Clinical trial NCT02956629
Conditions: Hepatitis C
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-11-16; Completion date: 2018-03-05
Enrollment: 282 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a nonrandomized, multi-site, open-label trial to evaluate a novel two-drug combination regimen (uprifosbuvir \[MK-3682\] 450 mg + ruzasvir \[RZR; MK-8408\] 180 mg once daily \[q.d.\] for 12 weeks) in male and female treatment-naïve (TN) or treatment-experienced (TE) participants with chronic hepatitis C virus (HCV) infection genotype (GT) GT1, GT2, GT3, GT4, GT5, or GT6 who have not previously received HCV direct-acting antiviral (DAA) therapy. Cirrhotic (C) and non-cirrhotic (NC) participants with and without human immunodeficiency virus (HIV) co-infection will be enrolled.

Detailed description:
Any GT that meets virologic futility criteria will be given the option of extending treatment with uprifosbuvir + RZR to 16 weeks with ribavirin (RBV) added.

Arms: arm 1: Male and female participants with HCV GT1a or GT1b infection take uprifosbuvir 450 mg + RZR 180 mg for 12 weeks. arm 2: Male and female participants with HCV GT2 infection take uprifosbuvir 450 mg + RZR 180 mg for 12 weeks. arm 3: Male and female participants with HCV GT3 infection take uprifosbuvir 450 mg + RZR 180 mg for 12 weeks. arm 4: Male and female participants with HCV GT4 infection take uprifosbuvir 450 mg + RZR 180 mg for 12 weeks. arm 5: Male and female participants with HCV GT5 infection take uprifosbuvir 450 mg + RZR 180 mg for 12 weeks. arm 6: Male and female participants with HCV GT6 infection take uprifosbuvir 450 mg + RZR 180 mg for 12 weeks.
Interventions: intervention 1: Uprifosbuvir intervention 2: Ruzasvir intervention 3: Ribavirin
Intervention descriptions: intervention 1: Participants take 3 tablets each containing 150 mg uprifosbuvir q.d. by mouth. intervention 2: Participants take 3 capsules each containing 60 mg RZR q.d. by mouth. intervention 3: RBV 200 mg capsules will be taken according to package instructions for a maximum of 16 weeks for any GT that meets virologic futility rules on uprifosbuvir + RZR alone.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02956629  
Document Date: 
26-Oct-2017
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


Product:  MK-3682 
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Confidential
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
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 11
2.0
TRIAL DESIGN........................................................................................................ 12
Trial Design ........................................................................................................... 12
2.1
Trial Diagram........................................................................................................ 13
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 14
Primary Objective(s) & Hypothesis(es) .............................................................. 14
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 14
3.2
Exploratory Objectives......................................................................................... 14
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 15
Background ........................................................................................................... 15
4.1
Pharmaceutical and Therapeutic Background .................................................... 15
4.1.1
Overview...................................................................................................... 15
4.1.1.1
Current Treatment of Chronic HCV ............................................................ 16
4.1.1.2
Background on Drugs Used in this Trial ............................................................ 18
4.1.2
Phase 1 Studies ............................................................................................ 18
4.1.2.1
Summary of Ongoing Phase 2 Clinical Trials ............................................. 19
4.1.2.2
4.1.2.2.1
MK-3682 PN011 and PN012................................................................ 19
Part A.............................................................................................. 19
4.1.2.2.1.1
Part B.............................................................................................. 20
4.1.2.2.1.2
Part C.............................................................................................. 23
4.1.2.2.1.3
4.1.2.2.2
MK-3682 PN021................................................................................... 23
4.1.2.2.3
MK-3682 PN035................................................................................... 24
Rationale................................................................................................................ 24
4.2
Rationale for the Trial and Selected Subject Population .................................... 24
4.2.1
Rationale for the Selected Subject Population.................................................... 25
4.2.2
Rationale for Study Design................................................................................. 27
4.2.3
Rationale for Dose Selection/Regimen............................................................... 27
4.2.4
Dose Selection for MK-3682....................................................................... 27
4.2.4.1
 
 
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Dose Selection for RZR............................................................................... 28
4.2.4.2
Rationale for Endpoints ...................................................................................... 29
4.2.5
Efficacy Endpoints....................................................................................... 29
4.2.5.1
4.2.5.1.1
Measurement of HCV RNA ................................................................. 30
Definition of Efficacy Endpoints ................................................... 30
4.2.5.1.1.1
Definition of Virologic Failure: Non-Response, Rebound, Virologic 
4.2.5.1.1.2
Breakthrough and Relapse ...................................................................... 30
4.2.5.1.2
Viral Resistance Measurements............................................................ 31
Safety Endpoints .......................................................................................... 31
4.2.5.2
Pharmacokinetic Endpoints ......................................................................... 31
4.2.5.3
Pharmacodynamic Endpoints....................................................................... 32
4.2.5.4
Planned Exploratory Biomarker Research................................................... 32
4.2.5.5
Future Biomedical Research........................................................................ 32
4.2.5.6
Benefit/Risk ........................................................................................................... 33
4.3
5.0
METHODOLOGY ................................................................................................... 35
Entry Criteria........................................................................................................ 35
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 35
5.1.1
Subject Inclusion Criteria.................................................................................... 35
5.1.2
Subject Exclusion Criteria .................................................................................. 38
5.1.3
Trial Treatment(s) ................................................................................................ 41
5.2
Dose Selection/Modification .............................................................................. 42
5.2.1
Dose Selection (Preparation) ....................................................................... 42
5.2.1.1
Dose Modification ....................................................................................... 43
5.2.1.2
Timing of Dose Administration .......................................................................... 43
5.2.2
Trial Blinding...................................................................................................... 43
5.2.3
Randomization or Treatment Allocation............................................................ 43
5.3
Stratification.......................................................................................................... 44
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 44
5.5
Rescue Medications & Supportive Care............................................................. 47
5.6
Diet/Activity/Other Considerations..................................................................... 47
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 47
5.8
Discontinuation of Treatment ............................................................................. 47
5.8.1
 
 
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Withdrawal from the Trial .................................................................................. 49
5.8.2
Subject Replacement Strategy............................................................................. 49
5.9
Beginning and End of the Trial ........................................................................... 49
5.10
Clinical Criteria for Early Trial Termination ................................................... 49
5.11
Criteria for Assessing Safety in the First 50 Subjects......................................... 49
5.11.1
Safety Criteria for Stopping Enrollment/Allocation At Any Time During the 
5.11.2
Trial..................................................................................................................... 50
Safety Criteria for Pausing Enrollment/Allocation............................................. 50
5.11.3
Efficacy Criteria for Stopping Enrollment/Allocation........................................ 51
5.11.4
6.0
TRIAL FLOW CHART ........................................................................................... 52
7.0
TRIAL PROCEDURES ........................................................................................... 56
Trial Procedures ................................................................................................... 56
7.1
Administrative Procedures.................................................................................. 56
7.1.1
Informed Consent......................................................................................... 56
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 56
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 57
Inclusion/Exclusion Criteria ........................................................................ 57
7.1.1.2
Subject Identification Card .......................................................................... 57
7.1.1.3
Medical History ........................................................................................... 57
7.1.1.4
Prior and Concomitant Medications Review ............................................... 57
7.1.1.5
7.1.1.5.1
Prior Medications.................................................................................. 57
7.1.1.5.2
Concomitant Medications..................................................................... 57
Assignment of Screening Number............................................................... 58
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 58
7.1.1.7
Trial Compliance (Medication).................................................................... 58
7.1.1.8
Clinical Procedures/Assessments........................................................................ 59
7.1.2
Physical Examination................................................................................... 59
7.1.2.1
Weight and Height Assessment ................................................................... 59
7.1.2.2
12-Lead ECG ............................................................................................... 59
7.1.2.3
Vital Signs.................................................................................................... 59
7.1.2.4
Birth Control Confirmation.......................................................................... 60
7.1.2.5
 
 
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Adverse Events ............................................................................................ 60
7.1.2.6
Noninvasive Methods of Cirrhosis Evaluation ............................................ 60
7.1.2.7
Laboratory Procedures/Assessments .................................................................. 60
7.1.3
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 61
7.1.3.1
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 62
7.1.3.2
7.1.3.2.1
Pharmacokinetics: Blood Collection for Plasma MK-3682 (and 
Metabolites), and Ruzasvir ................................................................... 62
7.1.3.2.2
Pharmacodynamics: Viral Kinetics ...................................................... 65
HCV Evaluation........................................................................................... 65
7.1.3.3
HIV Evaluation ............................................................................................ 66
7.1.3.4
HBV Evaluation........................................................................................... 66
7.1.3.5
Planned Genetic Analysis Sample Collection.............................................. 66
7.1.3.6
Future Biomedical Research Samples ......................................................... 66
7.1.3.7
Other Procedures................................................................................................. 67
7.1.4
Withdrawal/Discontinuation........................................................................ 67
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 67
Subject Blinding/Unblinding ....................................................................... 67
7.1.4.2
Domiciling ................................................................................................... 67
7.1.4.3
Calibration of Critical Equipment................................................................ 67
7.1.4.4
Visit Requirements.............................................................................................. 68
7.1.5
Screening...................................................................................................... 68
7.1.5.1
Rescreening.................................................................................................. 68
7.1.5.2
Treatment Period.......................................................................................... 69
7.1.5.3
Drug Administration .................................................................................... 69
7.1.5.4
Follow-up Visits........................................................................................... 70
7.1.5.5
Discontinued Subjects Continuing to be Monitored in the Trial ................. 70
7.1.5.6
Evaluation of Laboratory Safety Signals ..................................................... 71
7.1.5.7
Assessing and Recording Adverse Events .......................................................... 71
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 72
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 72
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 73
7.2.3
Serious Adverse Events ............................................................................... 73
7.2.3.1
 
 
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Events of Clinical Interest............................................................................ 74
7.2.3.2
Evaluating Adverse Events ................................................................................. 75
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 78
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 78
Statistical Analysis Plan Summary ..................................................................... 78
8.1
Responsibility for Analyses/In-House Blinding ................................................. 79
8.2
Hypotheses/Estimation ......................................................................................... 79
8.3
Analysis Endpoints ............................................................................................... 79
8.4
Efficacy/Pharmacokinetics Endpoints ................................................................ 80
8.4.1
Efficacy Endpoints....................................................................................... 80
8.4.1.1
Pharmacokinetics Endpoints........................................................................ 80
8.4.1.2
Exploratory Endpoints ................................................................................. 80
8.4.1.3
Safety Endpoints ................................................................................................. 80
8.4.2
Analysis Populations............................................................................................. 80
8.5
Efficacy Analysis Populations ............................................................................ 81
8.5.1
Safety Analysis Population ................................................................................. 82
8.5.2
Statistical Methods................................................................................................ 82
8.6
Statistical Methods for Efficacy Analyses .......................................................... 82
8.6.1
Statistical Methods for Safety Analyses ............................................................. 85
8.6.2
Summaries of Baseline Characteristics, Demographics, and other Analyses..... 86
8.6.3
Interim Analyses ................................................................................................... 86
8.7
Multiplicity ............................................................................................................ 87
8.8
Sample Size and Power Calculations .................................................................. 87
8.9
Efficacy Analysis ................................................................................................ 87
8.9.1
Safety Analysis ................................................................................................... 88
8.9.2
Subgroup Analyses and Effects of Baseline Factors.......................................... 89
8.10
Compliance (Medical Adherence) ....................................................................... 90
8.11
Extent of Exposure................................................................................................ 90
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 90
Investigational Product ........................................................................................ 90
9.1
Packaging and Labeling Information ................................................................. 91
9.2
 
 
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Clinical Supplies Disclosure................................................................................. 91
9.3
Storage and Handling Requirements.................................................................. 91
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 91
9.5
Standard Policies................................................................................................... 91
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 92
Confidentiality....................................................................................................... 92
10.1
Confidentiality of Data ....................................................................................... 92
10.1.1
Confidentiality of Subject Records ..................................................................... 92
10.1.2
Confidentiality of Investigator Information........................................................ 92
10.1.3
Confidentiality of IRB/IEC Information............................................................. 93
10.1.4
Compliance with Financial Disclosure Requirements....................................... 93
10.2
Compliance with Law, Audit and Debarment ................................................... 93
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 95
10.4
Quality Management System............................................................................... 95
10.5
Data Management................................................................................................. 95
10.6
Publications ........................................................................................................... 96
10.7
11.0
LIST OF REFERENCES......................................................................................... 97
12.0
APPENDICES......................................................................................................... 102
Merck Code of Conduct for Clinical Trials...................................................... 102
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 104
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.3
by Sample Types ................................................................................................. 108
List of Abbreviations and Definition of Terms ................................................ 109
12.4
13.0
SIGNATURES......................................................................................................... 112
Sponsor's Representative ................................................................................... 112
13.1
Investigator.......................................................................................................... 112
13.2
 
 
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LIST OF TABLES
Table 1
Treatment Regimen and Subject Characteristics.................................................. 13
Table 2
Efficacy of Approved and Investigational 12-Week DAA Regimens for 
Treatment-Naïve Non-Cirrhotic and Cirrhotic Subjects....................................... 17
Table 3
Preliminary results for PN011 and PN012 Part B for 8, 12 or 16 weeks of 
MK-3682B with or without RBV in GT1-, GT2-, and GT3-infected 
Subjects With and Without Cirrhosis; % of Subjects Achieving SVR4+ of 
Those Who Have Reached at least FW4 (as of 05 June 2016)............................. 22
Table 4
Current Efficacy Results for PN021 ..................................................................... 24
Table 5
Nomenclature for Describing HCV RNA Levels................................................. 30
Table 6
Laboratory Exclusion Criteria............................................................................... 41
Table 7
Trial Treatment ..................................................................................................... 41
Table 8
Rescue Medication................................................................................................ 42
Table 9
List of Prohibited Medications.............................................................................. 45
Table 10
List of Allowed Medications ................................................................................ 46
Table 11
Discontinuation Scenarios .................................................................................... 48
Table 12
Laboratory Tests ................................................................................................... 61
Table 13
Pharmacokinetic and Pharmacodynamic Sampling Time Points ......................... 64
Table 14
Evaluating Adverse Events................................................................................... 76
Table 15
Analysis Strategy for Efficacy Variables.............................................................. 84
Table 16
Analysis Populations, Criteria for Response, Non-Response, and 
Exclusion from Analysis Populations................................................................... 85
Table 17
Analysis Strategy for Safety Parameters............................................................... 86
Table 18
Two-Sided 95% Confidence Intervals for SVR12 (FAS Population) .................. 88
Table 19
Estimate of Incidence of a Specific AE and 95% Upper Confidence Bound 
Based on a Hypothetical Number of Subjects with that Specific AE................... 89
Table 20
Product Descriptions............................................................................................. 90
 
 
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LIST OF FIGURES
          
Figure 1
Trial Diagram...................................................................................................... 13
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
2.1
6.0
7.1.5.6
7.1.5.7
8.6.3
12.3
Trial Summary
Trial Design
Trial Flow Chart
Discontinued Subjects 
Continuing to be Monitored in 
the Trial
Evaluation of Laboratory 
Safety Signals
Summaries of Baseline 
Characteristics, Demographics, 
and Other Analyses
Approximate Blood/Tissue 
Volumes Drawn/Collected by 
Trial Visit and by Sample 
Types
The 3-year long-term follow-up
period has been removed from 
the trial.
These changes were made to 
remove the 3-year long-term 
follow-up period of the trial. 
Merck has made a strategic 
decision to discontinue the 
development of the 
investigational combination 
regimens MK-3682C 
(ruzasvir/uprifosbuvir) and 
MK-3682B 
(grazoprevir/ruzasvir/ 
uprifosbuvir).  As a result, there 
is no need to obtain long-term 
follow-up on the persistence of 
resistance substitutions to 
ruzasvir or uprifosbuvir. The 
3-year long-term follow-up 
period was observational; 
therefore, the removal of the 3-
year long-term follow-up will 
have no impact on the safety of 
the study participants. 
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-3682 + ruzasvir (RZR) for 12 weeks in Subjects with HCV GT1-
6 Infection
Sponsor Product Identifiers
MK-3682 + RZR
Trial Phase
Phase 2
Clinical Indication
Treatment of hepatitis C virus (HCV) infection
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Oral
Trial Blinding
Unblinded Open-label
Treatment Groups
Chronic HCV genotype (GT) 1-6 infected, treatment-naïve and 
interferon-based
treatment-experienced, 
with or 
without HIV 
infection, cirrhotic and non-cirrhotic subjects will be assigned to 
receive MK-3682 (450 mg) + RZR (180 mg) (MK-3682 + RZR) for 
12 weeks.
Approximately 250 subjects will be allocated to receive MK-3682 +
RZR for 12 weeks.  The first 50 subjects will be allocated to treatment 
regardless of GT.  If the general safety and tolerability of these first 50 
subjects is assessed to be acceptable after TW4, then the remaining 
targeted allocation of 200 subjects will be based on GT (GT1, GT2, 
GT3, GT4, GT5, or GT6).  The first 50 subjects will be included in 
the overall allocation target of the trial as shown below.  
MK-3682 + RZR for 12 weeks (n=250):

GT1 (n=50)

GT2 (n=50)

GT3 (n=50)

GT4 (n=50)

GT5 (n=25)

GT6 (n=25)
Note that the treatment regimen with MK-3682 + RZR for subjects 
with a particular GT will be extended to 16 weeks’ duration and 
ribavirin (RBV) will be added, if the efficacy criteria for stopping 
enrollment/treatment allocation are met for that particular GT.
Number of trial subjects
Approximately 250 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
46 weeks from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 42 weeks
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact.  After a screening phase of approximately 
45 days, 
each 
subject 
will 
receive
assigned 
treatment 
for 
approximately 12 weeks. After the end of treatment, each subject will 
be followed for 24 weeks.  For subjects who may have their treatment 
regimen modified to MK-3682 + RZR for 16 weeks + RBV, trial 
participation will be approximately 46 weeks.
Randomization Ratio
Not Applicable
A list of abbreviations used in this document can be found in Section 12.4.
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This is a nonrandomized, multi-site, open-label trial to evaluate a novel 2-drug combination 
regimen (MK-3682 450 mg and MK-8408 [hereafter referred to as ruzasvir (RZR)] 180 mg) 
in subjects with chronic hepatitis C virus (HCV) to be conducted in conformance with Good 
Clinical Practices (GCP).  Subjects with genotype (GT) GT1, GT2, GT3, GT4, GT5, or GT6
infection will be enrolled. Subjects may be treatment-naïve (TN) or treatment-experienced
(TE) with a prior interferon (IFN)-based therapy, but subjects may not have previously 
received treatment with HCV direct-acting antiviral (DAA) therapy. 
Subjects may be 
cirrhotic or non-cirrhotic, and mono-infected with HCV or co-infected with human 
immunodeficiency virus (HIV). Enrollment will be monitored in real-time, with a target 
allocation of approximately 25% to 30% cirrhotic subjects for each GT for GT 1-4. As the 
prevalence of GT5 and GT6 is lower, enrollment of these subjects may be limited. 
Enrollment of subjects with GT5 and GT6 is approximate with the assumption that full 
enrollment of these GTs may not be reached, and the proportion of cirrhotic subjects 
allocated for each of these GT5 and GT6 is not stipulated.
A total of approximately 250 subjects will be allocated to receive 12 weeks of treatment with 
MK-3682 (450 mg) + RZR (180 mg) (termed MK-3682 + RZR) with target allocation based 
on GT (GT1, GT2, GT3, GT4, GT5, or GT6) see Table 1.

The first 50 subjects will be allocated to treatment regardless of GT or fibrosis stage.  

After the first 50 subjects (of any GT) are allocated to treatment, additional allocation
will pause to assess general safety and tolerability. This will be assessed after these 
first 50 subjects complete TW4, as this allows for steady state of drug to be achieved 
for ≥2 weeks.  As detailed in Section 5.11.1, this pause in treatment allocation will 
allow for assessment of any drug-related safety events. 

These first 50 subjects will be included in the overall treatment allocation target of the 
trial, and counted towards the GT and fibrosis stage allocation targets shown in Table 1.

If general safety and tolerability is assessed to be acceptable, the remaining 
200 subjects will be allocated to treatment with an overall target allocation based on GT
(GT1, GT2, GT3, GT4, GT5, or GT6), see Table 1.  
For subjects who remain on treatment, the treatment regimen with MK-3682 + RZR for 
subjects with a particular GT will be extended to 16 weeks’ duration and ribavirin (RBV) 
will be added, if the efficacy criteria for stopping enrollment/treatment allocation are met for 
that particular GT (see Section 5.11.4).  For example, if efficacy criteria for stopping 
enrollment/treatment allocation are met for GT1-infected subjects at TW8, GT1-infected 
subjects already on treatment will receive MK-3682 + RZR for an additional 8 weeks (i.e., 
16 weeks’ total duration) + RBV for 8 weeks.
All subjects will be followed for 24 weeks after the end of treatment.  Safety and tolerability 
will be carefully monitored throughout the study by the Sponsor in accordance with standard 
procedures. 
 
