5.3 Efficacy, Pharmacokinetic, Pharmacogenetic and Safety Assessments/Variables Efficacy and Safety Measurements Assessed and Flow Chart 51

185 M Protocol Amendment 2 Table 2. Study Activities Treatment Period Activity Screening Study Treatment Lead-In Period ( 14 to 2 Days from Baseline) Day1/ Baseline a Study Day 3 (±1 day) Study Day 7 Optional b Study Day 10 (±2 days) Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24/ EOT/ Premature D/C from Treatment Unscheduled Visit for Management of CNI Meds Informed Consent X Provide RBV Medication Guides and Partner Risk Sheet c X Medical History d X X Physical Exam X X X X X X Vital Signs, Weight and Height X e X X X X X X X X X X X 12-Lead ECG X X X X Chemistry/Hematology/Urinalysis X X X X X X X X X X X X X X X f Sample for Cyclosporine or Tacrolimus Trough (Local and Central Lab) X X X X X X X X X X X X X X X Pharmacokinetic Samples X g X X X X X X X X X X X X X Pregnancy Test serum (s) urine (u) h X (s) X (u, s) X (u) X (u) X (u) X (u) X (u) X (u) FSH (females) i X HBsAg, Anti-HIV Ab and Anti-HCV Ab X 52

186 M Protocol Amendment 2 Table 2. Study Activities Treatment Period (Continued) Activity Screening Study Treatment Lead-In Period ( 14 to 2 Days from Baseline) Day1/ Baseline a Study Day 3 (±1 day) Study Day 7 Optional b Study Day 10 (±2 days) Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24/ EOT/ Premature D/C from Treatment Unscheduled Visit for Management of CNI Meds Drug/Alcohol Screen X Coagulation Panel X X X X X X X X X X X Hemoglobin A1C (diabetic patients only) HCV Genotype Liver Biopsy j Concomitant Medication Assessment X X X X X X X X X X X X X X X X X X Adverse Event Assessment X X X X X X X X X X X X X X Enrollment X Patient Reported Outcomes X X X X X Instruments (PROs) k Total Insulin X X X IL28B Pharmacogenetic Sample Optional Pharmacogenetic Sample l X X HCV RNA m X X X X X X X X X X X X X 53

187 M Protocol Amendment 2 Table 2. Study Activities Treatment Period (Continued) Activity Screening Study Treatment Lead-In Period ( 14 to 2 Days from Baseline) Day1/ Baseline a Study Day 3 (±1 day) Study Day 7 Optional b Study Day 10 (±2 days) Archive Plasma Sample X X X X X X X X X X X X X HCV Resistance Testing Sample X X X X X X X X X X X X IP 10 Sample X X X Study Drugs Dispensed X X X X X X Medication Event Monitoring System (MEMS) Cap Dispensed Study drugs Collected and Compliance Reviewed MEMS Cap Downloaded and Collected Wk = Week; EOT = End of treatment; D/C = Discontinuation a. All procedures will be performed prior to first dose. X Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24/ EOT/ Premature D/C from Treatment X X X X X X X X X X X X X X X X X X X b. An Optional Study Day 10 Visit may be done at the investigator's discretion for the management of concomitant immunosuppressant medications. c. Where applicable/locally available. d. Medical history will be updated at the Study Day 1 Visit. This updated medical history will serve as the Baseline for clinical assessment. e. Height will be measured at the Screening Visit only. Unscheduled Visit for Management of CNI Meds f. Unscheduled laboratory tests may be done at the investigator's discretion for the management of CNI and should include BUN and creatinine sent to the central laboratory. g. Intensive Pharmacokinetic Samples to be drawn prior to dosing and at 2 and 4 hours after DAA dosing on Study Day 1. 54

188 M Protocol Amendment 2 Table 2. Study Activities Treatment Period (Continued) h. Urine pregnancy testing is not required after the Day 1/Baseline Visit for female subjects with a documented history of bilateral tubal ligation, bilateral oophorectomy or hysterectomy or who are confirmed to be post-menopausal. i. FSH testing will be done as confirmation of post-menopausal status in women. j. For subjects who have not had a liver biopsy which was obtained within 6 months prior to the screening period but not less than 9 months post transplant. k. Short-Form 36 Version 2 health status survey (SF-36V2), EuroQol 5 Dimensions 5 Levels Health State Instrument (EQ-5D-5L), and Hepatitis C Virus Patient Reported Outcomes Instrument (HCVPRO), should be administered before any study procedures and in the order listed. l. If the optional Pharmacogenetic sample is not collected on Study Day 1, it may be collected at any other visit during the study. m. HCV RNA Samples to be drawn prior to dosing and at 2 and 4 hours after DAA dosing on Study Day 1. 55

189 M Protocol Amendment 2 Table 3. Study Activities Post-Treatment Period (PTP) Activity PTP Day 3 (± 1 Day) PTP Day 7 Optional a PTP Day 10 (±2 days) PTP Wk 2 PTP Wk 3 PTP Wk 4 PTP Wk 8 PTP Wk 12 PTP Wk 24 PTP Wk 36 Vital Signs and Weight X X X X X X X X X X X PTP Wk 48 or PT D/C Unscheduled Visit for Management of CNI Meds Chemistry/Hematology/Urinalysis X X X X X X X X Coagulation Panel X X X X X X X Cyclosporine or Tacrolimus trough X X X X X X X Monthly Pregnancy Test (females) b X X (Weeks 12, 16, 20, 24, 28) PRO Instruments c X X X X Concomitant Medication X X X X X X X X X X X X Assessment d Adverse Event Assessment e X X X X X X X X X X X X HCV RNA X X X X X X X X X HCV Resistance Samples X X X X X X X X X Archive Plasma Samples X X X X X X X X X IP-10 Sample X X Wk = Week; PTP D/C = Post-Treatment Period Discontinuation 56

190 M Protocol Amendment 2 Table 3. Study Activities Post-Treatment Period (PTP) (Continued) a. An Optional PTP Day 10 Visit may be done at the investigator's discretion for the management of concomitant immunosuppressant medications. b. Urine pregnancy testing is not required after Study Day 1 Visit for female subjects with a documented history of bilateral tubal ligation, hysterectomy, bilateral oophorectomy, or who are confirmed post-menopausal. At PTP Weeks 16, 20 and 28, subjects may have an unscheduled office visit for pregnancy testing or elect to perform the tests at home with test kits provided by the site. Additional testing may be required per local RBV label. c. Short-Form 36 Version 2 health status survey (SF-36V2), EuroQol 5 Dimensions 5 Levels Health State Instrument (EQ-5D-5L), and Hepatitis C Virus Patient Reported Outcomes Instrument (HCVPRO), should be administered before any study procedures and in the order listed. d. Only medications related to the treatment of HCV and medications prescribed in association with an SAE will be collected after 30 days post-dosing. e. Only SAEs will be collected after 30 days post-dosing. Note: Day 1 of the PTP is defined as the day after the last dose of study drugs. 57

191 M Protocol Amendment Study Procedures The study procedures outlined in Table 2 and Table 3 are discussed in detail in this section, with the exception of the assessment of concomitant medications (Section ), the management of tacrolimus and cyclosporine dosing (Section ), the collection of the IL28B sample (Section ), the optional sample for pharmacogenetic analysis (Section ), the collection of blood samples for pharmacokinetic analysis (Section 5.3.2), the use of MEMS caps and the monitoring of treatment compliance (Section 5.5.6) and the collection of adverse event information (Section 6.4). Informed Consent and RBV Information Signed study-specific informed consent will be obtained from the subject before any study procedures are performed. Details about how informed consent will be obtained and documented are provided in Section 9.3. Medical History A complete medical history, including date of transplant, type of donor (deceased or living), history of tobacco and alcohol use, will be taken from each subject during the Screening Visit. The subject's medical history will be updated at the Study Day 1 Visit. This updated medical history will serve as the baseline for clinical assessment. Concomitant Medication Assessment Use of medications (prescription or over-the-counter, including vitamins and herbal supplements) from 2 weeks prior to study drug administration through 30 days after last dose of study drug will be recorded in the ecrf at each study visit indicated in Table 2 and Table 3. Only medications associated with HCV treatment or a serious adverse event (SAE) and immunosuppressant medications (i.e., tacrolimus and cyclosporine) will be collected more than 30 days after the last dose of study drugs. 58

192 M Protocol Amendment 2 Physical Examination A complete physical examination will be performed at visits specified in Table 2 or upon subject discontinuation. A symptom-directed physical examination may be performed at any other visit, when necessary. The physical examination performed on Study Day 1 will serve as the baseline physical examination for clinical assessment. Any significant physical examination findings after the first dose will be recorded as adverse events. Vital Signs, Weight, Height Body temperature (oral), blood pressure, pulse and body weight will be measured at the visits specified in Table 2 and Table 3. The vital signs performed on Study Day 1 will serve as the baseline for clinical assessment. Blood pressure and pulse rate should be measured after the subject has been sitting for at least 3 minutes. The subject should wear lightweight clothing and no shoes during weighing. Height will only be measured at Screening; the subject will not wear shoes. 12-Lead Electrocardiogram A 12-lead resting ECG will be obtained at the visits specified in Table 2, or upon subject discontinuation (or as clinically needed). The Study Day 1 reading will serve as the baseline assessment. The ECGs will be evaluated by an appropriately trained physician at the site ("local reader"). The local reader from the site will sign, and date all ECG tracings and will provide his/her global interpretation as a written comment on the tracing using the following categories: Normal ECG Abnormal ECG not clinically significant Abnormal ECG clinically significant 59

193 M Protocol Amendment 2 Only the local reader's evaluation of the ECG will be collected and documented in the subject's source. The automatic machine reading (i.e., machine-generated measurements and interpretation that are automatically printed on the ECG tracing) will not be collected. The QT interval measurement (corrected by Fridericia formula, QTcF) will be documented in the ecrf only if the local reader's assessment is "prolonged QT." The original ECG tracing will be retained in the subject's records at the study site. Clinical Laboratory Tests Samples will be obtained at a minimum for the clinical laboratory tests outlined in Table 4 at the visits specified in Table 2 and Table 3. Blood samples for serum chemistry tests should ideally be collected following a minimum 8-hour fast (with the exception of the Screening Visit, which may be non-fasting). Subjects whose visits occur prior to the morning dose of study drugs should be instructed to fast after midnight. Subjects whose visits occur following the morning dose of study drugs should be instructed to fast after breakfast until the study visit occurs. Blood samples should still be drawn if the subject did not fast for at least 8 hours. Fasting status will be recorded in the source documents and on the laboratory requisition. The baseline laboratory test results for clinical assessment for a particular test will be defined as the last measurement prior to the initial dose of study drugs. Blood samples for tacrolimus or cyclosporine trough level estimation will be submitted for storage to the central laboratory. A second blood sample for tacrolimus and cyclosporine analysis will be sent to the local laboratory. At each blood draw, the date, time, and dosage of the last tacrolimus or cyclosporine dose as well as the date and time of the sample collection will be recorded in the electronic case report form (ecrf). Investigators will use the local laboratory results for management of tacrolimus or cyclosporine related adverse events or dose modifications during the study. Local results will be entered into the EDC system. 60

194 M Protocol Amendment 2 A central laboratory will be utilized to process and provide results for the clinical laboratory tests. Sites should refer to the laboratory manual provided by the central laboratory, the Sponsor, or its designee for instructions regarding the collection, processing, and shipping of all laboratory samples to the Central Laboratory. The certified laboratory chosen for this study is Covance. Depending on the location of the study site, samples will be sent to one of the following addresses: Local laboratory samples should be managed per standard medical practice for each institution. Depending on the location of the study site, samples will be sent to one of the following addresses: For sites in the USA: Covance For sites in Spain: Covance 61

195 M Protocol Amendment 2 Table 4. Clinical Laboratory Tests Hematology Clinical Chemistry Urinalysis Additional Tests Hematocrit Hemoglobin Red Blood Cell (RBC) count White Blood Cell (WBC) count Neutrophils Bands, if detected Lymphocytes Monocytes Basophils Eosinophils Platelet count (estimate not acceptable) ANC Prothrombin Time/INR Activated partial thromboplastin time (aptt) Reticulocyte count Blood Urea Nitrogen (BUN) a Creatinine a Total bilirubin Direct and indirect bilirubin Serum glutamic-pyruvic transaminase (SGPT/ALT) Serum glutamic-oxaloacetic transaminase (SGOT/AST) Alkaline phosphatase Sodium Potassium Calcium Inorganic phosphorus Uric acid Cholesterol Total protein Glucose Triglycerides Albumin Chloride Bicarbonate Magnesium Gamma-glutamyl transferase (GGT) Creatinine clearance (Cockcroft-Gault and MDRD calculations) Specific gravity Ketones ph Protein Blood Glucose Urobilinogen Bilirubin Leukocyte esterase Microscopic (reflex) Albumin i Urine Archive Specimen i HBsAg b Anti-HCV Ab b Anti-HIV Ab b FSH (all females) b Opiates b Barbiturates b Amphetamines b Cocaine b Benzodiazepines b Alcohol b Phencyclidine b Propoxyphene b Methadone b Urine and Serum Human Chorionic Gonadotropin (hcg) (females) c Total insulin d HCV RNA Hemoglobin A1C b,e IP-10 IL28B HCV genotype and subtype b Hepatitis A Antibody, Total f Hepatitis B Panel f Hepatitis E Virus IgG f Hepatitis E Virus IgM f Pharmacogenetic sample (optional) Tacrolimus level g Cyclosporine level h a. In addition to the Study Days outlined in Table 2 and Table 3, this is to be drawn at time of unscheduled visits for the management of CNIs. b. Performed only at Screening. c. Urine pregnancy testing is not required after Day 1 of the Treatment Period for female subjects who are confirmed to be post-menopausal or who have a documented history of prior bilateral tubal ligation, bilateral oophorectomy or hysterectomy. d. Performed on Day 1 (Treatment Period) only. e. Diabetic subjects only. f. May be performed as part of management of transaminase elevations. See Section 6.7.4, Management of Transaminase Elevations for details. g. For subjects taking tacrolimus only. h. For subjects taking cyclosporine only. i. Obtain if creatinine clearance level is confirmed < 50 ml/minute. See Section 6.7.5, Creatinine Clearance for details. 62

196 M Protocol Amendment 2 For any laboratory test value outside the reference range that the investigator considers clinically significant: The investigator will repeat the test to verify the out-of-range value. The investigator will follow the out-of-range value to a satisfactory clinical resolution. A laboratory test value that requires a subject to be discontinued from the study or study drugs or requires a subject to receive treatment to manage the laboratory value will be recorded as an adverse event. The management of laboratory abnormalities that may occur during the study are described in Section 6.7. Pregnancy Test A urine pregnancy test will be performed for all female subjects at all the visits specified in Table 2 and Table 3. In addition, a serum pregnancy test will be performed at Screening and Study Day 1 Visits and analyzed by the central laboratory. All urine pregnancy tests will be performed on-site during the study visit if there is a scheduled visit, as specified in Table 2 and Table 3, and monthly for a minimum of 7 months after the discontinuation of RBV, or according to the local RBV label and/or consistent with local treatment guidelines for RBV. Urine pregnancy tests are not required after Study Day 1 for female subjects with a documented history of bilateral tubal ligation, hysterectomy, bilateral oophorectomy, or for subjects who are confirmed to be postmenopausal. Confirmation of postmenopausal status measured by FSH will be obtained at the Screening Visit only. During the PTP where there is not a scheduled study visit, female subjects of childbearing potential may either have pregnancy testing performed at the site as an unscheduled study visit using an unscheduled test kit or a urine pregnancy test may be conducted by the subject at home with a pregnancy test kit provided by the site; site personnel should contact these female study subjects to capture the results of any study-related pregnancy 63

197 M Protocol Amendment 2 tests performed at home. The pregnancy test results will only be recorded in the subject's source records. If the subject elects to return to the study site for an unscheduled visit for pregnancy testing, the results of the urine pregnancy test will be recorded in the ecrf, unless serum pregnancy is elected. Serum pregnancy testing will be completed by the central laboratory and loaded into the clinical database. Hepatitis and HIV Screen HBsAg, anti-hcvab and anti-hiv Ab will be performed at Screening. The investigator must discuss any local reporting requirements to local health agencies with the subject. The site will report these results per local regulations, if necessary. The HBV HBsAg results will be reported by the central laboratory to the clinical database. Urine Screens for Drugs of Abuse Urine specimens will be tested at the Screening Visit for the presence of drugs of abuse. The panel for drugs of abuse will minimally include the drugs listed in Table 4. A positive screen is exclusionary, with the exception of a positive screen associated with documented short-term use or chronic stable use of a prescribed medication in that class (excluding methadone or buprenorphine). Subjects who otherwise meet all eligibility criteria, but have a positive urine alcohol screen, may have only the urine drug screen repeated. If the repeat urine drug screen is negative (except for cases in which the screen is positive for a prescribed drug), the subject may be considered eligible. Subjects with dietary habits that included food substances such as poppy seeds that may yield a positive test for opiates in urine should be advised to forego these foodstuffs since a positive test for opiates in the absence of relevant prescribed medication would be considered exclusionary. These analyses will be performed by the certified central laboratory chosen for the study. 64

198 M Protocol Amendment 2 HCV Genotype and Subtype Plasma samples for HCV genotype and subtype will be collected at the Screening Visit. Genotype and subtype will be assessed using the Versant HCV Genotype Inno-LiPA Assay, version 2.0 or higher (LiPA; Siemens Healthcare Diagnostics, Tarrytown, NY). Liver Biopsy Subjects who have not had a qualifying liver biopsy within the previous 6 months and at least 9 months post transplant but who otherwise meet all of the inclusion criteria and none of the exclusion criteria will undergo liver biopsy prior to enrollment. The subject will only be eligible if the biopsy performed within the previous 6 months or during the Screening Period shows evidence of evidence of fibrosis F2 (Metavir scale). This will be confirmed by the central pathology reader. HCV RNA Levels Plasma samples for HCV RNA levels will be collected as indicated in Table 2 and Table 3. Plasma HCV RNA levels will be determined for each sample collected by the central laboratory using the Roche COBAS TaqMan real-time reverse transcriptase-pcr (RT-PCR) assay v2.0. The lower limit of detection (LLOD) is 15 IU/mL and results below LLOD are reported as "HCV RNA not detected;" the LLOQ for this assay is 25 IU/mL and results below LLOQ but detectable are reported as "< 25 IU/mL HCV RNA detected." HCV Resistance Testing Sample A plasma sample for HCV resistance testing will be collected at the study visits, indicated in Table 2 and Table 3. Archive Plasma Sample Archive plasma samples will be collected at the study visits, indicated in Table 2 and Table 3. Archive plasma samples are being collected for possible additional analyses, including but not limited to, study drugs or metabolite measurements, viral load, 65

199 M Protocol Amendment 2 safety/efficacy assessments, HCV gene sequencing, HCV resistance testing, and other possible predictors of response, as determined by the Sponsor. Interferon Gamma-Induced Protein 10 (IP-10) Levels A plasma sample for IP-10 testing will be collected at the study visits indicated in Table 2 and Table 3. Patient Reported Outcomes (PRO) Instruments (Questionnaires) Subjects will complete the self-administered PRO instruments (where allowed per local regulatory guidelines) on the study days specified in Table 2 and Table 3. Subjects will be instructed to follow the instructions provided with each instrument and to provide the best possible response to each item. Site personnel shall not provide interpretation or assistance to subjects other than encouragement to complete the tasks. Subjects who are functionally unable to read any of the instruments may have site personnel read the questionnaires to them. Site personnel will encourage completion of each instrument at all visits and will ensure that a response is entered for all items. In this study, PRO instruments should be consistently presented so that subjects complete the SF-36V2 instrument first, the EQ-5D-5L, and finally the HCVPRO. PRO instruments should be completed prior to drug administration (on Day 1) and prior to any discussion of adverse events or any review of laboratory findings, including HCV RNA levels. HCV Patient Report Outcomes (HCVPRO) Instrument The HCVPRO has been developed specifically to capture the function and wellbeing impact of HCV conditions and treatment. The instrument has been preliminarily validated and further validation is ongoing. The HCVPRO contains 16 items important to HCV patients; items are totaled to a summary score. Higher HCVPRO score indicates a better state of health. Completion of the HCVPRO should require approximately 5 minutes. 66

200 M Protocol Amendment 2 EuroQol-5 Dimensions-5 Level (EQ-5D-5L) The EQ-5D-5L is a health state utility instrument that evaluates preference for health status (utility). The 5 items in the EQ-5D-5L comprise 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) each of which are rated on 5 levels of severity. Responses to the 5 items encode a discrete health state which is mapped to a preference (utility) specific for different societies. Subjects also rate their perception of their overall health on a separate visual analogue scale (VAS). The EQ-5D-5L should require approximately 5 minutes to complete. Short Form 36 Version 2 Health Status Survey The SF-36V2 is a general Health Related Quality of Life (HRQoL) instrument with extensive use in multiple disease states. The SF-36V2 instrument comprises 36 total items (questions) targeting a subject's functional health and wellbeing in 8 dimensions (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Scoring is totaled into a Physical Component Summary and a Mental Component Summary. Higher SF-36V2 scores indicate a better state of health. Completion of the SF-36V2 should require approximately 10 minutes. Enrollment and Assignment of Subject Numbers All screening activities must be completed and reviewed prior to enrollment. Subjects who meet the eligibility criteria will proceed to enrollment via the IRT system on Day 1 (Treatment Period). Subjects will initially be assigned a unique subject number at the Screening Visit. Enrolled subjects will retain this subject number throughout the study. Subject numbers will be 6-digit numbers with the first 3 digits representing the site and the last 3 digits assigned sequentially to the subjects within the site. The first 3 digits will be sequentially assigned to sites, starting with 100. The last 3 digits will be sequential for subjects within a site, starting with 601. So for example, within one site (100), subject numbers will be 67

201 M Protocol Amendment 2 assigned sequentially as follows: , , , and so forth. Similarly, at a second site (101), subject numbers will be assigned sequentially as follows: , , , and so forth. MEMS Caps At the Day 1 Visit (TP), subjects will be assigned 3 MEMS caps. To ensure that a dosing event is recorded for the first dose of study drug at the site on Study Day 1 of the TP, the site should place the MEMS cap on the bottles of study drug before dispensing the first dose. Additionally, at each visit, site personnel should download the MEMS dosing history data from the MEMS cap, review, and counsel the patient as appropriate regarding compliance. Additional information regarding Treatment Compliance and MEMS can be found in Section and Section Study Drugs Compliance for Kits Study drugs compliance will be recorded per kit in the IRT system. Study drugs will be collected at each drug dispensation visit after Day 1, as indicated in Table 2. The number of tablets of ABT-450/r/ABT-267, ABT-333, and of RBV remaining in each bottle will be recorded in the source and transferred to the IRT system along with the date of reconciliation Meals and Dietary Requirements All study drugs should be dosed together and administered with food. When cyclosporine or tacrolimus is scheduled to be taken (as per instruction from the investigator), it should be administered with food in combination with the morning dose of study drugs Blood Samples for Pharmacogenetic Analysis IL28B Sample One (required) 4 ml whole blood sample for DNA isolation will be collected from each subject at the Study Day 1 Visit for Interleukin 28B (IL28B) pharmacogenetic analysis. 68

