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NCT Number: NCT02956629 Document Date: 26-Oct-2017 Product: MK-3682 1 Protocol/Amendment No.: 041-05

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NCT Number: NCT02956629 Document Date: 26-Oct-2017 Product: MK-3682 1 Protocol/Amendment No.: 041-05 Official Protocol Title: A Phase 2, Open-Label Clinical Trial to Study the Efficacy and Safety of 12 weeks of the Combination Regimen of MK-3682 + Ruzasvir in Subjects with Chronic Hepatitis C Virus (HCV) Genotype 1, 2, 3, 4, 5 or 6 Infection NCT number: NCT02956629 Document Date: 26-Oct-2017 Product: MK-3682 1 Protocol/Amendment No.: 041-05 THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE STATION, NJ, U.S.A. SPONSOR: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (hereafter referred to as the Sponsor or Merck) One Merck Drive P.O. Box 100 Whitehouse Station, New Jersey, 08889-0100, U.S.A. Protocol-specific Sponsor Contact information can be found in the Investigator Trial File Binder (or equivalent). TITLE: A Phase 2, Open-Label Clinical Trial to Study the Efficacy and Safety of 12 weeks of the Combination Regimen of MK-3682 + Ruzasvir in Subjects with Chronic Hepatitis C Virus (HCV) Genotype 1, 2, 3, 4, 5 or 6 Infection IND NUMBER: 123,749 EudraCT NUMBER: 2016-003227-37 MK-3682-041-05 Final Protocol 26-Oct-2017 04S4YM04YJRT Confidential Product: MK-3682 2 Protocol/Amendment No.: 041-05 TABLE OF CONTENTS SUMMARY OF CHANGES................................................................................................ 10 1.0 TRIAL SUMMARY.................................................................................................. 11 2.0 TRIAL DESIGN........................................................................................................ 12 2.1 Trial Design ........................................................................................................... 12 2.2 Trial Diagram........................................................................................................ 13 3.0 OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 14 3.1 Primary Objective(s) & Hypothesis(es) .............................................................. 14 3.2 Secondary Objective(s) & Hypothesis(es)........................................................... 14 3.3 Exploratory Objectives......................................................................................... 14 4.0 BACKGROUND & RATIONALE.......................................................................... 15 4.1 Background ........................................................................................................... 15 4.1.1 Pharmaceutical and Therapeutic Background .................................................... 15 4.1.1.1 Overview...................................................................................................... 15 4.1.1.2 Current Treatment of Chronic HCV ............................................................ 16 4.1.2 Background on Drugs Used in this Trial ............................................................ 18 4.1.2.1 Phase 1 Studies ............................................................................................ 18 4.1.2.2 Summary of Ongoing Phase 2 Clinical Trials ............................................. 19 4.1.2.2.1 MK-3682 PN011 and PN012................................................................ 19 4.1.2.2.1.1 Part A.............................................................................................. 19 4.1.2.2.1.2 Part B.............................................................................................. 20 4.1.2.2.1.3 Part C.............................................................................................. 23 4.1.2.2.2 MK-3682 PN021................................................................................... 23 4.1.2.2.3 MK-3682 PN035................................................................................... 24 4.2 Rationale................................................................................................................ 24 4.2.1 Rationale for the Trial and Selected Subject Population .................................... 24 4.2.2 Rationale for the Selected Subject Population.................................................... 25 4.2.3 Rationale for Study Design ................................................................................. 27 4.2.4 Rationale for Dose Selection/Regimen ............................................................... 27 4.2.4.1 Dose Selection for MK-3682....................................................................... 27 MK-3682-041-05 Final Protocol 26-Oct-2017 04S4YM04YJRT Confidential Product: MK-3682 3 Protocol/Amendment No.: 041-05 4.2.4.2 Dose Selection for RZR ............................................................................... 28 4.2.5 Rationale for Endpoints ...................................................................................... 29 4.2.5.1 Efficacy Endpoints....................................................................................... 29 4.2.5.1.1 Measurement of HCV RNA ................................................................. 30 4.2.5.1.1.1 Definition of Efficacy Endpoints ................................................... 30 4.2.5.1.1.2 Definition of Virologic Failure: Non-Response, Rebound, Virologic Breakthrough and Relapse ...................................................................... 30 4.2.5.1.2 Viral Resistance Measurements............................................................ 31 4.2.5.2 Safety Endpoints .......................................................................................... 31 4.2.5.3 Pharmacokinetic Endpoints ......................................................................... 31 4.2.5.4 Pharmacodynamic Endpoints....................................................................... 32 4.2.5.5 Planned Exploratory Biomarker Research................................................... 32 4.2.5.6 Future Biomedical Research ........................................................................ 32 4.3 Benefit/Risk ........................................................................................................... 33 5.0 METHODOLOGY ................................................................................................... 35 5.1 Entry Criteria........................................................................................................ 35 5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 35 5.1.2 Subject Inclusion Criteria.................................................................................... 35 5.1.3 Subject Exclusion Criteria .................................................................................. 38 5.2 Trial Treatment(s) ................................................................................................ 41 5.2.1 Dose Selection/Modification .............................................................................. 42 5.2.1.1 Dose Selection (Preparation) ....................................................................... 42 5.2.1.2 Dose Modification ....................................................................................... 43 5.2.2 Timing of Dose Administration .......................................................................... 43 5.2.3 Trial Blinding...................................................................................................... 43 5.3 Randomization or Treatment Allocation............................................................ 43 5.4 Stratification.......................................................................................................... 44 5.5 Concomitant Medications/Vaccinations (Allowed & Prohibited) .................... 44 5.6 Rescue Medications & Supportive Care ............................................................. 47 5.7 Diet/Activity/Other Considerations..................................................................... 47 5.8 Subject Withdrawal/Discontinuation Criteria ................................................... 47 5.8.1 Discontinuation of Treatment ............................................................................. 47 MK-3682-041-05 Final Protocol 26-Oct-2017 04S4YM04YJRT Confidential Product: MK-3682 4 Protocol/Amendment No.: 041-05 5.8.2 Withdrawal from the Trial .................................................................................. 49 5.9 Subject Replacement Strategy............................................................................. 49 5.10 Beginning and End of the Trial ........................................................................... 49 5.11 Clinical Criteria for Early Trial Termination ................................................... 49 5.11.1 Criteria for Assessing Safety in the First 50 Subjects......................................... 49 5.11.2 Safety Criteria for Stopping Enrollment/Allocation At Any Time During the Trial..................................................................................................................... 50 5.11.3 Safety Criteria for Pausing Enrollment/Allocation ............................................. 50 5.11.4 Efficacy Criteria for Stopping Enrollment/Allocation........................................ 51 6.0 TRIAL FLOW CHART ........................................................................................... 52 7.0 TRIAL PROCEDURES ........................................................................................... 56 7.1 Trial Procedures ..................................................................................................
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