 
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Pharmacokinetic (PK) and Intensive Pharmacodynamic (PK/PD) Sub-studies
The purpose of the PK sub-study is to evaluate concentrations of MK-3682 and its 
metabolites, and RZR, as well as the PK-efficacy and PK-safety relationships.  The purpose 
of the intensive PK/PD sub-study is to evaluate whether early viral kinetics can aid in 
developing a PK/PD model that can predict combinations that may be efficacious with 
various treatment durations.  
Pharmacokinetics will be assessed in all subjects (including the first 50 and the subsequent 
200), as specified in Section 4.2.5.3. 
The intensive PK/PD group will only be offered to subjects once treatment allocation is 
opened to the subsequent 200 subjects (and will exclude the first 50 subjects). A subset of 
the remaining 200 subjects will participate in an intensive PK/PD group to include additional 
assessments for PK/PD.  A total of approximately 30 subjects, (5 subjects of each GT1-6,
regardless of fibrosis stage) who consent to participate, will undergo additional PD 
evaluations as specified in Section 4.2.5.4, and these subjects will also have additional 
electrocardiographs (ECGs) performed as specified in Section 7.1.2.3.  
Table 1
Treatment Regimen and Subject Characteristics 
Number of 
Subjects
Treatment 
Regimen
Characteristics
Genotype
Target Allocation
Fibrosis Stage
Total n=250
MK-3682 450 mg + 
RZR 180 mg for 12 
weeks
GT1a
n = 35
F0-F4
(target 25-30% 
cirrhotic)
GT1b
n = 15
GT2
n = 50
GT3
n = 50
GT4
n = 50
GT5
n = 25
F0-F4
GT6
n = 25
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
2.2
The trial design is depicted in Figure 1.
Figure 1
Trial Diagram
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
As this is an estimation study, there are no formal hypotheses.
Objectives for this study in male and female subjects infected with chronic HCV GT1, GT2, 
GT3, GT4, GT5, or GT6 infection who are at least 18 years of age are listed in Sections 3.1, 
3.2, and 3.3.
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective:  To evaluate the efficacy of co-administered MK-3682 (450 mg) + RZR
(180 mg) as assessed by the proportion of subjects achieving sustained virologic 
response (SVR) at 12 weeks post-treatment (SVR12) (defined as HCV ribonucleic 
acid [RNA] <lower limit of quantification [LLOQ] 12 weeks after the end of all study 
therapy).
2) Objective: To evaluate the safety and tolerability of co-administered MK-3682 
(450 mg) + RZR (180 mg).
Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective:  To evaluate the efficacy of co-administered MK-3682 (450 mg) + RZR
(180 mg) as assessed by the proportion of subjects achieving SVR at 24 weeks post-
treatment (SVR24) (defined as HCV RNA <LLOQ 24 weeks after the end of all study 
therapy).
2) Objective: To evaluate the efficacy of co-administered MK-3682 (450 mg) + RZR
(180 mg), as assessed by the proportion of subjects experiencing virologic failure 
(either on-treatment failure or relapse post-treatment) at Follow-up Week (FW) 12 
among subjects who do not discontinue study for non–treatment-related (e.g., 
administrative) reasons.
3) Objective: To evaluate the effect of baseline resistance-associated variants (RAVs) in 
nonstructural protein (NS) 5A and/or NS5B on the efficacy of co-administered MK-
3682 (450 mg) + RZR (180 mg), as assessed by the proportion of subjects with 
baseline RAVs achieving SVR12.
Exploratory Objectives
3.3
1) Objective: To evaluate the emergence of NS5A and/or NS5B RAVs in subjects who 
experience virologic failure.
2) Objective: To explore the relationship between genetic variation, including but not 
limited to variation in IL28B, and response to the treatment administered and 
mechanisms of disease. Variation across the human genome will be analyzed for 
association with clinical data collected in this study. See Sections 4.2.5.5, 4.2.5.6, 
and 12.2.
 
 
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4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-3682
and RZR.
Refer to the approved product labeling for detailed background information on RBV.
Pharmaceutical and Therapeutic Background
4.1.1

MK-3682 is an HCV NS5B polymerase nucleotide inhibitor (NI).

RZR (ruzasvir, MK-8408) is an HCV NS5A replication complex inhibitor (NS5AI).

RBV is a nucleoside (ribonucleic analog) inhibitor.  For subjects who remain on 
therapy, RBV will be added to the extended 16-week treatment regimen with MK-
3682 + RZR for subjects with a particular GT if efficacy criteria for stopping 
enrollment/treatment allocation are met for that GT.
Overview
4.1.1.1
The HCV can be divided into 6 GTs.  This study will evaluate a novel 2-drug combination 
regimen to treat subjects with chronic HCV GT1-6 infection.  Of the 6 HCV GTs, GT1 and 
GT3 are the most common, accounting for approximately 46% and 22% of all global 
infections, respectively.  Genotype 1 has a broad geographical distribution, being the most 
common GT in most of North America, Northern and Western Europe, South America, Asia,
and Australia [1]. Genotype 3 is most prevalent in South and Southeast Asia, although 
migration has resulted in an increased prevalence in Europe and North America.  Genotype 2
is the third most common GT worldwide; it has a broad geographical distribution.  
Genotype 4 is found predominantly in Africa and the Middle East [1] but is increasingly 
prevalent in the United States and Mediterranean Europe due to migration and increasing 
transmission through injection drug use [2].  Genotype 5 and GT6 are less common; they 
predominate in sub-Saharan Africa and in Asia, respectively [1].
With the advent of oral DAAs, effective interferon and ribavirin (RBV)-free combination 
regimens are now available for subjects chronically infected with certain GTs.  However, 
some subgroups of subjects, particularly treatment-experienced, cirrhotic subjects, do not 
achieve optimal rates of SVR with existing, approved 12-week regimens.  In addition, the 
currently available dosing regimens are different for different HCV GTs, with some regimens 
requiring prolonged treatment of up to 24 weeks and/or RBV, thus leading to complexity of 
treatment. Therefore, a regimen without the efficacy, safety, and convenience deficits of the 
existing regimen will be a substantial advance in the treatment of HCV infection.  
Different approaches can be undertaken to achieve a pangenotypic regimen.  Because HCV is 
an RNA virus capable of substantial mutation in response to targeted antiviral agents, highly 
efficacious treatments for HCV infection require combinations of DAAs that simultaneously 
attack multiple points of the viral replication cycle. Effective therapies can differ with 
respect to the number of DAAs included in a regimen, doses of the individual agents, 
treatment duration, and/or inclusion of RBV.  
 
 
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Merck is evaluating 2 regimens with potentially pangenotypic activity.  
The first regimen consists of 3 drugs: an NS3/4A inhibitor (grazoprevir, GZR), an NS5A 
inhibitor (RZR), and an NS5B inhibitor (MK-3682). MK-3682B, a fixed-dose combination 
(FDC) of MK-3682 (450 mg)/GZR (100 mg)/RZR (60 mg), is being evaluated in 3 ongoing 
Phase 2 trials (MK-3682 Protocol Number [PN]011, MK-3682 PN012, and MK-3682 
PN021).  Studies in treatment-naïve and or prior-peginterferon/RBV treatment failures have 
enrolled 609 GT1, GT2, GT3, and GT4-infected subjects. The studies have investigated 8-,
12-, or 16-week regimens of MK-3682B administered with or without RBV (see Section 
4.1.2.2).  MK-3682B is also being evaluated as a treatment for patients who have failed all-
oral, IFN-free DAA regimens.
Because MK-3682 and RZR are potent antiviral agents that inhibit the HCV NS5B RNA 
polymerase and NS5A replication complex, respectively, the combination of these 2 DAAs
may be a highly effective regimen.  This combination is currently being evaluated in MK-
3682 PN035, an ongoing Phase 2 study characterizing the efficacy and safety profile of a 12-
week regimen of MK-3682 450 mg + RZR at a dose of 60 mg.  Dosing in PN035 is ongoing, 
and efficacy results are not yet available.  
In studies of NS5A-inhibitor containing regimens (SOF/VEL, SOF/DCV, EBR/GZR), 
presence of certain substitutions in the NS5A gene prior to initiation of therapy can reduce 
efficacy; furthermore, patients who fail therapy often have treatment-emergent substitutions 
that confer resistance to NS5A inhibitors [3] [4] [5] [6] [7] [8] [9] [10].  Hence, it was of 
interest to evaluate whether administration of regimens that include higher doses of NS5A 
inhibitors could result in higher efficacy by overcoming baseline or treatment-emergent 
NS5A inhibitor resistant virions.  Such an approach is aided by the generally excellent safety 
profile of NS5A inhibitors developed to date.  PN041 is designed to evaluate this type of 
regimen.  In particular, PN041 will explore a regimen consisting of MK-3682 450 mg + RZR
180 mg.  In this regimen, the dose of RZR is 3-fold higher than that being tested in PN035 
(MK-3682 450 mg + RZR 60 mg) and in the PN011/PN012/PN021 (MK-3682 450 mg + 
RZR 60 mg + GZR 100 mg).
The preclinical and clinical profiles of MK-3682 and RZR demonstrate high potency against 
GT1-6 in vitro, supporting the use of this 2-drug combination in this trial (see Section 4.2.2). 
MK-3682 is at least equipotent to sofosbuvir (SOF), an approved NS5B inhibitor that 
anchors multiple current all-oral DAA therapies. In in vitro replicon studies, RZR is more 
potent against multiple HCV GTs and resistant variants compared with other NS5A
inhibitors, such as the approved drugs ledipasvir (LDV), daclatasvir (DCV), ombitasvir 
(OMB), elbasvir (EBR), and velpatasvir (VEL).  Therefore, a regimen that combines MK-
3682 and RZR may be sufficient to result in high efficacy in clearing HCV infection of all 
GTs.  The rationale for the subject population, study design, doses of each of the compounds, 
and the duration of therapy are provided in subsequent sections.
Current Treatment of Chronic HCV
4.1.1.2
Phase 2 or 3 trials have evaluated the efficacy of several all-oral, IFN-free regimens
administered for 12 weeks in GT1-6-infected subjects. As displayed in Table 2, treatment 
outcomes with the various approved and investigational DAA regimens have SVR12 rates 
 
 
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ranging from 58% to 100%. Some of these regimens are suboptimal in that they require use 
of RBV, and there is a risk of relapse among subjects with baseline NS5A RAVs. 
As previously introduced in Section 4.1.1.1 and detailed in Section 4.1.2.2, MK-3682B, an
FDC of MK-3682 (450 mg)/GZR (100 mg)/RZR (60 mg), is currently being evaluated in 3
ongoing Phase 2 trials (MK-3682 PN011, MK-3682 PN012, and MK-3682 PN021) in GT1-
6-infected subjects for 8- to 24-week durations with or without RBV. Preliminary data from 
these studies demonstrate excellent tolerability and very high efficacy of this 3-drug regimen 
when administered for 8 or 12 weeks in GT1- and GT3-infected subjects and for 12 weeks in 
GT2-infected subjects.
Table 2
Efficacy of Approved and Investigational 12-Week DAA Regimens for 
Treatment-Naïve Non-Cirrhotic and Cirrhotic Subjects
GT
Regimen
Non-
cirrhotic
(% SVR12)
Cirrhotic
(% SVR12)
Reference
Approved 12-Week Regimens for GT1
1
LDV/SOF
94%-99%
94%
[11] [12] [13] [14] [15]
SOF/VEL
98%
99%
[3]
Dasabuvir/ombitasvir/paritaprevir/ritonavir 
+ RBV
96%
92%
[16] [17] [18]
EBR/GZR 
94%
98%
[4] [5] [6]
Experimental 12-Week Regimens for GT1
1
ABT493/ABT530
100%
96%
[19] [20]
Approved 12-Week Regimens for GT2
2
SOF+RBV (FISSION, POSITRON, and 
VALENCE studies)
94%a
94%a
[21] [22] [23] [24]
SOF/VEL 
99%-100%b
99%-100%b
[3] [25]
Approved 12-Week Regimens for GT3
3
SOF+RBV
~80-85%a
~80-85%a
[24]
SOF/daclatasvir (DCV) 
92-98%
58-69%
[7] [8] [9] [10]
SOF/VEL
97%
91%
[25]
Experimental 12-Week Regimens for GT3
3
ABT493/ABT530
97%
100%
[19] [20]
 
 
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GT
Regimen
Non-
cirrhotic
(% SVR12)
Cirrhotic
(% SVR12)
Reference
Approved 12-Week Regimens for GT4
4
LDV/SOF
93%
100%
[26]
SOF/VEL
100%
100%
[3]
Ombitasvir/paritaprevir/ritonavir + RBV
100%
No data
[18] [27] [28]
EBR/GZR
96%
100%
[4] [5] [6] [29]
Experimental 12-Week Regimens for GT4
4
ABT493/ABT530
100%
No data
[30]
Approved 12-Week Regimens for GT5
5
LDV/SOF
97%
89%
[13] [31]
SOF/VEL
97%
100%
[13] [31]
Approved 12-Week Regimens for GT6
6
LDV/SOF
96%b
96%b
[13] [32]
SOF/VEL 
100%
100%
[3]
EBR = elbasvir; GZR = grazoprevir; LDV = ledipasvir; RBV = ribavirin; SOF = sofosbuvir; SVR=sustained virologic 
response; VEL = velpatasvir.
a
Cirrhotic state was not specified.
b
Value represents combined data from subjects with and without cirrhosis.
Background on Drugs Used in this Trial
4.1.2
Background data is provided for MK-3682 and RZR.  Refer to the MK-3682 and RZR IBs
for more information on the preclinical and clinical studies with these drugs.  Summaries of 
ongoing clinical trials are provided in Sections 4.1.2.1 and 4.1.2.2.
Refer to the product label for background information on RBV.
Phase 1 Studies
4.1.2.1
MK-3682 and RZR are currently being evaluated in multiple ongoing Phase 1 trials.  Please 
refer to the MK-3682 and RZR IBs for more detailed information on the Phase 1 clinical 
studies with MK-3682 and RZR.  
MK-3682 has been generally well-tolerated in healthy subjects and HCV-infected subjects in 
several Phase 1 clinical studies at single doses up to 900 mg, multiple doses up to 750 mg per 
day for 10 days, and in Phase 2a trials of 300 mg or 450 mg once daily for up to 24 weeks.
RZR has been generally well-tolerated in subjects in 8 RZR Phase 1 trials and in over in 
ongoing Phase 2a trials. RZR has been administered at doses up to 600 mg/day (10 times the 
proposed clinical dose), 100 mg given daily for 10 days, and 60mg once daily for up to 24 
weeks.  
 
 
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Summary of Ongoing Phase 2 Clinical Trials
4.1.2.2
MK-3682 and RZR are currently being evaluated in combination with GZR.  The 
combination of GZR
with EBR, a first generation NS5A inhibitor (EBR/GZR, 
ZEPATIERTM), was recently approved in the United States (US), Canada, European Union, 
and other countries for the treatment, with or without RBV, of chronic HCV GT1 or GT4 
infection in adults.  A fixed-dose combination tablet of MK-3682/GZR/RZR (MK-3682B) is 
currently being evaluated in 3 ongoing Phase 2 trials (MK-3682 PN011, MK-3682 PN012, 
and MK-3682 PN021) in GT1-6-infected subjects for 8- to 24-week durations with or 
without RBV. Brief summaries of the Phase 2 three-drug combination regimen studies 
containing MK-3682 and RZR are provided in Sections 4.1.2.2.1 and 4.1.2.2.3.
4.1.2.2.1 MK-3682 PN011 and PN012 
Part A
4.1.2.2.1.1
In Part A of MK-3682 PN011 and PN012, 93 GT1 (46 GT1a, 47 GT1b), 61 GT2, and 
86 GT3-infected TN, non-cirrhotic subjects with chronic HCV infection were dosed once-
daily for 8 weeks’ duration with 1 of 4 regimens including MK-3682 (300 mg or 450 mg), 
GZR (100 mg), and either EBR (50 mg) or RZR (60 mg).  
All regimens were highly efficacious in subjects infected with GT1. No subject experienced 
virologic breakthrough on therapy. 
Across treatment arms, 45/46 (98%) GT1a and 
46/47 (98%) GT1b subjects achieved SVR12. There was no observed impact of NS5A RAVs
(defined as any change from wild-type at 9 positions [24, 28, 30, 31, 32, 38, 58, 92, or 93]); 
23% of subjects had baseline NS5A RAVs, and all achieved SVR12.  No treatment-emergent 
RAVs were observed.  
In subjects infected with GT2, the MK-3682 (450 mg)/GZR/RZR regimen was highly 
effective (94%), but SVR rates were suboptimal among subjects who received the other 
regimens (60% to 71%).  The MK-3682 (450 mg)/GZR/RZR regimen achieved SVR12
among 94% (15/16) of GT2-infected subjects, despite a high prevalence of baseline NS5A 
RAVs (defined as any change from wild-type at 9 positions [24, 28, 30, 31, 32, 38, 58, 92, or 
93]) in 94% (15/16) subjects.  No treatment-emergent RAVs were observed. 
All regimens were highly efficacious in subjects infected with GT3.  Overall, 38/43 (88%) of 
subjects who received EBR and 40/43 (93%) of subjects who received RZR achieved SVR12.  
The MK-3682 (300 mg or 450 mg)/GZR/RZR regimens achieved SVR12 among 93% (40/43) 
of GT3-infected subjects, despite baseline NS5A RAVs (defined as any change from wild-
type at 10 positions [24, 28, 30, 31, 32, 38, 58, 62, 92, or 93]) in 47% (20/43) of subjects. 
One of the 3 relapsers in these arms had a treatment-emergent NS5A RAV (Y93H) at the 
time of failure.
All 240 subjects completed the full 8 weeks of dosing. All regimens were generally well 
tolerated, and no cardiac or renal safety signals were identified. The frequency and severity 
of adverse events (AEs) were comparable among the 4 treatment groups. The most frequent 
study drug-related AEs were headache (23%), fatigue (20%), and nausea (13%). One subject 
(1/240, 0.4%) experienced an alanine aminotransferase (ALT) increase >5× upper limit of 
normal (ULN) at Treatment Week (TW) 8 with a pattern consistent with the late ALT 
increases observed in the Phase 2 and 3 GZR studies, which rapidly resolved off study drug.  
 
 
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There were no drug-related serious adverse events (SAEs) and no subjects discontinued due 
to AEs.  
Part B
4.1.2.2.1.2
The results of Part A demonstrated that an 8-week regimen of MK-3682/GZR/RZR
(450 mg/100 mg/60 mg) was highly effective and well-tolerated in GT1-, GT2-, and GT3-
infected TN, non-cirrhotic subjects, supporting the selection of this regimen from the 4 tested 
in Part A for further evaluation among a diverse population of HCV-infected subjects, 
including those with additional HCV GTs, cirrhosis, prior treatment, and HIV/HCV-co-
infection.
In Part B of these studies, the combination regimen is being administered as FDC tablets, 
referred to as MK-3682B.  Each MK-3682B tablet contains MK-3682 (225 mg), 
GZR (50 mg), and RZR (30 mg), and is administered as 2 tablets once daily, for a total daily 
dose of MK-3682 450 mg, GZR 100 mg, and RZR 60 mg. Non-cirrhotic and cirrhotic, TN
and pegylated IFN/RBV (PR) treatment-experienced, GT1-GT6 subjects with or without 
HIV co-infection were planned to receive MK-3682B with or without RBV for 8, 12, or 16 
weeks of therapy, depending on the treatment arm.
As of 25 July 2016, 609 subjects have been enrolled in Part B: 153 GT1-infected (82 GT1a, 
71 GT1b) TN subjects with or without compensated cirrhosis, 135 GT2 TN subjects with or 
without cirrhosis, and 315 GT3-infected TN or TE (PR) subjects with or without 
compensated cirrhosis. Subjects were treated with MK-3682B, with or without RBV, for 8, 
12, or 16 weeks. Subjects could be mono-infected or HIV co-infected. Six subjects infected 
with GT4 have been enrolled, but results are not yet available for this genotype.
Results to date for GT1, GT2, and GT3-infected subjects are available (see Table 3).  One 
hundred twenty-six GT1-infected subjects have reached at least FW4.  All subjects had 
undetectable HCV RNA at the end of 8 or 12 weeks of treatment.  Of 41 subjects (19 GT1a, 
22 GT1b) who received 8 weeks of therapy and who have reached FW4, 100% (41/41) have 
achieved SVR4.  Fifteen subjects were cirrhotic (2 GT1a/13 GT1b).  Of 85 subjects 
(46 GT1a/39 GT1b) who received 12 weeks of therapy and who have reached FW4, 100% 
(85/85) have achieved SVR4.  Thirty-eight subjects were cirrhotic (17 GT1a/21 GT1b).  
Baseline next-generation sequencing (NGS) (15% sensitivity threshold) is available for 92 
subjects; 7.8% (4/51) GT1a and 26.8% (11/41) GT1b subjects had baseline NS5A RAVs at 
positions 30, 31, and 93. 
Of the GT2-infected subjects, 117 have ≥4 weeks of post-therapy follow-up (Table 3).  
Among all participants, 134/135 (99%) subjects had HCV RNA <LLOQ at the end of their 
assigned 8, 12, or 16 weeks of treatment. One cirrhotic subject who was randomized to 
12 weeks of MK-3682B + RBV had an HCV RNA that was 279 IU/mL at TW 12, despite 
being <LLOQ since TW2; HCV RNA was subsequently undetectable at FW4 and FW8.  
Compensated cirrhotic subjects were randomized to 12 or 16 weeks of treatment. Of the 117
subjects who have reached at least FW4, 39/45 (87%) of those assigned to 8 weeks of 
treatment (with or without RBV) have achieved SVR4+ and 71/71 (100%) of those assigned 
12 or 16 weeks of treatment (with or without RBV) have achieved SVR 4+.  Of note, SVR4+ 
was achieved for 100% (40/40) of cirrhotic subjects for whom data are available at this time. 
SVR4+ rates are comparable between arms of the same duration with or without RBV. In the 
 
 
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8-week arms, failures are associated with detection of baseline substitutions at NS5A amino 
acid 31.  Such substitutions are associated with an approximately 4-fold reduction in the 
potency of RZR in vitro.  Baseline NGS (15% sensitivity threshold) is currently available for 
35 of the 47 subjects receiving 8 weeks of treatment ± RBV; 43% (15/35) of subjects had 
NS5A L31M at baseline. SVR4+ for subjects with baseline L31M is 73% (11/15); for 
subjects with baseline 31L, SVR4+ is 95% (19/20). 
Of the GT3-infected subjects, 283 have reached at least FW4 (Table 3).  All subjects had 
undetectable HCV RNA at the end of their assigned 8, 12, or 16 weeks of treatment.  Of the 
283 subjects (189 non-cirrhotic, 94 cirrhotic) who have reached FW4, 98% (276/283) have 
achieved SVR4.  SVR4 rates are comparable between different durations of treatment, arms 
with and without RBV, and between non-cirrhotic and cirrhotic subjects and those with or 
without prior PR treatment-experience.  Baseline NGS (15% sensitivity threshold) is 
available for 145 subjects; 18.5% (23/124) GT3 subjects had baseline NS5A RAVs at 
positions 30, 31, and 93. SVR (last visit on record) for subjects without baseline RAVs at 
positions 30, 31, or 93 is 99% (121/122); for subjects with baseline RAVs, SVR4+ is 20/23 
(87%). 
 