202 M Protocol Amendment 2 This sample will not be used for any testing other than IL28B genotypes. Results of this testing will be made available to the investigator. Optional Sample for Pharmacogenetic Analysis A separate (optional) 4 ml whole blood sample for DNA isolation will be collected on Day 1 (Treatment Period) or at any time during the TP, from each subject who consents to provide the optional sample for pharmacogenetic analysis. If the optional pharmacogenetic sample is not collected at Day 1, it may be collected at any other visit during the study. The procedure for obtaining and documenting informed consent is discussed in Section 9.3. Results may not be included in the Clinical Study Report Drug Concentration Measurements Collection of Samples for Analysis Blood samples for assay of ABT-450, possible ABT-450 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ABT-267, possible ABT-267 metabolites, as well as ritonavir and RBV will be collected prior to dosing (0 hr), 2, and 4 hours post morning dose on Study Day 1 and at each subsequent study visit up to 24 weeks (irrespective of study drug dosing time) or upon subject discontinuation as specified in Table 3. Blood samples for assay of cyclosporine or tacrolimus will be collected in the lead in period, prior to dosing on Day 1, Day 3, Day 7, Day 10 (optional) and at each subsequent visit up to week 24 or upon subject discontinuation as specified in Table 3. Blood samples for assay of cyclosporine or tacrolimus will be also collected in Post-Treatment Period and at each subsequent visit up to PTP Week 4, and then PTP Week 24 or upon subject discontinuation as specified in Table 3. The time that each blood sample is collected will be recorded to the nearest minute. 69

203 M Protocol Amendment 2 A total of 14 blood samples are planned to be collected per subject for cyclosporine or tacrolimus pharmacokinetic analysis. A total of 15 blood samples are planned to be collected per subject for ABT-333, ABT-333 M1, ABT-450, ritonavir and ABT-267. The total number of blood samples planned for pharmacokinetic analysis is 870 for the entire treatment period. In addition, in the Post-Treatment Period, a total of 6 samples are planned to be collected per subject for cyclosporine or tacrolimus pharmacokinetic analysis. The total number of blood samples planned for pharmacokinetic analysis is 180 for the Post-Treatment Period. Also, at the investigators discretion extra blood draws for tacrolimus or cyclosporine level testing may be performed at any time as unscheduled visits during treatment as well as Post-Treatment Period. Blood samples for the assay of cyclosporine and tacrolimus trough level estimation will be collected prior to the morning dose, as indicated in Table 2 and Table 3. This sample will be analyzed by both the analytical and local laboratory. The date and time that each blood sample is collected and the date, time and dose of the subject's last immunosuppressant dose will be recorded in the ecrf. The samples to be analyzed by the local laboratory will be processed as per the local laboratory's standard practice. The samples which will be analyzed by the analytical laboratory will be processed as indicated in the lab manual provided by the central laboratory Handling/Processing of Samples Specific instructions for collection of blood samples and subsequent preparation and storage of the plasma samples for the pharmacokinetic assays of ABT-450, possible ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ritonavir and RBV will be provided by the central laboratory, the Sponsor, or its designee. Specific instructions for the collection of blood samples and subsequent preparation and storage of blood samples for the analysis of cyclosporine or tacrolimus will be provided in the laboratory manual provided by the central laboratory. Local laboratory analysis of 70

204 M Protocol Amendment 2 blood samples for cyclosporine and tacrolimus samples will be done as per the investigator's local laboratory policies and procedures Disposition of Samples The frozen plasma samples for the pharmacokinetic assays of ABT-450, possible ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ritonavir, RBV samples will be packed in dry ice sufficient to last during transport, and transferred from the study site to the central laboratory. An inventory of the samples included will accompany the package. The central laboratory will then ship the samples for the pharmacokinetic assays of ABT-450, ABT-267, ABT-333, ritonavir, and RBV to: Sample Receiving Phone: Fax: An inventory of the included samples will accompany the package and an electronic copy of the Manifests (including subject number, study day, the time of sample collection and barcode) will be sent to the contact person at sample.receiving@abbvie.com. The frozen blood samples for cyclosporine and tacrolimus will be packed in dry ice sufficient to last during transport from the study site to the central laboratory. Refer to the laboratory manual for further details. The central laboratory will then ship the samples for pharmacokinetic assay of cyclosporine to: 71

205 M Protocol Amendment 2 On the day of shipping, an electronic copy of the inventory should be ed to. The central laboratory will then ship the samples for pharmacokinetic assay of tacrolimus to: On the day of shipping, a copy of the inventory sheet should be ed to Measurement Methods Plasma concentrations of ABT-450, ritonavir, ABT-267, ABT-333, ABT-333 M1 metabolite, and RBV will be determined using validated assay methods under the supervision of the Drug Analysis Department at AbbVie. Plasma concentrations of 72

206 M Protocol Amendment 2 metabolites of ABT-450 and ABT-267, and other metabolites of ABT-333 may also be determined using non-validated methods. Blood concentrations of cyclosporine and tacrolimus will be determined using validated assays, at the labs indicated in Section , under the supervision of the Drug Analysis Department at AbbVie Efficacy Variables Virologic response will be assessed by HCV RNA in IU/mL at various time points from Day 1 through 48 weeks after completion of treatment Primary Variable The primary endpoint is the percentage of subjects with SVR 12 (HCV RNA < LLOQ 12 weeks after the last actual dose of study drugs) Secondary Variables The secondary endpoints are: The percentage of subjects with SVR 24 (HCV RNA < LLOQ 24 weeks after the last actual dose of study drugs); The percentage of subjects with virologic failure during treatment; The percentage of subjects with post-treatment relapse Resistance Variables The following resistance information will be tabulated and summarized: (1) for all subjects receiving study drug, the variants at each amino acid position at baseline identified by population nucleotide sequencing will be compared to the appropriate prototypic reference sequence, and (2) for subjects who experience virologic failure, the variants at the available post-baseline time points identified by population and/or clonal 73

207 M Protocol Amendment 2 nucleotide sequencing will be compared to baseline and the appropriate prototypic reference sequences Safety Variables The following safety evaluations will be performed during the study: adverse event monitoring and vital signs, physical examination, ECG, and laboratory tests assessments Pharmacokinetic Variables Individual plasma concentrations of ABT-450, ritonavir, ABT-267, ABT-333, ribavirin and possible metabolites will be tabulated and summarized. Individual blood concentrations of the cyclosporine and tacrolimus will be tabulated and summarized Pharmacogenetic Variables IL28B genotypes are associated with response to PegIFN and RBV and some PegIFN-free regimens. IL28B status in whole blood samples will be determined for each subject and analyzed as a factor contributing to the subject's response to study treatment. These IL28B genotype results may be analyzed as part of a multi-study assessment of IL28B and response to ABT-450, ABT-267, ABT-333, or drugs of these classes. The results may also be used for the development of diagnostic tests related to IL28B and study treatment, or drugs of these classes. The results of additional pharmacogenetic analyses may not be reported with the clinical study report. DNA samples from subjects who separately consent for additional pharmacogenetic analysis may be analyzed for genetic factors contributing to the subject's response to study treatment, in terms of pharmacokinetics, pharmacodynamics, efficacy, tolerability and safety. Such genetic factors may include genes for drug metabolizing enzymes, drug transport proteins, genes within the target pathway, or other genes believed to be related to drug response (including IL28B). Some genes currently insufficiently characterized or 74

208 M Protocol Amendment 2 unknown may be understood to be important at the time of analysis. Pharmacogenetic analyses will be limited to studying response to HCV therapy; no other analyses will be performed. 5.4 Removal of Subjects from Therapy or Assessment Discontinuation of Individual Subjects Each subject has the right to withdraw from the study at any time. In addition, the investigator may discontinue a subject from the study at any time if the investigator considers it necessary for any reason, including the occurrence of an adverse event or noncompliance with the protocol. If, during the course of study drugs administration, the subject prematurely discontinues during the TP, the procedures outlined for the Treatment Discontinuation Visit should be completed as defined in Table 2. It is recommended that this visit occur on the day of study drugs discontinuation, but no later than 2 days after their final dose of study drugs and prior to the initiation of any other anti-hcv therapy. However, these procedures should not interfere with the initiation of any new treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's condition. Following discontinuation of study drugs, the subject will be treated in accordance with the investigator's best clinical judgment. The date of the last dose of any study drugs and reason for discontinuation from the Treatment Period will be recorded in the EDC system. The subject should then begin the PTP where the subject will be monitored for 48 weeks for safety, HCV RNA levels, the emergence and persistence of resistant viral variants and PROs. If a subject is discontinued from study drugs (Treatment Period) or the Post-Treatment Period with an on going adverse event or an unresolved laboratory result that is significantly outside of the reference range, the investigator will attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result or adverse even is achieved. 75

209 M Protocol Amendment 2 If a subject discontinues from the PTP, the subject should return for post-treatment discontinuation procedures as defined in Table 3. The reason for discontinuation will also be recorded in the Study Discontinuation ecrf. In the event that a positive result is obtained on a pregnancy test for a subject or a subject reports becoming pregnant during the study, the administration of study drugs (including RBV) to that subject must be discontinued immediately and the subject may enter to Post-Treatment Period. Specific instructions regarding subject pregnancy can be found in Section 6.6. The investigator is also encouraged to report the pregnancy information to the voluntary RBV Pregnancy Registry. Subjects who are receiving study drugs and experience an episode of rejection of the transplanted liver that is histologically confirmed and/or which requires treatment with high dose steroids or other anti-rejection medication(s) will be required to discontinue study drugs and may enter the Post-Treatment Period. Treatment(s) of a rejection episode, e.g., by use of corticosteroids or other agents, will be captured in ecrf as part of the adverse reporting. For subjects discontinuing study drugs, investigators should be aware of the potential for consequent alterations in CNI levels and should contact the SDP to ensure that a plan is in place for appropriate CNI dose modification in the PTP. See Section for further information on the management of CNIs Virologic Failure Criteria The following criteria will be considered evidence of virologic failure while the subject is on study drugs: Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV RNA measurements > 1 log 10 IU/mL above nadir) at any time point during treatment; Failure to achieve HCV RNA < LLOQ by Week 6; 76

210 M Protocol Amendment 2 Confirmed HCV RNA LLOQ (defined as two consecutive HCV RNA measurements LLOQ) at any point during treatment after HCV RNA < LLOQ. Where required, confirmatory testing should be completed as soon as possible. If any of the above criteria are met, the subject will discontinue study treatment (Section 5.4.1). Subjects should remain on study treatment until the virologic failure has been confirmed. Subjects with HCV RNA < LLOQ at the end of treatment and who a confirmed HCV RNA LLOQ (defined as 2 consecutive HCV RNA measurements LLOQ) at any point in the Post-Treatment Period will be considered to have relapsed. Confirmation of an HCV RNA LLOQ in the Post-Treatment Period should be completed as soon as possible Discontinuation of Entire Study The Sponsor may terminate this study prematurely, either in its entirety or at any study site, for reasonable cause provided that written notice is submitted in advance of the intended termination. The investigator may also terminate the study at his/her site for reasonable cause, after providing written notice to the Sponsor in advance of the intended termination. Advance notice is not required by either party if the study is stopped due to safety concerns. If the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the investigator and subsequently provide written instructions for study termination. 5.5 Treatments Treatments Administered Each dose of open-label DAA study drugs (ABT-450/r/ABT-267 and ABT-333) and open-label ribavirin will be dispensed in the form of tablets. Study drugs will be dispensed at the visits listed in Table 2. 77

211 M Protocol Amendment 2 ABT-450/r/ABT-267 will be provided by the Sponsor as 75 mg/50 mg/12.5 mg tablets. ABT-450/r/ABT-267 will be taken orally as 2 tablets every morning which corresponds to a 150 mg ABT-450/100 mg ritonavir/25 mg ABT-267 dose QD. ABT-333 will be provided by the Sponsor as 250 mg tablets. ABT-333 will be taken orally as 1 tablet twice daily, which corresponds to a 250 mg dose BID. RBV will also be provided to the investigator by the Sponsor for use in this study. RBV will be provided as 200 mg tablets during the Treatment Period. RBV has weight-based dosing of 1000 mg to 1200 mg divided twice daily per local label. (For example, for subjects weighing less than 75 kg, RBV may be taken orally as 2 tablets in the morning and 3 tablets in the evening which corresponds to a 1000 mg total daily dose. Or for subjects weighing 75 kg or more, RBV may be taken orally as 3 tablets in the morning and 3 tablets in the evening which corresponds to a 1200 mg total daily dose.). However, in this special population with an increased risk of RBV associated anemia RBV dosing may be managed at the investigator's discretion for the treatment of HCV in liver transplant recipients. Subjects will be instructed to take study medication at the same time(s) every day. All cyclosporine or tacrolimus doses will be taken with the morning doses of study drugs and with food. All compounds including cyclosporine or tacrolimus should be taken together with food. This is important as taking the DAAs in combination with the CNIs at different times can significantly alter the level of the immunosuppressants. On the morning of Study Day 1, at the site, subjects will be administered study drugs by the study site personnel and receive instructions for self administration of all study drugs from Study Day 2 through Study Week 24 of the TP. The date and time of administration of the first dose of each drug will be recorded in the ecrf. Investigators should inform subjects not to take their morning CNI dose prior to the site visit on Study Day 1. Subjects should take the first study-appropriate dose of their CNI concurrently with the first dose of study drug at the site on the morning of Study Day 1. 78

212 M Protocol Amendment 2 Following enrollment, the site will use the IRT system to obtain the study drugs kit numbers to dispense at the study visits specified in Table 2. Study drugs must not be dispensed without contacting the IRT system, and only for subjects enrolled in the study through the IRT system. At the end of the TP or at the TP D/C Visit, the site will contact the IRT system to provide visit date information and study drugs return information for each kit (Section ). All subjects who receive at least one dose of study drugs who fail to achieve virologic suppression, or who experience virologic breakthrough on DAA therapy will be discontinued from treatment. These subjects and those who relapse post DAA therapy may be offered another AbbVie-sponsored treatment study comprising ABT-450/r + ABT PegIFN + RBV. Alternatively, the investigator can prescribe another regimen which will not be provided or reimbursed by AbbVie Identity of Investigational Products Information about the study drugs to be used in this study is presented in Table 5. Table 5. Identity of Investigational Products Investigational Product Manufacturer Mode of Administration Dosage Form Strength ABT-450/Ritonavir/ABT-267 AbbVie/Abbott Oral Tablet 75 mg/50 mg/ 12.5 mg ABT-333 AbbVie/Abbott Oral Tablet 250 mg Ribavirin Roche or Generic Manufacturer Oral Tablet 200 mg Packaging and Labeling ABT-450/r/ABT-267 will be supplied in bottles containing 64 tablets. ABT-333 will be supplied in bottles containing 64 tablets. RBV will be supplied in bottles containing 168 tablets each. 79

213 M Protocol Amendment 2 Each bottle will be labeled as required per country requirements. The labels must remain affixed to the bottles. All blank spaces should be completed by site staff prior to dispensing to subject Storage and Disposition of Study Drugs Study Drugs ABT-450/Ritonavir/ABT-267 bottles ABT-333 bottles Ribavirin bottles Storage Conditions 15 to 25 C (59 to 77 F) 15 to 25 C (59 to 77 F) 15 to 25 C (59 to 77 F) The investigational products are for investigational use only and are to be used only within the context of this study. The study drugs supplied for this study must be maintained under adequate security and stored under the conditions specified on the label until dispensed for subject use or returned to the Sponsor. Upon receipt of study drugs, the site will acknowledge receipt within the IRT system Assigning to Treatment Groups At the Screening Visit, all subjects will be assigned a unique subject number through the use of IRT. For subjects who do not meet the study selection criteria, the site personnel must contact the IRT system and identify the subject as a screen failure. Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be enrolled into the study on Study Day 1. Subjects who are enrolled will retain their subject number, assigned at the Screening Visit, throughout the study. For enrollment of eligible subjects into the study, the site will utilize the IRT system in order to receive unique study drugs kit numbers. The study drugs kit numbers will be assigned according to schedules computer-generated before the start of the study by the AbbVie Statistics Department. Contact information and user guidelines for IRT use will be provided to each site. Upon receipt of study drugs, the site will acknowledge receipt in the IRT system. 80

214 M Protocol Amendment Selection and Timing of Dose for Each Subject Study drugs dosing will be initiated at the Study Day 1 Visit. ABT-450/r/ABT-267 will be dosed every morning, and ABT-333 and RBV will be dosed BID. Study drugs and cyclosporine or tacrolimus should be taken together with food at approximately the same times in the morning every day. This is important as taking the DAAs in combination with the immunosuppressants at different times can significantly alter the level of the immunosuppressants Blinding This is an open-label study Data Monitoring Committee (DMC) An independent DMC will review safety data from this study and provide recommendations to the AbbVie Study Designated Physician as per the DMC charter. The charter also describes DMC membership, which will include individuals with experience in the management of patients with chronic HCV infection, and member responsibilities. The DMC will receive interim summaries of safety data according to a schedule and format specified in the charter. After each review, the DMC will communicate its recommendations to the Sponsor. The Sponsor will retain sole responsibility for study management, communication with study sites and regulatory authorities Treatment Compliance The investigator or his/her designated and qualified representatives will administer/dispense study drugs only to subjects enrolled in the study in accordance with the protocol. The study drugs must not be used for reasons other than that described in the protocol. All study drugs will be dispensed to subjects by study-site personnel under the direction of the investigator. 81

215 M Protocol Amendment 2 At the start of the study, each subject should receive counseling regarding the importance of dosing adherence with the treatment regimen with regards to virologic response and potential development of resistance. Subjects will be administered study drugs at the site at the Study Day 1 Visit. The start and stop dates of all study drugs will be recorded in the source documents and ecrfs. Subjects will be instructed to bring all bottles of study drugs (full, partial, or empty) to the study site at each drug dispensation visit indicated in Table 2. At every treatment visit study site personnel will inspect the contents of the bottles and record the status of each one as well as the exact number of remaining tablets of ABT-450/r/ABT-267, ABT-333, and RBV and the date of reconciliation in the IRT system. Reconciliation should occur when the bottle is returned at each visit indicated in Table 2. If poor adherence is noted, the subject should be counseled and this should be documented in the subject's source. Study drugs should not be interrupted for toxicity management or any other reason for more than 7 days consecutively. If study drugs need to be interrupted for more than 7 days consecutively, the Study Designated Physician should be contacted and consideration should be given to discontinue the subject. The date and time of administration of the first dose of each drug will be recorded in the source documents and the ecrf. A single date of last dose of all study drugs will be recorded in the source documents and the ecrf MEMS Caps All subjects will utilize a MEMS monitor (cap), manufactured by Advanced Analytical Research on Drug Exposure (AARDEX) on the bottles for study drug. The MEMS cap will be used to obtain daily dosing histories for study drugs for all subjects. In addition, MEMS data will be provided to the investigator to guide treatment compliance discussions and will be the primary data used to assess PK time relative to dose. 82

216 M Protocol Amendment 2 The MEMS cap is a threaded cap containing an internal electronic clock, with an integrated electronically erasable programmable read-only memory, a special micro-switch and battery. Once fastened onto the medication bottle, the MEMS cap silently records the date and time of all dosing events (event = opening + closing). This electronic monitor provides a means of objectively measuring a subject's adherence with the study medication. At the Study Day 1 Visit of the TP, subjects will be assigned the MEMs caps that will be placed on the bottles of study drugs in place of the original cap. The original cap should be saved so it can be placed back on the bottle upon return by the subject in order to store returned study drug. The MEMS cap must only be used by the subject to whom it was assigned. Each MEMS cap has a unique serial number that must be recorded in the subject's source documentation. It is suggested that the subject's subject number be written on his or her MEMS cap in permanent ink. The subjects will be instructed to open the bottle when it is time to take the medicine, to remove the proper amount of medication and promptly close the bottle, then ingest the prescribed dose. The subject should be instructed to transfer the MEMS cap to the next full bottle of study drug at the same time that they take their last dose from the current in-use bottle. The MEMS cap will be collected from the subject at the completion of study drugs as applicable. If MEMS caps cannot be imported into a participating study country or if other issues preclude the use of MEMS cap at a site(s), dosing histories will not be obtained for subjects enrolled at that site(s). Additional instructions for the subject on how to use the MEMS cap will be provided by the Sponsor. 83

217 M Protocol Amendment Drug Accountability The investigator or his/her representative will verify that study drugs supplies are received intact and in the correct amounts. This will be documented by signing and dating the Proof of Receipt (POR) or similar document and via recording in the IRT system. A current (running) and accurate inventory of study drugs will be kept by the investigator and will include lot number, POR number, number of tablets dispensed, subject number, initials of person who dispensed study drugs and date dispensed for each subject. An overall accountability of the study drugs will be performed and verified by the Sponsor monitor throughout the Treatment Period. Final accountability will be performed by the monitor at the end of study drugs treatment at the site. During the study, should an enrolled subject misplace or damage a study drugs bottle, the site must contact the IRT system to report the misplaced or damaged study drugs. If the bottles are damaged, the subject will be requested to return the remaining study drugs to the site. Replacement study drugs may only be dispensed to the subject by contacting the IRT system. Study drugs replacement and an explanation of the reason for the misplaced or damaged study drugs will be documented within the IRT system. Study drugs start dates and times for each drug and the date of the last dose of the regimen will be documented in the subject's source documents and recorded on the appropriate ecrf. The status of each bottle, number of each type of tablets remaining in each one returned, and the date of reconciliation will be documented in the IRT system. The monitor will review study drugs accountability on an ongoing basis. Upon completion of or discontinuation from the Treatment Period, all original bottles (containing unused study drugs) will be returned to the Sponsor (or designee) according to instructions from the Sponsor and according to local regulations following completion of drug accountability procedures. The number of tablets of each type of study drug returned will be noted on the drug accountability log and the IRT system (if not previously recorded) and appropriate drug return forms. Labels must remain attached to the containers. 84

