A Phase II, Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK

Official Protocol Title: A Phase II, Open-Label Clinical Trial to Study the Efficacy and Safety of the CombinationRegimen of MK-3682 + MK-8408 in Subjects with Chronic HCV Genotype 1, 2, 3, 4, 5 or 6 Infection NCT number: NCT02759315 Document Date: 26-Oct-2017 Product: MK-3682 1 Protocol/Amendment No.: 035-04 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 II, Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-3682 + MK-8408 in Subjects with Chronic HCV Genotype 1, 2, 3, 4, 5 or 6 Infection IND NUMBER: 123,749 EudraCT NUMBER: Not Applicable MK-3682-035-04 Final Protocol 26-Oct-2017 04S4N9 Confidential Product: MK-3682 2 Protocol/Amendment No.: 035-04 TABLE OF CONTENTS SUMMARY OF CHANGES................................................................................................ 10 1.0 TRIAL SUMMARY.................................................................................................. 12 2.0 TRIAL DESIGN........................................................................................................ 13 2.1 Trial Design ........................................................................................................... 13 2.2 Trial Diagram........................................................................................................ 14 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 Other Objectives (e.g., Tertiary, Exploratory, etc.)........................................... 15 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 HCV .......................................................................... 16 4.1.2 Pre-clinical and Clinical Trials ........................................................................... 18 4.1.2.1 Summary of Preclinical Data ....................................................................... 18 4.1.2.2 Summary of Clinical Data ........................................................................... 20 4.1.2.2.1 Phase 1 Studies ..................................................................................... 20 4.1.2.2.2 Summary of Ongoing Phase 2 Clinical Trials ...................................... 21 4.2 Rationale................................................................................................................ 26 4.2.1 Rationale for the Trial and Selected Subject Population .................................... 26 4.2.1.1 Rationale for the Trial.................................................................................. 26 4.2.1.2 Rationale for the Selected Subject Population............................................. 27 4.2.1.3 Rationale for Study Design.......................................................................... 28 4.2.2 Rationale for Dose Selection/Regimen/Modification......................................... 30 4.2.2.1 Dose Selection for MK-3682....................................................................... 30 4.2.2.2 Dose Selection for MK-8408....................................................................... 30 4.2.3 Rationale for Endpoints ...................................................................................... 31 4.2.3.1 Efficacy Endpoints....................................................................................... 31 MK-3682-035-04 Final Protocol 26-Oct-2017 04S4N9 Confidential Product: MK-3682 3 Protocol/Amendment No.: 035-04 4.2.3.1.1 Measurement of HCV RNA ................................................................. 31 4.2.3.1.1.1 Definition of Efficacy Endpoints ................................................... 32 4.2.3.1.1.2 Definition of Virologic Failure: Non-Response, Rebound, Virologic Breakthrough and Relapse ..................................... 32 4.2.3.1.2 Viral Resistance Measurements............................................................ 33 4.2.3.2 Safety Endpoints .......................................................................................... 33 4.2.3.3 Pharmacokinetic Endpoints ......................................................................... 33 4.2.3.4 Pharmacodynamic Endpoints....................................................................... 33 4.2.3.5 Planned Exploratory Biomarker Research................................................... 34 4.2.3.6 Future Biomedical Research ........................................................................ 34 4.3 Benefit/Risk ........................................................................................................... 34 5.0 METHODOLOGY ................................................................................................... 36 5.1 Entry Criteria........................................................................................................ 36 5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 36 5.1.2 Subject Inclusion Criteria.................................................................................... 36 5.1.3 Subject Exclusion Criteria .................................................................................. 39 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 (Escalation/Titration/Other).......................................... 42 5.2.2 Timing of Dose Administration .......................................................................... 42 5.2.3 Trial Blinding...................................................................................................... 43 5.3 Randomization or Treatment Allocation............................................................ 43 5.4 Stratification.......................................................................................................... 43 5.5 Concomitant Medications/Vaccinations (Allowed & Prohibited) .................... 43 5.6 Rescue Medications & Supportive Care ............................................................. 46 5.7 Diet/Activity/Other Considerations..................................................................... 46 5.8 Subject Withdrawal/Discontinuation Criteria ................................................... 46 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 Safety Criteria for Pausing Enrollment ............................................................... 49 MK-3682-035-04 Final Protocol 26-Oct-2017 04S4N9 Confidential Product: MK-3682 4 Protocol/Amendment No.: 035-04 5.11.2 Safety Criteria for Stopping Enrollment and Early Trial Termination ............... 49 5.11.3 Efficacy Criteria for Stopping Enrollment.......................................................... 50 5.12 Clinical Criteria for Trial Modification.............................................................. 50 5.12.1 Efficacy Criteria for Modification of Treatment Duration ................................. 50 6.0 TRIAL FLOW CHART ........................................................................................... 51 7.0 TRIAL PROCEDURES ........................................................................................... 56 7.1 Trial Procedures ................................................................................................... 56 7.1.1 Administrative Procedures.................................................................................. 56 7.1.1.1 Informed Consent......................................................................................... 56 7.1.1.1.1 General Informed Consent.................................................................... 56 7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research................................................................................................ 57 7.1.1.2 Inclusion/Exclusion Criteria ........................................................................ 57 7.1.1.3

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