 
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Table 3
Preliminary results for PN011 and PN012 Part B for 8, 12 or 16 weeks of MK-
3682B with or without RBV in GT1-, GT2-, and GT3-infected Subjects With and 
Without Cirrhosis; % of Subjects Achieving SVR4+ of Those Who Have Reached 
at least FW4 (as of 05 June 2016)
Regimen
Non-Cirrhotic1
n/N (% SVR)
Cirrhotic1
n/N (% SVR)
Total1
n/N (% SVR)
GT1a 8 weeks
17/17 (100%)
2/2 (100%)
19/19 (100%)
GT1b 8 weeks
9/9 (100%)
13/13 (100%)
22/22 (100%)
GT1a 12 weeks
29/29 (100%)
17/17 (100%)
46/46 (100%)
GT1b 12 weeks
18/18 (100%)
21/21 (100%)
39/39 (100%)
GT2 8 weeks 
14/16 (88%)
--
14/16 (88%)
GT2 8 weeks, RBV
25/29 (86%)
--
25/29 (86%)
GT2 12 weeks 
31/31 (100%)
10/10 (100%)
41/41 (100%)
GT2 12 weeks, RBV
--
10/10 (100%)
10/10 (100%)
GT2 16 weeks 
--
21/21 (100%)
21/21 (100%)
GT3 8 weeks
TN: 15/16 (94%)
TE: 15/15 (100%)
--
30/31 (97%)
GT3 8 weeks, RBV
TN: 35/35 (100%)
TE: 13/14 (93%)
--
48/49 (98%)
GT3 12 weeks
TN: 34/35 (97%)
TE: 14/14 (100%)
TN: 13/14 (93%)
TE: 9/9 (100%)
70/72 (97%)
GT3 12 weeks, RBV
TN: 35/35 (100%)
TE: 13/14 (93%)
TN: 15/15 (100%)
TE: 9/9 (100%)
72/73 (99%)
GT3 16 weeks
TE: 10/11 (91%)
TN: 10/10 (100%)
TE: 17/17 (100%)
37/38 (97%)
GT3 16 weeks, RBV
--
TE: 19/20 (95%)
19/20 (95%)
C = cirrhotic; GT = genotype; NC = noncirrhotic; RBV = ribavirin; SVR = sustained virologic response; 
TE = treatment experienced; TN = treatment naïve.
1
SVR4/8/12 (last visit on record) in subjects with ≥4 weeks of post-therapy follow-up, as of 05 June 2016.
Treatment in Part B was generally well tolerated.  There were no observed cardiac or renal 
safety signals.  One GT1-infected patient died due to a bacterial sepsis considered unrelated 
to study drug.  The most frequent study drug-related adverse events in >5% of all patients in 
all study arms were fatigue, headache, and nausea.  
 
 
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The results to date suggest that MK-3682B for 8 or 12 weeks is effective and well tolerated 
in GT1-infected treatment-naïve, non-cirrhotic, and cirrhotic patients, and MK-3682B for 12 
weeks is effective and well tolerated in GT2-infected treatment-naïve, non-cirrhotic and 
compensated cirrhotic subjects, and MK-3682B for 8 or 12 weeks is effective and well-
tolerated in GT3-infected treatment-naïve or treatment-experienced, non-cirrhotic and 
cirrhotic patients.  Addition of RBV to a 12 week regimen did not appear to improve 
efficacy.
Part C
4.1.2.2.1.3
Part C of PN011 and PN012 is evaluating a re-treatment regimen for subjects in Part A who 
failed therapy.  GT1-, GT2-, and GT3-infected initially TN non-cirrhotic subjects who 
relapsed after 8 weeks of therapy with any of the 4 regimens in Part A were offered re-
treatment with 16 weeks of MK-3682B plus RBV.  Twenty-four of 26 eligible subjects were 
enrolled, 2 with GT1, 14 with GT2, and 8 with GT3 infection.  At the time of relapse 
following initial therapy, NS5A RAVs were detected in 0% (0/2) GT1, 93% (13/14) GT2,
and 88% (7/8) GT3 subjects.  NS3 RAVs were detected in 50% (1/2) GT1, 100% (14/14) 
GT2, and 100% (8/8) GT3 subjects.  NS5B RAVs were detected in 50% (1/2) GT1, 0% 
(0/14) GT2, and 0% (0/8) GT3 subjects, and 88% (21/24) subjects had RAVs in >1 class.  
One GT2-infected patient withdrew after a single dose with AEs of vomiting and tachycardia 
considered related to MK-3682B + RBV.  One GT2-infected patient discontinued RBV 4 
days before the scheduled completion of 16 weeks of therapy due to an AE of rash thought to 
be RBV-related. This subject completed 16 weeks of MK-3682B.  The remaining 22 subjects 
completed the full 16 weeks of dosing.  
All subjects had undetectable HCV RNA at the end of treatment.  All 23 subjects (2 GT1, 
13 GT2, and 8 GT3) have reached at least FW4; 100% have achieved SVR4.  As of 22 July 
2016, 20 subjects (2 GT1, 10 GT2, and 8 GT3) have reached FW12; 100% have achieved 
SVR12.  Treatment was generally well tolerated, and no cardiac or renal safety signals were 
identified. The most frequent study drug-related AEs in >10% of all subjects were headache, 
fatigue, nausea, rash, pruritus, insomnia, decreased hemoglobin, and cough.  The study 
results to date suggest that a 16-week regimen of MK-3682B plus RBV is effective and well-
tolerated in GT1, GT2, and GT3-infected non-cirrhotic subjects who had previously failed 8 
weeks of treatment with a 3-drug regimen, despite a high prevalence of baseline NS3 and 
NS5A RAVs.  
4.1.2.2.2 MK-3682 PN021
MK-3682 PN021 is an ongoing Phase 2 randomized, multicenter, open-label trial to evaluate 
the safety and efficacy of MK-3682B for 16 weeks with RBV or 24 weeks without RBV in 
non-cirrhotic and compensated cirrhotic subjects with GT1 infection who have failed a 
previous DAA regimen.  A subsequent cohort will enroll GT3 patients. Ninety-four GT1 
patients have been randomized in this trial (80 [85%] GT1a; 14 [15% GT1b]). Patients had 
failed >8 weeks of ledipasvir/SOF (59 [63%]), ≤8 weeks of LDV/SOF (13 [14%]) or
EBR/GZR (22 [23%]). Forty patients (43%) had cirrhosis. As of 21-July-2016, of the 94 
enrolled subjects 2 have discontinued and 33 have completed treatment; all 92 subjects who 
have reached TW8 have achieved undetectable HCV RNA on treatment.  To date, 22
subjects in the 16 week/RBV arm have reached FW4; all have achieved SVR4 (Table 4).  
 
 
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Table 4
Current Efficacy Results for PN021
Proportion of Patients with HCV RNA <15 IU/mL [n/m, (%)]
Treatment Week 4
Treatment Week 8
SVR4 (16 weeks/RBV)
85/92 (92%)
92/92 (100%)
22/22 (100%)
4.1.2.2.3 MK-3682 PN035
MK-3682 PN035 is an ongoing Phase 2 study that is currently evaluating the efficacy and 
safety profile of a 12-week regimen of MK-3682 450 mg + RZR 60 mg among subjects 
infected with GT1-6.  As of 11-July-2016, 122 subjects have started treatment. All subjects 
have had rapid suppression of HCV viral loads and there have been no virologic 
breakthroughs on treatment.  
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Currently approved HCV IFN-free DAA regimens, such as LDV/SOF, SOF/VEL, 
ombitasvir/paritaprevir/dasabuvir/ritonavir+RBV,
and EBR/GZR, have better efficacy, 
tolerability, and convenience than earlier therapies.  However, they are not uniformly 
effective across the 6 HCV GTs.  The most effective regimens are for GT1 HCV, which 
accounts for approximately 46% of infections worldwide [1].  Genotypes 2 and 3 HCV, the 
next most common GTs, were historically grouped together in treatment guidelines.  
However, recent studies have shown that infection with GT3, especially in subjects with 
cirrhosis, is more difficult to treat [25] [8] [9].  In addition, although GT5 and GT6 have a 
more limited geographic distribution than GT1-4, they predominate in certain regions of the 
world and represent an unmet medical need with limited clinical experience.  In addition, 
even though several IFN-free combinations are now available for treatment of HCV, 
clinicians must still take into account the GT and even the subtype, as well as patterns of 
antiviral resistance in the choice of a regimen.  The development of a single, uniform, and 
pangenotypic regimen that will be safe and effective in all patient populations would 
represent a substantial advance in the treatment of HCV infection by greatly simplifying 
treatment paradigms and reducing the need for pretreatment testing and on-treatment 
monitoring.  The clinical potential of the combination of MK-3682 and RZR, both once-daily 
medications, is suggested by their non-overlapping viral targets, the pangenotypic in vitro
potencies of both MK-3682 and RZR, the proven success of other HCV NIs in combination 
with other NS5A inhibitors, and the high efficacy rates from the investigational 3-drug 
regimen containing MK-3682, GZR, and RZR.
As previously described in Section 4.1.2, the investigational 3-drug regimen containing MK-
3682, RZR, and GZR is being explored as a strategy to use 3 DAA agents, each directed at a 
different target of the hepatitis virus life cycle.  As part of a comprehensive clinical 
development program, the combination of MK-3682 and RZR is currently being evaluated in 
MK-3682 PN035, an ongoing Phase 2 study characterizing the efficacy and safety profile of 
MK-3682 at a dose of 450 mg and RZR at a dose of 60 mg for 12 weeks duration.  Dosing in 
PN035 is ongoing, and efficacy results are not yet available.  PN041 is designed to explore 
 
 
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RZR at a dose of 180 mg as part of the 2-drug DAA regimen of MK-3682 (450 mg) and RZR
(180 mg).  The purpose of PN041 is to evaluate the use of a higher dose of RZR as a 
potential strategy to develop a highly efficacious pangenotypic DAA regimen for the 
treatment of chronic HCV. The rationale for dose selection is provided in Section 4.2.4.2.
Rationale for the Selected Subject Population
4.2.2
The rationale for the population selected for this trial is as follows:

Genotype:  The efficacy of the 2-drug regimen in subjects with chronic HCV-GT1-6
will be evaluated to allow for an initial assessment of the 2-drug combination regimen 
of MK-3682 and RZR as a pangenotypic therapy for HCV.  The preclinical profiles 
of MK-3682 and RZR demonstrate high potency against GT1-6 in vitro.  In addition, 
the preliminary data from Phase 2 studies of MK-3682/GZR/RZR demonstrate 
excellent tolerability and high efficacy of this 3-drug regimen when administered in 
GT1, GT2, and GT3.  Taken together, these data support the clinical evaluation of the 
combination of MK-3682 and RZR as a pangenotypic therapy for HCV.  
In preclinical in vitro experiments, MK-3682 and RZR were shown to have high 
potency against all GTs.  
o
The triphosphate of MK-3682, MK-3682-NTP, is a potent, pangenotypic 
inhibitor of HCV NS5B polymerase, with mean IC50 values of 0.144 ± 
0.011 μM (GT1a), 0.238 ± 0.024 μM (GT1b), 0.250 ± 0.005 μM (GT2a), 
0.156 ± 0.012 μM (GT3a), 0.149 ± 0.016 μM (GT4a), 0.233 ± 0.003 μM 
(GT5a), and 0.097 ± 0.006 μM (GT6a).  
o
RZR is a potent, pangenotypic inhibitor of NS5A, with low EC90 against 
GT1a (0.002 nM), GT1b (0.003 nM), GT2a (0.001 nM), GT2b (0.036 nM), 
GT3a (0.006 nM), GT4a (0.011 nM), GT5a (0.001 nM) and GT6 (0.004 nM) 
in replicon assays.  

Treatment-Naïve: TN subjects who have never received medical therapy for HCV 
and have no evidence of cirrhosis represent the largest proportion of the HCV-
infected population worldwide.  Historically, these subjects have had a high response 
rate to HCV DAA therapies.

Treatment-Experienced Subjects:  This study will also include subjects who have 
previously failed treatment with IFN-based therapies, because subjects who have 
failed prior interferon-based treatment are among the populations at highest need for 
effective HCV treatments.  Although the efficacy rates in IFN-based TE populations 
have historically been lower than in TN populations, more recent IFN-free DAA 
therapies combining highly potent drugs have demonstrated high rates of SVR12 in 
TE subjects that are comparable to those achieved in TN subjects [12] [15] [3] [22] 
[33] [25] [34]. Given the comparable SVR12 rates observed following some all-oral 
DAA regimens in TE and TN subjects, TE subjects will be permitted to enroll in this 
study.  As stated in Sections 2.1 and 4.2.3, this study includes duration modification 
rules to limit the potential for subjects to be at risk for virologic failure. Subjects who 
have failed prior DAA regimens will not be included in this study to allow further 
 
 
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evaluation of the efficacy of this 2-drug regimen in TN and PR TE subjects, some of 
whom will have baseline RAVs.  The DAA failure population may have a higher 
prevalence of baseline RAVs so is best addressed at a later time.  

Non-cirrhotic Subjects: Non-cirrhotic subjects represent a large proportion of the 
HCV-infected population worldwide.  Historically, these subjects have had a high 
response rate to HCV DAA therapies.

Compensated Cirrhotic Subjects:  Subjects with cirrhosis who are at increased risk 
for progression to decompensated cirrhosis and liver complications are one of the 
more challenging groups in need of new therapeutic approaches.  Although the 
efficacy rates in cirrhotic populations have historically been lower than in 
non-cirrhotics, requiring longer treatment durations or the addition of RBV to achieve 
equivalent SVR rates, more recent IFN-free DAA therapies combining highly potent 
drugs have demonstrated rates of SVR12 in compensated cirrhotic subjects that are 
comparable with those achieved in non-cirrhotic subjects [4] [3] [25] [34].  Given the 
comparable SVR12 rates observed following 12 weeks of all-oral IFN-free DAA 
regimens in non-cirrhotic and compensated cirrhotic subjects, including the 3-drug 
regimen of MK-3682/GZR/RZR in non-cirrhotic and compensated cirrhotic subjects, 
subjects with compensated cirrhosis will be permitted to enroll in this study.  In 
addition, as stated in Sections 2.1, 4.2.3, and 5.11, this study includes limitations on 
the number of cirrhotics, stopping rules, and duration modification rules to limit the 
potential for subjects to be at risk for virologic failure. Subjects with advanced or 
decompensated cirrhosis will not be included in this study.

HIV Co-infected Subjects:  HIV co-infected subjects are included in this trial 
because HCV infection is a leading cause of morbidity and mortality among those 
with HIV-1 [35].  Compared to the general population, the overall prevalence of HCV 
infection is higher among those infected with HIV-1.  In fact, one-fourth to one-third 
of subjects infected with HIV in the US and Europe are co-infected with HCV [36].  
Compared to subjects infected with HCV alone, HIV/HCV co-infected subjects have 
higher baseline HCV viral loads (VLs) and more rapid progression of liver disease, 
including more rapid hepatic fibrosis as well as an increased risk of cirrhosis, end-
stage liver disease, and hepatocellular carcinoma.  Subjects with HIV/HCV co-
infection are also more susceptible to developing anemia, and they may have more 
rapid progression to acquired immunodeficiency syndrome (AIDS) and AIDS-related 
death [29]. Recent DAA therapies have demonstrated rates of SVR12 that are 
comparable with those achieved in HCV disease-matched mono-infected subjects.  In 
particular, HIV subjects co-infected with HCV GT1 or GT4 had similarly high 
efficacy following EBR/GZR therapy in Phase 3 studies compared to those who were 
not HIV-infected [6].  Given the comparable SVR12 rates observed following all-oral 
IFN-free DAA regimens in mono-infected and co-infected subjects, HIV/HCV co-
infected subjects will be permitted to enroll in this study.  A comprehensive set of 
drug-interaction trials has defined the antiretroviral therapies that can be co-
administered with MK-3682, GZR, and RZR (Section 5.5).
 
 
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Rationale for Study Design
4.2.3
The pangenotypic preclinical profiles of MK-3682 and RZR, as well as the preliminary 
efficacy results from the 3-drug, 8- and 12-week regimens of MK-3682/GZR/RZR in GT1, 
GT2, and GT3 support the proposed evaluation in this protocol of the safety and efficacy of 
MK-3682 + RZR in TN or prior IFN-based TE, non-cirrhotic and compensated cirrhotic 
GT1-, GT2-, GT3-, GT4-, GT-5, and GT-6-infected subjects.  A treatment duration of 12
weeks for all GTs using the MK-3682 + RZR combination in this study is supported by the 
equipotent or superior in vitro potency profiles of MK-3682 and RZR (Section 4.2.2)
compared to other compounds of the same classes, such as the approved NI/NS5A regimens 
of LDV/SOF and SOF/VEL, that have demonstrated high efficacy rates against GT1-6 after 
12 weeks of treatment as 2-drug IFN-free DAA regimens.  Ribavirin is not proposed to be 
evaluated in this trial given the high efficacy rates observed with other 2-drug all-oral DAA 
regimens without RBV, such as LDV/SOF and SOF/VEL, and the equipotent or superior in 
vitro potency profiles of MK-3682 and RZR compared to these regimens.
Since this is an estimation study, no comparator or placebo is used.  No statistical 
comparisons are planned for efficacy and safety data.  A target number of GT1-, GT2-, GT3-, 
and GT4-infected subjects are specified in order to provide sufficient confidence of the 
estimated treatment response rate in these GTs, since they are the most prevalent GTs 
globally.  Since subjects with GT5 and GT6 are uncommon outside of certain geographic 
areas, the study will enroll approximately a stated number of subjects with the assumption 
that full enrollment of these GTs may not be reached.
Treatment allocation will pause after the first 50 subjects complete the TW4 visit.  This will 
allow general safety and tolerability to be assessed after these first 50 subjects complete 
TW4, an assessment of 20% of the overall allocation target.  The TW4 time point allows for 
steady state of drug to be achieved for ≥2 weeks.  The criteria described in Section 5.11.1 
provide a conservative approach to expanding treatment allocation to the subsequent 200 
subjects.  These criteria will allow the identification of safety concerns, while not allowing 
the trial to be stopped unnecessarily.  
Treatment allocation may be stopped or paused at any time during the trial if certain criteria 
are met, as detailed in Section 5.11. If efficacy criteria for stopping enrollment/treatment 
allocation are met (Section 5.11.4), then no additional subjects of that particular GT will be 
allocated to treatment in the trial.  In addition, the treatment regimen will be modified for all 
subjects of that GT still on treatment by extending the duration of treatment with MK-3682 + 
RZR to 16 weeks and adding RBV to the regimen.  
Rationale for Dose Selection/Regimen
4.2.4
Dose Selection for MK-3682
4.2.4.1
The 450-mg dose of MK-3682 was chosen for the MK-3682B FDC regimen based on the 
dose-response analysis generated by monotherapy data from MK-3682 PN001, by the 
exposure data from the tablet formulation from MK-3682 PN003 and by dose ranging data 
from PN011 and PN012 Part A.  This analysis suggests that the 450-mg dose of MK-3862 in
the tablet formulation will be well on the plateau of the dose-response curve and would 
 