218 M Protocol Amendment Discussion and Justification of Study Design Discussion of Study Design and Choice of Control Groups The 3 DAA regimen of ABT-450/r/ABT ABT-333 with RBV is being evaluated in the current study based on data from Phase 2b Study M Available data from Study M indicate that, when dosed in treatment-naïve subjects for 12 weeks, the 3 DAA regimen of ABT-450/r +ABT ABT RBV shows higher SVR 12 results (77 of 79 subjects, 97.5%) as compared to the 2 DAA arms of ABT-450/r + ABT RBV (71 of 79 subjects, 90%) or ABT-450/r + ABT RBV (35 of 41 subjects, 85%). The 3 DAA regimen without ribavirin showed high SVR 12 rates (24 of 25 subjects, 96%) in genotype 1b subjects; genotype 1a subjects showed a lower SVR 12 rate (43 of 52 subjects, 83%) as compared to the 3DAA + RBV regimen (52 of 54 subjects, 96%). Thus, the 3 DAA + RBV regimen dosed for 12 weeks provides the highest possibility of achieving SVR in treatment-naïve genotype 1 subjects. Based upon the results of high SVR rates in three Phase 2 studies, including the largest study, Study M (discussed in detail in Section 3.0), AbbVie plans to evaluate ABT-450/r/ABT-267 and ABT-333 coadministered with RBV in adult liver transplant recipients with chronic HCV genotype 1 infection in a multicenter, open-label, Phase 2 study. A placebo-controlled trial was not considered to be appropriate in post liver transplant subjects due to the interim risk of hepatic progression during the study for placebo recipients. The use of an active comparator arm was considered in the study design. The approved direct acting antiviral agents telaprevir and boceprevir, in combination with PegIFN and ribavirin result in improved treatment outcomes for those with HCV. However, there is a paucity of data describing efficacy and safety in liver transplant recipients and these agents are not currently indicated for use in this patient population. Given the not inconsiderable toxicities, low SVR rates and high discontinuation rates with PegIFN/RBV, as well as the potential for dropout among those who would not receive the DAA/RBV therapy in a comparator study and due to the overall expected higher efficacy 85

219 M Protocol Amendment 2 and lower toxicities rates with the DAA/RBV therapy it was decided not to add a PegIFN/RBV comparator arm to this Phase 2 study. ABT-450/r with ABT-267 and ABT-333 combined with RBV have been well-tolerated for up to 24 weeks in HCV infected subjects in Study M Available data suggest that 12 weeks of treatment with DAAs and RBV is sufficient for subjects with HCV, as illustrated by available clinical data in Study M However, the duration of therapy required to cure HCV in the post transplant setting has not yet been defined. The observed overall lower responses to PegIFN-RBV suggest that this is a difficult to population. Consequently, the duration of treatment for this population will be 24 weeks. Given the above considerations, it is anticipated that the study design will maximize the probability of success in this harder-to-cure population while avoiding the side-effects of pegylated interferon. It is anticipated that SVR rates with this regimen will exceed those of the current standard of care, PegIFN-RBV. Also, DMC oversight will further ensure the safety of all subjects Appropriateness of Measurements Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized in this study. HCV RNA assays are standard and validated. Clonal and population sequencing methods are experimental. SF-36V2 and EQ-5D-5L PRO instruments are standards in the literature and thoroughly validated; the HCVPRO is preliminarily validated Suitability of Subject Population The selection of subjects infected with HCV genotype 1 virus will allow for the assessment of safety, pharmacokinetics and antiviral activity of ABT-450/r, ABT-267, ABT-333 and RBV dosed in combination. This study will restrict enrollment to HCV genotype 1-infected liver transplant recipients who are either treatment-naïve or treatment-experienced prior to liver transplant with standard IFN or PegIFN (with or 86

220 M Protocol Amendment 2 without RBV) and who have no evidence of advanced liver disease, thereby limiting risk of unanticipated pharmacokinetic or other adverse effects not observed in prior dosing in healthy volunteers or HCV-infected subjects. HCV-infected subjects with transaminase levels up to 5 times the ULN will be allowed to enroll, as many patients with chronic HCV infection who are otherwise healthy, have stable elevations of AST and ALT levels ( 5 ULN) and are considered representative of the population who will receive ABT-450/r, ABT-267, and ABT-333. A portion of the HCV-infected liver transplant recipients have a relatively high BMI. Because of the acceptable safety and pharmacokinetic profiles of ABT-450/r, ABT-267 and ABT-333 in Phase 1 and Phase 2 studies, this protocol will enroll subjects with a BMI up to 38 kg/m 2. Since DAA interaction studies have only been conducted with cyclosporine and tacrolimus, the study will only enroll subjects who are on stable doses of either of these two widely used drugs. Individuals who are clinically stable at 12 or more months after an uncomplicated transplant are anticipated to have discontinued corticosteroids or at least may only be on low maintenance corticosteroid doses. The requirements for HbA1C ( 8%) and calculated creatinine clearance ( 55mL/min) are to limit the impact of prior CNI toxicity or diabetes on renal function in this population Selection of Doses in the Study Doses of the three DAAs to be used in this study have shown significant antiviral activity both as monotherapy, in combination with PegIFN + RBV, and in combination with each other and RBV. Doses comparable to, and higher than the DAA doses to be administered in this study have been studied in single- and multiple-dose healthy volunteer studies and administered to HCV-infected subjects as monotherapy or in combination with PegIFN RBV and found to be generally safe and well-tolerated. Of note, coadministration of ABT-450/r, ABT-267 and ABT-333 at the doses planned for use in this study do not clinically significantly impact plasma exposures compared to administration as single agents thus dose adjustments based on drug interactions are not required. The DAAs to be administered in this study have been evaluated in approximately 570 subjects in Study M Of these, approximately 240 subjects received the specific combination 87

221 M Protocol Amendment 2 of ABT-450/r (dosed 100/100 or 150/100 mg QD) + ABT-267 (25 mg QD) + ABT-333 (400 mg BID) + RBV (weight based dosing). As noted in Section 3.0, overall the regimen was associated with high SVR 12 rates and was well-tolerated. ABT-450/r The ABT-450/r doses of 100/100 and 150/100 mg evaluated in the Phase 2 studies using the ABT-450 SDD tablet provided high ITT SVR 12 rates in treatment-naïve (100% and 95%, respectively) and treatment-experienced (91% and 95.5%, respectively) subjects when dosed with ABT-333 and ABT RBV. The higher ABT-450 dose of 150 mg, administered with 100 mg ritonavir has been selected to advance into Phase 3 studies as it provides an optimal balance between safety and suppression of resistant variants. In combination with other DAAs ± RBV, the highly fit, moderately resistant R155K viral variant was observed in a lower fraction of patients who had virologic failure at the 150/100 and 200/100 mg ABT-450/r dose (SDD tablet of ABT-450) as compared to the 100/100 mg ABT-450/r dose. This finding is consistent with monotherapy data for ABT-450/r where the higher 200/100 mg dose of ABT-450/r selected fewer resistant variants including R155K as compared to the lower 50/100 and 100/100 mg doses of ABT-450/r. Higher ABT-450 doses were also associated with higher SVR 24 rates when combined with pegifn and RBV. Thus, based on resistance profile and SVR 24 data with pegifn + RBV, higher doses provide better efficacy. However, ABT-450 doses of 200/100 and 250/100 mg (SDD tablet) were associated with a greater incidence of asymptomatic Grade 3+ ALT elevations (~4% at doses 200/100 versus ~0.5% at lower doses) suggesting that doses < 200/100 mg SDD tablet might have a more favorable safety profile. The ABT mg dose from the ABT-450/r/ABT-267 co-formulation planned for this study has a ~60% higher exposure as compared to the 150/100 mg SDD formulation but the exposure is ~50% lower than that from the 200/100 mg SDD formulation. The 150 mg ABT-450 dose from the coformulation will hence minimize the incidence of 88

222 M Protocol Amendment 2 asymptomatic, transient Grade 3 ALT elevations while maximizing virologic suppression and minimizing the appearance of resistant variants. The maximum dose of ABT-450/r/ABT mg/50 mg/12.5 mg tablets will not exceed 150 mg/100 mg/25 mg per day for 24 weeks. ABT-267 An ABT-267 dose of 25 mg has been selected to advance into Phase 3 studies. Compared to higher doses, the 25 mg QD dose provided comparable viral load decline following monotherapy and lower potential to decrease ABT-450 exposures. Following 2 to 3 days of ABT-267 monotherapy at doses of 1.5 mg to 200 mg QD, the 25 mg dose of ABT-267 showed viral load decline comparable to higher doses with none of the rebound between doses seen at lower doses. Preliminary resistance analysis following monotherapy suggests that doses significantly greater than 25 mg would be needed to improve the resistance profile as a variety of NS5A resistant mutants were observed following monotherapy with doses of 5 to 200 mg. In addition, higher ABT-267 doses have been associated with decreases in ABT-450 exposures; the ABT mg dose resulted in ~80% lower ABT-450 exposures when ABT mg was dosed with 100 mg ritonavir. Hence doses > 25 mg could decrease the exposures of the "anchor" molecule ABT-450, without providing significant benefit in terms of improved efficacy. Additionally, available data from the Phase 2b study indicates that when ABT mg QD dose is combined with ABT-450, ABT-333 and RBV for 12 weeks, very high SVR 12 rates were observed in treatment-naïve and treatment experienced subjects (> 90%). The co-formulated ABT-450/r/ABT-267 formulation used in the current study has ABT-267 bioavailability comparable to the ABT mg tablet used in Phase 2 studies. Hence, the ABT-267 dose in the current study is the 25 mg dose, as it provides exposures that maximizes efficacy without compromising ABT-450 exposures. The maximum dose of ABT-450/r/ABT mg/50 mg/12.5 mg tablets will not exceed 150 mg/100 mg/25mg per day for 24 weeks. 89

223 M Protocol Amendment 2 ABT-333 An ABT-333 dose of 250 mg BID using the optimized tablet formulation that is expected to provide exposures comparable to the 400 mg BID dose used in Phase 2 studies and has been selected to advance into Phase 3 studies. This is based on comparable efficacy and better safety profile compared to exposures at higher ABT-333 doses. Comparable viral load decline following monotherapy (approximately 1 log 10 IU/mL) was observed at exposures greater than that achieved with the 400 mg BID dose evaluated in Phase 2 studies. Additionally, the 400 and 800 mg BID doses resulted in identical SVR rates (63%) when combined with pegifn and RBV for 12 weeks followed by 36 weeks of pegifn + RBV, indicating that increasing ABT-333 dose > 400 mg BID did not improve efficacy. Additionally, available data from the Phase 2b study indicates that when ABT mg BID dose is combined with ABT-450, ABT-267 and RBV for 12 weeks, very high SVR 12 rates were observed in treatment-naïve and treatment-experienced subjects (> 90%). While both the 400 mg BID and 800 mg BID doses of ABT-333 in combination with pegifn and RBV were well tolerated by HCV-infected subjects for 12 weeks, the 800 mg BID dose was associated with a greater mean hemoglobin reduction compared to the 400 mg BID dose and compared to placebo plus pegifn and RBV. The optimized formulation used in the current study has a higher bioavailability and is expected to provide comparable exposures to the 400 mg tablet formulation used in Phase 2 studies. Hence, the ABT-333 dose in the current study is the 250 mg optimized formulation dosed BID as it provides exposures that maximizes efficacy and a superior safety profile compared to higher ABT-333 doses. The maximum dose of ABT mg tablets administered in this study will not exceed 500 mg per day for 24 weeks. 90

224 M Protocol Amendment 2 Ribavirin The recommended daily dose of RBV in this study is 1000 to 1200 mg, divided twice daily, and based on subject weight. This dose is approved for treatment of adult patients with chronic hepatitis C infection in combination with PegIFN. The same dose is selected for this study because its safety profile has been well characterized when administered with PegIFN, including the incidence of hemolytic anemia, and there are well-defined dose reduction criteria in the event of RBV-induced anemia. In addition, this dose was studied in the absence of PegIFN in Studies M12-267, M12-746, M and M11-652, and was found to be generally safe and well-tolerated. The maximum RBV dose administered in this study will not exceed 1200 mg, divided twice daily for 24 weeks. However, in this special population with an increased risk of RBV associated anemia RBV dosing may be managed by the investigator consistent with local practice for the treatment of HCV in liver transplant recipients such that total doses of RBV doses less than 1200 mg per day may be preferred. 6.0 Adverse Events The investigator will monitor each subject for clinical and laboratory evidence of adverse events on a routine basis throughout the study. The investigator will assess and record any adverse event in detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the adverse event to study drugs (DAAs or RBV), and any action(s) taken. For serious adverse events considered as having "no reasonable possibility" of being associated with study drugs, the investigator will provide an "Other" cause of the event. For adverse events to be considered intermittent, the events must be of similar nature and severity. Adverse events, whether in response to a query, observed by site personnel, or reported spontaneously by the subject will be recorded. All adverse events will be followed to a satisfactory conclusion. 91

225 M Protocol Amendment Definitions Adverse Event An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not the event is considered causally related to the use of the product. Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from accidental or intentional overdose, drug abuse, or drug withdrawal. Any worsening of a pre-existing condition or illness is considered an adverse event. Worsening in severity of a reported adverse event should be reported as a new adverse event. Laboratory abnormalities and changes in vital signs are considered to be adverse events only if they result in discontinuation from the study, necessitate therapeutic medical intervention, meets protocol specific criteria (see Section 6.7 regarding toxicity management) and/or if the investigator considers them to be adverse events. An elective surgery/procedure scheduled to occur during a study will not be considered an adverse event if the surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been pre-planned prior to study entry. However, if the pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition for which the elective surgery/procedure is being done will be considered an adverse event Serious Adverse Events If an adverse event meets any of the following criteria, it is to be reported to the Sponsor as a serious adverse event (SAE) within 24 hours of the site being made aware of the serious adverse event. 92

226 M Protocol Amendment 2 Death of Subject Life-Threatening Hospitalization or Prolongation of Hospitalization Congenital Anomaly Persistent or Significant Disability/Incapacity Important Medical Event Requiring Medical or Surgical Intervention to Prevent Serious Outcome An event that results in the death of a subject. An event that, in the opinion of the investigator, would have resulted in immediate fatality if medical intervention had not been taken. This does not include an event that would have been fatal if it had occurred in a more severe form. An event that results in an admission to the hospital for any length of time or prolongs the subject's hospital stay. This does not include an emergency room visit or admission to an outpatient facility. An anomaly detected at or after birth, or any anomaly that results in fetal loss. An event that results in a condition that substantially interferes with the activities of daily living of a study subject. Disability is not intended to include experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle). An important medical event that may not be immediately life-threatening or result in death or hospitalization, but based on medical judgment may jeopardize the subject and may require medical or surgical intervention to prevent any of the outcomes listed above (i.e., death of subject, life-threatening, hospitalization, prolongation of hospitalization, congenital anomaly, or persistent or significant disability/incapacity). Additionally, any elective or spontaneous abortion or stillbirth is considered an important medical event. Examples of such events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. For serious adverse events with the outcome of death, the date and cause of death will be recorded on the appropriate case report form. 93

227 M Protocol Amendment Adverse Event Severity The investigator will use the following definitions to rate the severity of each adverse event: Mild Moderate Severe The adverse event is transient and easily tolerated by the subject. The adverse event causes the subject discomfort and interrupts the subject's usual activities. The adverse event causes considerable interference with the subject's usual activities and may be incapacitating or life-threatening. 6.3 Relationship to Study drugs The investigator will use the following definitions to assess the relationship of the adverse event to the use of study drugs. Assessment of relatedness will be made with respect to the DAAs (ABT-450/r/ABT-267 and ABT-333) and with respect to RBV: Reasonable Possibility No Reasonable Possibility An adverse event where there is evidence to suggest a causal relationship between the study drugs and the adverse event. An adverse event where there is no evidence to suggest a causal relationship between the study drugs and the adverse event. For causality assessments, events assessed as having a reasonable possibility of being related to the study drugs will be considered "associated." Events assessed as having no reasonable possibility of being related to study drugs will be considered "not associated." In addition, when the investigator has not reported a causality or deemed it not assessable, the Sponsor will consider the event associated. If an investigator's opinion of no reasonable possibility of being related to study drugs is given for a serious adverse event, then another cause of event must be provided by the investigator. 94

228 M Protocol Amendment Adverse Event Collection Period All adverse events reported from the time of study drug administration until 30 days following discontinuation of study drug administration have elapsed will be collected, whether solicited or spontaneously reported by the subject. In addition, serious adverse events will be collected from the time the subject signed the study-specific informed consent until the end of their participation in the study. Adverse event information will be collected as shown in Figure 3. Figure 3. Adverse Event Collection SAEs SAEs and Non-Serious AEs Elicited and/or Spontaneously Reported SAEs Consent Signed Study drug Start Study Drug Stopped 30 Days or After Study Drug Stopped End of Study 6.5 Adverse Event Reporting In the event of a serious adverse event, whether associated with study drugs or not, the investigator will notify the Antiviral Safety Management Team within 24 hours of the site being made aware of the serious adverse event by entering the serious adverse event data into the EDC system. Serious adverse events that occur prior to the site having access to the RAVE system or if RAVE is not operable should be faxed to the Antiviral Safety Management Team within 24 hours of being made aware of the serious adverse event. 95

229 M Protocol Amendment 2 For serious adverse event concerns, contact the Antiviral Safety Team at: Antiviral Safety Team For any subject safety concerns, please contact the physician listed below: Primary Study-Designated Physician: Eoin Coakley, MD Associate Medical Director The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with Directive 2001/20/EC. The reference document used for SUSAR reporting in the EU countries will be the most current versions of the Investigator's Brochure or label. 96

230 M Protocol Amendment Pregnancy Subjects and their partners should avoid pregnancy and males should avoid sperm donation throughout the course of the study, starting with Study Day 1 and for 7 months after the last dose of RBV (or per local RBV label) and/or consistent with local treatment guidelines for RBV. Pregnancy in a study subject must be reported to the Sponsor within 1 working day of the site becoming aware of the pregnancy. Subjects who report a positive pregnancy test during the Treatment Period must be notified to stop all study medication (Section 5.4.1) and may enter the Post-Treatment Period. The site must complete and fax to the Sponsor the appropriate pregnancy-specific forms that will require the collection of maternal information and fetal outcome information. The investigator is also encouraged to report the pregnancy information to the voluntary RBV Pregnancy Registry. Pregnancy in a study subject is not considered an adverse event. However, the medical outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is considered a serious adverse event and must be reported to the Sponsor within 24 hours of the site becoming aware of the event. 6.7 Toxicity Management For the purpose of medical management, all adverse events and laboratory abnormalities that occur during the study must be evaluated by the investigator. A table of Clinical Toxicity Grades for evaluating laboratory abnormalities is provided in Appendix C. This table should be used in determination of the appropriate toxicity management as discussed in Section and Section A drug-related toxicity is an adverse event or laboratory value outside of the reference range that is judged by the investigator or the Sponsor as having a "reasonable possibility" of being related to the study drugs (Section 6.3). A toxicity is deemed "clinically significant" based on the medical judgment of the investigator. Laboratory abnormalities will be managed as deemed clinically appropriate by the investigator until resolved. 97

231 M Protocol Amendment 2 Study drugs should not be interrupted for toxicity management for more than 7 consecutive days. If study drugs need to be interrupted for more than 7 consecutive days, consideration should be given to discontinue the subject and the Study Designated Physician should be contacted. During the study, timeliness of EDC data entry to reflect study drugs interruptions and/or RBV dose modifications and consequent required adverse events ensures that the AbbVie Safety Team (medical monitor, safety monitor, DMC) have the data necessary for signal detection at safety data review and DMC meetings. The investigator should ensure that any study drugs interruptions or RBV dose modifications and consequent required adverse events are entered into the appropriate ecrfs. Safety surveillance, via regular review of safety labs will be performed by AbbVie personnel and/or its designee. If during these reviews, an issue is identified which warrants discontinuation of study drugs by a subject, the investigator will be notified. The toxicity management guidelines below should be followed. Because of the potential impact of interruption/discontinuation of DAAs/RBV on CNI levels, investigators should contact the SDP when an interruption/discontinuation is anticipated or required by protocol to ensure that a plan for appropriate CNI dose modification is in place. Similarly for those recommencing DAA's/RBV after an interruption the investigator should contact the SDP to ensure that a plan for appropriate CNI dose adjustment is in place. Where an interruption is required the study drugs should not be interrupted for more than 7 days. If study drugs need to be interrupted for more than 7 days, the Study Designated Physician should be contacted and consideration should be given to discontinue the subject Grades 1 or 2 Laboratory Abnormalities and Mild or Moderate Adverse Events Subjects who develop a study drug-related (reasonable possibility) mild or moderate adverse event or Grades 1 or 2 laboratory abnormality (other than uric acid, cholesterol, 98

232 M Protocol Amendment 2 triglycerides and total bilirubin and those discussed separately in Toxicity Management sections for hemoglobin parameters [Section 6.7.3], hepatic transaminase parameters [Section 6.7.4] and creatinine clearance parameters [Section 6.7.5]) may continue study drugs with follow-up per study protocol. If the adverse event or laboratory parameter does not improve or normalize within 2 scheduled study visits and an etiology other than study drugs has not been determined, then the SDP can be contacted to further discuss subject management. Subjects may continue study drugs; study drug interruption is not required Grades 3 or 4 Laboratory Abnormalities and Severe or Serious Adverse Events Grades 3 4 Laboratory Abnormalities With the exception of Grade 3 or greater elevations in uric acid, total cholesterol or triglycerides, if a subject experiences a Grade 3 or greater laboratory parameter during the study (other than those discussed in the toxicity management Sections through below), the abnormal laboratory test should be repeated. If the Grade 3 or greater abnormality is confirmed, the study drugs should be interrupted and the laboratory parameter followed until it reaches Grade 1. The study drugs can be restarted if the laboratory parameter reaches Grade 1 within 7 days of study drug interruption. If study drugs are interrupted and restarted and abnormality recurs, then all study drugs should be permanently discontinued. If the abnormality does not improve to Grade 1 or less within 7 days of interruption, the study drugs should be permanently discontinued. If the investigator believes that the confirmed Grade 3 or greater laboratory abnormality can be managed medically without interruption, then the AbbVie Study Designated Physician should be contacted to discuss continued study drug administration with medical management. If the laboratory abnormality does not improve with medical management within 2 scheduled study visits, then study drugs should be interrupted and the laboratory abnormality followed. If the laboratory abnormality improves within 7 days of study drug interruption, study drugs may be restarted. If the laboratory 99

233 M Protocol Amendment 2 abnormality recurs upon restart, then study drugs should be permanently discontinued. If the laboratory abnormality does not improve within 7 days, then study drugs should be permanently discontinued. Immunosuppressant levels should be monitored at the investigator's discretion during periods of interruption and reinitiation of study drugs. Severe Adverse Event If a subject experiences a severe drug-related (reasonable possibility) adverse event (other than those based on abnormal lab parameters discussed in Sections through 6.7.5) during the study, the study drugs should be interrupted. Study drugs may be restarted if the adverse event improves or resolves within 7 days of the interruption. If study drugs are interrupted and restarted and adverse event recurs, then study drugs should be permanently discontinued. If the adverse event does not improve or resolve within 7 days of the interruption the study drugs should be permanently discontinued. If the investigator believes that the severe drug-related (reasonable possibility) adverse event can be managed medically without interruption, then the Study Designated Physician should be contacted to discuss continued study drugs administration with medical management. If the severe adverse event does not improve with medical management within 2 scheduled study visits, then study drugs should be interrupted. If the severe adverse event improves within 7 days of the interruption, then study drugs may be restarted. If the severe adverse event recurs upon restart, then study drugs should be permanently discontinued. If the severe adverse event does not improve within 7 days of the interruption, then study drugs should be permanently discontinued. If a subject experiences a severe adverse event which in the opinion of the investigator is considered unrelated to study drugs (no reasonable possibility) and which can be managed medically without interruption of study drugs, then the SDP should be contact to discuss continued study drug administration with medical management. A severe adverse event and any associated dose interruptions (or discontinuations) should be entered into the appropriate ecrfs. 100