 
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provide improved protection against loss of efficacy than would the 300 mg of the tablet 
formulation, while still maintaining margins to preclinical safety exposures.  Efficacy of the 
MK-3682 300 mg and 450 mg dose arms in GT3-infected subjects in PN012 Part A showed 
SVR12 of 39/42 (93%) and 39/44 (89%), respectively.  In GT2-infected subjects in MK-3682 
PN011 Part A, slightly higher efficacy was observed in subjects on the 450-mg dose of MK-
3682, with an SVR12 rate of 77% (24/31) versus 70% (21/30) on the 300-mg dose.  The 
highest efficacy in GT2-infected subjects was observed in the MK-3682 (450 mg)/GZR/RZR
arm with an SVR12 rate of 94% (15/16), supporting the selection of this regimen for Part B.  
In addition, the 450-mg dose of MK-3682 has demonstrated an acceptable safety profile 
when administered once daily for up to 24 weeks in Phase 2 studies, with no difference 
compared with the 300 mg dose.  Therefore, 450 mg was selected as the dose to be evaluated 
in this protocol.
Dose Selection for RZR
4.2.4.2
Based on the available safety, tolerability, PK, and PD data, 180 mg and 60 mg doses of 
RZR, respectively, were chosen to be evaluated in combination with a 450 mg dose of MK-
3682 in this protocol and in the ongoing PN035.   
Preliminary PD data from RZR PN003 have demonstrated that 60 mg of RZR monotherapy 
for 5 days achieved >3 log10 mean maximal viral load reduction in HCV GT1-, GT2-, and 
GT3-infected subjects. Additionally, the efficacy was similar across doses of 10- to 60-mg 
doses. The mean maximum VL reduction was -3.82 in GT2 and -2.83 in GT3 following 10 
mg of RZR for 5 days, and -3.03 in GT3 following 30 mg of RZR for 5 days. However, a less 
robust VL reduction (-1.75 log10 IU/mL) at a 120-mg dose was observed in GT3-infected
subjects due to baseline or treatment-emergent RAVs in the 3 GT3-infected subjects. One 
subject had S62L/Y93H RAVs at baseline and a treatment-emergent maximal VL reduction 
of -0.34 log10 IU/mL; 1 subject had no detectable RAVs at baseline but had both S62L and 
Y93H treatment-emergent RAVs and a -1.85 log10 IU/mL VL reduction; and the third subject 
had an A30K RAV at baseline and a Y93H/Y treatment-emergent RAV and -3.06 log10
IU/mL VL reduction. The results from monotherapy study suggested that RZR at a dose of 
equal or greater than 10 mg is associated with a robust VL decline, but RZR monotherapy 
may not exhibit full efficacy against some GT3 RAVs and therefore supports the further 
evaluation of RZR at a dose equal to or greater than 10 mg in combination with other 
antiviral agents.  For detailed information, please refer to the RZR IB. 
The high efficacy rates from the Phase 2 studies of the 3-drug regimen containing MK-3682
450 mg, RZR 60 mg, and GZR 100 mg in GT1-, GT2, and GT3-infected subjects support the 
continued development of the MK-3682B regimen with a 60-mg dose of RZR. PN035 is 
currently being conducted to evaluate the 2-drug regimen of MK-3682 (450 mg) and RZR
(60 mg).
Given that GZR is highly effective in GT1-infected subjects, it is possible that a higher dose 
of RZR may be needed to compensate for the removal of GZR in a 2-drug regimen. The 
current study (evaluating RZR 180 mg) is proposed to examine the dose response of RZR in 
combination with MK-3682 as a potential highly efficacious 2-drug regimen.
The higher dose of RZR selected for this trial, 180 mg, is supported by the preclinical safety 
margin and the predicted PK. RZR at the 60-mg dose has demonstrated excellent tolerability 
 
 
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when administered alone or as an MK-3682B FDC regimen in combination with MK-3682 
and GZR (Section 4.1.2.2.1). The steady state exposures of RZR 180 mg in HCV subjects 
are anticipated to be 3- to 30-fold below the exposures achieved in preclinical safety 
assessment toxicity studies and ancillary pharmacology studies. In the thorough QT study
(MK-8408 PN007), a supratherapeutic dose of 600 mg RZR did not cause QTc prolongation
and was generally well tolerated; there were no SAEs, deaths, or ECIs reported. This dose
yielded a margin for maximum plasma concentration (Cmax) of approximately 2.9-fold and 
AUC0-24 of approximately 2.3-fold relative to RZR steady state exposure at the 60-mg dose. 
Additionally, multiple doses of RZR were generally well tolerated after 100 mg once daily 
for 10 days in healthy subjects and 120 mg once daily for 5 days in HCV-infected subjects.
The steady state exposures of RZR 180 mg in HCV subjects are anticipated to be similar to 
the clinical exposures achieved in the RZR thorough QT study, and expected to be well 
tolerated based on the preclinical and clinical exposures achieved to date in RZR program. 
The 180 mg dose was also chosen for this study because RZR exhibits less than dose-
proportional PK over the 200 to 600 mg dose range; a dose greater than 180 mg is predicted 
to result in limited additional increase in RZR exposure.  For detailed information, please 
refer to the RZR IB. 
Taken together, the available data supported the evaluation of RZR in combination with MK-
3682 as a highly efficacious 2-drug regimen, and this study PN041 (MK-3682 450 mg and 
RZR 180 mg) and the ongoing PN035 (MK-3682 450 mg and RZR 60 mg) will provide a
robust dataset to further elucidate the dose response of RZR in combination with MK-3682 
as a 2-drug regimen.
The single entity fit-for-purpose capsule formulation of RZR shows a moderate negative food 
effect, with a 50% decrease in C24hr when co-administered with a high-fat meal.  As such, in 
this study, subjects will be instructed to take study drugs on an empty stomach after an 
overnight fast, at least 1 hour before the morning meal.  Drugs should be taken with water, 
but without food.  A drug-drug interaction study with MK-3682 and RZR (MK-3682 PN008)
showed no clinically significant drug interactions, thus supporting the coadministration of 
these drugs without need for dose adjustment.
Rationale for Endpoints
4.2.5
Efficacy Endpoints
4.2.5.1
The primary measurement for efficacy in this study is the plasma HCV RNA level.  
Long-term suppression of HCV RNA, typically reported as SVR, has been associated with 
improved outcomes in subjects with chronic HCV infection as measured by biochemical and 
histological remission of liver disease.  Most available data suggest that SVR following 
antiviral therapy reduces the risk of progression to cirrhosis and may prevent the 
development of severe liver complications as well as improve survival [37].
The primary evaluation of efficacy in this trial is based on SVR12, the same endpoint used for 
all investigational and approved DAAs. Since a high degree of concordance has been 
observed between SVR12 and SVR24 [38], SVR12 is now being used as the primary endpoint 
for registration of DAAs. A secondary evaluation of efficacy is based on SVR24 and for this 
study this will be a secondary endpoint [39].
 
 
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4.2.5.1.1 Measurement of HCV RNA
HCV-RNA 
levels 
in 
plasma 
will 
be 
measured 
using 
the 
Roche 
COBAS®
AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each subject 
at various time points prior to, during, and after dosing, as indicated in the Trial Flow Chart 
(Section 6.0).  Samples are collected and processed as per instructions provided by the 
manufacturer.
Results from the sample collected at the screening visit are used to determine eligibility.  
Samples collected at other time points, after Day 1, are used for efficacy analyses and to 
identify subjects who meet virologic failure criteria.
The nomenclature detailed in Table 5 will be used when describing HCV RNA levels:
Table 5
Nomenclature for Describing HCV RNA Levels
Abbreviation
Definition
HCV RNA Level
TND
Target not detected
HCV RNA not detected
TD(u)
Target detected but unquantifiable
HCV RNA <LLOQ
TD(q)
Target detected, quantifiable
HCV RNA ≥LLOQ
HCV = hepatitis C virus; LLOQ = lower limit of quantification; RNA = ribonucleic acid.
Definition of Efficacy Endpoints
4.2.5.1.1.1
Efficacy will be defined at different time points during the trial. Specific primary and 
secondary endpoints are:

SVR12: Subject has HCV RNA <LLOQ 12 weeks after the end of all study therapy.

SVR24: Subject has HCV RNA <LLOQ 24 weeks after the end of all study therapy.

Virologic failure rate among subjects who do not discontinue the study for 
non-treatment-related reasons at FW12.
Definition of Virologic Failure: Non-Response, Rebound, Virologic 
4.2.5.1.1.2
Breakthrough and Relapse
Lack of efficacy at different time points in the trial will be categorized as:

Non-response: Subject has HCV RNA detected at end of treatment without HCV 
RNA <LLOQ having been achieved while on treatment (note that breakthrough is 
distinguished below). 

Rebound: Subject has a rebound defined as >1 log10 IU/mL increase in HCV RNA 
from nadir while on treatment and confirmed from a separate blood draw within 
2 weeks.
 
 
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
Virologic breakthrough: Subject has a confirmed HCV RNA ≥LLOQ (target detected, 
quantifiable
[TD(q)])
after being <LLOQ previously
while on treatment.  
Confirmation is defined as an HCV RNA ≥LLOQ from a separate blood draw 
repeated within 2 weeks.

Relapse: Subject has a confirmed HCV RNA ≥LLOQ [TD(q)] following end of all 
study therapy, after becoming undetectable (target not detected [TND]) at end of 
treatment. Confirmation is defined as an HCV RNA ≥LLOQ from a separate blood 
draw repeated within 2 weeks.
4.2.5.1.2 Viral Resistance Measurements
Resistance-associated variants of the HCV can lead to failure of therapy.  This is one of the
most important considerations when treating with a DAA.  To better understand and 
document the potential for RAVs to impact treatment with MK-3682 + RZR, blood samples 
for viral resistance assays will be collected at Baseline (Day 1) to determine pre-existing 
RAVs to MK-3682 and RZR.  Next-generation sequencing will be performed with a 15% 
sensitivity threshold. Additional resistance testing on these samples may be performed.  
Blood samples for resistance testing are also collected during the follow-up period, as well as 
at the virologic failure confirmation visit (should this occur) for genotypic and investigational 
assays to assess emergence of resistance to MK-3682 and/or RZR following treatment 
initiation.  Resistance-associated variants will be assessed for any subject who has detectable 
virus above 1000 IU/mL and has met a virologic failure criteria.  Subjects who fail due to 
early discontinuation of study medication and continue in the trial may also have samples 
collected and tested for RAVs at each follow-up visit, if the virus is detectable and >1000 
IU/mL.
Safety Endpoints
4.2.5.2
The safety and tolerability of the study regimen will be assessed by a clinical evaluation of 
AEs and inspection of other study parameters including vital signs, physical examinations, 
12-lead ECGs, and standard laboratory safety tests at appropriate time points as specified in 
the Trial Flow Chart (Section 6.0).  Adverse events are graded and recorded according to 
Section 7.2.  Subjects may be asked to return for unscheduled visits in order to perform 
additional safety monitoring.
Pharmacokinetic Endpoints
4.2.5.3
The primary PK endpoints for MK-3682 (and metabolites) and RZR are trough plasma 
concentration (Ctrough).  PK samples will be collected from all subjects on each visit as 
described in the Trial Flow Chart (Section 6) and in Table 13 (Pharmacokinetic and 
Pharmacodynamic Sampling Time Points).  These samples will be used to evaluate PK 
concentrations, and PK/AE relationships of MK–3682 (and metabolites) and RZR, as 
appropriate.  The predose time points outlined were chosen in order to capture Ctrough for all 
compounds.  The frequency of Ctrough collections will allow a thorough assessment of both 
subject drug concentrations and drug compliance, should a breakthrough occur.  In addition, 
the postdose time points, in conjunction with the other samples, will be used for PK-safety 
and PK-efficacy modeling.
 
 
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Pharmacodynamic Endpoints
4.2.5.4
As described in Section 7.1.3.2, a subgroup of the study population will be included in an 
intensive viral kinetic sub-study. The purpose of this sub-study is to determine whether early 
viral kinetics can aid in developing a PK/PD model that can predict combinations that may 
be efficacious with various treatment durations. 
These subjects will have HCV RNA samples collected during Week 1 as described in the 
Trial Flow Chart (Section 6.0) and in Table 13 (Pharmacokinetic and Pharmacodynamic
Sampling Time Points). In addition, PK samples will also be collected as described in Table 
13.  These samples will be used to evaluate the PK/PD relationships of MK-3682 (and 
metabolites) and RZR, as appropriate.
Planned Exploratory Biomarker Research
4.2.5.5
Planned Genetic Analysis
Understanding genetic determinants of drug response and the molecular basis of disease is an 
important endeavor during medical research. This research will evaluate whether genetic 
variation within a clinical trial population correlates with response to the treatment(s) under 
evaluation and/or disease. If genetic variation is found to predict efficacy or adverse events, 
the data might inform optimal use of therapies in the patient population. Knowledge of the 
molecular basis of disease contributes to the development of novel biomarkers and the 
identification of new drug targets. This research contributes to understanding molecular basis 
of disease and the genetic determinants of efficacy and safety associated with the treatments 
in this study.
In addition to studying variation across the human genome, for example, IL28B genetic
variants will specifically be investigated for understanding variation in clinical endpoints for 
example, but not limited to, SVR and other efficacy and safety measurements.
Future Biomedical Research
4.2.5.6
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting/retaining specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 – Collection and 
Management of Specimens for Future Biomedical Research.
 
 
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Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
There remains a critical need for new HCV therapies.  The treatment regimen combining an 
HCV NS5B NI (MK-3682), and an NS5A complex inhibitor (RZR), has the potential to 
provide efficacy across multiple GTs and across diverse patient populations, and improve 
treatment by eliminating the need for RBV and shortening the duration of therapy. The 
improved potency against RAVs observed with earlier generation NS5A inhibitors suggests 
that MK-3682 in combination with RZR may provide a stronger barrier to the development 
of resistance and increased activity in the setting of baseline resistance variants.
MK-3682
MK-3682 is a potent HCV NS5B NI with pangenotypic activity and a high barrier to 
resistance that, in combination with complementary HCV DAAs, has the potential to benefit 
an expanded spectrum of HCV-infected subjects, including those with currently 
difficult-to-treat GTs of HCV and individuals who have failed previous treatments.  Among 
all the known DAA classes, NIs have displayed the broadest HCV genotypic coverage and 
the highest barrier to the development of resistance.  
MK-3682 belongs to a class of uridine-based nucleotide analogs, e.g., SOF, that have been 
generally well tolerated.  However, there have been postmarketing reports of symptomatic 
bradycardia, including one fatal cardiac arrest and cases requiring pacemaker insertion, in 
subjects taking the antiarrhythmic drug amiodarone together with either LDV/SOF or SOF in 
combination with another DAA. 
The toxicity potential of MK-3682 has been well characterized in in vitro mitochondrial 
toxicity assays, a battery of in vitro and in vivo genetic toxicity studies, safety pharmacology 
studies, and 4-week, 3-month and 6-month repeat-dose oral toxicity studies in rats and 
monkeys.  In vitro and in vivo preclinical data demonstrate that MK-3682 and its metabolite, 
M6, at the exposures observed in the clinic, have limited potential for class toxicities 
associated with nucleotides, including myopathy and mitochondrial toxicity. No observed
adverse effect levels (NOAELs) in the rat and Cynomolgus monkey at 1000 mg/kg/day 
provide adequate margins of safety relative to anticipated human doses and support daily oral 
dosing of humans for up to 6 months in duration. In summary, the toxicity studies identified 
minimal differences between control and treated animals, all of which were not considered 
adverse. Preclinical studies identified the liver and potentially kidney as potential target 
organs. There was no evidence of cardiovascular toxicity in studies up to 3 months’ duration, 
based on histopathology in the rat and monkey and echocardiography, electrocardiography, 
and serum biomarker evaluations in the monkey. Overall, the preclinical toxicity profile of 
MK-3682 via the oral route of administration supports the continuation of clinical trials.  
To date, MK-3682 has been generally well-tolerated in healthy subjects and HCV-infected 
subjects in several Phase 1 clinical studies at single doses up to 900 mg, multiple doses up to 
 
 
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750 mg per day for 10 days, and in Phase 2a trials of 300 mg or 450 mg once daily for up to 
24 weeks. Review of the safety data has revealed no clinically significant abnormalities in 
routine physical examinations including vital signs. There have been no dose-related or other 
patterns observed in the clinical, ECG, or laboratory data. In the clinical studies proposed, 
available safety data (clinical and laboratory AEs, vital signs, laboratory safety tests, and 
ECGs) will be carefully monitored. 
Phase 2 studies have demonstrated that a regimen of MK-3682 (450 mg)/GZR/RZR is highly 
effective in GT1, 2, and 3-infected subjects. Overall, MK-3682, as a component of a 
combination DAA regimen, has the potential to substantially improve HCV treatment 
outcomes, benefiting many HCV-infected individuals.
RZR
RZR is a potent HCV NS5A complex inhibitor with pangenotypic activity that has the 
potential to benefit individuals requiring treatment of HCV infection, even if the individual is 
infected with currently difficult-to-treat GTs. The improved potency of RZR against RAVs 
observed with earlier generation NS5A inhibitors suggests that RZR will have improved 
efficacy in individuals who have experienced treatment failures with other anti-HCV 
regimens and/or have NS5A RAVs at baseline. 
RZR has favorable safety findings in safety assessment toxicity studies and ancillary 
pharmacology studies, supporting the continued evaluation of RZR in clinical trials in adults. 
The 2-week, 3-month, 6-month, and 9-month rat and dog toxicity studies provide substantial 
preclinical safety margins for doses proposed to be administered in future clinical trials. RZR
has been given to approximately 217 subjects and subjects in 8 RZR Phase 1 trials and in 
over 800 subjects in ongoing Phase 2a trials (RZR in combination with MK-3682 and GZR 
in HCV GT1-, GT2-, and GT3-infected subjects). RZR has been administered at doses up to 
600 mg/day, 100 mg given daily for 10 days, and 60 mg once daily for up to 24 weeks.  No 
SAEs have been reported in any individual receiving RZR. There were no consistent 
treatment-related changes in labs, vital signs, or ECG safety parameter values.  Adverse 
events in subjects receiving RZR monotherapy have been mild to moderate in intensity and 
transient in duration.  The totality of the safety data indicates that RZR is well-tolerated.
Definitive embryo-fetal developmental toxicity studies conducted in concordance with the 
International Conference on Harmonization
(ICH)
of Technical Requirements for 
Registration of Pharmaceuticals for Human Use M3 (R2) guidance have been completed in 
rats and rabbits for MK-3682 and RZR.  While data support the inclusion of women of 
childbearing potential in clinical trials with MK-3682 and RZR, inclusion of women of 
childbearing potential should be in accordance with the study protocol and applicable 
regulatory guidance. 
Based on the preclinical data and the clinical experience to date in healthy subjects and 
HCV-infected subjects, the risk/benefit assessment is favorable for proceeding with the 
proposed clinical study with the 2-drug combination of MK-3682 + RZR.
 
 
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Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with chronic HCV GT1, GT2, GT3, GT4, GT5, or GT6 infection who 
are at least 18 years of age will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. be ≥18 years of age on day of signing informed consent
2. have HCV RNA (≥10,000 IU/mL in peripheral blood) at the time of screening
3. have documented chronic HCV GT1, GT2, GT3, GT4, GT5, or GT6 (with no evidence 
of non-typeable or mixed GT) infection as follows:
a.
positive for anti-HCV antibody, HCV RNA, or HCV GT1, GT2, GT3, GT4, GT5,
or GT6 at least 6 months before Day 1, or
b. positive for anti-HCV antibody or HCV RNA with a liver biopsy consistent with 
chronic HCV infection (such as the presence of fibrosis) before Day 1
4. have liver disease staging assessment as follows:
a. Absence of cirrhosis (F0 to F3) defined as any one of the following:
i.
a liver biopsy performed within 24 months of Day 1 of this study showing 
absence of cirrhosis
ii.
Fibroscan® performed within 12 months of Day 1 of this study with a 
result of ≤12.5 kPa, or
iii.
a Fibrosure® (Fibrotest®) performed during screening with a score of ≤0.48 
and an aspartate aminotransferase (AST) to platelet ratio index (APRI) of 
≤1
b. Compensated cirrhosis (F4) defined as any one of the following:
i.
a liver biopsy performed prior to Day 1 of this study showing cirrhosis
ii.
Fibroscan® performed within 12 months of Day 1 of this study showing 
cirrhosis with result >12.5 kPa, or
iii.
a Fibrosure® (Fibrotest®) performed during screening with a score of
>0.75 and an APRI of >2
APRI formula: AST ÷ lab ULN for AST × 100 ÷ (platelet count ÷ 100).  APRI 
calculation to be provided by the testing laboratory.
 
 
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NOTE: In the absence of a definitive diagnosis of presence or absence of cirrhosis by 
the above criteria, a liver biopsy or Fibroscan® is required. Liver biopsy results 
supersede the results obtained by Fibroscan® or Fibrosure®.
5. have an HCV treatment status that is one of the following:
a.
HCV treatment naïve (defined as no prior exposure to any IFN-containing 
regimen, RBV, or other approved or experimental HCV-specific DAA agent).
b. HCV treatment experienced (defined as prior virologic failure after treatment with 
an IFN-containing regimen, with or without RBV, or intolerance to an IFN-
containing regimen).  Subjects cannot have previously received treatment with 
HCV-specific DAA agent.
6. meet one of the following categories:
a) The subject is a male who is not of reproductive potential, defined as a male who 
has azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition).  
b) The subject is a female who is not of reproductive potential, defined as a female 
who either: (1) is postmenopausal (defined as at least 12 months with no menses 
in women ≥45 years of age); (2) has had a hysterectomy and/or bilateral 
oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at 
least 6 weeks prior to screening; OR (3) has a congenital or acquired condition 
that prevents childbearing.
c) The subject is a female or a male who is of reproductive potential and agrees to 
avoid becoming pregnant or impregnating a partner beginning at least 2 weeks
prior to administration of the initial dose of study drug, and for 6 months after 
taking the last dose of study drug (or longer if dictated by local regulations) by 
complying with 1 of the following:  (1) practice abstinence† from heterosexual 
activity OR (2) use (or have their partner use) 2 forms of acceptable contraception 
during heterosexual activity.  Acceptable methods of contraception are as 
follows‡:

intrauterine device (with or without local hormone release)

diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

cervical cap with spermicide (nulliparous women only)

contraceptive sponge (nulliparous women only) 

male condom with spermicide or female condom with spermicide (cannot 
be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, 
or subcutaneous contraceptive injection
 
 
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If male, subjects must agree to use a condom with spermicide or abstain from sexual 
intercourse during the trial until 6 months after taking the last dose of study drug 
(or longer if dictated by local regulations).
Spermicides alone are not an acceptable method of contraception.
Subjects must be completely informed of the unknown risks of pregnancy and agree 
not to become pregnant during the time they are participating in this trial.
If there is any question that a subject will not be reliable in the use of appropriate 
contraceptive methods, they should not be entered into the trial.
NOTE:  Subjects whose study medication regimen includes only MK-3682 + RZR
(and are not treated at any time with RBV) should avoid becoming pregnant or 
impregnating a partner for at least 14 days after taking the last dose of study drug.  
Acceptable methods of contraception for these subjects during this time include:
Single method (one of the following is acceptable):
•
intrauterine device (IUD)
•
vasectomy of a female subject’s male partner 
•
contraceptive rod implanted into the skin
Combination method (requires use of two of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)  
•
contraceptive sponge (nulliparous women only) 
•
male condom or female condom (cannot be used together)
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, 
or subcutaneous contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method 
of contraception if it is consistently employed as the subject’s preferred and 
usual lifestyle and if considered acceptable by local regulatory agencies and 
ERCs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, 
post-ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception. 
‡If 
a 
contraceptive 
method 
listed 
above 
is 
restricted 
by 
local 
regulations/guidelines, then it does not qualify as an acceptable method of 
contraception for subjects participating at sites in this country/region.
7. understand the study procedures, alternative treatments available, risks involved with
the study, and voluntarily agrees to participate by giving written informed consent.  The 
subject may also provide consent for FBR. However, the subject may participate in the 
main trial without participating in FBR.
 