234 M Protocol Amendment 2 Immunosuppressant levels should be monitored at the investigator's discretion during periods of interruption and reinitiation of study drugs. Serious Adverse Event If a subject experiences a serious drug-related (reasonable possibility) adverse event (other than those based on abnormal lab parameters discussed in Sections through 6.7.5) during the study, the study drugs should be permanently discontinued. If a subject experiences a serious adverse event considered unrelated (no reasonable possibility) to study drugs the study drugs may be continued. If the study drugs are interrupted because it is deemed necessary for clinical management, the interruption should not exceed 7 days. Because of the potential impact of interruption/discontinuation of study drugs on CNI levels, investigators should contact the SDP when an interruption/discontinuation is anticipated or required by protocol to ensure that a plan for appropriate CNI dose modification is in place. Similarly, for those recommencing study drugs after an interruption the investigator should contact the SDP to ensure that a plan for appropriate CNI dose adjustment is in place. The investigator should ensure that all serious adverse events are reported to AbbVie Safety within 24 hours of awareness. Serious adverse event follow-up information, including associated dose interruptions (or discontinuations), also needs to be reported to the Sponsor within 24 hours of awareness by entering updated SAE information into the appropriate ecrfs Management of Decreases in Hemoglobin Reductions in hemoglobin are a well characterized side effect of RBV exposure. Hemoglobin abnormalities should be managed according to Table 6. Management will be different for subjects without a history of known cardiac disease and subjects with known cardiac disease. If a subject experiences a hemoglobin decrease (as outlined in Table 6), a confirmatory test should be performed. If the hemoglobin decrease is confirmed, the management guidelines in Table 6 should be followed. 101

235 M Protocol Amendment 2 Use of hematologic growth factors such as erythropoietin, filgrastim or blood transfusions are permitted. Management of hematologic growth factor therapy is the responsibility of the investigator, and growth factors will not be provided by the Sponsor. Alternate management of hemoglobin decreases requires approval of the Study Designated Physician. Use of hematologic growth factors or blood transfusion should be recorded in the ecrf. In considering the management of RBV for a subject with a reduced hemoglobin, an investigator might wish to bear in mind the impact of the HCV subtype, 1a or 1b, on the treatment outcomes in Study M (see Introduction, discussion regarding virologic outcomes by HCV subtype in Study M11-652). 102

236 M Protocol Amendment 2 Table 6. Management of Hemoglobin Decreases Hemoglobin < 10.0 g/dl but 8.5g/dL Hemoglobin < 8.5 g/dl Hemoglobin decrease of 2 g/dl during a 4-week treatment period (Hb 10 g/dl) without symptoms and/or signs of cardiac disease Hemoglobin decrease of 2 g/dl during a 4-week treatment period (Hb 10 g/dl) with symptoms and/or signs of cardiac disease Hemoglobin < 10 g/dl Hemoglobin in Patients with No Cardiac Disease Study drugs may be continued; Consider RBV dose reduction. Continue to monitor hemoglobin per protocol. If hemoglobin increases to 10 g/dl, may increase RBV; with gradual dose increases towards original dose. If Hb decreases to < 8.5 g/dl, see appropriate row below. Contact SDP for discussion regarding work up, management of subject and study drugs. Enter into appropriate ecrfs and create corresponding adverse event (AE) if subject is discontinued or requires medical intervention. Hemoglobin in Patients with History of Stable Cardiac Disease Study drugs may be continued. Consider RBV dose reduction. Continue to monitor hemoglobin levels per protocol. If a subsequent hemoglobin result is greater than the level that triggered the dose reduction the investigator may elect to increase RBV; with gradual dose increases towards original dose. If hemoglobin does not increase; investigator may work up subject and manage as medically appropriate. If hemoglobin decreases to < 10 g/dl see appropriate row below. If the subject has symptoms consistent with their cardiac disease; work up and manage subject as medically appropriate; manage RBV per the rows above; AbbVie Study Designated Physician may be contacted to further discuss subject's management. Study drugs may be continued. Contact SDP for discussion regarding work up, management of the subject and study drugs. Enter into appropriate ecrfs and create corresponding adverse event (AE) Management of Transaminase Elevations In the setting of elevations in ALT investigators will follow the management described in Table 7. If at any time an investigator suspects rejection of the transplanted liver while the subject is receiving study drug, then dose adjustment of tacrolimus or cyclosporine 103

237 M Protocol Amendment 2 may be performed per the investigator's usual practice and the event captured on ecrf. If the abnormality is non-responsive to CNI adjustment and/or if the investigator wishes to empirically augment the immunosuppressive regimen, e.g., by commencement of high dose steroids or to add specific anti-rejection agents but without the availability of a liver biopsy confirming rejection, then study drugs should be discontinued. If the investigator wishes to continue study drugs, then the study designated physician should be contacted to obtain permission. If a liver biopsy is performed as part of the evaluation of rejection and the histologic findings are consistent with rejection as determined by the local pathologist, the investigator should follow the usual management of rejection and study drugs should be discontinued. Liver biopsy tissue obtained during the trial to evaluate rejection or other pathologic process should be read locally and the result recorded in the subject source documents. Liver biopsy slides should also be sent to the central pathologist for central reading. If the investigator wishes to continue study drugs in the setting of histologically confirmed rejection, then the study designated physician should be contacted in obtain permission. Because of the potential impact of interruption/discontinuation of study drugs on CNI levels investigators should contact the SDP when an interruption/discontinuation is anticipated or required by protocol to ensure that a plan for appropriate CNI dose modification is in place. If the findings of the liver biopsy are not consistent with rejection or if the clinical suspicion of rejection is low or the liver biopsy results are pending and the subject experiences an ALT level 5 ULN that is 2 Baseline, confirmatory testing should be performed. If the ALT level is confirmed 5 ULN and 2 Baseline and the HCV RNA is declining or is undetectable, then management should be per Table 7. If liver biopsy has not been performed, consideration should be made to performing a liver biopsy. If the investigator wishes to pursue alternative management of study drugs in the setting of ALT increases approval of the Study Designated Physician must first be obtained. 104

238 M Protocol Amendment 2 Table 7. Management of Confirmed ALT Levels Greater than or Equal to 5 ULN and Greater than or Equal to 2 Baseline ALT 10 ULN or with symptoms and signs of hepatitis present ALT 5 ULN but < 10 ULN without symptoms or signs of hepatitis Note: Discontinue study drugs. If rejection has been ruled out or liver biopsy results are pending. Fill in hepatic questionnaire, update concomitant medications ecrf and obtain appropriate additional testing (e.g., liver biopsy, serology for hepatitis A, B, and E, urine for drug screen). Evaluation and management as medically appropriate. Continue study drugs if rejection is not suspected and repeat LFTs and INR within 3 days and as clinically indicated until resolution. If ALT values during follow-up are increased from the prior values or there is increasing INR, or symptoms/signs of hepatitis then interrupt study drugs and manage as appropriate. SDP approval is required to restart subject on study drugs. If results of the liver biopsy become available and are consistent with rejection, study drugs should be discontinued and appropriate management and monitoring per usual practice should be performed. Fill in hepatic questionnaire, update concomitant medications ecrf, and as appropriate consider obtaining additional testing (e.g., liver biopsy, serology for hepatitis A, B, and E, urine for drug screen) Creatinine Clearance Creatinine clearance (CrCl) will be calculated throughout the study using Cockcroft-Gault method. CrCl values will be provided to the investigators. For a confirmed CrCl < 50mL/min the following should be performed if indicated: (1) Obtain a urine sample for urinalysis and urine for albumin, and another urine specimen for archive. Urine albumin testing will be performed on all samples with confirmed creatinine clearance < 50mL/min. Testing on the archival urine sample will be performed only as requested. 105

239 M Protocol Amendment 2 (2) Creatinine and chemistries should be repeated within 7 days and as clinically indicated until resolution. (3) Ribavirin dose should be adjusted per local label. Alternative management of RBV dose in the setting of reduced renal function will require approval of the AbbVie Study Designated Physician. (4) Concomitant medication dose reduction or discontinuation based on CrCL should be done, if applicable. (5) The Study Designated Physician should be contacted to discuss whether dose modification or drug substitution may be required for concomitant medications which may be impacted by the DAA regimen. If anti-hypertensive medications are adjusted, vital signs may be monitored to ensure appropriate blood pressure control. In addition, dose adjustment of cyclosporine or tacrolimus per the investigator's usual practice may be required. If CrCl does not improve by 2 scheduled study visits (2 CrCl values still < 50 ml/min) the SDP should be contacted to discuss further medical management, including management of study drugs. If CrCl improves, consideration should be given to the readjustment of any dose modifications that have been made. The investigator should ensure that any concomitant medication changes, RBV dose reductions, and study drugs discontinuations, as well as consequent related adverse events are captured on an ecrf. 106

240 M Protocol Amendment Protocol Deviations The investigator should not implement any deviation from the protocol without prior review and agreement by the Sponsor and in accordance with the Independent Ethics Committee (IEC)/Independent Review Board (IRB) and local regulations, except when necessary to eliminate an immediate hazard to study subjects. When a deviation from the protocol is deemed necessary for an individual subject, the investigator must contact the following AbbVie personnel: Primary Contact: Such contact must be made as soon as possible to permit a review by the Sponsor to determine the impact of the deviation on the subject and/or the study. Any significant protocol deviations affecting subject eligibility and/or safety must be reviewed and/or approved by the IEC/IRB and regulatory authorities, as applicable, prior to implementation. 8.0 Statistical Methods and Determination of Sample Size 8.1 Statistical and Analytical Plans There will be interim analyses after all subjects have completed treatment or prematurely discontinued study drugs, and after the last subject has reached Post-Treatment Week 12 or prematurely discontinued study. For each of these interim analyses, appropriate 107

241 M Protocol Amendment 2 database clean up procedures will be performed. There will be no statistical adjustment employed due to these analyses as this is a single arm, open-label trial and no changes to the trial design will be made as a result of these analyses. SAS (SAS Institute, Inc., Cary, NC) for the UNIX operating system will be used for all analyses. All confidence intervals will be 2-sided with an α level of Descriptive statistics will be provided, such as the number of observations (N), mean, and standard deviation (SD) for continuous variables and counts and percentages for discrete variables. Efficacy, safety, and demographic analyses will be performed on the intent-to-treat (ITT) population defined as all enrolled subjects who receive at least one dose of study drugs. No data will be imputed for any efficacy or safety analysis except for the PRO questionnaires and for analyses of the HCV RNA endpoints of RVR, EOTR, and all SVR endpoints. If a respondent answers at least 50% of the items in a multi-item scale of the SF-36v2, the missing items will be imputed with the average score of the answered items in the same scale. In cases where the respondent did not answer at least 50% of the items, the score for that domain will be considered missing. The Mental and Physical Component Summary measures will not be computed if any domain is missing. For the HCVPRO total score, if a respondent answers at least 12 of the 16 items, the missing items will be imputed with the average score of the answered items. In cases where the respondent did not answer five or more items, the total score will be considered missing. For EQ-5D-5L index and VAS scores, no imputation will be performed for missing items. HCV RNA values will be selected for the analyses of HCV RNA endpoints of RVR, EOTR, and all SVR endpoints based on the defined visit windows. When there is no HCV RNA value in a visit window based on defined visit windows, the closest values before and after the window, regardless of the value chosen for the subsequent and preceding window, will be used for the flanking imputation described below. For flanking imputation, if a subject has a missing HCV RNA value at a Post-Baseline Visit but with undetectable or unquantifiable HCV RNA levels at both the preceding 108

242 M Protocol Amendment 2 value and succeeding value, the HCV RNA level will be considered undetectable or unquantifiable, respectively, at this visit for this subject. Subsequent to this flanking imputation, if a subject is missing a value for the visit window associated with the analysis, the subject will be imputed as a visit failure (i.e., not undetectable or unquantifiable) for analyses of RVR and EOTR. Following flanking imputation for SVR analyses (e.g., SVR 12, SVR 24 ), if there is no value in the appropriate window but there is an HCV RNA value after the window, then it will be imputed into the SVR window. Subsequent to this imputation, if a subject is missing a value for the window associated with the SVR analysis, the subject will be imputed as a failure (i.e., not undetectable or unquantifiable). Relapse is defined as confirmed HCV RNA LLOQ in the PTP for subjects with HCV RNA < LLOQ at Final Treatment Visit who complete treatment. If the last available post-treatment value is LLOQ, then the subject will be considered a relapse and will not require confirmation. Virologic failure during treatment includes subjects who fail to suppress at the end of treatment (confirmed HCV RNA LLOQ at Final Treatment Visit) or experience virologic breakthrough which is defined as confirmed HCV RNA LLOQ (defined as two consecutive HCV RNA measurements LLOQ) at any point during treatment after HCV RNA < LLOQ Demographics Demographics and baseline characteristics will be summarized for the ITT population. Demographics include age, weight, and BMI, and the frequency of gender, race and ethnicity. Baseline characteristics will include HCV genotype 1 subtype (1a, 1b, or other), IL28B genotype ([CC, CT, or TT] and [CC or non-cc]), baseline HCV RNA levels ([continuous] and [< 800,000 IU/mL or 800,000 IU/mL]), baseline IP-10 ([continuous] and [< 600 pg/ml or 600 pg/ml]), baseline HOMA-IR (< 3 mu mmol/l 2 or 3 mu mmol/l 2 ), treatment status prior to liver 109

243 M Protocol Amendment 2 transplantation (treatment-naïve, treatment-experienced), time since liver transplantation (months), donor type (living or deceased), immunosuppressant medication (tacrolimus or cyclosporine), and tobacco (user, ex-user, or non-user) and alcohol use (drinker, ex-drinker, or non-drinker) status. Summary statistics (N, mean, median, SD, and range) will be generated for continuous variables (e.g., age and BMI). The number and percentage of subjects will be presented for categorical variables (e.g., gender and race) Efficacy All efficacy analyses will be performed on the intent-to-treat (ITT) population, defined as all subjects who were enrolled and received at least one dose of study drugs Primary Efficacy Endpoint The primary efficacy endpoint is the percentage of subjects with SVR 12 (HCV RNA < LLOQ 12 weeks after the last actual dose of study drugs). The simple percentage of subjects with SVR 12 will be calculated and a 2-sided 95% confidence interval will be calculated using the normal approximation to the binomial Secondary Efficacy Endpoints The secondary efficacy endpoints are: 1) SVR 24 (HCV RNA < LLOQ 24 weeks after the last actual dose of study drugs), 2) virologic failure during treatment (defined as confirmed HCV RNA LLOQ after HCV RNA < LLOQ during treatment or confirmed HCV RNA LLOQ at the end of treatment) and 3) post-treatment relapse (defined as confirmed HCV RNA LLOQ between end of treatment and 12 weeks after the last dose of study drugs among subjects completing treatment and with HCV RNA < LLOQ at the end of treatment). The simple percentage of subjects with SVR 24, the simple percentage of subjects with virologic failure and the simple percentage of subjects with post-treatment relapse will be calculated and a corresponding 2-sided 95% confidence interval will be calculated using the normal approximation to the binomial. 110

244 M Protocol Amendment Subgroup Analysis The percentage (and 2-sided confidence intervals) of subjects with SVR 12 will be presented by the following subgroups: IL28B genotype (CC or non-cc), (CC, CT, or TT); HCV genotype 1 subtype (1a, 1b, other); Baseline HCV RNA level (< 800,000 IU/mL or 800,000 IU/mL); Baseline IP-10 (< 600 ng/ml or 600 ng/ml); Sex (Male versus female); Age (< 65 versus 65 years); Race (black versus non-black); Ethnicity (Hispanic versus none); Geographic Region (North America or Spain); BMI (< 30 or 30 kg/m 2 ); History of Diabetes (yes/no) Additional Efficacy Endpoints The following additional efficacy endpoints will be summarized and analyzed as specified. the percentage of subjects with RVR (HCV RNA < LLOQ at Week 4) the percentage of subjects with EOTR (HCV RNA < LLOQ at Week 24) the percentage of subjects with unquantifiable HCV RNA at each Post-Baseline Visit throughout the Treatment Period using only subjects with data in each visit window (i.e., no imputation for missing data); the percentage of subjects meeting each and any virologic failure criteria during treatment; 111

245 M Protocol Amendment 2 the percentage of subjects with HCV RNA < LLOQ 4 weeks after the last actual dose of study drugs (SVR 4 ); the percentage of subjects with HCV RNA < LLOQ 12 weeks after the last planned dose of study drugs (SVR 12planned ); the percentage of subjects with HCV RNA < LLOQ 24 weeks after the last planned dose of study drugs (SVR 24planned ); the percentage of subjects who completed study drugs with HCV RNA < LLOQ at the Final Treatment Visit who subsequently relapse at any time post-treatment; time to suppression of HCV RNA during the Treatment Period; time to relapse at anytime post-treatment. The percentage of subjects with RVR, EOTR, SVR 4, SVR 12planned, and SVR 24planned, and relapse will be calculated as a simple percentage and 2-sided 95% confidence intervals will be calculated using the normal approximation to the binomial; missing data will be imputed as described in Section 8.1. All other endpoints will be presented using data as observed, i.e., not performing any missing data imputations. From HCV RNA levels, the time to suppression on treatment and time to relapse post-treatment will be calculated for each subject, and the median time will be estimated using Kaplan-Meier methodology for right censored observations Patient Reported Outcomes The following exploratory analyses of patient reported outcomes (PROs) will be performed: mean change from baseline in HCVPRO total score to each applicable post-baseline time point; mean change from baseline in EQ-5D-5L health index score and VAS score to each applicable post-baseline time point; 112

246 M Protocol Amendment 2 mean change from baseline in the SF-36V2 Mental Component Summary (MCS) and Physical Component Summary (PCS) scores to each applicable post-baseline time point the percentage of subjects with no decrease from baseline in SF-36 MCS and PCS greater than or equal to the minimal important difference (MID); Summary statistics (n, mean, SD, median, minimum and maximum) at each visit and for change from baseline to each visit will be provided for the HCVPRO total score, the EQ-5D-5L health index and VAS scores, and the SF-36V2 PCS and MCS scores. For HCVPRO total score, a continuous plot will be provided with percent change from baseline to Final Treatment Visit on the horizontal axis and the cumulative percent of subjects experiencing up to that change on the vertical axis. The MID for the SF-36V2 will be a decrease of 5 points from baseline to the Final Treatment Visit for both the MCS and PCS scores. The percentage of subjects with a change from Baseline to Final Treatment Visit in the MCS and PCS scores > the appropriate MID will be calculated. Additional analyses of PROs will be performed as useful and appropriate Resistance Analyses The genes of interest for sequencing in this study are those encoding amino acids 1 to 181, NS5A amino acids 1 to 215, and NS5B amino acids 300 to 591. Only samples with an HCV RNA level of 1000 IU/mL will undergo sequence analysis in order to allow accurate assessment of products of amplification. Therefore, if the HCV RNA level at the time of virologic failure is < 1000 IU/mL, the sample closest in time after the failure with an HCV RNA level 1000 IU/mL will be used. For each DAA target, resistance-associated signature amino acid variants will be identified by AbbVie Clinical Virology. Amino acid positions where resistance-associated variants have been identified in vitro and/or in vivo: 155, 156, and 113

247 M Protocol Amendment in NS3 for ABT-450; 28, 30, 31, 58, and 93 in NS5A for ABT-267; 316, 368, 414, 448, 553, 554, 555, 556, 558, 559, and 561 in NS5B for ABT-333. This list may be expanded if treatment-emerged resistance-conferring variants are identified at additional amino acid positions in DAA-treated patients. The following resistance variable will be summarized for all enrolled subjects who were treated with study drug and who have resistance data available: The variants at each amino acid position by nucleotide population sequencing at baseline compared to the appropriate prototypic reference sequence. The following resistance variable will be summarized for all subjects who experience virologic failure and who have resistance data available: The variants at each amino acid position by nucleotide population and/or clonal sequencing for each post-baseline time point that is analyzed compared to baseline and prototypic reference sequences. For all subjects, the baseline HCV amino acid sequence as determined by population nucleotide sequencing will be compared to the appropriate prototypic reference amino acid sequence for each DAA target (NS3, NS5A, and NS5B). A listing by subject of all variants present at baseline at signature resistance-associated amino acid positions relative to the appropriate prototypic reference amino acid sequence will be provided for each DAA target (NS3, NS5A, and NS5B). Furthermore, for those subjects who experience virologic failure, the HCV amino acid sequence as determined by population sequencing at selected time points (including but not limited to those listed below) will be compared with the baseline and appropriate prototypic reference amino acid sequences. Included time points are (1) time of virologic failure or sample closest in time after failure with an HCV RNA level of 1000 IU/mL, (2) 24 weeks post-treatment, provided that resistance-associated variants were detected by either population or clonal sequencing at the time of failure, and (3) 48 weeks post-treatment, provided that resistance-associated variants were detected by either population or clonal sequencing at Post-Treatment 114

248 M Protocol Amendment 2 Week 24. Listings by subject of all variants relative to the baseline amino acid sequence (i.e., those variants that emerge on treatment) will be provided for each DAA target (NS3, NS5A, and NS5B). In addition, listings by subject of variants at signature resistance-associated amino acid positions relative to baseline and the appropriate prototypic reference amino acid sequences will also be produced. For subjects who experience virologic failure, clonal sequencing of a given target (NS3, NS5A, or NS5B) will be performed at the time of virologic failure only if no variants are detected at signature resistance-associated amino acid positions by population sequencing. In addition, at Post-Treatment Weeks 24 and 48, clonal sequencing of a given target will be performed if population sequencing was performed at that time point and no variants were detected at signature resistance-associated amino acid positions. If resistance-associated variants are not detected by clonal sequencing in a given target for a subject at the time of failure or in a post-treatment sample, then that target will not be sequenced in subsequent samples from that subject. For the subset of samples for which clonal sequencing is performed, the amino acid variants determined by clonal sequencing will be summarized by counting the number of clones whose amino acid sequence does not match that of the population baseline sequence at each time point and amino acid position, out of the total number of clones analyzed. A subject who experiences virologic failure will be considered to have emerged/enriched variants if at any time point after baseline a variant (that was not detected at baseline) is detectable by population sequencing, or alternatively if at any time point after baseline the increase from baseline in percentage of clones of any variant by clonal sequencing is greater than 20%. If there are at least 2 subjects of the same subgenotype with an emerged/enriched variant meeting this definition, then the number and percentage of subjects with emerged/enriched variants from baseline will be summarized by amino acid position and variant. A separate listing of all these subjects and the emerged variants will be provided. To evaluate linkage between emerged or enriched variants by population sequencing, when post-baseline variants are present within a target at 2 or more signature 115

249 M Protocol Amendment 2 resistance-associated amino acid positions, and no mixture is detected at either position, these will be reported as linked variants. A listing by subject and time point of the linked variants will be provided. Furthermore, where clonal sequencing is performed, the number of clones that have the same multiple variants within a DAA target at 2 signature resistance-associated amino acid positions will be determined. A listing by subject and time point of the linked variants will be provided Safety All subjects who receive at least one dose of study drugs will be included in the safety analyses Adverse Events Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 16 Treatment-emergent events are defined as any event that begins or worsens in severity after initiation of study drugs through the last dose of study drugs. The number and percentage of subjects with treatment-emergent adverse events will be tabulated by primary MedDRA System Organ Class (SOC) and preferred term. The tabulation of the number of subjects with treatment-emergent adverse events also will be provided with further breakdown by severity rating and relationship to study drugs. Subjects reporting more than one adverse event for a given MedDRA preferred term will be counted only once for that term using the most severe incident for the severity rating table and the most related for the relationship to study drugs table. Subjects reporting more than one type of event within a SOC will be counted only once for that SOC. Additional analyses will be performed if useful and appropriate Clinical Laboratory Data Clinical laboratory tests will be summarized at each visit during the Treatment Period. The baseline value will be the last measurement prior to the initial dose of study drugs. 116

250 M Protocol Amendment 2 Mean changes from Baseline to each treatment and post-treatment visit will be summarized. Laboratory data values will be categorized as low, normal, or high based on reference ranges of the laboratory used in this study. The number and percent of subjects who experience post-baseline shifts in clinical laboratory values from low/normal to high and high/normal to low based on the normal range will be summarized. In addition, the number and percentage of subjects with post-baseline values meeting pre-specified criteria for Potentially Clinically Significant (PCS) laboratory values will be summarized. Additional analyses will be performed if useful and appropriate Vital Signs Data Vital sign measurements will be summarized at each visit during the TP, mean changes in temperature, systolic and diastolic blood pressure, pulse, and weight from Baseline to each treatment and post-treatment visit will be summarized descriptively. The baseline value will be the last measurement prior to the initial dose of study drugs. Frequencies and percentages of subjects with post-baseline values meeting pre-defined criteria for PCS vital sign values will also be summarized Pharmacokinetic and Exposure-Response Analyses Plasma concentrations of ABT-450, possible ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ritonavir and ribavirin will be tabulated for each subject and group. Blood concentrations of cyclosporine and tacrolimus will be tabulated for each subject and group. Summary statistics will be computed for each time and visit. Plasma concentration data from this study may be combined with data from other studies and analyzed using the following general methodology. 117

251 M Protocol Amendment 2 Population pharmacokinetic analyses will be performed using the actual sampling time relative to dosing. Pharmacokinetic models will be built using a non-linear mixed-effect modeling approach with the NONMEM software (version VI, or higher version). The structure of the starting pharmacokinetic model will be based on the pharmacokinetic analysis of data from previous studies. Apparent oral clearance (CL/F) and apparent volume of distribution (V/F) of the PK analytes will be the pharmacokinetic parameters of major interest in the NONMEM analyses. If necessary, other parameters, including the parameters describing absorption characteristics, may be fixed if useful in the analysis. The evaluation criteria described below will be used to examine the performance of different models. The objective function of the best model is significantly smaller than the alternative model(s). The observed and predicted concentrations from the preferred model are more randomly distributed across the line of unity (a straight line with zero intercept and a slope of one) than the alternative model(s). Visual inspection of model fits standard errors of model parameters and change in inter-subject and intra-subject error. Once an appropriate base pharmacokinetic model (including inter- and intra-subject error structure) is developed, empirical Bayesian estimates of individual model parameters will be calculated by the posterior conditional estimation technique using NONMEM. The relationship between these conditional estimates CL/F and V/F values with only potentially physiologically relevant or clinically meaningful covariates (such as subject age, sex, body weight, concomitant medications, laboratory markers of hepatic or renal function, etc.) will be explored using either stepwise forward selection method, or generalized additive method (GAM) or another suitable regression/smoothing method at a significance level of After identification of all relevant covariates, a stepwise backward elimination of covariates from the full model will be employed to evaluate the significance (at P < 0.005, corresponding to an increase in objective function > 7.88 for one degree of freedom) of each covariate in the full model. 118

252 M Protocol Amendment 2 In general, all continuous covariates will be entered in the model, initially in a linear fashion, with continuous covariates centered around the median value. Linear or non-linear relationships of primary pharmacokinetic parameters with various covariates may also be explored. For example: TVCLi = + Theta(2) (Comedication [1,2, ] + Theta(3) (WTi-median value) + Theta(4) (AGEi - median value). Where TVCLi = Typical value of clearance for an individual i1, Theta(1) is the intercept and Theta(2) - (4) are regression parameters relating the fixed effects (weight and age centered on the median value) to clearance. Relationship between exposure and clinical observations (antiviral activity) will be explored. Exposure-response relationships for primary and secondary efficacy variables and/or some safety measures of interest may also be explored. The relationship between exposure (e.g., population pharmacokinetic model predicted concentrations over time or average concentrations or AUC or trough concentrations of the individual model-predicted pharmacokinetic profiles, or some other appropriate measure of exposure) and antiviral activity will be explored. Exposure response relationships will be explored using a semi-mechanistic viral dynamic model and/or logistic regression analyses. The viral dynamic model will account for target cell growth and death, infection of target cells, infected cell infection and death rate, production of virus by infected cells, and inhibition of production of virus by the various DAAs. Effect of ribavirin will be explored on infection of target cells by virus. Models will explore mutation of the wild type to single and/or double mutant species depending on the available clinical resistance data. Additional adjustments to the structural and error models will be made during model development as appropriate. 119

253 M Protocol Amendment 2 Logistic regression analyses will explore the relationship between exposure and one or more virologic endpoints (e.g., RVR, EVR, SVR 4, SVR 12, relapse following end of treatment and breakthrough on treatment). Additionally, relationship between exposure and safety endpoints of interest may also be explored. 8.2 Determination of Sample Size It is planned to enroll 30 subjects to this study. With a sample size of 30 subjects and an observed SVR 12 rate of 80%, the 2-sided 95% confidence interval, using the normal approximation to the binomial, will be (65.7%, 94.3%) with a width of 28.6%. Subjects who do not have data at PTP Week 12 (after performing the described imputation) count as failures for SVR 12 so no adjustment for dropout is applicable. The 2-sided 95% confidence intervals using the normal approximation to the binomial for various SVR 12 rates, given a sample size of 30 are presented in Table 8. Table 8. 2-Sided 95% Confidence Intervals Using the Normal Approximation to the Binomial for SVR 12 Rates Observed SVR 12 Rate 2-Sided 95% CI N = 30 60% (42.5%, 77.5%) 70% (53.6%, 86.4%) 80% (65.7%, 94.3%) From the perspective of safety assessment, the probability that a given adverse event would not be observed in a group of 30 subjects is shown in the second column of Table 9 for various true population incidence rates. With 30 subjects, the probability is at least 96% to observe an adverse event with an incidence rate of 10% or higher. 120

254 M Protocol Amendment 2 Table 9. Probability of Not Observing an Adverse Event or Lab Abnormality for Various True Incidence Rates True Incidence Rate Probability of Not Observing < < < Randomization Methods There is no randomization in this study. All enrolled subjects will receive ABT-450/r/ABT ABT-333 coadministered with RBV for 24 weeks. 9.0 Ethics 9.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, the Investigator's Brochure, the informed consent and all other forms of subject information related to the study (e.g., advertisements used to recruit subjects) and any other necessary documents be reviewed by an IEC/IRB. The IEC/IRB will review the ethical, scientific and medical appropriateness of the study before it is conducted. IEC/IRB approval of the protocol, informed consent and subject information and/or advertising, as relevant, will be obtained prior to the authorization of drug shipment to a study site. Any amendments to the protocol will require IEC/IRB approval prior to implementation of any changes made to the study design. The investigator will be required to submit, maintain and archive study essential documents according to International Conference on Harmonization (ICH) GCP. 121

255 M Protocol Amendment 2 Any serious adverse events that meet the reporting criteria, as dictated by local regulations, will be reported to both responsible Ethics Committees and Regulatory Agencies, as required by local regulations. During the conduct of the study, the investigator should promptly provide written reports (e.g., ICH Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB of any changes that affect the conduct of the study and/or increase the risk to subjects. Written documentation of the submission to the IEC/IRB should also be provided to the Sponsor. 9.2 Ethical Conduct of the Study The study will be conducted in accordance with the protocol, ICH guidelines, applicable regulations and guidelines governing clinical study conduct and the ethical principles that have their origin in the Declaration of Helsinki. Responsibilities of the clinical investigator are specified in Appendix A. 9.3 Subject Information and Consent The investigator or his/her representative will explain the nature of the study to the subject, and answer all questions regarding this study. Prior to any study-related screening procedures being performed on the subject, the informed consent statement will be reviewed and signed and dated by the subject, the person who administered the informed consent, and any other signatories according to local requirements. A copy of the informed consent form will be given to the subject and the original will be placed in the subject's medical record. An entry must also be made in the subject's dated source documents to confirm that informed consent was obtained prior to any study-related procedures and that the subject received a signed copy. IL28B genotypes will be determined for each subject. Consent for determination of IL28B status will be included in the study informed consent. Additional pharmacogenetic analysis, other than IL28B analysis will only be performed if the subject has voluntarily signed and dated the IEC/IRB approved pharmacogenetic and informed consents, after the nature of the testing has been explained and the subject has had the opportunity to ask 122

256 M Protocol Amendment 2 questions. The subject must provide consent specific to pharmacogenetic before the pharmacogenetic testing is performed. If the subject does not consent to the additional pharmacogenetic testing it will not impact the subject's participation in the study Source Documents and Case Report Form Completion 10.1 Source Documents Source documents are defined as original documents, data and records. This may include hospital records, clinical and office charts, laboratory data/information, subjects' diaries or evaluation checklists, pharmacy dispensing and other records, recorded data from automated instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays. Data collected during this study must be recorded on the appropriate source documents. The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB review, and regulatory inspection(s), providing direct access to source data documents Case Report Forms Case report forms (CRF) must be completed for each subject screened/enrolled in this study. These forms will be used to transmit information collected during the study to the Sponsor and regulatory authorities, as applicable. The CRF data for this study are being collected with an EDC system called Rave provided by the technology vendor Medidata Solutions Incorporated, NY, USA. The EDC system and the study-specific electronic case report forms (ecrfs) will comply with Title 21 CFR Part 11. The documentation related to the validation of the EDC system is available through the vendor, Medidata, while the validation of the study-specific ecrfs will be conducted by the Sponsor and will be maintained in the Trial Master File at the Sponsor. The investigator will document subject data in his/her own subject files. These subject files will serve as source data for the study. All ecrf data required by this protocol will 123

257 M Protocol Amendment 2 be recorded by investigative site personnel in the EDC system. All data entered into the ecrf will be supported by source documentation. The investigator or an authorized member of the investigator's staff will make any necessary corrections to the ecrf. All change information, including the date and person performing the corrections, will be available via the audit trail, which is part of the EDC system. For any correction, a reason for the alteration will be provided. The ecrfs will be reviewed periodically for completeness, legibility, and acceptability by the Sponsor personnel (or their representatives). The Sponsor (or their representatives) will also be allowed access to all source documents pertinent to the study in order to verify ecrf entries. The principal investigator will review the ecrfs for completeness and accuracy and provide his or her electronic signature and date to ecrfs as evidence thereof. Medidata will provide access to the EDC system for the duration of the trial through a password-protected method of internet access. Such access will be removed from investigator sites at the end of the site's participation in the study. Data from the EDC system will be archived on appropriate data media (CD-ROM, etc.) and provided to the investigator at that time as a durable record of the site's ecrf data. It will be possible for the investigator to make paper printouts from that media Data Quality Assurance Computer logic and manual checks will be created to identify items such as inconsistent study dates. Any necessary corrections will be made to the ecrf Use of Information Any pharmacogenetic research that may be done using DNA samples from this study will be experimental in nature and the results will not be suitable for clinical decision making or patient management. Hence, neither the investigator, the subject, nor the subject's physician (if different from the investigator) will be informed of individual subject pharmacogenetic results, should analyses be performed, nor will anyone not directly 124

258 M Protocol Amendment 2 involved in this research. Correspondingly, genetic researchers will have no access to subject identifiers. Individual results will not be reported to anyone not directly involved in this research other than for regulatory purposes. Aggregate pharmacogenetic information from this study may be used in scientific publications or presented at medical conventions. Pharmacogenetic information will be published or presented only in a way that does not identify any individual subject Completion of the Study The investigator will conduct the study in compliance with the protocol and complete the study within the timeframe specified in the contract between the investigator and the Sponsor. Continuation of this study beyond this date must be mutually agreed upon in writing by both the investigator and the Sponsor. The investigator will provide a final report to the IEC/IRB following conclusion of the study, and will forward a copy of this report to the Sponsor or their representative. The investigator must retain any records related to the study according to local requirements. If the investigator is not able to retain the records, he/she must notify the Sponsor to arrange alternative archiving options. The Sponsor will select the signatory investigator from the investigators who participate in the study. Selection criteria for this investigator will include level of participation as well as significant knowledge of the clinical research, investigational drug and study protocol. The signatory investigator for the study will review and sign the final study report in accordance with the European Medicines Agency (EMA) Guidance on Investigator's Signature for Study Reports. The end-of-study is defined as the date of the last subject's last visit. 125

259 M Protocol Amendment Investigator's Agreement 1. I have received and reviewed the investigator's Brochure for ABT-450, ABT-267, ABT-333 and the product labeling for ritonavir and RBV. 2. I have read this protocol and agree that the study is ethical. 3. I agree to conduct the study as outlined and in accordance with all applicable regulations and guidelines. 4. I agree to maintain the confidentiality of all information received or developed in connection with this protocol. 5. I agree that all electronic signatures will be considered the equivalent of a handwritten signature and will be legally binding. Protocol Title: Protocol Date: 08 April 2013 Open-label, Single Arm, Phase 2 Study to Evaluate the Safety and Efficacy of the Combination of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered with Ribavirin (RBV) in Adult Liver Transplant Recipients with Genotype 1 Hepatitis C Virus (HCV) Infection Signature of Principal Investigator Date Name of Principal Investigator (printed or typed) 126

260 M Protocol Amendment Reference List 1. Wiesner RH, Sorrell M, Villamil F; International Liver Transplantation Society Expert Panel. Report of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C. Liver Transpl. 2003;9(11):S Berenguer M, Palau A, Aguilera V, et al. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation. Am J Transplant. 2008;8(3): Gane EJ, Roberts SK, Stedman CAM, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo controlled, dose-escalation trial. The Lancet. 2010;376 (9751a): Zeuzem S, Asselah T, Angus PW, et al. Strong antiviral activity and safety of IFN sparing treatment with the protease inhibitor BI , the HCV polymerase inhibitor BI and ribavirin in patients with chronic hepatitis C. Hepatology. 2010;52 (Suppl.):876A. 5. Lok AS, Gardiner DF, Lawitz E, et al. Combination therapy with BMS and BMS alone or with PegIFN and RBV results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders [Abstract]. Hepatology. 2010;52 (Suppl.):877A. 6. Gane EJ, Stedman CA, Hyland RH, et al. Once Daily PSI-7977 plus RBV: Pegylated interferon-alfa not required for Complete Rapid viral response in Treatment-naive Patients with HCV GT2 or GT3. 62 nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4 8, Abstract

261 M Protocol Amendment 2 7. Chayama K, Takahashi S, Kawakami Y, et al. Dual Oral Combination Therapy with the NS5A Inhibitor BMS and the NS3 Protease Inhibitor BMS Achieved 90% Sustained Virologic Response (SVR 12 ) in HCV Genotype 1b-Infected Null Responders. 62 nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4 8, Abstract LB INCIVEK (telaprevir) [package insert]. Vertex Pharmaceuticals Incorporated; Cambridge, MA. 9. Victrelis (boceprevir) [package insert]. Schering Corporation, a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 10. Kwo PY, Ghabril M, Lacerda M, et al. Use of telaprevir plus peg interferon/ribavirin for null responders post OLT with advanced fibrosis/cholestatic hepatitis C. Abstract 845 DDW May 19 22, 2012; San Diego, California. 11. Coilly A, Roche B, Botta-Fridlund D, et al. Efficacy and safety of protease inhibitors for severe hepatitis c recurrence after liver transplantation: a first multicentric experience. J Hepatol. 2012;vol. 56:S Coilly A, Furlan V, Roche B, et al. Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence. Antimicrob Agents Chemother. 2012;56(11): doi: /AAC Abbott. ABT-450 Investigator's Brochure Edition Abbott. ABT-267 Investigator's Brochure Edition Abbott. ABT-333 Investigator's Brochure Edition Medical Dictionary for Regulatory Activities (MedDRA), version

262 M Protocol Amendment 2 Appendix A. Responsibilities of the Clinical Investigator Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site location. In signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is agreeing to the following: 1. Conducting the study in accordance with the relevant, current protocol, making changes in a protocol only after notifying AbbVie, except when necessary to protect the safety, rights or welfare of subjects. 2. Personally conducting or supervising the described investigation(s). 3. Informing all subjects, or persons used as controls, that the drugs are being used for investigational purposes and complying with the requirements relating to informed consent and ethics committees [e.g., independent ethics committee (IEC) or institutional review board (IRB)] review and approval of the protocol and amendments. 4. Reporting adverse experiences that occur in the course of the investigation(s) to AbbVie and the site director. 5. Reading the information in the Investigator's Brochure/safety material provided, including the instructions for use and the potential risks and side effects of the investigational product(s). 6. Informing all associates, colleagues, and employees assisting in the conduct of the study about their obligations in meeting the above commitments. 129

263 M Protocol Amendment 2 7. Maintaining adequate and accurate records of the conduct of the study, making those records available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, and retaining all study-related documents until notification from AbbVie. 8. Maintaining records demonstrating that an ethics committee reviewed and approved the initial clinical investigation and all amendments. 9. Reporting promptly, all changes in the research activity and all unanticipated problems involving risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, institution director) and/or directly to the ethics committees and AbbVie. 10. Following the protocol and not make any changes in the research without ethics committee approval, except where necessary to eliminate apparent immediate hazards to human subjects. 130

264 M Protocol Amendment 2 Appendix B. List of Protocol Signatories Name Title Functional Area 131

265 M Protocol Amendment 2 Appendix C. Clinical Toxicity Grades 132

266 M Protocol Amendment 2 133

267 M Protocol Amendment 2 134

268 M Protocol Amendment 2 Appendix D. Protocol Amendment: List of Changes The summary of changes is listed in Section 1.1. Specific Protocol Changes: Section 1.2 Synopsis Heading "Diagnosis and Main Criteria for Inclusion/Exclusion:" "Main Exclusion:" Add: new medication to list in Criterion 2 "Hormonal contraceptives*" Section 1.2 Synopsis Heading "Diagnosis and Main Criteria for Inclusion/Exclusion:" "Main Exclusion:" Add: footnote "*" to medication list in Criterion 2 * Use of hormonal contraceptives requires SDP approval. Section 3.0 Introduction Subsection Combination Dosing in HCV-Infected Subjects in Study M Fourth paragraph, fifth sentence previously read: Grade 3 (or higher) elevations of alanine aminotransferase (ALT) occurred in 5 subjects (all without bilirubin elevation) all of whom were asymptomatic. Has been changed to read: Grade 3 (or higher) elevations of alanine aminotransferase (ALT) occurred in 5 subjects (all without bilirubin elevation) all of whom were asymptomatic; some of these elevations were seen in subjects taking concomitant hormonal contraceptives. Section Exclusion Criteria Following fourth bullet in Criterion 4 Sub-bullet previously read: currently using at least one effective method of birth control at the time of screening and two effective methods of birth control while receiving study 135

269 M Protocol Amendment 2 Has been changed to read: drugs (as outlined in the subject information and consent form or other subject information documents), starting with Study Day 1 and for 7 months after stopping study drug as directed by the local ribavirin label. (Note: Contraceptives containing ethinyl estradiol or depot progesterone are not considered effective while receiving study drug treatment.) currently using at least one effective method of birth control at the time of screening and two effective methods of birth control while receiving study drugs (as outlined in the subject information and consent form or other subject information documents), starting with Study Day 1 and for 7 months after stopping study drug as directed by the local ribavirin label. (Note: Hormonal contraceptives, including oral, topical, injectable or implantable varieties, may not be used while receiving study drug treatment.) Table 1. Medications Contraindicated for Use with the Study Drug Regimen Add: new medication "Hormonal contraceptives*" Table 1. Medications Contraindicated for Use with the Study Drug Regimen Add: footnote "*" * Use of hormonal contraceptives requires SDP approval. Section Prohibited Therapy Add: third paragraph Hormonal contraceptives (including oral, topical, injectable or implantable varieties) may not be used from 2 weeks prior to the first dose of study drug until 2 weeks after the end of study drug dosing unless approved by the Study Designated Physician. Post-menopausal hormone replacement therapy may be used at the discretion of the Investigator. 136

270 M Protocol Amendment 2 Appendix B. List of Protocol Signatories Previously read: Name Title Functional Area Has been changed to read: Name Title Functional Area 137

271 Document Approval Study M Open-label, Single Arm, Phase 2 Study to Evaluate the Safety and Efficacy of the Combination of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered with Ribavirin (RBV) in Adult Liver Transplant Recipients with Genotype 1 Hepatitis C Virus (HCV) Infection - Amendment 2 - EudraCT Apr2013 Version: 1.0 Date: 08-Apr :59:36 PM Abbott ID: F9F6803D0DBF en Signed by: Date: Meaning Of Signature:

272 M Statistical Analysis Plan Version April Title Page Statistical Analysis Plan Study M Open-label, Phase 2 Study to Evaluate the Safety and Efficacy of the Combination of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 With or Without Ribavirin (RBV) in Adult Liver Transplant Recipients with Genotype 1 Hepatitis C Virus (HCV) Infection Date: 25 April

273 M Statistical Analysis Plan Version April Table of Contents 1.0 Title Page Table of Contents Introduction Study Objectives, Design and Procedures Objectives Primary Objectives Secondary Objectives Design Diagram Sample Size Interim Analysis Analysis Populations Definition for Analysis Populations Variables Used for Stratification of Randomization Analysis Conventions Definition of Baseline and Final Assessment Definition of Analysis Windows Missing Data Imputation Demographics, Baseline Characteristics, Medical History, and Previous/Concomitant Medications Demographic and Baseline Characteristics Medical History Previous Treatment and Concomitant Medications Patient Disposition Study Drug Exposure and Compliance Exposure Compliance Pharmacokinetic Variables Efficacy Analysis General Considerations Primary Efficacy Analysis Secondary Efficacy Analyses