 
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For HIV co-infected subjects, these additional 2 criteria must also be met:
8. have HIV-1/HIV-2 infection documented at any time prior to study entry (Day 1) by 
any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay 
(E/CIA) test kit and confirmed by a licensed Western blot or a second antibody test by 
a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 p24 antigen, or 
plasma HIV-1 RNA VL.
9. meet 1 of the following criteria:
a.
not currently on antiretroviral therapy (ART) and has no plans to initiate ART 
treatment while participating in this study, must have CD4+ T-cell count 
>500 cells/mm3 at time of screening, or
b. have well controlled HIV on ART, defined as the following:
i. must have CD4+ T-cell count >200 cells/mm3 at time of screening
ii. must have achieved and maintained virologic suppression (defined as 
confirmed HIV RNA level <LLOQ of available assay) for at least 8 weeks 
prior to screening
iii. must have been on a stable regimen (without changes in drugs or dose 
modification) for at least 4 weeks prior to study entry (Day 1)
The combination ART regimen must not contain any antiretroviral medications
other than: abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, 
rilpivirine or tenofovir.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. is under the age of legal consent, is mentally or legally incapacitated, has significant 
emotional problems at the time of pre-study screening visit or expected during the 
conduct of the study, or has a history of a clinically significant psychiatric disorder 
which, in the opinion of the investigator, would interfere with the study procedures.
2. has evidence of decompensated liver disease manifested by the presence of or history 
of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy, or other 
signs or symptoms of advanced liver disease. 
3. is cirrhotic AND has a Child-Turcotte-Pugh score >6, corresponding to a Child Class 
B or C
NOTE: To calculate the Child-Turcotte-Pugh score and classification, refer to the 
following website: http://www.mdcalc.com/child-pugh-score-cirrhosis-mortality/.
4. is hepatitis B surface antigen (HBsAg) positive at screening.
NOTE:  Subjects who are HBsAg negative at screening, but who are hepatitis B core 
antibody (anti-HBc) positive at screening may be included.  For all anti-HBc positive 
subjects, hepatitis B virus (HBV) deoxyribonucleic acid (DNA) will be assessed at 
 
 
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screening, and both HBV DNA and HBsAg will be monitored during the trial.  
Additional details can be found in Section 7.1.3.5 ‒ HBV Evaluation and Section 
7.2.3.2 ‒ Events of Clinical Interest.
5. is coinfected with HIV AND has a history of opportunistic infection in the preceding 
6 months prior to screening.
NOTE: A list of these events may be found in Appendix B of the following 
document: http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm
6. has a history of malignancy ≤5 years prior to signing informed consent except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or 
carcinoma in situ; or is under evaluation for other active or suspected malignancy.
7. has cirrhosis AND liver imaging within 6 months of Day 1 showing evidence of 
hepatocellular carcinoma (HCC) or is under evaluation for HCC.
NOTE: If liver imaging within 6 months prior to Day 1 is not available, imaging is 
required during screening.
8. is taking or plans to take any of the prohibited medications listed in the protocol 
(Section 5.5) or is taking herbal supplements, including but not limited to St. John’s 
wort (Hypericum perforatum), from 2 weeks prior to Day 1 through 2 weeks after the 
study treatment period.
9. is currently participating or has participated in a study with an investigational 
compound within 30 days of signing informed consent and is not willing to refrain 
from participating in another such study during the course of this study through 24 
weeks after the study treatment period (FW 24).
10. is a female subject who is pregnant or breastfeeding, or expecting to conceive or 
donate eggs from Day 1 through 6 months after the last dose of study drug or longer 
if dictated by local regulations, OR a male subject who is expecting to donate sperm 
from Day 1 through 6 months after the last dose of study drug or longer if dictated by 
local regulations.
NOTE: Female subjects whose study medication regimen includes only MK-3682 + 
RZR (and are not treated at any time with RBV) should avoid conceiving or donating 
eggs for at least 14 days after taking the last dose of study drug.  Male subjects whose 
study medication regimen includes only MK-3682 + RZR (and are not treated at any 
time with RBV) should avoid impregnating a partner or donating sperm for at least 14 
days after taking the last dose of study drug.
11. is a male whose female partner(s) is/are pregnant (this is a contraindication for RBV 
use).
12. has any of the following conditions:
 
 
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a.
Organ transplants (including hematopoietic stem cell transplants) other than 
cornea and hair.
b. Poor venous access that precludes routine peripheral blood sampling required 
for this trial.
c.
Subject with a history of gastric surgery (e.g., stapling, bypass) or subject with 
a history of malabsorption disorders (e.g., celiac sprue disease).
d. has clinically relevant drug or alcohol abuse within 12 months of screening
that may interfere with subject treatment, assessment, or compliance with the 
protocol.
e.
Any clinically significant cardiac abnormalities/dysfunction that may interfere 
with subject treatment, assessment, or compliance with the protocol, including 
but not limited to: unstable angina, unstable congestive heart failure, unstable
arrhythmia; subjects currently under evaluation for a potentially clinically
significant cardiac abnormality/dysfunction are also excluded.
f.
Any major medical condition, clinically-significant illness (other than HCV),
pre-study laboratory or ECG abnormality, or history of any illness, which, in 
the opinion of the investigator, might interfere with subject treatment, 
assessment, compliance with the protocol, or confound the results of the study 
or pose additional risk in administering the study drug to the subject.
g. History of a medical/surgical condition that resulted in hospitalization within 
the 3 months prior to enrollment, other than for minor elective procedures.
NOTE: Elective procedures will be permitted following 14 days after taking 
the last dose of study drug.
h. Medical/surgical conditions that may result in a need for hospitalization 
during the period of the study. 
i.
Any medical condition requiring, or likely to require, chronic systemic 
administration of corticosteroids, tumor necrosis factor (TNF) antagonists, or 
other immunosuppressant drugs during the course of the trial through FW24.
j.
Life-threatening SAE during the screening period.
k. Evidence of history of chronic hepatitis not caused by HCV, including but not 
limited to drug-induced hepatitis, hemochromatosis, Wilson’s disease, 
α1-antitrypsin deficiency, alcoholic liver disease, and autoimmune hepatitis
(See Exclusion Criterion #4 regarding evidence of history of Hepatitis B).
NOTE:  Subjects with history of acute non-HCV-related hepatitis, which 
resolved >6 months before study entry, can be enrolled.  
13. has exclusionary laboratory values at the screening visit as listed in Table 6.
NOTE:  If any of the laboratory exclusion criteria in Table 6 are met, the site 
may have the abnormal value retested 1 time.  
 
 
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Table 6
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Values
Creatinine Clearance
(estimated glomerular filtration rate, 
eGFR)1
<50 mL/min/1.73 m2
Hemoglobin
<10 g/dL
Platelets
<50 × 103/μL
Serum Albumin
<3.0 g/dL
International normalized ratio (INR)
>1.7 unless subject has a stable INR on an anticoagulant 
regimen
ALT
>10× ULN
AST
>10× ULN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; eGFR = estimated 
glomerular filtratrion rate; INR = international normalized ratio; ULN = upper limit of normal.
1 
Creatinine clearance will be evaluated as an eGFR based on the modification of diet in renal 
disease (MDRD) equation: eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if 
female) × (1.212 if black) Scr, std: serum creatinine measured with a standardized assay.
14. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Trial Treatment(s)
5.2
The treatment to be used in this trial is outlined below in Table 7.
Table 7
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Perioda
Use 
MK-3682
(150-mg tablets)
450 mg
Daily 
(3 tablets 
once daily)
Oral
12 weeks
Experimental
RZR (60-mg 
capsules)
180 mg
Daily 
(3 capsules 
once daily)
Oral
Experimental
a If the efficacy criteria for stopping enrollment/treatment allocation are met for that particular GT, the treatment 
regimen with MK-3682 + RZR for subjects with a particular GT still receiving treatment will be extended to a total
duration of 16 weeks and RBV will be added to the regimen (see Table 8 and Section 5.11.4).
Rescue medication to be used in this trial if efficacy criteria for stopping 
enrollment/treatment allocation are met for a particular GT (see Section 5.11.4) is outlined 
below in Table 8.  Ribavirin should be dosed according to the approved local prescribing 
information.
 
 
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Table 8
Rescue Medication
Drug
Weight
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/ 
Treatment Period
Use
MK-3682
(150-mg 
tablets)
NA
450 mg
Daily 
(3 tablets 
once 
daily)
Oral
Total of 16 weeks
Rescue 
Medication
RZR (60-mg 
capsules)
NA
180 mg
Daily 
(3 
capsules 
once 
daily)
Oral
Total of 16 weeks
Rescue 
Medication
Ribavirin 
only if 
treatment 
duration is 
extended 
Per approved local prescribing 
information 
Oral
Maximum of 
16 weeks
Rescue 
Medication
All clinical supplies indicated above will be provided centrally by the Sponsor or locally by 
the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number.
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
The first dose of trial treatment will be administered at the trial site at Visit 2 (Day 1). The 
doses to be taken at other visits at which a pre-dose PK sample is to be collected will also be
administered at the trial site.  See Section 5.2.2 for specific dosing instructions.  Subsequent 
dosing will be performed once daily by the subject (i.e., unsupervised at his/her home) at 
approximately the same time each day.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
Dose Selection (Preparation)
5.2.1.1
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
 
 
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Dose Modification
5.2.1.2
Dose modification of MK-3682 or RZR is not permitted. See Section 5.2.2 for instructions if 
for any reason MK-3682 or RZR needs to be interrupted.  For any other dose modifications 
that occur, consult the Sponsor Protocol team.
Ribavirin
Dose modification of RBV is permitted per the approved local prescribing information.
Timing of Dose Administration
5.2.2
MK-3682 and RZR
All doses of MK-3682 and RZR should be taken on an empty stomach after an overnight 
fast, at least 1 hour before the morning meal.  Study medications should be taken with water 
but without food.  In addition, subjects should fast overnight prior to reporting to the study 
site for dosing on Treatment Day 1 (Visit 2) and for all other visits at which a pre-dose PK 
sample is to be collected.  For study visits after Visit 2, if there are cases in which a morning 
visit is not feasible and a subject is seen in the afternoon, the subject should take their study 
medication in the morning, after an overnight fast, as per their regular schedule and PK 
samples will still be collected during these visits.
If a subject misses a dose of MK-3682 or RZR and it is less than 8 hours before the next 
dose, the missed dose should be skipped and the normal dosing schedule resumed.  Subjects 
should not double the next dose in order to compensate for what has been missed. 
If a subject misses a dose of MK-3682 or RZR and it is greater than 8 hours before the next 
dose, the missed dose should be taken at least 2 hours after last meal and 1 hour before next 
meal and the normal dosing schedule resumed.  
If for any reason MK-3682 or RZR needs to be interrupted, the entire regimen should be 
interrupted and can be interrupted for up to 3 days.  If the interruption lasts for more than 
3 days, consult the Sponsor Protocol team.
Ribavirin
Dosing of RBV should follow the approved local prescribing information.
Trial Blinding 
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
5.3
In this nonrandomized, open-label trial, subjects will be assigned to receive MK-3682 +
RZR. 
Treatment allocation will occur centrally using an interactive voice response 
system/integrated web response system (IVRS/IWRS). Ribavirin will be locally sourced and 
dispensed by the site if the treatment regimen is extended.
 
 
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Stratification
5.4
Subjects will be stratified by GT according to the following plan.  After the first 50 subjects 
(of any GT) are allocated to treatment, allocation will pause to assess general safety and 
tolerability.  If general safety and tolerability is assessed to be acceptable, the subsequent
200 subjects will be allocated to treatment with an overall allocation target based on GT 
(GT1, GT2, GT3, GT4, GT5, or GT6).  The first 50 subjects will be included in the overall 
treatment allocation target of the trial, and counted towards the GT and fibrosis stage 
allocation targets (see Section 2.1).
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Prohibited Medication
It is important for investigators to review each medication (prescription and non-prescription) 
the subject is taking before starting the study and at each study visit.

All concomitant medications/therapies should be reviewed and data collected through 
2 weeks after the study treatment period.  Subjects should be questioned about any 
new drugs/vaccines they are taking/have taken or changes to any previously reported 
drugs/vaccines.
o
Drugs known to be hepatotoxic (i.e., drugs with a warning of hepatotoxicity in 
the package insert) should be avoided. Investigators are encouraged to review 
each 
medication 
for 
potential 
hepatotoxicity 
by 
searching 
the 
www.livertox.nih.gov website.

To minimize the risk of adverse drug interactions, every effort should be made to 
limit the number of concomitant drugs to those that are truly essential.

Non-study HCV medications/therapies, including interferon, are prohibited through 
FW24. Any use should be reported throughout the subject’s participation in the trial.
Listed below (Table 9) are specific restrictions for concomitant therapy during the course of 
the trial.  
The following medications/therapies are not permitted from 2 weeks prior to Day 1 through 
2 weeks after the study treatment period.
 
 
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Table 9
List of Prohibited Medications
Category
Examples
Known hepatotoxic drugs, 
including but not limited to 
the following:
etifoxine, isoniazid, nitrofurantoin
Herbal supplements:
All herbal supplements are prohibited (e.g., silymarin [milk 
thistle] and St. John’s wort)
Antiarrhythmic 
agents, 
including but not limited to 
the following:
amiodarone, quinidine, bepridil, disopyramide, flecainide, 
lidocaine (systemic), mexiletine, propafenone
Strong 
inhibitors 
of 
CYP3A, including but not 
limited to the following:
clarithromycin, telithromycin, itraconazole, ketoconazole, 
nefazodone
Strong 
and 
moderate 
CYP3A inducers, including 
but not limited to the 
following:
Anti-infectives: nafcillin, rifampin
Anticonvulsants: carbamazepine, phenytoin, phenobarbital
Endothelin antagonists: bosentan
Wakefulness-Promoting Agents: modafinil
Herbal Products: St. John’s wort
Gastric acid modifiers: 
H2 blockers
Proton-pump inhibitors
Note: antacids, such as calcium carbonate or aluminum 
hydroxide-based product, will be allowed during the study, 
but it is recommended they be taken either 4 hours before or 
after dosing of MK-3682 and RZR (see Allowed Medication 
below)
HIV medications (note that 
not all prohibited HIV 
medications are listed):
efavirenz
etravirine
nevirapine
ritonavir
all boosted and unboosted HIV protease inhibitors
Note: see Allowed Medication below for list of permitted 
HIV medications
HMG-CoA 
reductase 
inhibitors (statins):
rosuvastatin greater than a daily dose of 10 mg (see Allowed 
Medications, below)
atorvastatin, fluvastatin, lovastatin, or simvastatin greater 
than a daily dose of 20 mg (see Allowed Medications, 
below).  
CYP = Cytochrome P450; HIV = human immunodeficiency virus; HMG-CoA = 3-hydroxy-3-
methylglutaryl coenzyme A.
Allowed Medications
The following concomitant medications (Table 10) are allowed in this study.
 
 
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Table 10
List of Allowed Medications
Antihypertensives:
ACE inhibitors or ARBs: enalapril, captopril, lisinopril, ramipril, 
valsartan, losartan, telmisartan
Beta blockers: atenolol, metoprolol, propranolol (NOTE: for other 
beta blockers, please consult with the Sponsor)
Calcium-channel blockers: amlodipine, diltiazem, verapamil
(NOTE: for other calcium-channel blockers, please consult with 
the Sponsor)
hydralazine, clonidine, minoxidil, isosorbide nitrates
Anemia: 
erythropoietin
Anti-coagulants:
warfarin, heparin, low molecular weight heparin, aspirin, 
fondaparinux, desirudin, acenocoumarol
Diuretics:
HCTZ, furosemide, spironolactone, triamterene
Hypoglycemic agents:
insulin, sitagliptin, glipizide, metformin
Contraceptives:
oral contraceptive pills, progesterone injects, intrauterine devices 
Antidepressants/anxiolytics:
citalopram, paroxetine, duloxetine, escitalopram, fluoxetine, 
bupropion, 
trazodone, 
diazepam, 
clonazepam, 
temazepam, 
lorazepam
Acid reflux:
Antacids: stomach acid neutralizers, such as calcium carbonate or 
aluminum hydroxide-based products, are permitted, but it is 
recommended that they be taken either 4 hours before or after 
dosing of MK-3682 and RZR
HIV medications:
abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, 
rilpivirine, tenofovir
HMG-CoA reductase 
inhibitors (statins):
pravastatin and pitavastatin: may be coadministered without dose 
adjustment
rosuvastatin: use the lowest possible effective dose of rosuvastatin, 
but do not exceed a daily dose of 10 mg  
atorvastatin, simvastatin, fluvastatin, lovastatin: use the lowest 
possible effective dose of atorvastatin, but do not exceed a daily 
dose of 20 mg  
Opioid agonist therapy:
Subjects on stable doses of methadone or buprenorphine/naloxone 
may be enrolled in this study, if not excluded per Exclusion 
Criteria in Section 5.1.3.
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; HCTZ = hydrochlorothiazide; 
HIV = human immunodeficiency virus; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A.
In general, P-glycoprotein substrates with narrow therapeutic ranges (e.g., digoxin and 
colchicine) are not prohibited, but their levels have the potential to be increased.  Therefore, 
subjects taking these medications should be monitored closely.  
Given that the lists above are not comprehensive, the investigator should use his/her medical 
judgment when a subject presents with a medication not on the list or consult with the 
Sponsor.
 
 
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Rescue Medications & Supportive Care
5.6
The treatment regimen with MK-3682 + RZR for subjects with a particular GT will be 
extended to 16 weeks’ duration and RBV will be added, if the efficacy criteria for stopping 
enrollment/treatment allocation are met for that particular GT. 
Diet/Activity/Other Considerations
5.7
MK-3682 and RZR should be taken with water and without food (on an empty stomach after 
an overnight fast and at least 1 hour before the morning meal).  For subjects whose treatment 
regimen is modified to include RBV, dosing of RBV should follow the approved local 
prescribing information. 
Subject Withdrawal/Discontinuation Criteria
5.8
Discontinuation of Treatment
5.8.1
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the trial will still continue to participate in the trial as specified in 
Section 6.0, Trial Flow Chart and Section 7.1.5.6, Discontinued Subjects Continuing to be 
Monitored in the Trial.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
Table 11 provides reasons why a subject must be discontinued from treatment but should
continue to be monitored in the trial, as well as reasons why a subject must be discontinued 
from treatment and the trial.
 
 
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Table 11
Discontinuation Scenarios
Reason for Discontinuation Scenario
Action
The subject has a medical condition or personal circumstance 
which, in the opinion of the investigator and/or Sponsor, places the 
subject at unnecessary risk through continued participation in the 
trial or does not allow the subject to adhere to the requirements of 
the protocol.
Discontinue from Treatment and 
Trial
Subject meets criteria for HCV virologic breakthrough or rebound 
(see Section 4.2.3.1.1.2)
Discontinue from Treatment (should 
continue to monitor in the trial)
Subject becomes pregnant during the trial.
Discontinue from Treatment (should 
continue to monitor in the trial)
A physician investigator feels it is in the best interest of the subject 
to discontinue.
Discontinue from Treatment (should 
continue to monitor in the trial)
The subject’s ALT or AST increases to >500 IU/L and is confirmed 
with repeat test within one week.
Discontinue from Treatment (should 
continue to monitor in the trial)
The subject’s ALT or AST increases to >3x the nadir value, is >3x 
ULN (confirmed with repeat test within one week), and there is a 
simultaneous increase in total bilirubin > 2x ULN and/or INR is 
increased from the baseline value and is >1.5 (unless the subject is 
on anticoagulation).
Discontinue from Treatment (should 
continue to monitor in the trial)
The subject’s ALT or AST increases to >3x nadir, is >3x ULN 
(confirmed with repeat test within one week), and is temporally 
associated with signs or symptoms of liver inflammation that are of 
moderate or severe intensity and deemed by the investigator to be at 
least possibly related to study therapy.
Discontinue from Treatment (should 
continue to monitor in the trial)
The subject’s serum creatinine increases to Grade 3 or higher 
(>1.8× upper limit of normal), confirmed with repeat test within one 
week.
Discontinue from Treatment (should 
continue to monitor in the trial)
The 
subject’s 
creatinine 
clearance 
(eGFR) 
decreases 
to 
<50 mL/min/1.73 m2, confirmed with repeat test within one week. 
Creatinine clearance will be evaluated as an estimated GFR 
(eGFR), based on the modification of diet in renal disease (MDRD) 
equation:
eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-
0.203 × (0.742 if female) × (1.212 if black)
Scr, std: serum creatinine measured with a standardized assay
Discontinue from Treatment (should 
continue to monitor in the trial)
The subject has a Grade 4 laboratory AE, or a life-threatening 
clinical AE, or an AE that results in or prolongs an existing in-
subject hospitalization, that is assessed as study drug-related
Discontinue from Treatment (should 
continue to monitor in the trial)
SAE assessed by the physician investigator as possibly or probably 
related to study medication. Investigator may continue the subject 
in the trial, if it is deemed to be in the best interest of the subject to 
stay on the study treatment after consultation with Sponsor.
May Discontinue from Treatment 
(should continue to monitor in the 
trial)
Failure to comply with the dosing, evaluations, or other 
requirements of the trial.
May Discontinue from Treatment 
(should continue to monitor in the 
trial)
Note: Clinical management of HIV-1 virologic failure will be handled by site investigators 
according to current HIV treatment guidelines and local standard of care. Subjects with HIV 
virologic failure may continue in the trial unless treatment with a prohibited concomitant 
medication (Section 5.5) is required to construct a new HIV treatment regimen.
 