274 M Statistical Analysis Plan Version April Additional Efficacy Analysis Resistance Analysis Patient Reported Outcome Handling of Multiplicity Efficacy Subgroup Analysis Safety Analysis General Considerations Analysis of Adverse Events Treatment-Emergent Adverse Events Tabulations of Treatment-Emergent Adverse Events Listing of Adverse Events Analysis of Laboratory Data Variables and Criteria Defining Abnormality Statistical Methods Analysis of Vital Signs and Weight Variables and Criteria Defining Abnormality (If Applicable) Statistical Methods Summary of Changes References...50 List of Tables Table 1. Two-Sided 95% Confidence Intervals Using the Normal Approximation to the Binomial for SVR 12 Rates...8 Table 2. Probability of Not Observing an Adverse Event or Lab Abnormality for Various True Incidence Rates... 8 Table 3. Analysis Time Windows for HCV RNA and Resistance Endpoints (Treatment Period) Table 4. Analysis Time Windows for HCV RNA and Resistance Endpoints (Post-Treatment Period) Table 5. Analysis Time Windows for PRO Instruments Table 6. Laboratory Data and Vital Sign Visit Windows (Treatment Period)

275 M Statistical Analysis Plan Version April 2014 Table 7. Laboratory Data and Vital Sign Visit Windows (Post-Treatment Period) Table 8. Baseline Fibrosis Stage Table 9. Criteria for Potentially Clinically Significant Hematology Values Table 10. Criteria for Potentially Clinically Significant Chemistry Values Table 11. Definitions of CTCAE Grade 1, 2, 3, and Table 12. Criteria for Potentially Clinically Significant Vital Sign Values

276 M Statistical Analysis Plan Version April Introduction This statistical analysis plan (SAP) describes the statistical analysis to be completed by the AbbVie Statistics and Statistical Programming Departments for study Protocol M It provides details to guide the analyses for baseline, efficacy, and safety variables and describes the populations and variables that will be analyzed and the statistical methods that will be utilized. Analyses will be performed using SAS Version 9.3 (SAS Institute, Inc., Cary, NC) or later under the UNIX operating system. This is the first version of SAP for Protocol M Any deviations from the planned statistical analysis will be described and justified in the final clinical study report, as appropriate. 4.0 Study Objectives, Design and Procedures 4.1 Objectives Primary Objectives The primary objectives of this study are to assess safety and efficacy (the percentage of subjects achieving a 12-week sustained virologic response, SVR 12 (HCV ribonucleic acid [RNA] < lower limit of quantification [LLOQ] 12 weeks following treatment) of coformulated ABT-450/r and ABT-267 (ABT-450/r/ABT-267) and ABT-333 with or without RBV for 24 weeks in HCV genotype 1 infected adult liver transplant recipients Secondary Objectives The secondary objectives of this study are to assess the percentage of subjects with SVR 24 (HCV RNA < LLOQ 24 weeks following treatment), the percentage of subjects with virologic failure during treatment, and the percentage of subjects with relapse post-treatment. 5

277 M Statistical Analysis Plan Version April Design Diagram This is a Phase 2, open-label, multi-center study evaluating the safety and efficacy of the ABT-450/r/ABT-267 and ABT-333, with and without RBV for 24 weeks in adult liver transplant recipients with recurrent HCV genotype 1 infection. Approximately 70 HCV genotype 1 infected treatment-naïve or treatment-experienced adults ([cifn or PegIFN] with or without RBV) will be enrolled into the study at approximately 17 sites. The study design includes two cohorts of subjects: Cohort 1 (consisting of Arm A) and Cohort 2 (consisting of Arms B and C). Cohort 2 will be enrolled after Cohort 1 is enrolled. Subjects within Cohort 2 will be assigned to a study arm based on their HCV sub-genotype and prior HCV treatment experience. HCV sub-genotype 1b infected subjects who are treatment-naïve or who received prior IFN therapy (post-transplant) and were treatment responders will be enrolled and assigned to Study Arm C. All other subjects enrolled in Cohort 2 will be assigned to Study Arm B. The duration of the study for an individual subject will be up to 72 weeks (not including a screening period of up to 35 days duration and a Study Treatment Lead-In Period of up to 14 days duration), as shown in Figure 1. The Lead-In Period is applicable to Cohort 1 (Arm A) only. This study will consist of two parts: a 24-week Treatment Period (TP) and a 48-week Post-Treatment Period (PTP). Figure 1. Study Schematic Cohort 1 (Study Arm A): 6

278 M Statistical Analysis Plan Version April 2014 Cohort 2 (Study Arms B and C): Cohort 1 has completed enrollment under the original protocol, including amendments 1 and 2, and consists of 34 subjects. Cohort 2 will begin enrollment under amendment 3 of the protocol (to include subsequent versions, as applicable) and will consist of approximately 40 subjects, some with IFN/RBV treatment failure post liver transplant and subjects with more advanced liver fibrosis but who are non-cirrhotic. 4.3 Sample Size It is planned to enroll 30 subjects in Cohort 1 (Arm A) and 40 subjects in Cohort 2 (Arm B and Arm C) in this study. With a sample size of 30 subjects and an observed SVR 12 rate of 80%, the 2-sided 95% confidence interval, using the normal approximation to the binomial, will be (65.7%, 94.3%) with a width of 28.6%. Subjects who do not have data at PTP Week 12 (after performing the described imputation) count as failures for SVR 12 so no adjustment for dropout is applicable. The 2-sided 95% confidence intervals using the normal approximation to the binomial for various SVR 12 rates, given a sample size of 30 are presented in Table 1. 7

279 M Statistical Analysis Plan Version April 2014 Table 1. Two-Sided 95% Confidence Intervals Using the Normal Approximation to the Binomial for SVR 12 Rates Observed SVR 12 Rate 2-Sided 95% CI (N = 30) 60% (42.5%, 77.5%) 70% (53.6%, 86.4%) 80% (65.7%, 94.3%) From the perspective of safety assessment, the probability that a given adverse event would not be observed in a group of 30 subjects is shown in the second column of Table 2 for various true population incidence rates. With 30 subjects, the probability is at least 96% to observe an adverse event with an incidence rate of 10% or higher. Table 2. Probability of Not Observing an Adverse Event or Lab Abnormality for Various True Incidence Rates True Incidence Rate Probability of Not Observing < < < Interim Analysis There will be interim analyses after all subjects in Cohort 1 (Arm A) have reached Post-Treatment Week 12 or prematurely discontinued study and after all subjects in Cohort 2 (Arm B and Arm C) have reached Post-Treatment Week 12 or prematurely discontinued study. For each of these overall interim analyses, appropriate database clean up procedures will be performed. There will be no statistical adjustment employed due to these analyses as this is an open-label trial and no changes to the trial design will be made as a result of these analyses. 8

280 M Statistical Analysis Plan Version April 2014 The data for the interim analysis will be stored in Oracle Clinical, transferred into SAS datasets, and any new data after the interim analysis will be added as a new version of the SAS datasets. 5.0 Analysis Populations 5.1 Definition for Analysis Populations Intent-to-Treat (ITT) Population Subjects who receive at least one dose of study drug will be included in the ITT population. Analyses of efficacy and resistance data will be performed on the ITT population. Safety Population Subjects who receive at least one dose of study drug will be included in the safety population. Safety and demographic analyses will be performed on the safety population according to actual treatment received during the entire treatment period even if this differs from the assigned treatment. If all subjects take the treatment to which they were assigned, the Safety Population will be the same as the ITT Population. 5.2 Variables Used for Stratification of Randomization There is no randomization in this study. All enrolled subjects in Cohort 1 (Arm A) received the combination ABT-450/r/ABT ABT-333 coadministered with RBV for 24 weeks. Subjects with HCV genotype 1 who meet eligibility criteria for Cohort 2 will be assigned via IRT to Arm B or Arm C based on HCV sub-genotype and prior HCV treatment experience (if sub-genotype 1b). 9

281 M Statistical Analysis Plan Version April Analysis Conventions 6.1 Definition of Baseline and Final Assessment Definition of Baseline The baseline value refers to the last non-missing measurement collected before the first dose of study drug is received. If multiple measurements are recorded on the same day, the last measurement recorded prior to dosing will be used as Baseline. If these multiple measurements occur at the same time or time is not available for the day, the average of these measurements (for continuous data) and the worst (in the direction of more concerned value) among these measurements (for categorical data) will be considered as the baseline value. The same baseline value will be used for both the Treatment Period and the PT Period. Safety assessments that are related to a serious adverse event that occurred on the first dose day are excluded when applying this algorithm. Definition of Study Days (Days Relative to the First Dose of Study Drug) Study Days are calculated for each time point relative to the first dose of study drug. Study Days are negative values when the time point of interest is prior to the first study drug dose day. Study Days are positive values when the time point of interest is after the first study drug dose day. The day of the first dose of study drug is defined as Study Day 1, and the day prior to the first dose of study drug is defined as Study Day 1 (i.e., there is no Study Day 0). Definition of Study Drug End Days (Days Relative to the Last Dose of Study Drug) For all subjects who receive at least one dose of study drug, study drug end days are calculated relative to the last dose of study drug. The last day of study drug is defined as Study Drug End Day 0. Days before it have negative study drug end days and days after it have positive study drug end days. 10

282 M Statistical Analysis Plan Version April 2014 Definition of Final Treatment Visit Value The Final Treatment Visit value is defined as the last non-missing measurement collected after Study Day 1 and on or before Study Drug End Day 2. Definition of Final Post-Treatment Visit Value The final post-treatment visit value is defined as the last non-missing measurement collected after Study Drug End Day Definition of Analysis Windows For efficacy analyses of HCV RNA and resistance, the time windows specified in Table 3 and Table 4 describe how efficacy data are assigned to protocol specified time points during the Treatment and PT Periods, respectively. All time points and corresponding time windows are defined based on the blood sample collection date and time (if applicable). Table 5 will be used for visit windows of analyses of health-related quality of life (QoL) patient reported outcomes (PROs) collected throughout the study. If more than one assessment is included in a time window, the assessment closest to the nominal time should be used. If two observations are equally distant to the nominal time, the latest one will be used in analyses. The only exception to this is for the SVR windows (e.g., SVR 4, SVR 12, SVR 24, SVR 12planned, and SVR 24planned ); for these windows, the last value in the window will be used. If multiple measurements on the same day are received for a safety laboratory parameter or a vital sign parameter, the average of the values will be used in analyses. For summaries of shifts from baseline and potentially significant values, multiple values on the same day will not be averaged; all values will be considered for these analyses. For laboratory data and vital signs, the time windows specified in Table 6 and Table 7 describe how data are assigned to protocol specified time points. 11

283 M Statistical Analysis Plan Version April 2014 Table 3. Analysis Time Windows for HCV RNA and Resistance Endpoints (Treatment Period) Scheduled Visit Nominal Day (Study Day) Time Window (Study Days Range) Time Window (Hours Post AM Dose Range) Day 1/Baseline a 1 a 1 0 if on Day 1 b Day to 5 Day to 10 Week to 17 Week to 24 Week to 35 Week to 49 Week to 70 Week to 98 Week to 126 Week to 154 Week to 182 Final Treatment Visit c SVR 12planned d SVR 24planned d a. Day of first dose of study drug. 2 to 2 days after last dose of study drug to to 378 b. If dosing time or draw time is missing, the scheduled time will be used on Day 1. c. The last value within the window will be used to define Final Treatment Visit Value. The lower and upper bound of the Final Treatment Visit window are Study Day 2 and Study Drug End Day 2, respectively. d. For SVR windows, the last value in the window will be used. Note: All data, except for SVR 12planned and SVR 24planned, must also be within 2 days of the last dose of study drug. The result closest to the scheduled time point will be used, except for SVR 12planned and SVR 24planned. For SVR windows, the last value in the window will be used. 12

284 M Statistical Analysis Plan Version April 2014 Table 4. Analysis Time Windows for HCV RNA and Resistance Endpoints (Post-Treatment Period) Scheduled Visit a Nominal Day (Study Drug End Day) Time Window (Study Drug End Days Range) Post-Treatment Day to 5 Post-Treatment Day to 10 Post-Treatment Week to 21 Post-Treatment Week to 42 Post-Treatment Week to 70 Post-Treatment Week to 126 Post-Treatment Week to 210 Post-Treatment Week to 294 Post-Treatment Week to 378 SVR 4 b SVR 12 b SVR 24 b 28 3 to to to 210 a. Post-Treatment Visits are applicable for subjects who received at least one dose of study drug. b. For SVR windows, the last value in the window will be used. Note: The result closest to the scheduled time point will be used, except for SVR 4, SVR 12, and SVR 24. For SVR windows, the last value in the window will be used. Data must also have Study Drug End Day > 2 for all windows. Study Drug End Day 0 is defined as the day of the last dose of study drug. 13

285 M Statistical Analysis Plan Version April 2014 Table 5. Analysis Time Windows for PRO Instruments Scheduled Visit Nominal Day (Study Day) Time Window (Study Days Range) Day 1/Baseline a 1 1 Week to 42 Week to 70 Week to 126 Week to 182 Final Treatment Visit b Scheduled Visit 2 to 2 days after last dose of study drug Nominal Day (Study Drug End Day) Time Window (Study Drug End Days Range) Post-Treatment Week to 56 Post-Treatment Week to 126 Post-Treatment Week to 252 Post-Treatment Week to 378 Final Post-Treatment Visit c > 2 days after last dose of study drug a. Day of first dose of study drug. A value is considered to be Baseline if it is the last non-missing value on or before Study Day 1. b. The last value within the window will be used to define Final Treatment Visit Value. The lower and upper bound of the Final Treatment Visit window are Study Day 2 and Study Drug End Day 2, respectively. c. The last post-treatment value will be used to define Final Post-Treatment Visit value; the lower bound of the Final Post-Treatment Visit window is Study Drug End Day 3. Note: The result closest to the scheduled time point will be used. For visits through Week 12, data must also be within 2 days of the last dose of study drug. For post-treatment visits, data must also have Study Drug End Day > 2 where Study Drug End Day 0 is defined as the day of the last dose of study drug. 14

286 M Statistical Analysis Plan Version April 2014 Table 6. Laboratory Data and Vital Sign Visit Windows (Treatment Period) Scheduled Time Nominal Day (Study Day) Time Window (Study Days Range) Hematology, Clinical Chemistry, and Urinalysis Vital Signs Day 1/Baseline a Day to 4 N/A Day to 8 2 to 11 Day to 11 N/A Week to to 17 Week to to 24 Week to to 35 Week to to 49 Week to to 70 Week to to 98 Week to to 126 Week to to 154 Week to to 182 Final Treatment Visit b a. Day of first dose of study drug. 2 to 2 days after last dose of study drug b. The last value within the window will be used to define Final Treatment Visit Value. The lower and upper bound of the Final Treatment Visit window are Study Day 2 and Study Drug End Day 2, respectively. Note: The result closest to the scheduled time point will be used. Data must also be within 2 days of the last dose of study drug. 15

287 M Statistical Analysis Plan Version April 2014 Table 7. Laboratory Data and Vital Sign Visit Windows (Post-Treatment Period) Nominal Day (Study Drug End Day) Time Window (Study Drug End Days Range) Hematology, Clinical Chemistry, and Urinalysis Vital Signs Post-Treatment Day to 4 3 to 4 Post-Treatment Day to 8 5 to 8 Post-Treatment Day to 11 9 to 11 Post-Treatment Week to to 17 Post-Treatment Week to to 24 Post-Treatment Week to to 42 Post-Treatment Week 8 a 56 N/A 43 to 70 Post-Treatment Week 12 a 84 N/A 71 to 126 Post-Treatment Week 24 a 168 N/A 127 to 210 Post-Treatment Week 36 a 252 N/A 211 to 294 Post-Treatment Week to to 378 Final Post-Treatment Visit b a. No scheduled laboratory data collected at these PT visits. > 2 days after last dose of study drug b. The last post-treatment value will be used to define Final Post-Treatment Visit value; the lower bound of the Final Post-Treatment Visit window is Study Drug End Day 3. Note: Post-Treatment Visits are applicable for subjects who received at least one dose of study drug. The result closest to the scheduled time point will be used. Data must also have Study Drug End Day > 2 where Study Drug End Day 0 is defined as the day of the last dose of study drug. 6.3 Missing Data Imputation Data will be imputed for HCV RNA analyses of RVR, EOTR, and SVR and for analyses of QoL questionnaires. HCV RNA HCV RNA values will be selected for analysis based on the analysis windows defined in Section 6.2. If an HCV RNA value is missing within a study visit window, then the missing HCV RNA value will be imputed via a flanking imputation approach. When 16

288 M Statistical Analysis Plan Version April 2014 there is no HCV RNA value in a defined visit window, the HCV RNA values immediately preceding and succeeding the window will be used for the flanking imputation regardless of the values chosen in the preceding and succeeding windows. If a subject has a missing HCV RNA value at a post-baseline visit but with undetectable or unquantifiable HCV RNA levels at both the preceding value and the succeeding value, then the HCV RNA level will be imputed as undetectable or unquantifiable, respectively, at this visit for this subject. In addition, if a subject has an unquantifiable HCV RNA level at the preceding value and an undetectable HCV RNA level at the succeeding value, or vice versa, the HCV RNA level will be imputed as unquantifiable at this visit for this subject. If a subject is missing an HCV RNA value for the visit window associated with the analysis of RVR and EOTR, then a flanking imputation approach will be used. If an HCV RNA value is missing within the SVR windows, then a backward imputation approach will be carried out where if the nearest HCV RNA value after the SVR window is unquantifiable or undetectable, then it will be used to impute the HCV RNA value in the SVR window. If a subject starts another treatment for HCV, then all HCV RNA values for this subject measured on or after the start date of the new HCV treatment will be excluded from analyses. The subject will be considered a failure for summaries of viral response at all the time points after the start of the new HCV treatment. If a subject is missing an HCV RNA value for the visit window associated with the analysis of RVR, EOTR, or SVR after performing the imputations described above, then this value will be imputed with an HCV RNA value from a local laboratory if present; otherwise, the HCV RNA value for this visit will be missing. Subjects with missing HCV RNA data in the analysis window, after imputations, will be imputed as a failure. 17

289 M Statistical Analysis Plan Version April 2014 HCV RNA Analyses for Relapse and Virologic Failure If HCV RNA values from the central laboratory are missing but a local laboratory value is present in the appropriate time period, then the local laboratory value will be used to assess post-treatment relapse and on-treatment virologic failure. Quality of Life Questionnaires If more than 4 items of the 16-item HCV-PRO are missing responses, then the total score is set to missing. When four or fewer items are missing, the mean of the non-missing items will be used to impute the responses for the missing item(s) and a total score will be calculated. For EQ-5D-5L, no imputation will be performed for missing items. For SF-36 QoL questionnaires, if a respondent answers at least 50% of the items in a multi-item scale of SF-36, the missing items will be imputed with the average score of the answered items in the same scale. In cases where the respondent did not answer at least 50% of the items, the score for that domain will be considered missing. The Mental and Physical Component measure will not be computed if any domain is missing. 7.0 Demographics, Baseline Characteristics, Medical History, and Previous/Concomitant Medications Demographics, baseline characteristics, medical history, and previous/concomitant medications will be summarized by study arm on the safety population. 7.1 Demographic and Baseline Characteristics Demographics include age, weight, body mass index (BMI), and the frequency of gender, race, ethnicity, age category (< 50 yrs and 50 yrs; < 65 yrs and 65 yrs), BMI (< 30 kg/mg 2 and 30 kg/m 2 ). Baseline characteristics will include HCV genotype 1 subtype (1a, 1b and other 1), transplant recipient IL28B genotype (CC, CT and TT; CC and non-cc), baseline log 10 HCV RNA levels (continuous), baseline HCV RNA levels 18

290 M Statistical Analysis Plan Version April 2014 (< 800,000 IU/mL or 800,000 IU/mL), baseline HOMA-IR (fasting glucose [MMOL/L] fasting insulin [MCIU/ML] 22.5, < 3 mu mmol/l 2 and 3 mu mmol/l 2 ), baseline IP-10 (continuous), baseline IP-10 (< 600 ng/l and 600 ng/l), prior HCV treatment history (IFN/pegIFN-naïve, IFN/pegIFN-experienced, unknown), type of response to prior IFN/pegIFN-based therapy (non-responder, responder, other), timing of prior IFN/pegIFN-based therapy (pre-transplant, post-transplant), time since liver transplantation (months), donor type (living or deceased), baseline fibrosis stage (Metavir F0-F1, F2, or F3 and higher), immunosuppressive medications (tacrolimus or cyclosporine), history of diabetes, and tobacco and alcohol use status. Subjects who do not have a fasting glucose value and a fasting insulin value at Baseline will be excluded from the summary of baseline HOMA-IR. IL28B rs will be resulted as C/C, C/T, T/T, or Unable to Assign Genotype by the central laboratory. History of diabetes is defined as presence of "Metabolic/Diabetes mellitus" on the MH ecrf. Baseline fibrosis stage is defined for subjects with non-missing liver biopsy scores. Subjects will be categorized as F0 F1, F2, F3, or F4 according to Table 8. Table 8. Baseline Fibrosis Stage Baseline Fibrosis Stage, Metavir Equivalents Liver Biopsy Metavir, Batts-Ludwig, Knodell, IASL, Scheuer, or Laennec Score Liver Biopsy Ishak Score F0 F1 0 or 1 0, 1, or 2 F2 2 3 F3 3 4 F4 4 5 or 6 Summary statistics (N, mean, median, standard deviation, and range) will be generated for continuous variables (e.g., age and BMI). The number and percentage of subjects will be presented for categorical variables (e.g., gender, race and ethnicity). 19

291 M Statistical Analysis Plan Version April Medical History Medical history data will be summarized and presented using body systems and conditions/diagnoses as captured on the ecrf. The body systems will be presented in alphabetical order and the conditions/diagnoses will be presented in alphabetical order within each body system. The number and percentage of subjects with a particular condition/diagnosis will be summarized for each study arm and overall. Subjects reporting more than one condition/diagnosis within a body system will be counted only once for that body system. 7.3 Previous Treatment and Concomitant Medications Prior medications, prior HCV medications, concomitant medications and Post-Treatment HCV medications will be summarized by study arm. A prior medication is defined as any medication taken prior to the date of the first dose of study drug. A prior HCV medication is defined as any medication entered in the Prior HCV medication ecrf for a subject. A concomitant medication is defined as any medication that started prior to the date of the first dose of study drug and continued to be taken after the first dose of study drug or any medication that started on or after the date of the first dose of study drug, but not after the date of the last dose of study drug. A Post-Treatment HCV medication is defined as any medication taken on or after the last dose of study drug and entered as a Post-Treatment HCV medication on the ecrf. The number and percentage of subjects who take medications will be summarized by generic drug name based on the WHO Drug Dictionary for prior medications, prior HCV medications, concomitant medications and Post-Treatment HCV medications. 8.0 Patient Disposition The number of subjects for each of the following categories will be summarized overall and by investigator for each study arm and overall. enrolled subjects subjects who took at least one dose of study drug 20