 
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For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
see Section 6.0 – Trial Flow Chart, and Section 7.1.5.6 – Discontinued Subjects Continuing 
to be Monitored in the Trial for those procedures to be completed at each specified visit.
Subjects may be allowed to begin treatment again if deemed medically appropriate upon 
consultation with the SPONSOR.
Withdrawal from the Trial
5.8.2
Subjects may withdraw from the trial at any time for any reason.  If a subject withdraws from 
the trial, they will no longer receive treatment or be followed at scheduled protocol visits.
A subject must be withdrawn from the trial if:
○
The subject or legal representative (such as parent or legal representative) withdraws 
consent from the trial.
○
The subject is lost to follow-up.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 7.1.4 – Other Procedures.
Subject Replacement Strategy
5.9
A subject who discontinues from treatment or withdraws from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, withdraws 
from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the 
investigator).
Clinical Criteria for Early Trial Termination
5.11
Early trial termination will be the result of the criteria specified below:
Criteria for Assessing Safety in the First 50 Subjects 
5.11.1
The following criteria apply to stopping further allocation after the first 50 subjects have 
commenced treatment, and not continuing allocation to reach the overall target of n=250.
These criteria will be assessed after the last of the first 50 subjects reaches TW4, as this 
allows for steady state of drug to be achieved for ≥2 weeks.
If >3 out of the first 50 subjects receiving MK-3682 + RZR experience any of the following, 
study therapy will be discontinued in all subjects and no additional subjects will be enrolled
or allocated to treatment. 
 
 
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
The subject has a Grade 4 laboratory abnormality, or a life-threatening clinical AE, or 
an AE that results in or prolongs an existing hospitalization, or death, that is assessed 
to be study drug related.

The subject’s ALT or AST increases to >500 IU/L, is assessed to be study drug 
related, and is not associated with virologic failure.

The subject’s serum creatinine increases to Grade 3 or higher (>1.8 × ULN), 
confirmed with repeat test within 1 week, that is assessed to be study drug related.

The subject’s creatinine clearance (eGFR) decreases to <50 mL/min/1.73 m2, 
confirmed with repeat test within 1 week, that is assessed to be study drug related.  
Note: Creatinine clearance will be evaluated as an eGFR based on the modification of 
diet in renal disease (MDRD) equation:
eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if black)
Scr, std: serum creatinine measured with a standardized assay
Safety Criteria for Stopping Enrollment/Allocation At Any Time During the 
5.11.2
Trial
If >12 subjects receiving MK-3682 and RZR, at any time during the trial, experience any 1 of 
the following, the trial will terminate.

The subject has a Grade 4 laboratory abnormality, or a life-threatening clinical AE, or 
an AE that results in or prolongs an existing hospitalization, or death, that is assessed 
to be study drug related.

The subject’s ALT or AST increases to >500 IU/L, is assessed to be study drug 
related, and is not associated with virologic failure.

The subject’s serum creatinine increases to Grade 3 or higher (>1.8 × ULN), 
confirmed with repeat test within 1 week, that is assessed to be study drug related.

The subject’s creatinine clearance (eGFR) decreases to <50 mL/min/1.73 m2, 
confirmed with repeat test within 1 week, that is assessed to be study drug related. 
Note: Creatinine clearance will be evaluated as an eGFR based on the modification of 
diet in renal disease (MDRD) equation: 
eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if black)
Scr, std: serum creatinine measured with a standardized assay
Safety Criteria for Pausing Enrollment/Allocation
5.11.3
If ≥3 subjects receiving MK-3682 and RZR experience any of the following during the study, 
treatment allocation will be paused:

The subject has a Grade 4 laboratory abnormality, or a life-threatening clinical AE, or 
an AE that results in or prolongs an existing hospitalization, or death, that is assessed 
to be study drug related.
 
 
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Subjects who are tolerating treatment may continue to receive study therapy, but no 
additional subjects will be allocated to treatment until the Sponsor has reviewed all safety 
data on subjects.
Efficacy Criteria for Stopping Enrollment/Allocation
5.11.4
The efficacy criteria for stopping enrollment/treatment allocation are:
1. A total of ≥3 out of the first 10 subjects in the per-protocol (PP) population (see 
Section 8.5.1 for definition) for each GT (GT1-6) receiving 12 weeks of therapy 
experience virologic failure (non-response, rebound, breakthrough, or relapse) by 
FW4, or 
2. >5 subjects in the PP population for GT1-4, and >3 subjects in the PP population 
for GT5-6, experience virologic failure at any point in the trial.
If either of these criteria is met, then no additional subjects of that particular GT would be 
allocated to treatment in the trial.  Additionally, the Sponsor will review the results, and if the 
majority of failures are due to relapses (i.e., >50%), the treatment regimen will be modified 
for all subjects of that GT still on treatment.  If the treatment regimen is modified, the 
duration will be extended to 16 weeks and RBV will be added to the regimen (investigators 
will review considerations and contraindications to RBV with subjects impacted).
Criteria for HIV-infected Subjects
If a total of ≥2 HIV-infected subjects across all arms experience confirmed loss of HIV-1 
virologic suppression at any time, then no additional HIV co-infected subjects will be 
enrolled.
Loss of virologic suppression is defined as HIV-1 RNA ≥200 copies/mL, 
confirmed on 2 consecutive tests at least 2 weeks apart in subjects compliant with their HIV 
ARV therapies.
Remaining co-infected subjects who are already on trial treatment will 
continue their assigned HCV treatment regimen while their HIV regimen is being reassessed.
 
 
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6.0 TRIAL FLOW CHART
Trial Period
Treatment Period
Follow-up Period
Unscheduled
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Intensive PK/PD group:
Screening
Day 11
Day 2
Day 3
Day 5
Day 7
TW2
TW4
TW6
TW8
TW10
TW12
TW142
TW162
FW 4
FW 8
FW 12
FW 16
FW 20
FW 24
Viral 
Failure 
Confirmation 
(HCV or HIV)
Early 
Discontinuation 
Visit
Main Study Group
n/a
n/a
n/a
Visit Window
-45d
n/a
n/a
+2d
-1d 
to 
+2d
-2d 
to 
+2d
-7 to +7 days
-7 to +14 days
-2 to +2 weeks
n/a
n/a
Administrative Procedures
Informed Consent
X
Informed 
Consent 
for 
Future 
Biomedical Research
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
X
Medical History
X
Prior & Concomitant Medication 
Review3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment Allocation 
X
Study Medication Diary: Distribute 
and/or and Review Instructions
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Reconcile Study Medication/Assess 
Compliance
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Contact
X
X
Clinical Procedures/Assessments
Comprehensive Physical 
Examination4
X
Focused PE4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
12-Lead Electrocardiogram
X
X
X5
X5
X
X
X
X
X
X
Vital 
Signs 
(heart 
rate, 
blood 
pressure, temperature)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject 
Confirmation 
of 
Birth 
Control
X
X
X
X
X
X
X
X
X
X
X
X6
X6
X6
X7
X7
Review Adverse Events8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
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Trial Period
Treatment Period
Follow-up Period
Unscheduled
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Intensive PK/PD group:
Screening
Day 11
Day 2
Day 3
Day 5
Day 7
TW2
TW4
TW6
TW8
TW10
TW12
TW142
TW162
FW 4
FW 8
FW 12
FW 16
FW 20
FW 24
Viral 
Failure 
Confirmation 
(HCV or HIV)
Early 
Discontinuation 
Visit
Main Study Group
n/a
n/a
n/a
Visit Window
-45d
n/a
n/a
+2d
-1d 
to 
+2d
-2d 
to 
+2d
-7 to +7 days
-7 to +14 days
-2 to +2 weeks
n/a
n/a
Laboratory Safety Evaluations
Chemistry & Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Pregnancy Test (females of 
child bearing potential only)9
X
X
X
X
X
X
X
X
X
X
X
X6
X6
X6
X7
X7
HBV Evaluations10
HBsAg
X
X
X
X
X
X
X
X
X
Anti-HBc
X
Anti-HBs
X
HBV DNA
X
X
X
X
X
X
X
X
X
Pharmacokinetics11
MK-3682 and Metabolites
X
X11
X11
X
X
X
X
X
X
X12
X12
RZR
X
X11
X11
X
X
X
X
X
X
X12
X12
Meal Information for PK
X
X11
X11
X
X
X
X
X
X
X12
X12
HCV Evaluations
HCV RNA13
X
X
X11
X11
X11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X14
HCV Genotype Determination
X
Liver Imaging15
X
Plasma for HCV Viral Resistance16
X
X
X
X
X
X
X14
Blood for genetic analysis17
X
HIV Evaluations18
HIV Serology
X
HIV RNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for HIV Viral Resistance
X19
CD4+ T-cell Count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug Administration20
Dispense MK-3682 (open-label)
X
X
X
X
Dispense RZR (open-label)
X
X
X
X
Only if treatment duration is 
extended,
dispense RBV (open-
label)
X
X
X
X
 
 
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AE = adverse event; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface antibody; d = day; DNA = deoxyribonucleic acid; FBR = future biomedical research; 
FU = Follow-up; FW = Follow-up Week; HBsAg = hepatitis B surface antigen; HBV DNA = hepatitis B virus deoxyribonucleic acid; HCV = hepatitis C virus; HIV = human
immunodeficiency virus; IRB/IEC = Institutional Review Board/Independent Ethics Committee; n/a = not applicable; PD = pharmacodynamics; PE = physical examination; 
PK = pharmacokinetics; RBV = ribavirin; RNA = ribonucleic acid; RZR = ruzasvir; TW = Treatment Week
1
Procedures on Visit 2, Day 1 should be performed prior to the first dose unless specified otherwise.
2
TW14 and TW16 will only occur for those subjects whose treatment duration may be extended.  PK sample scheme for these subjects remain the same with the 
addition of TW16 time point.
3
Non-study HCV medications/therapies are prohibited through FW24. Any use should be reported throughout the subject’s participation in the trial.
4
A comprehensive PE will be done at screening. For all other visits, a focused PE will be conducted when clinically indicated. 
5
Additional ECGs will be collected on subjects in the Intensive PK/PD group at Day 3 and Day 7.
6
This procedure only applies to female subjects of child bearing potential whose treatment regimen is modified to include RBV.
7
This procedure is performed only when the visit occurs prior to FW4.  For female subjects of child bearing potential whose treatment regimen is modified to include RBV, 
urine pregnancy test and birth control confirmation should be performed when the visit occurs anytime through FW24.
8
All AEs that occur after the consent form is signed but before treatment allocation must be reported by the investigator if they cause the subject to be excluded from the trial, 
or are the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment, or a procedure.  From 
the time of treatment allocation through 14 days following cessation of treatment, all AEs must be reported by the investigator.  The reporting timeframe for AEs meeting any 
serious criteria is described in Section 7.2.3.1.
9
For subjects whose treatment regimen is modified to include RBV, when study visits are spaced more than 1 month apart in the follow-up period, urine pregnancy test kits 
will be dispensed to female subjects of childbearing potential so that monthly pregnancy testing can continue for 6 months after dosing (or longer if dictated by local 
regulations).  The test results must be provided to the investigator and/or site personnel.  Subjects should be instructed to contact the investigator and/or site personnel 
immediately if the result of the self-pregnancy test is positive.  A serum pregnancy test will be performed whenever a urine pregnancy test yields a positive result.
10
HBsAg, anti-HBc, and anti-HBs will be assessed at screening in all subjects.  For all anti-HBc positive subjects, HBV DNA will also be assessed at screening, and both HBV 
DNA and HBsAg will be monitored during the trial.
11
PK samples will be collected as described in Section 7.1.3.2.  Only subjects in the Intensive PK/PD group will have PK samples collected on Day 3, and post dose on Day 7.  
These subjects will also have additional HCV RNA samples collected postdose on Day 1-2, Day 3, and Day 5.
12
PK samples and meal information for PK are to be collected at HCV/HIV viral confirmation or early discontinuation visits that occur only during the study treatment period.
13
Leftover main study plasma will be stored at the end of the study for FBR if the subject consents to FBR.
14
If a subject is a confirmed viral failure during therapy (i.e., breakthrough), then sample collection for HCV RNA and Viral Resistance/Biomarker is not needed for the early 
discontinuation visit.
15
For cirrhotic subjects only, imaging is required within 6 months of randomization to evaluate for hepatocellular carcinoma. If liver imaging within 6 months prior to Day 1 is 
not available, imaging is required during screening.
16
Blood samples will be collected for HCV viral resistance testing at Day1, virologic failure confirmation visits, and all follow-up visits after virologic failure confirmation or 
after early study medication discontinuation if the subject has quantifiable HCV RNA and is not the result of a virologic failure during therapy (i.e., rebound, breakthrough).  
Leftover main study plasma will be stored at the end of the study for FBR if the subject consents to FBR.
17
This sample will be drawn for IL28B genotyping and for planned analysis of the association between genetic variants in DNA and drug response.  If the IRB/IEC does not 
approve of the planned analysis of the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, data analysis will be 
limited to IL28B.  Leftover extracted DNA will be stored for FBR if the subject signs the FBR consent.
18
HIV serology (HIV-1 and HIV-2) will be performed at screening for all subjects.  HIV RNA and CD4+ T cell count at screening will only be processed for those subjects who 
have positive HIV serology.  HIV evaluations will only be performed at Day 1 and subsequent visits as indicated in subjects that are HIV co-infected.
19
In subjects who are HIV co-infected, blood samples will be collected for HIV viral resistance at the time of HIV RNA failure confirmation visit.
 
 
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20
Study medication will be dispensed at Day 1 and then every 4 weeks thereafter: Week 4 and Week 8. If the treatment regimen is extended, MK-3682 + RZR also will be 
dispensed at Week 12. RBV should be locally sourced and dispensed by the site if the treatment regimen is extended. Note that the duration of treatment with MK-3682 + 
RZR for subjects with a particular GT may be extended to 16 weeks’ duration and RBV added to the regimen if the efficacy criteria for stopping enrollment/treatment 
allocation are met for that particular GT.  For example, if efficacy criteria for stopping enrollment/treatment allocation are met for GT1-infected subjects at TW8, GT1-
infected subjects already on treatment will receive MK-3682 + RZR for an additional 8 weeks (i.e., 16 weeks’ total duration) + RBV for 8 weeks.
All doses of MK-3682 and RZR should be taken on an empty stomach after an overnight fast, at least 1 hour before the morning meal.  Study medications should be taken 
with water but without food.  In addition, subjects should fast overnight prior to reporting to the study site for dosing on Treatment Day 1 (Visit 2) and for all other visits at 
which a pre-dose PK sample is to be collected. MK-3682 and RZR (open-label) will be provided by the Sponsor to cover a maximum of 32 days of dosing (4 weeks + 4
days).  An unscheduled visit must occur to get additional drug if the subject will run out of study drug prior to the next scheduled visit.  If dosing is missed or interrupted (see 
Section 5.2.2), the assigned study therapy regimen should still be completed.  
For subjects whose treatment regimen is modified to include RBV, RBV is to be dosed according to the approved local prescribing information.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
7.1.1.3
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee.
Prior and Concomitant Medications Review
7.1.1.5
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before starting the trial.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
through 2 weeks after the study treatment period.  The investigator or qualified designee will 
discuss with the subject the necessity of not taking any concomitant medications or herbal 
preparations with known suspected hepatotoxic potential.  If medications with potential 
hepatotoxicity cannot be discontinued in a subject, the investigator or qualified designee 
must discuss the inclusion of the subject with the Sponsor’s clinical director who must 
approve the use of the medication prior to inclusion of the subject in the trial.  To minimize 
the risk of adverse drug interactions, every effort should be made to limit the number of 
concomitant drugs to those that are truly essential.  Non-study HCV medications/therapies 
are prohibited through FW24.  Any use should be reported throughout the subject’s 
participation in the trial.
 
 
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Assignment of Screening Number
7.1.1.6
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.  
Assignment of Treatment/Randomization Number
7.1.1.7
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance (Medication)
7.1.1.8
The investigator/study coordinator will give the subject a Study Medication Diary (SMD) to 
be completed during the study period. The investigation/study coordinator will be responsible 
for entering the subject’s identification (treatment/randomization number), treatment period, 
and other pertinent subject information before giving the SMD to the subject. The subject 
will be instructed to record dates/times and the number of tablets/capsules of study drug
doses (Note:  RBV is a rescue medication and should be reported as a concomitant 
medication; it should not be reported on the SMD.) on the SMD for the entire time period. 
Only the subject should enter information on the SMD. The subject is to return the completed 
SMD at each scheduled visit. At all visits during the treatment period, site personnel must 
verify the accuracy of the SMD by comparing entries with amounts of unused study drug. If 
a discrepancy is noted, investigator/study coordinator must discuss the discrepancy with the 
subject, and the explanation must be documented. Only the subject shall make any changes to 
the entries on the SMD. The subject will initial the SMD to confirm that the information is 
accurate. The investigator/study coordinator will be responsible for transferring the 
appropriate information from the diary onto the appropriate case report form (CRF).
Interruptions from the protocol specified treatment plan, as outlined in Section 5.2, require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff at 
the Day 1 visit.
 
 
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Clinical Procedures/Assessments
7.1.2
Physical Examination
7.1.2.1
All physical examinations
must be performed by the principal investigator or 
sub-investigator (physician, physician assistant, or nurse practitioner).
A complete physical examination, performed at the Screening visit, includes the following 
assessments: general appearance, head, eyes, ears/nose/throat, neck, lymph nodes, skin, 
lungs, heart, abdomen, musculoskeletal, and neurologic evaluations. Breast, rectal, and 
genitourinary/pelvic examinations should be performed when clinically indicated. For all 
other visits, a focused physical examination will be performed when clinically indicated. Any 
significant changes between the screening visit and other physical examinations performed 
prior to the initiation of therapy should be noted in the Medical History electronic CRF 
(eCRF). Any significant changes after receiving study drug at Day 1 must be reported as AEs 
and entered on the AE eCRF.  If a subject is discontinued for any reasons during the 
treatment period, every attempt should be made to perform a final physical examination.
Weight and Height Assessment
7.1.2.2
The subject’s weight and height should be assessed as mentioned in the Trial Flow Chart 
(Section 6.0). Clinically significant changes from Day 1 in weight should also be captured as 
AEs in the eCRF.
12-Lead ECG
7.1.2.3
Special care must be taken for proper lead placement.  Subjects should be shaved as 
necessary for proper lead placement.  Subjects should be resting in a semi-recumbent 
position for at least 10 minutes prior to having ECG readings obtained. However, clinically 
significant findings from the screening ECG must be captured in the medical history eCRF. 
For ECGs performed during treatment or during the follow-up period, any clinically 
significant changes compared with the screening ECG must be captured as AEs.
All subjects will have 12-lead ECGs performed at screening, Day 1, TW2, TW4, TW8, 
TW12, FW4, and FW12.  In addition, the subset of subjects in the Intensive PK/PD group 
will also have 12-lead ECGs performed at Day 3 and Day 7.
Vital Signs
7.1.2.4
Vital signs will include heart rate, blood pressure, and oral temperature. Subjects should be 
resting in a semi-recumbent or sitting position for at least 10 minutes prior to having vital 
sign measurements obtained.
Oral temperatures should be taken, but if oral is not possible, a tympanic, rectal, or axillary 
temperature may be taken (note: temporal is allowed).
After the screening visit, the site should indicate whether or not the result is clinically 
significant and if any subsequent changes constitute an AE.
 
 
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Birth Control Confirmation
7.1.2.5
Care must be taken to avoid pregnancy in female subjects of childbearing potential, and for 
the female partners of childbearing potential of male subjects, who have their treatment 
regimen with MK-3682 + RZR extended to 16 weeks’ duration and RBV added to the 
regimen.
Confirmation must be obtained by site personnel that subjects and their partner(s) are using 
acceptable methods of contraception (see Subject Inclusion Criteria, Section 5.1.2). This 
assessment must be documented in the subject’s study chart at each specified visit (see Trial 
Flow Chart, Section 6.0).
Adverse Events
7.1.2.6
Refer to Section 7.2 for details on assessing and recording AEs.
Noninvasive Methods of Cirrhosis Evaluation
7.1.2.7
FibroScan®: This method for assessing liver cirrhosis has gained increasing acceptance.  In 
the US, this methodology is Food and Drug Administration (FDA) approved and, in other 
countries, it is often the preferred method of assessment. FibroScan® results are influenced 
by a number of confounders including ALT, ascites, and underlying disease. Hepatitis C is 
one of the best studied and is the disease state with the most reproducible/reliable results. 
FibroScan® has been evaluated in many liver diseases for the staging of liver fibrosis, and has 
been demonstrated to be very effective for differentiating cirrhosis (F4) from no cirrhosis 
(<F4), but it is less capable of differentiating gradations of fibrosis.  In a large study by 
Castera, et al [40], a population of patients with chronic HCV infection, a cutoff of 12.5 kPa 
was selected for cirrhotics. At this cutoff, the sensitivity and specificity of the test for 
cirrhosis were 87% and 91%, respectively, and the negative predictive value was 95%. Since 
this analysis was assessed specifically in subjects with chronic HCV infection, the cutoff 
value >12.5 kPa used by Castera was selected to include cirrhotics in the current study.
FibroTest® + APRI: Various methodologies have been developed in order to improve the 
sensitivity and specificity of blood tests used to diagnose cirrhosis in patients with chronic 
HCV infection. One such algorithm, the sequential algorithm for fibrosis evaluation (SAFE), 
which uses a combination of FibroTest® and the APRI, is very accurate for diagnosing 
cirrhosis [41]. For cirrhosis, the SAFE for F4 algorithm provides a diagnostic accuracy of 
89.5% with a negative predictive value of 94.6%. Using this algorithm, it is estimated that 
only 6.2% of the patients would need a liver biopsy to confirm the diagnosis of cirrhosis. 
The cutoff values for excluding cirrhotics using the 2 tests, without the use of liver biopsy, 
are ≤1 and ≤0.48 for FibroTest® and APRI when the SAFE for F4 is used. This study uses 
this method with one variation, which is the more stringent requirement that both the APRI 
and FibroTest® need to be consistent with no cirrhosis (i.e., APRI is ≤1 AND FibroTest®
≤0.48). 
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below (see Table 12). The total amount of blood/tissue to be drawn/collected over 
the course of the trial (from pre-trial to post-trial visits), including approximate blood/tissue 
 
 
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volumes drawn/collected by visit and by sample type per subject can be found in Section
12.3.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
7.1.3.1
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 12. Sample 
collection, storage and shipment instructions will be provided in the operations/laboratory 
manual.
Table 12
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Bilirubin
HCV GT
Hemoglobin
ALP
Blood
HIV-1 and HIV-2 serology 
(screening only)
Platelet count
ALT
Glucose
PT/INR
WBC (total and 
differential)
AST
Ketone
PTT
Erythrocytes (RBC 
count)
Creatinine
Leukocyte esterase
Choriogonadotropin beta  
(Urine pregnancy test kits to 
sites)
Creatinine clearance (eGFR)
Nitrites
Serum human chorionic 
gonadotropin (reflex when 
urine pregnancy test is 
“positive”)
Creatine kinase
pH
Plasma HCV RNA
Gamma-glutamyltransferase
Protein
Fibrosure® (Fibrotest) as 
requested by site for entry 
criteria (may be performed 
locally)
Glucose (serum glucose) 
Specific gravity
APRI calculation (screening 
only)
Amylase
Bacteria
CD4+ T-cell count (at 
screening in all subjects, 
then in HIV/HCV 
coinfected subjects only at 
subsequent visits)
Lipase
Squamous epithelial 
cells
Plasma HIV-1 RNA (at 
screening in all subjects, 
then in HIV/HCV 
coinfected subjects only at
subsequent visits)
 
 
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Hematology
Chemistry
Urinalysis
Other
Potassium
RBC
HBsAg (at screening in all 
subjects, then at certain
subsequent visits for 
subjects who are anti-HBc 
positive)
Sodium
WBC
Anti-HBc (screening only)
Total bilirubin 
Anti-HBs (screening only)
Direct bilirubin
HBV DNA (for subjects 
who are anti-HBc positive, 
at screening and at certain 
subsequent visits)
Indirect bilirubin
Total protein
Blood urea nitrogen
ALP = alkaline phosphatase; ALT = alanine aminotransferase; Anti-HBc = hepatitis B core antibody; Anti-HBs = hepatitis 
B surface antibody; APRI = aspartate aminotransferase to platelet ratio index; AST = aspartate aminotransferase; 
eGFR = estimated glomerular filtration rate; GT = genotype; HBsAg = hepatitis B surface antigen; HBV DNA = hepatitis B 
virus deoxyribonucleic acid; HCV = hepatitis C virus; HIV = human immunodeficiency virus; INR = international 
normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell; RNA = ribonucleic 
acid; WBC = white blood cell count.
Subjects should be fasted for all on-treatment visits to allow for appropriate PK analysis.  
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2
The decision as to which plasma samples collected will be assayed for evaluation of PK will 
be collaboratively determined by the Departments of Quantitative Pharmacology and 
Pharmacometrics (QPP) and the appropriate department within Clinical Research.  If 
indicated, these samples may also be assayed and/or pooled for assay in an exploratory 
manner for metabolites and/or additional PD markers. The time points for both PK and viral 
kinetic sample collection are detailed in Table 13.  
7.1.3.2.1 Pharmacokinetics: Blood Collection for Plasma MK-3682 (and Metabolites),
and Ruzasvir
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual. 
Sample Collection
Pharmacokinetic samples will be collected from all enrolled subjects according to the PK 
sampling schemes shown in Table 13. 

Subjects in the Intensive PK/PD Group will be providing additional PK samples on 
Day 3 (pre-dose) and on Day 7 (post-dose) that are not being collected from the other 
subjects in the study.
 
 
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Dosing and Sample Collection Instructions

As specified previously in Section 5.2.2, Timing of Dose Administration, all doses of 
MK-3682 and RZR should be taken on an empty stomach after an overnight fast, at 
least 1 hour before the morning meal, with water but without food.  

On all PK visits where a pre-dose sample will be collected, the visit should occur 
prior to the subject’s regular time for taking their study medication and the subject 
should withhold their dose until after the visit.  

For pre-dose PK visits after Visit 2 (Day 1), if this visit time is not feasible, the 
subject should be instructed to take their study medication as per their regular 
schedule. PK samples should still be collected during the visit.  
Note: While every effort should be made to schedule visits with PK draws so that they occur 
within the window specified in Table 13; when this is not possible, the PK samples should 
still be collected even if out of window.

The date and time of each PK sample as well as the date and time of the last dose of 
MK-3682 and RZR prior to the PK sample will be recorded.
Recording and Entering Meal Information

Subjects will be provided with a meal diary with instructions for recording meal data 
that includes what they eat/drink and the time of the meal. Subjects should record 
ALL meal data from 48 hours BEFORE the PK visit through the day of the PK visit.

The site will be responsible for entering the appropriate data from the meal diary, as 
well as the qualitative fat content of the meal, in the eCRF according to the eCRF 
Entry Guidelines.  Meal data should be entered by the site as follows:
o
For visits where only a predose PK sample is collected, enter meal data for up 
to 5 hours before, and up to 2 hours after the MK-3682 and RZR dose 
administered on the day prior to the predose PK visit.
o
For visits where a postdose PK sample is also collected, also enter meal data 
for up to 5 hours before, and up to 2 hours after the MK-3682 and RZR
dose administered at the study site.
o
For subjects who may take multiple meals during the time window, only the 
meal closest to the last dose prior to the PK samples will be entered.
 
 
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Table 13
Pharmacokinetic and Pharmacodynamic Sampling Time Points
Visit 
Number
Study 
Day/Week
Time Relative 
to Dose of
MK-3682/
RZR 1, 2
All Subjects
Intensive PK/PD Group Subjects
PK Time 
Points for 
MK-3682 and 
RZR
PK Time Points for 
MK-3682 and RZR
PD (Viral Kinetic)
Time Points 
2
Day 1
Predose
X
X
X
2-3
Day 1 – Day 2
2, 4, 8, 12, 24, 
and 32 hours 
postdose
n/a
n/a
X
4
Day 3
Predose
n/a
X3
X
5
Day 5
n/a
n/a
n/a
X
6
Day 7
Predose
X
X3
X
0.5-, 2-, and 4-
hour postdose
n/a
X3
n/a
7
Week 2
Predose
X
X
n/a
8
Week 4
Predose
X
X
n/a
0.5- and 2-hour 
postdose
X
X
n/a
9
Week 6
Predose
X
X
n/a
10
Week 8
Predose
X
X
n/a
12
Week 12
Predose
X
X
n/a
14
Week 164
Predose
X
X
n/a
21
HCV/HIV
Viral Failure 
Confirmation 
Visit5
n/a
X5
X
n/a
22
Early 
Discontinuation 
Visit5
n/a
X5
X
n/a
ECG = electrocardiogram; HCV = hepatitis C virus; HIV = human immunodeficiency virus; n/a = not applicable; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s); RZR = ruzasvir.
1
Time relative to last dose of MK-3682 and RZR must be recorded in the electronic case report form.
2
After study Visit 2, if there are cases in which a morning visit is not feasible and a subject is seen in the afternoon, 
the subject should take their study medication in the morning, after an overnight fast, as per their regular schedule 
(in accordance with Section 5.2.2 Timing of Dose Administration) and PK samples will still be collected during 
these visits.
3
ECGs will be collected on ALL subjects on screening, Day 1, TW2, TW4, TW8, TW12, FW4 and FW12; 
Additional ECGs will be collected on subjects in the Intensive PK/PD Group subjects on Day 3 and Day 7.
4
Week 16 only applies for those subjects whose treatment duration may be extended. PK sampling scheme for 
these subjects remain the same with the addition of TW16 time point. 
5
PK samples and meal information for PK are to be collected at HCV/HIV viral confirmation or early 
discontinuation visits that occur only during the study treatment period.
Note: Approximately 4 mL of blood will be collected at each specified time point for plasma PK assessment of MK-
3682 (and metabolites).
Approximately 4 mL of blood will be collected at each specified time point for plasma PK assessment of RZR.
Note: The date and time of the PK sample collection for all MK-3682 (and metabolites) and RZR PK samples must be 
recorded in the electronic case report form.
Note: At the time of PK sample collection, subjects will be asked to provide information regarding the time/date of 
the last MK-3682 and RZR dose prior to the PK sample collection. (This can also be obtained by referencing 
the subject's study medication diary.)
 
 
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7.1.3.2.2 Pharmacodynamics: Viral Kinetics
HCV RNA samples also will be collected at the Week 1, 2, 4, 6, 8, 10 and 12 visits for all 
subjects during treatment (and Week 14 and 16 visits for subjects whose treatment duration 
may be extended).
Additional samples for HCV RNA will be collected on a subset of 
subjects in the Intensive PK/PD group (see Table 13).  The data from this sub-study will be 
used to validate the existing viral dynamics model for MK-3682 and RZR. A total of 
approximately 30 subjects, the first 5 subjects for each GT1-6 who consent to participate, 
will undergo additional PK and PD evaluations and have electrocardiographs (ECGs) 
performed.
See Section 6.0 Trial Flow Chart and Table 13 for detailed information on sample collection 
and visits.
HCV Evaluation
7.1.3.3
The following specimens are to be obtained for HCV evaluation as part of 
efficacy/pharmacogenetic measurements:

Samples for HCV GT evaluation must be obtained for inclusion in the study. All 
baseline samples will be genotyped using the FDA-approved Abbot HCV Real Time 
Genotype II assay that detects HCV GTs 1a, 1b, 2, 3, 4, 5, and 6 through the use of 
GT-specific fluorescent-labeled oligonucleotide probes in a real-time reverse 
transcription polymerase chain reaction (RT-PCR) assay. The RT-PCR reaction uses 
3 sets of HCV-specific amplification primers targeting the 5’untranslated 
region (UTR) (for all GTs) and NS5B regions from GT1a and 1b. The assay has 
accuracy of >96% for GT1, 1a, 1b, 2, 3, and 5; 89% for GT5, and 83% for GT6; with 
100% specificity in HCV serologically negative plasma samples.

Blood must be drawn from each subject to assess HCV RNA plasma levels at various 
time points as shown in the Trial Flow Chart (Section 6.0). HCV RNA in plasma will 
be measured using a COBAS™
AmpliPrep/COBAS™
Taqman HCV Test, 
version 2.0® assay with an LLOQ of 15 IU/mL. Leftover plasma may be used for 
viral resistance testing if needed. Also, leftover plasma may be used for FBR only if 
the subject signed for FBR consent.

Blood must be drawn from each subject to assess viral resistance mutation and 
processed as instructed by the central laboratory manual. Leftover plasma may be 
used for FBR only if the subject signed for FBR consent.

Protein and metabolites may be measured from blood samples to compare biomarkers 
measured prior to treatment to biomarkers measured at several time points during 
treatment that correlate with subject response to treatment (e.g., sustained viral 
response).

Samples collected for genetic analysis are obtained at Day 1. Any leftover DNA may 
be used for FBR only if the subject signs for FBR consent.
NOTE: Samples may also be used for future assay development and validation if the subject 
signed for FBR consent.
 
 
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HIV Evaluation
7.1.3.4
The following specimens are to be obtained for HIV evaluation:

Blood must be drawn from each subject to assess HIV RNA plasma levels at 
screening as shown in the Trial Flow Chart (Section 6.0). HIV RNA in plasma will be 
measured using a COBAS™AmpliPrep/COBAS™TaqMan HIV-1 Test, version 2.0®
assay with a LLOQ of 20 IU/mL.

Blood must be drawn from each subject with HIV co-infection to assess immunologic 
status. CD4+ T-cell counts will be obtained at screening as shown in the Trial Flow 
Chart (Section 6.0).

In the event of HIV virologic breakthrough, a sample for HIV viral resistance is to be 
collected at the viral failure confirmation visit.
The following nomenclature will be used when describing HIV RNA levels:

HIV-1 RNA <LLOQ, TND

HIV-1 RNA <LLOQ, Target Detected

HIV-1 RNA IU/mL
HBV Evaluation
7.1.3.5

Blood must be drawn from each subject to assess HBsAg, anti-HBc, and anti-HBs at 
screening.

For subjects who are anti-HBc positive, HBV DNA will be assessed at screening, and 
both HBV DNA and HBsAg will be monitored during the trial.  The results of these 
assessments will be used to determine HBV reactivation, which will be reported as an 
Event of Clinical Interest as specified in Section 7.2.3.2.  

Subjects who develop HBV reactivation will be managed by site investigators 
according to current treatment guidelines and/or local standard of care.  

Subjects who develop HBV reactivation may continue in the trial at the discretion of 
the site investigators.  
Planned Genetic Analysis Sample Collection
7.1.3.6
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the laboratory manual.
Future Biomedical Research Samples
7.1.3.7
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Leftover main study plasma from HCV RNA stored for future research

Leftover main study plasma from viral resistance and biomarkers stored for future 
research
 
 
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Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
Subjects who discontinue treatment prior to completion of the treatment regimen should be 
encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research.  Subjects may 
withdraw consent at any time by contacting the principal investigator for the main trial.  If 
medical records for the main trial are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com).  Subsequently, 
the subject's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the subject of completion of withdrawal.  Any analyses in progress at 
the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results.  
No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Subject Blinding/Unblinding
7.1.4.2
This is an open label trial; there is no blinding for this trial.
Domiciling
7.1.4.3
The subjects who are participating in the Intensive PK/PD group will report to the clinical 
research unit (CRU) on the morning of Day 1 prior to trial drug administration and will 
remain either in the unit or in a local facility until completion of the 32-hour blood draw after 
the first dose of study medication. At the discretion of the investigator, subjects may be 
requested to remain in the CRU longer.
Calibration of Critical Equipment
7.1.4.4
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
 
 
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reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
none
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
7.1.5.1
Within 45 days prior to allocation, potential subjects will be evaluated to determine that they
fulfill the entry requirements as set forth in Section 5.1.  Verification should be obtained to 
confirm the subject’s cirrhosis status and the subject’s fibrosis score must be captured to 
support secondary data analysis.  The investigator will discuss with each potential subject the 
nature of the study, its requirements, and its restrictions.  Screening procedures may be 
repeated after consultation with the Sponsor.
Subjects will be instructed that they are required to use an acceptable method of birth control 
(see Subject Inclusion Criteria Section 5.1.2) from at least 2 weeks prior to Day 1, throughout 
treatment, and for 14 days after the last dose of study medication, or if a subject’s treatment 
duration is extended with MK-3682 + RZR + RBV, for 6 months after the last dose of study 
medication, or longer if dictated by local regulations.
Subjects will be instructed about the restrictions for concomitant medications, as noted in 
Section 5.5.
All screening procedures listed for Visit 1 in the Trial Flow Chart must be completed and 
subject eligibility confirmed by the investigator prior to the subject’s allocation and drug 
administration.
All subjects will be given a Subject Identification Card (Section 7.1.1.3), at the time of 
screening, identifying them as participants in a research study. The Subject Identification 
Card will contain contact information (including direct telephone numbers) to be utilized in 
the event of an emergency.
Rescreening
7.1.5.2
Subjects who have previously completed the screening visit (Visit 1) and were deemed 
eligible for randomization/allocation into this study, but failed to be randomized or allocated 
within the 45-day window, may be rescreened to re-evaluate study eligibility.  To reconfirm 
the subject's eligibility, all pre-study evaluations should be repeated, after approval from the 
Sponsor, except for the following:

HCV GT determination

Hepatitis B virus screening
 
 
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
HIV-1 serology

Liver biopsy/Fibroscan/ FibroSure® (Fibrotest®)

Liver imaging

12-lead ECG
If any of the laboratory, ECG, or Fibroscan exclusion criteria are met, the site may have the 
abnormal value retested one time.
Treatment Period
7.1.5.3
Treatment Day 1 (Visit 2)
Subjects should fast overnight prior to reporting to the study site for dosing on Treatment 
Day 1 (Visit 2).
Pre- and Post-Treatment Procedures
Day 1 procedures listed on the Trial Flow Chart should be performed prior to dosing unless 
specified otherwise.  For female subjects of reproductive potential, a urine pregnancy test 
will be performed at the site prior to study drug initiation.  If the urine pregnancy test result is 
negative, the subject will be eligible for allocation and the remainder of the pretreatment 
(Day 1) testing/procedures will be performed.  If the urine pregnancy test result is positive, a 
serum pregnancy test will be performed.  If the result of the serum pregnancy test is positive, 
the subject must not be randomized or allocated to treatment in the study.  
Blood and urine will be collected for assay of safety evaluations, including plasma HCV 
RNA, plasma HIV RNA (only for HIV co-infected subjects), and PK measurements. These 
samples will be sent to the appropriate central laboratory(ies) following the procedure(s) set 
forth in the manual(s).
Additional samples will be collected for genetic evaluation of host parameters related to the 
response of HCV subjects to MK-3682 and RZR.
Drug Administration
7.1.5.4
Following completion of the Day 1 procedures and confirmation of eligibility, the site 
pharmacist or study coordinator will contact the interactive voice response system/interactive 
web response system (IVRS/IWRS) for assignment of the drug regimen to be administered 
and duration of treatment. Sites should not call IVRS for drug administration until the subject 
has met all criteria for the study and are ready to receive the first dose of study medication on 
Day 1. 
The first dose of prescribed study medications should be administered at the Day 1 visit.  
Study medications should be taken on an empty stomach after an overnight fast, at least 
1 hour before the morning meal.  Study medications should be taken with water but without 
food.  In addition, subjects should fast overnight prior to reporting to the study site for dosing 
on Treatment Day 1 (Visit 2) and for all other visits at which a pre-dose PK sample is to be 
collected.  All other dosing after the Day 1 visit will be performed by the subject (i.e., 
unsupervised at his/her home) and recorded on the subject’s SMD provided during the visit.  
 
 
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Subjects should complete study therapy as defined by their assigned treatment regimen and 
per Section 5.2.
Additional instructions related to drug administration on PK visit days are provided in 
Section 7.1.3.2.1.  
Follow-up Visits
7.1.5.5
At the completion of study therapy, subjects will return to the study site for follow-up visits 
at 4, 8, 12, and 24 weeks after the last dose of study drug.  Follow-up visits at 16 and 
20 weeks after the last dose of study drug will be virtual visits, meaning site personnel will 
have telephone contact with the subject to make sure that he/she is doing well and to give a 
reminder for the Follow-up Week 24 visit.
Discontinued Subjects Continuing to be Monitored in the Trial
7.1.5.6
Discontinuation During Treatment Period
Subjects who discontinue therapy in the trial prior to the last scheduled treatment visit should 
have an Early Discontinuation visit and then continue into follow-up visits.
At a minimum, the following information should be collected:

The reason the subject discontinued

The date of the last dose of study medications from the trial

The date of the last assessment and/or contact. A follow-up contact (telephone or 
visit) will be arranged as appropriate

(Serious) Adverse events (per reporting requirements outlined in Section 7.2)
Final assessments: 

Every effort should be made to ensure that all procedures and evaluations scheduled 
for the Early Discontinuation Visit are performed.

Retrieve all study medications from the subject.
Discontinuation for Virologic Failure
Subjects who discontinue because they have met criteria for virologic failure (Section 
4.2.5.1.1.2) while on study therapy should complete an Early Discontinuation Visit as 
outlined in the Trial Flow Chart (Section 6.0) and return to the study site for follow-up visits
at 4, 8, 12, and 24 weeks following confirmation of virologic failure.  
Subjects who meet the virologic failure criterion for relapse (HCV RNA ≥LLOQ following 
the end of all study therapy, after becoming undetectable [TND] at the end of treatment) will 
return to the study site for the remainder of their follow-up visits (e.g., 4, 8, 12, and 24 
weeks) as outlined in the Trial Flow Chart (Section 6.0).
 