292 M Statistical Analysis Plan Version April 2014 subjects who completed study drug subjects who discontinued from study drug subjects who completed the study subjects who discontinued from the study The number and percentage of subjects who discontinued study drug will be summarized by reason (all reasons) and by primary reason (per ecrf) for each study arm and overall. The number and percentage of subjects who discontinued from the study will be summarized by reason (all reasons) and by primary reason as recorded on the ecrf for each study arm and overall. The number and percentage of screened subjects who screen failed and the reasons for screen failure (inclusion/exclusion criteria, withdrew consent, lost to follow-up, and/or other) will be summarized. A CSR listing of reason for screen failure will be provided for all subjects who screen failed. The number and percentage of subjects by study arm for the Treatment Period, as applicable, will be summarized for: Subjects with interruptions of all study drugs for toxicity management; Subjects with any RBV dose modifications; Subjects with RBV dose modification due to decrease in hemoglobin; Subjects with RBV dose modification due to decrease in creatinine clearance; Subjects with RBV dose modification due to other reasons. Subjects with any RBV dose modification to 0 mg (i.e., RBV interruption). Reasons for study drug interruptions and RBV dose modifications will be presented in the CSR listings. 21

293 M Statistical Analysis Plan Version April Study Drug Exposure and Compliance 9.1 Exposure The duration of exposure to study drug in the Treatment Period will be summarized for each treatment arm and overall in the safety population. Duration of exposure is defined for each subject as the last study drug dose date minus the first study drug dose date plus 1 day. Descriptive statistics (mean, standard deviation, median, minimum, and maximum) will be presented. Study drug duration also will be summarized with frequencies and percentages using the following categories: 1 15 days, days, days, days, days, days, and > 150 days. 9.2 Compliance At each protocol-specified visit during the Treatment Period, the total number of capsules/tablets dispensed and returned is recorded for each type of study drug. The compliance for each study drug (ABT-450/r/ABT-267, ABT-333, and RBV) within the Treatment Period will be calculated as the percentage of capsules or tablets taken relative to the total tablets prescribed, respectively. The total number of tablets prescribed will be equal to the total number of tablets that should have been taken per the protocol for the duration that the subject was in the Treatment Period (date of last dose to date of first dose + 1). Study drug interruptions due to an adverse event or other planned interruptions recorded on the ecrf will be subtracted from the duration. For RBV compliance, RBV dose modifications due to adverse events, toxicity management, or weight change as recorded on the RBV Dose Modifications ecrf will be used to modify the total number of tablets that should have been taken. A subject is considered to be compliant if the percentage is between 80% and 120%. Compliance will be calculated for each subject and summarized with the mean, median, standard deviation, minimum, and maximum. In addition, the percentage of compliant subjects will be calculated for each study drug. 22

294 M Statistical Analysis Plan Version April 2014 In addition, DAA study drug (ABT-450/r/ABT-267 and ABT-333) and RBV adherence will be assessed by using the Medication Event Monitoring systems (MEMS, AARDEX Group Ltd., Switzerland) throughout the study. The MEMS data will be downloaded from the vendor's web system, and a report of compliance will be supplied by AARDEX Pharmacokinetic Variables Plasma concentrations of ABT-450, possible ABT-450 metabolites, ABT-267, possible ABT-267 metabolites, ABT-333, ABT-333 M1 metabolite, other possible ABT-333 metabolites, ritonavir and ribavirin will be tabulated for each subject and group. Blood concentrations of cyclosporine and tacrolimus will be tabulated for each subject and group. Summary statistics will be computed for each time and visit. The plasma concentration data across all visits after Week 2 will be summarized based on time after the last dose at each visit, followed by binning of the concentrations in different time intervals based on time after the last dose. The time after last dose for DAAs will be determined based on the MEMS dosing time. CNI trough levels will be summarized by binning of the concentrations in different time intervals based on time after the last dose. The time after last dose for CNI will be determined based on the EDC recorded dosing time. Pharmacokinetic analyses will be addressed in the pharmacokinetic report and/or clinical study report. Population pharmacokinetic analyses and exposure response analyses are planned to be addressed in a separate report for the study or as part of meta-analyses along with other Phase 2 studies. 23

295 M Statistical Analysis Plan Version April Efficacy Analysis 11.1 General Considerations General Considerations Treatment effects will be evaluated using 2-sided 95% confidence intervals using the normal approximation to the binomial, provided that the sample size is large enough (i.e., the number of subjects with the event is 5 and the number of subjects without the event is 5). Otherwise, 95% confidence intervals using the binomial exact method will be provided. Efficacy analyses will be performed on the ITT population. For efficacy analyses that treat HCV RNA as a quantitative variable, a log 10 transformation will be performed. Analyses will be performed using the log 10 transformed HCV RNA from Roche COBAS TaqMan real-time reverse transcriptase PCR (RT-PCR) assay V2. For this assay, the LLOD is 15 IU/mL and the LLOQ is 25 IU/mL. HCV RNA results that are detectable but not quantifiable are reported as "< 25 IU/mL HCV RNA DETECTED" and those that are undetectable are reported as "HCV RNA NOT DETECTED" in the database. Analyses that treat HCV RNA as a categorical variable (HCV RNA < LLOQ or HCV RNA < LLOD) will be based on these categories. The notation "HCV RNA < LLOQ" is used to represent all HCV RNA values < 25 IU/mL, including values reported as "HCV RNA NOT DETECTED" or "< 25 IU/mL HCV RNA DETECTED." HCV RNA LLOQ are all quantifiable values of 25 IU/mL or greater. Definitions for Efficacy Endpoints Note that a confirmed quantifiable post-treatment value is defined as any two consecutive post-treatment HCV RNA measurements LLOQ. During treatment, a confirmed quantifiable value is defined as any two consecutive HCV RNA values LLOQ, either both during treatment or at the final treatment measurement and the next consecutive post-treatment measurement. 24

296 M Statistical Analysis Plan Version April 2014 Rebound = confirmed HCV RNA LLOQ after HCV RNA < LLOQ during treatment, or confirmed increase from nadir in HCV RNA (two consecutive HCV RNA measurements > 1 log 10 IU/mL above nadir) at any time point during treatment. A single rebound value ( LLOQ or > 1 log 10 above nadir) followed by lost to follow-up will be considered a rebound (i.e., will not require confirmation). On-treatment virologic failure = Rebound or HCV RNA LLOQ persistently during treatment with at least 6 weeks ( 36 days) of treatment. RVR (rapid virologic response) = HCV RNA < LLOQ in the Week 4 window. EOTR (end of treatment response) = HCV RNA < LLOQ in the Week 24 window. SVR 4 = HCV RNA < LLOQ in the SVR 4 window (4 weeks after the last actual dose of study drug) without any confirmed quantifiable ( LLOQ) post-treatment value before or during that SVR window. SVR 12 = HCV RNA < LLOQ in the SVR 12 window (12 weeks after the last actual dose of study drug) without any confirmed quantifiable ( LLOQ) post-treatment value before or during that SVR window. SVR 12planned = HCV RNA < LLOQ in the SVR 12planned window (12 weeks after the last planned dose of study drug [i.e., Week 36]) without any confirmed quantifiable ( LLOQ) post-treatment value before or during that SVR window. SVR 24 = HCV RNA < LLOQ in the SVR 24 window (24 weeks after the last actual dose of study drug) without any confirmed quantifiable ( LLOQ) post-treatment value before or during that SVR window. SVR 24planned = HCV RNA < LLOQ in the SVR 24planned window (24 weeks after the last planned dose of study drug [i.e., Week 48]) without any confirmed quantifiable ( LLOQ) post-treatment value before or during that SVR window. 25

297 M Statistical Analysis Plan Version April 2014 Relapse 12 = confirmed HCV RNA LLOQ between Final Treatment Visit and 12 weeks after last actual dose of study drug (up to and including the SVR 12 assessment time point) for a subject with HCV RNA < LLOQ at Final Treatment Visit who completes treatment. Completion of treatment is defined as a study drug duration 154 days. Relapse 24 = confirmed HCV RNA LLOQ within the SVR 24 window for a subject who achieved SVR 12 and has HCV RNA data available in the SVR 24 window. Relapse overall = confirmed HCV RNA LLOQ between Final Treatment Visit through the last HCV RNA measurement collected in the PT Period for a subject with HCV RNA < LLOQ at Final Treatment Visit who completes treatment. Completion of treatment is defined as a study drug duration 154 days. Relapse late = confirmed HCV RNA LLOQ at any time after the SVR 24 assessment time point for a subject who achieved SVR 24 and has post-svr 24 HCV RNA data available. If the last available post-treatment value is LLOQ, then the subject will be considered a relapse (i.e., will not require confirmation). Relapse analyses will exclude subjects who do not have any post-treatment HCV RNA values. Reasons for SVR 12 Non-Response Subjects who do not achieve SVR 12 (SVR 12 non-responders) will be categorized as having: 1. On-treatment virologic failure (see On-treatment virologic failure definition); 2. Relapse (defined according to the Relapse 12 definition for subjects who complete treatment [study drug duration 154 days]); 3. Prematurely discontinued study drug with no on-treatment virologic failure (defined as any SVR 12 non-responder who prematurely discontinued study drug [study drug duration < 154 days] and did not meet the On-treatment virologic failure definition); 26

298 M Statistical Analysis Plan Version April Missing follow-up data in the SVR 12 window (defined as any subject who completed study drug without data in the SVR 12 window after applying the imputation rules and not meeting the above definitions of [1], [2], or [3]); 5. Other (defined as any SVR 12 non-responder not meeting the above definitions of [1] [4], such as a subject with a single quantifiable value within the SVR 12 window followed by an undetectable value beyond the SVR 12 window). Reasons for SVR 24 Non-Response Subjects who do not achieve SVR 24 (SVR 24 non-responders) will be categorized as having: 1. On-treatment virologic failure (see On-treatment virologic failure definition); 2. Relapse (defined according to the Relapse 12 definition for subjects who complete treatment [study drug duration 154 days]); 3. Relapsed after achieving SVR 12 (see Relapse 24 definition); 4. Prematurely discontinued study drug with no on-treatment virologic failure (defined as any SVR 24 non-responder who prematurely discontinued study drug [study drug duration < 154 days], did not meet the On-treatment virologic failure, Relapse 12, or Relapse 24 definitions); 5. Missing follow-up data in the SVR 24 window (defined as any subject who completed study drug without data in the SVR 24 window after applying the imputation rules and not meeting the above definitions of [1], [2], [3] or [4]); 6. Other (defined as any SVR24 non-responder not meeting the above definitions of [1] [5]). 27

299 M Statistical Analysis Plan Version April Primary Efficacy Analysis The primary efficacy endpoint is the percentage of subjects with SVR 12 (HCV RNA < LLOQ 12 weeks after the last actual dose of study drugs). The simple percentage of subjects with SVR 12 will be calculated for each study arm and a 2-sided 95% confidence interval will be calculated using the normal approximation to the binomial Secondary Efficacy Analyses The secondary efficacy endpoints are: 1. The percentage of subjects with SVR 24 (HCV RNA < LLOQ 24 weeks after the last actual dose of study drugs), 2. The percentage of subjects with virologic failure during treatment (defined per On-treatment virologic failure definition) out of all ITT subjects, 3. The percentage of subjects with post-treatment relapse (defined per Relapse 12 definition. The simple percentage of subjects with SVR 24, the simple percentage of subjects with virologic failure during treatment and the simple percentage of subjects with post-treatment relapse (Relapse 12 ) will be calculated for each study arm and a corresponding 2-sided 95% confidence interval will be calculated using the normal approximation to the binomial Additional Efficacy Analysis The following additional efficacy endpoints will be summarized for each study arm and analyzed as specified: the percentage of subjects with RVR (HCV RNA < LLOQ at Week 4 of the Treatment Period), 28

300 M Statistical Analysis Plan Version April 2014 the percentage of subjects with EOTR (HCV RNA < LLOQ at Week 24 of the Treatment Period), the percentage of subjects with undetectable or unquantifiable HCV RNA at each Post-Baseline Visit throughout the Treatment Period using only subjects with data in each visit window (using data from the central laboratory as observed, i.e., no imputation for missing data), time to suppression in HCV RNA during the Treatment Period, the percentage of subjects with SVR 4, SVR 12planned, and SVR 24planned, time to relapse at anytime post treatment, the percentage of subjects who completed study drugs with HCV RNA < LLOQ at the Final Treatment Visit who subsequently relapse at any time post treatment (Relapse overall ), the percentage of subjects who achieved SVR 12 and subsequently relapsed during the SVR 24 window (Relapse 24 ); the percentage of subjects who achieved SVR 24 and subsequently relapsed (Relapse late ). The percentage of subjects with RVR, EOTR, SVR 4, SVR 12planned, and SVR 24planned will be calculated and 2-sided 95% confidence intervals will be calculated using the normal approximation to the binomial distribution; imputations for missing data will be performed as described in Section 6.3 for analyses of SVR, RVR, and EOTR where a missing response will be imputed as a failure after performing the described imputation. All other endpoints will be presented using data as observed. The number and percent of subjects who achieve SVR 12 will be presented along with the number of subjects who do not achieve SVR 12 by reason for non-response (defined in Section 11.1). The non-responders will be presented in a listing. In the final CSR, the number and percent of subjects who achieve SVR 24 will be presented along with the number of subjects who do not achieve SVR 24 by reason for non-response. The non-responders will be presented in a listing. 29

301 M Statistical Analysis Plan Version April 2014 A listing displaying the first occurrence of rebound will be provided for subjects who rebound at anytime during treatment. The percentage of subjects with Relapse 24, Relapse late, Relapse overall will be calculated and 2-sided 95% confidence intervals will be calculated using the normal approximation to the binomial distribution. The number of completers (defined as study drug duration 154 days) who relapse within the SVR 4 window, within the SVR 12 window, within the SVR 24 window, outside of the SVR 24 window (study drug end day > 210), and anytime post-treatment (study drug end day 3) will be summarized along with a corresponding listing displaying the first occurrence of relapse. This summary will be performed for subjects with HCV RNA < LLOQ at Final Treatment Visit who completed study drug and who had at least one PT HCV RNA value. A similar table and listing will be provided of Preterm Relapses for subjects who prematurely discontinued study drug (defined as study drug duration < 154 days). From HCV RNA levels, the time to relapse post-treatment will be calculated for each subject treated with study drug and displayed graphically using a Kaplan-Meier (KM) curve. For time to relapse analyses, time to event will be measured as the number of days from the last dose of study drug to event or censoring time. The time of relapse post treatment is defined as the first of two consecutive HCV RNA values LLOQ between the end of the treatment period and end of the PT Period amongst subjects who completed study drug with HCV RNA < LLOQ at the Final Treatment Visit. Subjects who do not relapse will be censored at the date corresponding to the last available HCV RNA value within the PT Period. Time to relapse will be performed only for subjects with HCV RNA < LLOQ at Final Treatment Visit for subjects who completed study drug, defined as a study drug duration 154 days, and who had at least one PT HCV RNA value. The time to suppression on treatment will be calculated for each subject treated with study drug and displayed graphically using a KM curve. For time to suppression analyses, time 30

302 M Statistical Analysis Plan Version April 2014 to event will be measured as the number of days from the first dose of study drug to event or censoring time. The time of suppression is defined as the first of two consecutive HCV RNA values < LLOQ during the Treatment Period. Subjects who do not suppress will be censored at the date of the last HCV RNA value within the Treatment Period. In the final CSR, the concordance between SVR 12 and SVR 24 will be assessed by the agreement between SVR 12 and SVR 24 and the positive predictive value (PPV) and negative predictive value (NPV) of SVR 12 on SVR 24. The agreement between SVR 12 and SVR 24 is the percentage of subjects with both SVR 12 and SVR 24 and the percentage of subjects without SVR 12 or SVR 24 out of all subjects in the analyses population. The PPV of SVR 12 on SVR 24 is the proportion of subjects who achieve SVR 12 and SVR 24 out of all subjects who achieved SVR 12. The NPV of SVR 12 on SVR 24 is the proportion of subjects who do not achieve SVR 12 and SVR 24 out of all subjects who did not achieve SVR Resistance Analysis If possible, subjects who do not achieve SVR 12 will have resistance testing conducted if (1) they have on-treatment rebound; (2) they have post treatment relapse, with a study drug duration 154 days or (3) they have at least 6 weeks of treatment and fail to suppress by Week 6 (i.e., meet virologic stopping criteria). Subjects meeting one of these criteria will be referred to as subjects in the primary virologic failure (PVF) population, and a listing by subject that includes HCV subgenotype, IL28B genotype, reason for SVR 12 non-response, time point(s) sequenced as closest to time of VF, and HCV RNA value at the VF time point(s) will be produced for these subjects. In addition, all listings described below will display HCV subgenotype and reason for SVR 12 non-response in the subject identifier for each subject. A separate listing will delineate all subjects in the PVF population for whom no sequencing was performed (e.g., lost to follow-up while HCV RNA 1000 IU/mL). Subjects who do not achieve SVR 12 who do not meet the above criteria for the PVF population (e.g., those with less than 6 weeks of therapy who failed to suppress), but have a time point with HCV RNA 1000 IU/mL after treatment discontinuation, will 31

303 M Statistical Analysis Plan Version April 2014 have the sample at that time point sequenced. For subjects who are lost to follow-up with less than 6 weeks of therapy while not virally suppressed (e.g., HCV RNA never < LLOQ or have increase in viral load post nadir), the sample at the latest available time point with HCV RNA 1000 IU/mL will be sequenced. These subjects will be included in the listing described above for subjects in the PVF population with post-baseline sequencing available. Only samples with an HCV RNA level of 1000 IU/mL will undergo resistance analysis in order to allow accurate assessment of products of amplification. Therefore if the HCV RNA level at the time of virologic failure (VF) is < 1000 IU/mL, the sample closest in time after the failure with an HCV RNA level 1000 IU/mL will be used if available. Clonal sequencing of a given target will be performed only if no variants are detected at signature resistance-associated amino acid positions by population sequencing in that sample. In addition, clonal sequencing may be performed if there is a complex mixture of amino acids at one or more signature resistance-associated position that cannot be resolved by population sequencing. For subjects who do not achieve SVR 12, the genes of interest for population sequencing from all evaluated time points are those encoding complete NS3/4A, NS5A, and NS5B, while for clonal sequencing they are those encoding NS3 amino acids 1 181, NS5A amino acids 1 215, and NS5B amino acids For sequencing of baseline samples from SVR 12 -achieving subjects, the genes of interest for population sequencing are those encoding NS3 amino acids 1 360, NS5A amino acids 1 215, and NS5B amino acids The prototypic reference sequences used for analysis will be H77 for genotype 1a (GenBank Accession ID NC_004102) and Con1 for genotype 1b (GenBank Accession ID AJ238799). For each DAA target, resistance associated signature amino acid variants will be identified by AbbVie Clinical Virology. Amino acid positions where resistance-associated variants have been identified in vitro and/or in vivo: 1) for ABT-450: 36, 56, 155, 156, and 168 in NS3 for genotype 1a; 155, 156, and 168 in NS3 for genotype 1b; 2) for ABT-267: 28, 30, 31, 32, 58, and 93 in NS5A for genotype 1a; 32

304 M Statistical Analysis Plan Version April , 29, 30, 31, 32, 58, and 93 in NS5A for genotype 1b; and 3) for ABT-333: 316, 414, 446, 448, 451, 553, 554, 555, 556, 558, 559, and 561 in NS5B for genotype 1a; 316, 368, 411, 414, 445, 448, 553, 556, 558, and 559 in NS5B for genotype 1b. Although resistance-associated amino acid variants have not been identified in NS3 at position 80 for ABT-450, it will be included in the list of signature positions due to the impact of variants at this position on resistance for other NS3 protease inhibitors. The following definitions will be used in the resistance analyses: Baseline variant: a variant (by population sequencing) in a baseline sample determined by comparison of the amino acid sequence of the baseline sample to the appropriate prototypic reference amino acid sequence for a given DAA target (NS3, NS5A, or NS5B). Post-baseline variant by population sequencing: an amino acid variant in a post-baseline time point sample that was not detected at baseline in the subject and is detectable by population sequencing. Post-baseline variant by clonal sequencing: a variant at a signature resistance associated amino acid position that was not present in a subject by population sequencing at baseline that is detected in a post-baseline sample from that subject by clonal sequencing in at least 2 clones from that sample (among the subset of subjects for whom clonal sequencing is performed). Emerged variant by population sequencing: a post-baseline variant that is observed in 2 or more subjects of the same subgenotype by population sequencing. Linked variant by population sequencing: 2 or more signature resistance associated or emerged amino acid variants identified within a target by population sequencing, and no mixture of amino acids is detected at either position. Linked variant by clonal sequencing: at least 2 clones from a given sample containing the same 2 or more signature resistance-associated amino acid variants by clonal sequencing. 33

305 M Statistical Analysis Plan Version April 2014 Baseline samples will be sequenced by population sequencing for all subjects. A listing by subject of all baseline variants relative to the appropriate prototypic reference sequence at signature resistance-associated amino acid positions will be provided for each DAA target (NS3, NS5A, and NS5B). In addition, the number and percentage of subjects with baseline variants relative to prototypic reference sequence at signature resistance-associated amino acid positions by amino acid position and variant within a DAA target compared to prototypic reference sequence will be summarized by HCV subgenotype (1a or 1b). The following analyses will be performed on the samples from subjects who are in the PVF population and have post-baseline resistance data available. The HCV amino acid sequence as determined by population sequencing at the time of VF or the sample closest in time after VF with an HCV RNA level of 1000 IU/mL will be compared with the baseline and appropriate prototypic reference amino acid sequences. A listing by subject of all post-baseline variants detected by population sequencing relative to the baseline amino acid sequences will be provided for each DAA target (NS3, NS5A, and NS5B). A listing by subject of all emerged variants by population sequencing relative to baseline amino acid sequences will be provided for each DAA target. In addition, a listing by subject of all post-baseline variants (by population sequencing) at signature resistance-associated amino acid positions relative to the appropriate prototypic reference amino acid sequence will be provided. The number and percentage of subjects with emerged variants by amino acid position and variant within a DAA target in a treatment sample compared to baseline will be summarized overall and by HCV subgenotype (1a or 1b). For all subjects who are in the not in the PVF population but have post-baseline sequence data available, a listing by subject of all post-baseline variants detected by population sequencing relative to the baseline amino acid sequences will be provided for each DAA target (NS3, NS5A, and NS5B). 34

306 M Statistical Analysis Plan Version April 2014 Linkage between emerged or signature variants by population sequencing will be evaluated. A listing by subject and time point of the linked variants by population sequencing for each target will be provided. Similar analyses as those described above will be performed for treated subjects who experience VF after Post-Treatment Week 12, and the analyses will be provided in the final CSR. For the subset of samples for which clonal sequencing is performed, listings by subject of post-baseline variants by clonal sequencing will be provided for each DAA target. In addition, listings of linked variants by clonal sequencing by subject, DAA target, and time point will be provided. All clonal sequencing results will be reported in the final CSR. For all subjects who do not achieve SVR 12, the persistence of resistance-associated substitutions that emerged for each target (NS3, NS5A, and NS5B) will be assessed by population sequencing (with clonal sequencing performed if no resistance associated variants are detected by population sequencing) at Post-Treatment Weeks 24 and 48. Listings by subject and time point of all post baseline variants relative to the baseline amino acid sequence will be provided for each DAA target (NS3, NS5A and NS5B). If resistance-associated variants are not detected by either population or clonal sequencing in a given target for a subject either at the time of failure or in a post treatment sample, then that target may not be sequenced in subsequent samples from that subject. All persistence data will be reported in the final CSR. Resistance datasets will be submitted to the Agency according to the revised template supplied on 25 February 2013 (courtesy copy of Draft Guidance, "Attachment to Guidance on Antiviral Product Development Conducting and Submitting Virology Studies to the Agency; Guidance for Submitting HCV Resistance Data") Patient Reported Outcome The following instruments will be used to collect patient reported outcomes (PROs): HCVPRO, EQ-5D-5L, and SF-36 version 2 (SF-36v2). The HCVPRO, EQ 5D-5L, and 35

307 M Statistical Analysis Plan Version April 2014 SF 36v2 will be collected at Baseline, Weeks 4, 8, 12 and 24, and Post-Treatment Weeks 4, 12, 24 and 48. Missing data for each instrument will be handled as described in Section 6.3. The following exploratory analyses of PROs will be performed: mean change from baseline in HCVPRO total score to each applicable post baseline time point; mean change from baseline in EQ-5D-5L health index score and VAS score to each applicable post-baseline time point; mean change from baseline to each applicable post-baseline time point in the SF-36v2 Mental Component Summary (MCS) and Physical Component Summary (PCS) measures; continuous plots of the percent change from Baseline to Final Treatment Visit in the SF-36v2 PCS and MCS, HCVPRO total score, EQ-5D-5L health index score and VAS on the horizontal axis and the cumulative percent of subjects experiencing up to that change on the vertical axis; percentage of subjects without a decrease from Baseline to Final DB Treatment Visit in the SF-36v2 PCS and MCS that is greater than or equal to the minimally important difference (MID) of five points. The HCVPRO consists of 16 items with 5 response choices (1, 2, 3, 4, or 5) that are recoded to 0, 1, 2, 3, or 4, respectively, when deriving the total score. The total score is the sum of all 16 items and is converted to a score between 0 and 100 by ScaledScore = Sum * 100/64. Subject's responses to the self-administered HCVPRO instrument will be assessed for the total score. Subject's responses to the EQ-5D-5L will be combined into a unique health state using a 5-digit code with 1 digit from each of the 5 dimensions. The EQ-5D-5L states will be converted into a single preference-weighted health utility index score by applying country-specific weights (if available) or US weights (if not available). 1,2 The VAS score will be measured separately. The SF-36v2 2 measures dimensions of a patient's functional health and well-being in 8 domains and also provides 2 summary scores that characterize a patient's mental (MCS) and physical 36

308 M Statistical Analysis Plan Version April 2014 (PCS) health status. The score for each of the 8 domains ranges from 0 to 100 and will be normalized according to the user manual. 3 The standardization of the normalized scores will provide the norm-based scores with a mean of 50 and a SD of 10. The two summary scores are based on the norm-based scores. Per the SF-36v2 instrument manual, score for any item with multiple responses will be set to "missing." Missing item responses will be handled as described in Section 6.1. Subject's responses to the SF-36v2 will be summarized for the PCS and MCS measures. Summary statistics (n, mean, SD, median, minimum and maximum) for the change from baseline to each applicable visit will be provided for the HCVPRO total score, EQ 5D 5L index and VAS scores, and the SF-36v2 PCS and MCS scores. An MID of 5 will be used for the change from Baseline to Final DB Treatment Visit in the SF-36v2 PCS and MCS. The percentage of subjects in each treatment group with a change from Baseline to Final DB Treatment Visit > 5 will be presented along with 95% confidence intervals Handling of Multiplicity There will be no adjustment for multiple endpoints Efficacy Subgroup Analysis To evaluate the impact of various baseline characteristics on treatment effect, analyses will be performed for the primary efficacy variable of SVR 12 in each study arm using the following subgroups: Transplant recipient IL28B genotype (CC or non-cc), (CC, CT, or TT); HCV genotype 1 subtype (1a, 1b, other); Baseline HCV RNA level (< 800,000 IU/mL or 800,000 IU/mL); Baseline IP-10 (< 600 ng/ml or 600 ng/ml); Sex (Male versus female); Age (< 65 versus 65 years); 37

309 M Statistical Analysis Plan Version April 2014 Race (black versus non-black); Ethnicity (Hispanic versus none); Geographic Region (North America or Europe); BMI (< 30 or 30 kg/m 2 ); History of Diabetes (yes/no); Treatment status pre-transplant and post-transplant (treatment-naïve, treatment-experienced: non-responder, responder, other); and Baseline fibrosis stage (F0 F1, F2, or F3). The number and percentage of subjects achieving SVR 12 within each subgroup will be provided for all subgroups Safety Analysis 12.1 General Considerations All subjects who receive at least one dose of study drug will be included in the safety analyses Analysis of Adverse Events Treatment-Emergent Adverse Events Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events are defined as any event that begins or worsens in severity after initiation of study drug through 30 days after the last dose of study drug. Events where the onset date is the same as the study drug start date are assumed to be treatment-emergent. If an incomplete onset date was collected for an adverse event, the event will be assumed to be treatment-emergent unless there is other evidence that confirms that the event was not treatment-emergent (e.g., the event end date was prior to the study drug start date). 38

310 M Statistical Analysis Plan Version April Tabulations of Treatment-Emergent Adverse Events Adverse event data will be summarized for each study arm and presented using primary MedDRA system organ classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA coding dictionary used for the study at the time of database lock. The actual version of the MedDRA coding dictionary used will be noted in the clinical study report. The system organ classes will be presented in alphabetical order and the preferred terms will be presented in alphabetical order within each system organ class. Adverse Event Overview An overview of adverse events will be presented consisting of the number and percentage of subjects experiencing at least one event for each of the following adverse event categories: Treatment-emergent adverse events; Treatment-emergent adverse events with a "reasonable possibility" of being related to DAAs; Treatment-emergent adverse events with a "reasonable possibility" of being related to RBV; Treatment-emergent severe adverse events; Treatment-emergent serious adverse events; Treatment-emergent adverse events leading to discontinuation of study drug; Treatment-emergent adverse events leading to interruption of study drug; Treatment-emergent adverse events leading to RBV dose modification; Treatment-emergent adverse events leading to death; and Subject deaths as collected on the death case report form. Adverse Event by SOC and PT The following summaries of adverse events will be generated: Treatment-emergent adverse events; 39

311 M Statistical Analysis Plan Version April 2014 Treatment-emergent adverse events with a "reasonable possibility" of being related to DAAs; Treatment-emergent adverse events with a "reasonable possibility" of being related to RBV; Treatment-emergent serious adverse events; Treatment-emergent moderate or severe adverse events; Treatment-emergent severe adverse events; Grade 3 or 4 (see definition below) treatment-emergent adverse events; Treatment-emergent adverse events leading to discontinuation of study drug; Treatment-emergent adverse events leading to interruption of study drug; Treatment-emergent adverse events leading to RBV dose modifications; Treatment-emergent adverse events leading to death; and Treatment-emergent adverse events leading to concomitant medication use (events with other action taken of "concomitant medication prescribed"). The number and percentage of subjects experiencing treatment-emergent adverse events will be tabulated according to SOC and PT. Subjects reporting more than one adverse event for a given PT will be counted only once for that term (most severe incident for the severity tables and most related incident for the relationship tables). Subjects reporting more than one type of adverse event within a SOC will be counted only once for that SOC. Subjects reporting more than one type of adverse event will be counted only once in the overall total. Adverse Events by Frequency of PT The number and percentage of subjects experiencing treatment-emergent adverse events will be tabulated according to preferred term and sorted by frequency. A similar summary will be provided for moderate to severe treatment-emergent adverse events and treatmentemergent adverse events with a "reasonable possibility" of being related to DAAs. 40

312 M Statistical Analysis Plan Version April 2014 Adverse Events by Maximum Severity Treatment-emergent adverse events will also be summarized by maximum severity of each preferred term. A similar summary will be provided for treatment-emergent adverse events with a "reasonable possibility" of being related to DAAs. If a subject has an adverse event with unknown severity, then the subject will be counted in the severity category of "unknown," even if the subject has another occurrence of the same event with a severity present. The only exception is if the subject has another occurrence of the same adverse event with the most extreme severity "Severe." In this case, the subject will be counted under the "Severe" category. Adverse Events by Maximum Relationship Treatment-emergent adverse events will also be summarized by maximum relationship of each PT to DAAs or RBV in separate tables, as assessed by the Investigator. If a subject has an adverse event with unknown relationship, then the subject will be counted in the relationship category of "unknown," even if the subject has another occurrence of the same event with a relationship present. The only exception is if the subject has another occurrence of the same adverse event with a relationship assessment of "Reasonable Possibility." In this case, the subject will be counted under the "Reasonable Possibility" category. Adverse Events by Maximum Severity Grade Level Treatment-emergent adverse events will be summarized by maximum severity grade level of each preferred term. Each preferred term will be assigned a grade level based on severity and seriousness, adapted from the Division of AIDS (DAIDS) table for grading severity of adverse events. All serious adverse events will be categorized as Grade 4. Nonserious adverse events categorized by the investigators as mild, moderate, or severe will be categorized as Grade 1, Grade 2, or Grade 3, respectively. If a subject has a nonserious adverse event with unknown severity, then the subject will be counted in the severity grade level category of "unknown," even if the subject has another occurrence of the same event with a severity present. The only exception is if the subject has another 41

313 M Statistical Analysis Plan Version April 2014 occurrence of the same adverse event with the most extreme severity "Severe." In this case, the subject will be counted under the "Grade 3" category. Similarly, if a subject has an adverse event with unknown seriousness, then the subject will be counted in the severity grade level category of "unknown" unless the subject has another occurrence of the same adverse event that is marked serious. In this case, the subject will be counted under the "Grade 4" category. Adverse Events of Special Interest Specific treatment-emergent adverse events of special interest, which may be searched using Standardized or Company MedDRA Queries, will be summarized and include hepatic-related events, bilirubin-related events, rash-related events, and anemia. The search criteria for each of the adverse events of interest are as follows: Hepatic-related events SMQ "Drug-related hepatic disorders severe events only" (broad search) Bilirubin-related events SMQ "Cholestasis and jaundice of hepatic origin" (broad search) Drug Induced Rash CMQ "Drug induced rash" (Version or later) Severe Cutaneous Reactions SMQ "Severe cutaneous adverse reactions" (narrow search) Anemia SMQ "Haematopoietic erythropenia" (broad search) plus the following preferred terms: Haemolytic Anaemia, Coombs negative haemolytic anaemia, Coombs positive haemolytic anaemia. For each adverse event of interest (hepatic, bilirubin, drug induced rash, severe cutaneous reaction, and anemia), the number and percentage of subjects experiencing at least 42

314 M Statistical Analysis Plan Version April 2014 one treatment-emergent adverse event in the search for the events of interest will be presented for each treatment arm and overall and by SOC and PT. A listing of treatment-emergent adverse events for subjects meeting the search criterion will be provided for each adverse event of special interest Listing of Adverse Events The following listings will be provided. Listing of subject numbers associated with treatment-emergent adverse events grouped by the primary MedDRA SOC and MedDRA PT. Listing of all treatment-emergent serious adverse events. Listing of all treatment-emergent adverse events leading to death. Listing of treatment-emergent adverse events leading to discontinuation of study drug (all study drugs). Listing of treatment-emergent adverse events leading to interruption of study drug (all study drugs). Listing of treatment-emergent adverse events leading to RBV dose modifications. Listing of all serious adverse events (from the time the subject signed the study specific informed consent through the End of the Study) Analysis of Laboratory Data Data collected from the central and local laboratories, including additional laboratory testing due to an SAE, will be used in all analyses Variables and Criteria Defining Abnormality Hematology variables include: ANC, aptt, bands, basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, neutrophils, PT, INR, platelet count, reticulocyte count, RBC count, and WBC count. 43

315 M Statistical Analysis Plan Version April 2014 Chemistry variables include: albumin, ALT (SGPT), AST (SGOT), alkaline phosphatase, bicarbonate, BUN, calcium, chloride, cholesterol (total), creatinine, creatinine clearance, direct and indirect bilirubin, GGT, glucose, inorganic phosphorus, magnesium, potassium, sodium, total bilirubin, total protein, triglycerides, and uric acid. Urinalysis variables include: specific gravity, ketones, ph, protein, albumin, blood, glucose, urobilinogen, bilirubin, and leukocyte esterase. The Criteria for Potentially Clinically Significant Laboratory Findings are described in Table 9 and Table 10. Table 9. Criteria for Potentially Clinically Significant Hematology Values Test/Units Very Low (VL) Very High (VH) Hemoglobin (mmol/l) (g/dl) (g/l) Platelets count (cells/mm 3 ) (cells/l) White Blood Cell count (cells/mm 3 ) (cells/l) Absolute Neutrophil count (cells/mm 3 ) (cells/l) Lymphocyte count (cells/mm 3 ) (cells/l) Eosinophil count aptt (cells/mm 3 ) (cells/l) International Normalized Ratio Note: < 4.9 < 8.0 < 80 < < < 2000 > < > < 1000 < < 500 < > 5000 > > 2 ULN > 2 ULN A post-baseline value must be more extreme than the baseline value to be considered a PCS finding. 44

316 M Statistical Analysis Plan Version April 2014 Table 10. Criteria for Potentially Clinically Significant Chemistry Values Test/Units Very Low (VL) Very High (VH) ALT/SGPT AST/SGOT Alkaline Phosphatase Total Bilirubin (mg/dl) Creatinine (mcmol/l) (mg/dl) Creatinine Clearance (ml/min) < 50 BUN Uric Acid (mcmol/l) (mg/dl) Phosphate (mmol/l) (mg/dl) Calcium, Serum (mmol/l) (mg/dl) < 0.6 < 2.0 < 1.75 < 7.0 > 5 ULN and 2 baseline > 5 ULN and 2 baseline > 1.5 ULN 2.0 ULN > 5 ULN > > 12.0 > 3.1 > 12.5 Calcium, Ionized (mmol/l) < 0.9 > 1.6 Sodium (mmol/l) < 130 > 155 Potassium (mmol/l) < 3.0 > 6.0 Magnesium (mmol/l) (mg/dl) Glucose (mmol/l) (mg/dl) Albumin (g/l) (g/dl) Protein (g/l) (g/dl) < 0.4 < 0.9 < 2.2 < 40 < 20 < 2 < 50 < 5.0 > 1.23 < 3.0 > 13.9 >

317 M Statistical Analysis Plan Version April 2014 Table 10. Criteria for Potentially Clinically Significant Chemistry Values (Continued) Test/Units Very Low (VL) Very High (VH) Cholesterol (mmol/l) (mg/dl) Triglycerides Note: (mmol/l) (mg/dl) > > 400 > 5.7 > 500 A post-baseline value must be more extreme than the baseline value to be considered a PCS finding Statistical Methods Clinical laboratory tests will be summarized by study arm at each visit during the Treatment Period. The baseline value will be the last measurement on or before the day of the first dose of study drug. This same baseline value will be used for all change from baseline tables in the Treatment and Post Treatment Periods. Mean changes from baseline to each post-baseline visit, including applicable post treatment visits, will be summarized for each protocol-specified laboratory parameter with the baseline mean, visit mean, change from baseline mean, standard deviation, and median. During the Treatment Period, laboratory data values will be categorized as low, normal, or high based on normal ranges of the laboratory used in this study. Shift tables from baseline to minimum value (related to the normal range), maximum value (related to the normal range) and final values during the Treatment Period (Study Drug End Day 2) will be created. The shift tables will cross tabulate the frequency of subjects with baseline values below/within/above the normal range versus minimum/maximum/final values below/within/above the normal range. The shift tables will also cross tabulate the frequency and percentage of subjects with baseline values below/within the normal range versus minimum/maximum/final values below/within/above the normal range. The shift tables will also cross tabulate the frequency and percentage of subjects with baseline 46

318 M Statistical Analysis Plan Version April 2014 values within/above the normal range versus minimum/maximum/final values below/within/above the normal range. Frequencies and percentages of subjects with post-baseline values during the Treatment Period (Study Drug End Day 2) meeting Criteria for Potentially Clinically Significant Laboratory Values (Table 9 and Table 10) will be summarized by study arm. A post-baseline value must be more extreme than the baseline value to be considered a PCS finding. A separate listing will be provided that presents all of the laboratory values for the subjects meeting PCS criteria during treatment. For hemoglobin and the liver function tests (LFTs) of ALT, AST, alkaline phosphatase, and total bilirubin, the number and percentage of subjects in each study arm with a maximum CTCAE Grade of 1, 2, 3, or 4 (see definitions in Table 11) at any post-baseline visit (regardless of the baseline value) through the end of treatment (i.e., Final Treatment Value) will be summarized. All LFT tables will include summary rows for the number and percentage of subjects with at least Grade 2 and at least Grade 3 laboratory abnormalities. The hemoglobin table will include a summary row for the number and percentage of subjects with at least a Grade 2 laboratory abnormality. Accompanying listings of all ALT, AST, total, indirect and direct bilirubin, and alkaline phosphatase will be created for any subject who had at least a Grade 3 ALT, AST, alkaline phosphatase, or total bilirubin. A listing of hemoglobin, total neutrophils, platelet count and white blood cell count results will be provided for subjects with hemoglobin abnormalities. The hemoglobin by maximum CTCAE grade table, described above, will also be summarized for subjects with and without treatment-emergent adverse events of dyspnea (defined by preferred terms of "dyspnea" or "dyspnea exertional"). For subjects with a Grade 3 or higher total bilirubin elevation, a listing of treatment emergent adverse events consider possible elevated bilirubin symptoms (defined as preferred terms within the "Cholestasis and jaundice of hepatic origin" [broad search] SMQ, excluding preferred terms within the "Investigations" SOC) will be provided. 47

319 M Statistical Analysis Plan Version April 2014 Table 11. Definitions of CTCAE Grade 1, 2, 3, and 4 Test Grade 1 Grade 2 Grade 3 Grade 4 ALT/SGPT > ULN 3 ULN > 3 5 ULN > 5 20 ULN > 20 ULN AST/SGOT > ULN 3 ULN > 3 5 ULN > 5 20 ULN > 20 ULN Alkaline Phosphatase > ULN 2.5 ULN > ULN > 5 20 ULN > 20 ULN Total Bilirubin > ULN 1.5 ULN > ULN > 3 10 ULN > 10 ULN Hemoglobin Decreased < LLN 100 g/l < g/l < g/l < 65 g/l The number and percentage of subjects in each study arm meeting the following criteria during the Treatment Period will be summarized: ALT 3 ULN and total bilirubin value 2 ULN; ALT 3 ULN and total bilirubin value < 2 ULN; ALT > 5 ULN (equivalent to Grade 3 or higher) and total bilirubin value < 2 ULN; ALT < 3 ULN and total bilirubin 2 ULN. For each criterion, the analysis will check to see if the subject meets the criterion at any time within the Treatment Period (i.e., draw dates do not need to be concurrent). A subject or event will be counted if the post-baseline laboratory values meet the above criteria regardless of the baseline laboratory value (i.e., the post-baseline laboratory value does not need to be worse than the baseline laboratory value). The maximum ratio relative to the ULN will be used to determine if subjects meet the criteria listed above. For subjects meeting the ALT 3 ULN and total bilirubin value 2 ULN criterion during the Treatment Period, a corresponding listing of all ALT, AST, alkaline phosphatase, and total, direct, and indirect bilirubin values will be provided. 48

320 M Statistical Analysis Plan Version April Analysis of Vital Signs and Weight Variables and Criteria Defining Abnormality (If Applicable) Vital sign variables are temperature, sitting systolic blood pressure, sitting diastolic blood pressure, sitting pulse rate, and weight. The Criteria for Potentially Clinically Significant Vital Sign Findings are presented in Table 12. Table 12. Criteria for Potentially Clinically Significant Vital Sign Values Test/Measurement Very Low (VL) Very High (VH) Systolic Blood Pressure Diastolic Blood Pressure Heart Rate Weight Temperature 90 mmhg AND A decrease of 20 mmhg from baseline 50 mmhg AND A decrease of 15 mmhg from baseline 50 bpm AND A decrease of 15 bpm from baseline A decrease of 15% from baseline 180 mmhg AND An increase of 20 mmhg from baseline 105 mmhg AND An increase of 15 mmhg from baseline 120 bpm AND An increase of 15 bpm from baseline An increase of 15% from baseline > 38.3 C AND An increase of 1.1 C from baseline Statistical Methods Vital signs will be summarized by study arm at each visit during the Treatment Period. The baseline value will be the last measurement on or before the day of the first dose of study drug. This same baseline value will be used for all change from baseline tables in the Treatment and Post-Treatment Periods. Mean changes from baseline to each post-baseline visit, including applicable post treatment visits, will be summarized for each vital sign parameter with the baseline mean, visit mean, change from baseline mean, standard deviation, and median. 49

321 M Statistical Analysis Plan Version April 2014 Frequencies and percentages of subjects with post-baseline values during the Treatment Period (Study Drug End Day 2) meeting Criteria for Potentially Clinically Significant Vital Signs Values (Table 12) will be summarized by study arm. A post-baseline value must be more extreme than the baseline value to be considered a PCS finding. A separate listing will be provided that presents all of the vital sign values for the subjects meeting the PCS vital sign criteria during treatment Summary of Changes There is no statistical change between the latest version of the protocol (Section 8.1 of Study M Protocol Amendment 3) and this SAP References 1. Szende A, Williams A, editors. Measuring self-reported population health: an international perspective based on EQ-5D-5L. EuroQol Group Monographs Volume 1. SpringMed, Rabin R, Oemar M, Oppe M, et al. EQ-5D-5L User Guide: Basic Information on How to Use the EQ-5D-5L Instrument, Version 1.0. April Ware JE Jr, Kosinski M, Bjorner JB, et al. User's Manual for the SF-36v2 Health Survey. 2 nd ed. Lincoln, RI: QualityMetric Incorporated;