 
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Discontinuation During Follow-Up Period
Subjects who discontinue during the follow-up period (e.g., follow-up visits at 4, 8, 12, and 
24 weeks after end of treatment) for reasons other than virologic failure should complete an 
Early Discontinuation Visit as outlined in the Trial Flow Chart.  
At a minimum, the following information should be collected:

The reason the subject discontinued

The date of the last assessment and/or contact. A follow-up contact (telephone or 
visit) will be arranged as appropriate

SAEs (per reporting requirements outlined in Section 7.2)
Evaluation of Laboratory Safety Signals
7.1.5.7
Laboratory safety measurements will be evaluated throughout the study to assess potential 
safety signals as outlined in the Trial Flow Chart (Section 6.0).
If a subject has 1 or more of the laboratory ECI criteria (Section 7.2.3.2) at the last dosing 
visit, then the subject should return to the site weekly for additional monitoring until the 
values normalize.  
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
 
 
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procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is any dose in excess of the prescribed dose of MK-3682 or RZR.  
For RBV, overdose is a dose that exceeds 1600 mg/day.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial.
Pregnancies and lactations of subjects and female partners of male subjects from the time the 
consent form is signed but before treatment allocation/randomization must be reported by the 
investigator if they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.  Pregnancies and lactations of subjects 
and female partners of male subjects that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product or that 
occur through 6 months (or longer if dictated by local regulations) for subjects receiving a 
ribavirin-containing regimen must be reported. All reported pregnancies  must be followed to 
the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
 
 
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Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 14 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
 
 
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Events of Clinical Interest
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
2. first instance of ALT or AST >500 IU/L from the initiation of study therapy 
through 14 days following treatment.*
3. first instance of ALT or AST >3x nadir AND >3X ULN from the initiation of 
study therapy through 14 days following treatment.*
*Note: The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require and additional evaluation for an underlying etiology. The trial site guidance 
for assessment and the follow up of these criteria can be found in the Investigator Trial 
File Binders (or equivalent)
4. first instance of eGFR <50 mL/min/1.73 m2 from the initiation of study therapy 
through 14 days following treatment.  Creatinine clearance will be evaluated as 
an estimated GFR (eGFR), based on the modification of diet in renal disease 
(MDRD) equation:
eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) 
× (1.212 if black)
Scr, std: serum creatinine measured with a standardized assay
5. first instance of serum creatinine Grade 2 or higher (>1.3 × ULN) and elevated 
from baseline from the initiation of study therapy through 14 days following 
treatment.
6. HBV reactivation defined as either:
a.
sero-reversion from HBsAg negative to HBsAg positive, OR
 
 
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b. detectable HBV DNA in subjects who were previously undetectable or ≥1 log 
increase in HBV DNA from baseline.
Note: As detailed in Section 7.1.3.5, subjects who develop HBV reactivation will 
be managed by site investigators according to current treatment guidelines and/or 
local standard of care.  Subjects who develop HBV reactivation may continue in 
the trial at the discretion of the site investigators.  
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 14. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 14 for instructions in evaluating adverse events.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
 
 
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Table 14
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.  (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event? The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a supplemental statistical analysis plan (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly identified in 
the CSR.  
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan (SAP)
are summarized below; the 
comprehensive plan is provided in Sections 8.2 through 8.12.
Study Design Overview
This is a Phase 2, nonrandomized, multi-site, open-label trial to study 
the efficacy and safety of the combination regimen of MK-3682 +
RZR in subjects with chronic HCV GT1, GT2, GT3, GT4, GT5, or 
GT6 infection. All subjects will receive MK-3682 450 mg + RZR 180 
mg for 12 weeks.  Subjects can be treatment-naïve or treatment-
experienced with a prior IFN-based therapy, cirrhotic or non-cirrhotic, 
and mono-infected with HCV or co-infected with HIV.
Approximately 250 subjects will be assigned to receive treatment, 
with target allocation based on GT (GT1, GT2, GT3, GT4, GT5, or 
GT6).  
All subjects will be followed for 24 weeks after the end of study 
therapy.
Treatment Assignment
All subjects will receive MK-3682 + RZR for 12 weeks.
Analysis Populations
Efficacy:  Full Analysis Set (FAS), Per Protocol (PP), and modified 
Full Analysis Set (mFAS).
Safety:  All Subjects as Treated (ASaT)
Primary Endpoint(s)
Proportion of subjects achieving SVR12
Key Secondary Endpoints
Proportion of subjects achieving SVR24; 
Proportion of subjects experiencing virologic failure at FW12 among 
all subjects who do not discontinue study for non–treatment-related 
reasons.
Statistical Methods for Key 
Efficacy Analyses
For the primary efficacy analysis based on the FAS population, the 
proportions of subjects achieving SVR12 will be estimated in each GT, 
and 95% confidence intervals (CIs) for these rates will be calculated 
using the Clopper-Pearson method [42]. The missing data approach of 
Missing=Failure (M=F) will be utilized for the primary analysis. The 
same Clopper-Pearson method will be used to analyze all binary 
endpoints based on the mFAS population and for the PP population for 
each GT, and Treatment-Related Discontinuation=Failure (TRD=F)
will be used as the missing data approach for both analysis 
populations.
 
 
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Statistical Methods for Key 
Safety Analyses
The ASaT population will be used for safety analyses. The proportion 
of subjects with AEs of elevated laboratory values that are reported as 
ECIs (as described in Section 7.2.3.2) during the study therapy period 
will be provided along with the corresponding 95% CIs.
In addition, the broad clinical and laboratory AE categories consisting 
of the percentage of subjects with any AE, a drug-related AE, an SAE, 
an AE which is both drug-related and serious, and who discontinued 
due to an AE will be summarized in the same manner. 
Interim Analyses
An assessment of safety for the first 50 subjects will be made. (See 
Section 5.11.1 for the criteria for assessing safety in the first 50 
subjects.) In addition, an assessment for efficacy will be made for the 
first 10 per-protocol subjects enrolled in each GT, and on an ongoing 
basis to determine whether there is a need to modify the treatment 
regimen.  (See Section 5.11.4 for the criteria for assessing efficacy and 
the initiation of treatment modifications).  Finally, throughout the 
course of this open-label study, efficacy and safety will be monitored 
for trends and programmatic decisions.
  Multiplicity
No multiplicity adjustment is planned for the study.
Sample Size and Power 
Approximately 250 subjects will be allocated to treatment, with 35
GT1a-, 15 GT1b-, 50 GT2-, 50 GT3-, 50 GT4-, 25 GT5- and 25 GT6-
infected subjects. 
If the SVR12 rate is approximately 97.1% for GT1a (34 successes out 
of 35), the exact 95% CI is (85.1, 99.9). If the SVR12 rate is 
approximately 93.3% for GT1b (14 successes out of 15), the exact 
95% CI is (68.1, 99.8). 
For GT2, GT3, and GT4 where 50 subjects are targeted for treatment 
allocation, if the SVR12 rate is 98% (49 successes out of 50), the exact 
95% CI is (89.4, 99.9).  If the SVR12 rate is 94% (47 successes out of 
50), the exact 95% CI is (83.5, 98.7).
For GT5 and GT6 where 25 subjects are targeted for treatment 
allocation, if the SVR12 rate is 96% (24 successes out of 25), the exact 
95% CI is (79.6, 99.9).  If the SVR12 rate is 92% (23 successes out of 
25), the exact 95% CI is (74.0, 99.0).
Detailed information for varying SVR rates is in Section 8.9.1. 
Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This trial is being conducted as an open-label study, i.e., subjects, investigators, and Sponsor 
personnel will be aware of subject treatment assignments after each subject is enrolled and 
treatment is assigned. 
Hypotheses/Estimation
8.3
Objectives of the study are stated in Section 3.0.
Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated are listed in Section 8.4.1.
 
 
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Efficacy/Pharmacokinetics Endpoints
8.4.1
Efficacy Endpoints
8.4.1.1
An initial description of efficacy measures is provided in Section 4.2.5.1.
The primary efficacy endpoint is the proportion of subjects achieving SVR12. 
The secondary efficacy endpoints are the following:
1. The proportion of subjects achieving SVR24;
2. The proportion of subjects experiencing virologic failure (either on-treatment failure 
or relapse post-treatment) through FW12 among all subjects who do not discontinue 
study for non–treatment-related reasons.
Pharmacokinetics Endpoints
8.4.1.2
Additional details are in Section 4.2.5.3. 
The primary PK endpoint for MK-3682 (and metabolites) and RZR is Ctrough.
Exploratory Endpoints
8.4.1.3
1. The emergence of RAVs to MK-3682 or RZR when administered as part of a 
combination regimen. 
2. The proportion of subjects with HCV RNA <LLOQ (either target detected but 
unquantifiable [TD(u)] or TND) at TW4, TW8, end of treatment, FW4, and FW8.
3. The collection of the viral kinetics in a subset of subjects will be used to explore the 
impact of early viral load decline on sustained viral response in each treatment arm.
4. The relationship between genetic variation, including but not limited to variation in 
IL28B, and response to the treatment administered and mechanisms of disease. 
Variation across the human genome will be analyzed for association with clinical data 
collected in this study.
5. The proportion of HIV co-infected subjects who develop HIV-1 virologic failure 
during protocol therapy.
6. Change from baseline in CD4+ T-cell counts in the HIV co-infected population.
7. The proportion of anti-HBc positive subjects at screening who develop HBV 
reactivation (see Section 7.2.3.2).
Safety Endpoints
8.4.2
An initial description of safety measures is provided in Section 4.2.5.2 and ECIs are defined 
in Section 7.2.3.2.  
Analysis Populations
8.5
If the need arises to extend the treatment duration to 16 weeks and add RBV to the treatment 
regimen, data displays for both efficacy and safety will be adjusted to reflect the actual 
treatment received.  
 
 
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Efficacy Analysis Populations
8.5.1
Full Analysis Set (FAS) 
The FAS population will serve as the primary population of efficacy data in this study.  The 
FAS population consists of all subjects who are assigned to treatment and receive at least 
1 dose of study treatment in this study.  
Per Protocol (PP)
The PP population will serve as a supportive analysis population. The PP population 
excludes subjects due to important deviations from the protocol that may substantially affect 
the results of the primary and secondary efficacy endpoints. Non-virologic failures that are 
due to administrative (non-treatment-related) reasons will be excluded.  Potential violations 
that may result in the exclusion of a subject from the PP population also include the 
following:

The subject did not meet specific inclusion/exclusion criteria (for example, the 
subject is infected with a mixed GT infection or non-typeable GT).

The subject received concomitant medications that are prohibited due to their 
potential to result in a clinically significant lowering of the MK-3682 or RZR
concentrations 
(see 
Section 
5.5 
for 
specific 
details 
of 
prohibited 
medications). Further, any co-administered medication currently unidentified, but for 
which subsequent clinical drug-drug interaction data indicate that co-administration 
with MKs leads to a clinically significant lowering of MK concentrations, may also 
exclude a subject from the per-protocol population.. 

Other violations may be identified during the course of data collection and they will 
be listed specifically in the CSR.
A subject with important deviations from the protocol at treatment allocation (Day 1) will be 
excluded from the PP population. For subjects with important deviations from the protocol 
as described above during the course of treatment, data obtained subsequent to the violation 
will be excluded from analysis.  
Modified Full Analysis Set (mFAS)
The mFAS population will be used for supportive analysis of the efficacy endpoints of SVR12
and SVR24 and as primary analysis for the endpoint of the proportion of subjects 
experiencing virologic failure at FW12 as a primary analysis.  The mFAS population is a 
subset of the FAS population, with subjects excluded for study discontinuation for reasons 
unrelated to the treatment regimen.  Examples include loss to follow-up, discontinuation 
from the study due to non-drug related AEs, informed consent withdrawal, and other non-
virologic failures.
The final determination on the exclusion of subjects from various analysis populations will 
be made prior to the final database lock and will be documented in a separate memo.  Details 
on the approach to handling missing data are provided in Section 8.6 Statistical Methods.
 
 
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Safety Analysis Population
8.5.2
The ASaT population will be used for the analysis of safety data in this study. The ASaT 
population consists of all allocated subjects who received at least 1 dose of study treatment. 
Subjects will be included in the treatment group corresponding to the study treatment they 
actually received for the analysis of safety data using the ASaT population.  In this study
with a single treatment regimen, the ASaT population is the same as the FAS population. For 
reporting consistency, the terms FAS for efficacy and ASaT for safety will be maintained.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.6 Statistical Methods. 
Statistical Methods
8.6
There will be no statistical testing conducted to address the objectives of this study. A 
summary of the analysis strategy for efficacy variables is shown in Table 15.  The analysis 
strategy for safety is described in Section 8.6.2.
Statistical Methods for Efficacy Analyses
8.6.1
Missing Values
A missing data point for a given study visit may be due to any one of the following reasons: a 
visit occurred but data were not collected or were unusable; a visit did not occur; or a subject 
discontinued from the study before reaching the visit. Subjects who prematurely discontinued 
the assigned treatment are encouraged to remain in the study for follow-up, if possible. 
The HCV RNA outcome is categorized as TND, TD (u), and TD (q). There are 3 types of 
missing data handled by different approaches.
1. Intermittent missing: If a missing data point is immediately preceded and followed by 
non-missing HCV RNA outcomes, the missing value would be imputed to the worst 
outcome of the two. For example, if a missing data point is preceded by TD(q) and 
followed by TD(u) or TND, then the missing value would be imputed as TD(q); if a 
missing data point is preceded by TD(u) and followed by TND, then the missing 
value would be imputed as TD(u); when a missing value is flanked by two TND, then 
the missing value would be imputed as TND.
2. Non-intermittent missing related to the study drug: For missing values due to 
premature study discontinuations due to treatment-related reasons either for safety or 
efficacy, the missing values will be considered as treatment failures.
3. Non-intermittent missing for reasons unrelated to the study drug: For missing data 
due to premature study discontinuations with reasons unrelated to treatment such as 
loss to follow-up, protocol deviation, withdrawal of consent, administrative reasons, 
etc., the missingness mechanism is unlikely to be related to subjects’ response to the 
HCV treatment, and therefore the missing at random assumption is reasonable.
 
 
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The following 2 approaches will be used to handle non-intermittent missing data due to 
premature discontinuations, depending on the analytical strategy, as described in the section 
below and in Table 15.
1. Treatment-Related Discontinuation=Failure (TRD=F) approach: Subjects
with
treatment-related missing data (type #2 above) will be considered as failure; whereas 
the subjects who have the non-treatment-related missing value (type #3 above) and 
who do not have virologic failure during the observed study period will be excluded 
from the analysis for the time points following their study withdrawal. Note that 
subjects with documented virologic failure during the treatment or follow-up period, 
even if they withdrew prematurely due to reasons not related to study drug, are 
classified as failures.
2. Missing=Failure (M=F) approach: Subjects with any non-intermittent missing data 
(i.e., type #2 and #3 above) will be imputed as failures, regardless of the reason for 
study discontinuation.
In addition, a missing baseline/Day 1 HCV RNA result will be replaced with a screening 
result, if available.
Proportions of Subjects With Virologic Responses and Virologic Failures
For the primary efficacy analysis, the proportions of subjects achieving SVR12 for each GT 
will be provided and 95% CIs for these rates will be calculated using the Clopper-Pearson 
method [42]. The same method will be used to analyze all binary endpoints including SVR4, 
SVR8, SVR24, and virologic response rates at TW4, TW8, and end of treatment.
For the primary analyses using the FAS population, the M=F missing data approach will be 
utilized.  In these analyses, only subjects with HCV RNA levels <LLOQ for any type of 
HCV infection at a given time point will be considered to have achieved the endpoint.  
For all analyses conducted using the PP and mFAS populations, the missing data approach of 
TRD=F will be utilized.  In addition, for all analyses based on these 2 populations, a subject 
will be considered to have achieved a response for a particular endpoint if the HCV RNA 
levels for the infection he/she had at baseline are <LLOQ. For example, if a subject has HCV 
RNA levels ≥LLOQ at a particular time point, but those RNA levels correspond to an 
infection that is of a different GT and/or subtype compared to the infection detected at 
baseline and the baseline infection has been cleared, then the subject is considered to have 
achieved response for the given endpoint.
To estimate the secondary efficacy endpoint of proportion of subjects experiencing virologic 
failure at FW12 for each GT, 95% CIs for these rates will be calculated in the mFAS analysis 
population using the Clopper-Pearson method [42]. The missing data approach of TRD=F 
described previously will be utilized for this analysis. 
Table 15 includes a summary of the key efficacy analyses, and Table 16 includes a summary 
of the analysis populations and various criteria to assess the primary endpoint (SVR12) and 
secondary endpoints (SVR24 and proportion of subjects experiencing virologic failure at 
FW12). 
 
 
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Table 15
Analysis Strategy for Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical Method
Analysis
Population
Missing Data
Approach
Primary
Proportion of subjects
achieving SVR12 by genotype 
P
95% CI
(Clopper-
Pearson)
FAS
M=F
Proportion of subjects
achieving SVR12 by genotype 
S
95% CI (Clopper-
Pearson)
mFAS
TRD=F
Proportion of subjects
achieving SVR12 by genotype 
S
95% CI (Clopper-
Pearson)
PP
TRD=F
Secondary
Proportion of subjects
achieving SVR24 by genotype 
P
95% CI (Clopper-
Pearson)
FAS
M=F
Proportion of subjects
achieving SVR24 by genotype
S
95% CI (Clopper-
Pearson)
mFAS
TRD=F
Proportion of subjects
achieving SVR24 by genotype 
S
95% CI (Clopper-
Pearson)
PP
TRD=F
Proportion of subjects 
experiencing virologic failure 
at FW12 by genotype 
P
95% CI
(Clopper-
Pearson)
mFAS
TRD=F
CI = confidence interval; FAS = Full Analysis Set; M=F = Missing=Failure; mFAS = modified Full Analysis
Set; P = primary approach; PP = Per Protocol; S = secondary approach; TRD=F = Treatment-Related
Discontinuation=Failure.
 
 
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Table 16
Analysis Populations, Criteria for Response, Non-Response, and Exclusion from 
Analysis Populations
Analysis Population
Criteria for Response
Criteria for Non-
Response
Criteria for exclusion
from analysis population
FAS (Primary for 
SVR12 and SVR24)
HCV RNA < LLOQ
HCV RNA ≥ LLOQ
Subject did not receive at least  
1 dose of study medication
PP (Supportive for 
SVR12 and SVR24)
HCV RNA < LLOQ
for baseline infection1
HCV RNA ≥LLOQ
demonstrated to be
due to reinfection
(detectable HCV RNA 
for a viral strain other 
than that detected at 
baseline after
clearance of baseline
infection1)
HCV RNA ≥ LLOQ for
baseline infection1
Subject has important 
deviations from the protocol 
including discontinuation from 
the study for non-treatment 
related reasons and other 
violations such as violation of
inclusion/exclusion criteria and 
use of prohibited concomitant 
medications (see Section 8.5.1)
mFAS (Supportive
for SVR12, SVR24; 
Primary for the 
proportion of 
subjects 
experiencing 
virologic failure at 
FW12)
HCV RNA < LLOQ
for baseline infection1
HCV RNA ≥LLOQ
demonstrated to be
due to reinfection
(detectable HCV RNA 
for a viral strain other 
than that detected at 
baseline after
clearance of baseline
infection1)
HCV RNA ≥ LLOQ for
baseline infection1
Subject discontinued from the
study for non-treatment related
reasons.
FAS = Full Analysis Set; FW12 = Follow-up Week 12; GT = genotype; LLOQ = lower limit of quantification; mFAS = 
modified Full Analysis Set; PP = Per Protocol; RNA = ribonucleic acid; SVR12 = sustained virologic response after 
12 weeks of treatment; SVR24 = sustained virologic response after 24 weeks of treatment.
1
Baseline infection: GT(s) and subtype(s) present at baseline based on sequencing and genotyping assay
Subject Virologic Failure: Non-response, Rebound, Virologic Breakthrough, Relapse 
and Reinfection
Summary statistics will be provided to describe the rates of occurrence of subject non-
response, rebound, virologic breakthrough, and relapse. Definitions for subject non-response, 
rebound, virologic breakthrough, and relapse are in Section 4.2.5.1.1.2. Reinfection will be 
defined as having detectable virus of a different GT than that detected at baseline as 
determined by sequencing.  Those with reinfection will be considered treatment success in 
the mFAS and PP analyses as long as HCV RNA < LLOQ is achieved for the baseline 
infection.  
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory parameters. The 95% CIs for the safety parameters will be estimated 
 
 
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using the Clopper-Pearson method [42], which is a conservative exact method of providing 
CIs in this estimation study.
The analysis of safety parameters will follow a tiered approach (Table 17). The tiers differ 
with respect to the analyses that will be performed.  
The first tier includes (1) AEs of elevated laboratory values that are reported as ECIs 
described in Section 7.2.3.2; (2) at least 1 AE; (3) a drug-related AE; (4) an SAE; (5) a 
serious and drug-related AE, and (6) an AE leading to discontinuation.  Point estimates and 
95% CIs will be provided.
The second tier includes specific AEs by SOC, vital signs, 12-lead ECGs, and standard 
laboratory safety tests at time points specified in the Trial Flow Chart (Section 6.0). Point 
estimates will be provided.
Missing safety laboratory, vital signs, or ECG values will be handled using the Data-As-
Observed approach, that is, any missing value will be excluded from the analysis.  The only 
exception is when a Baseline/Day 1 result is missing, this will be replaced with the latest pre-
treatment result, if available.
Missing safety laboratory, vital signs, or ECG values will be handled using the Data-As-
Observed approach, that is, any missing value will be excluded from the analysis.  The only 
exception is when a Baseline/Day 1 result is missing, this will be replaced with the latest pre-
treatment result, if available.
The primary safety analysis will summarize the safety data for subjects during the treatment 
period plus 14 days of follow-up. 
Table 17
Analysis Strategy for Safety Parameters
Safety Endpoint1
95% CI
Descriptive Statistics
AEs of elevated laboratory values that are reported as ECIs
X
X
Any AE
X
X
Any SAE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs or PDLCs
X
Change from Baseline Results (laboratory, vital signs, ECG)
X
AE = adverse event; ECG = electrocardiogram; ECI = event of clinical importance; n/a = not applicable; PDLC = pre-
defined limit of change; SOC = system organ class; X = results will be provided.
1
Adverse Experience references refer to both Clinical and Laboratory AEs.
Summaries of Baseline Characteristics, Demographics, and other Analyses
8.6.3
Summaries of demographic and baseline characteristics, PK analyses, and analyses for the 
exploratory endpoints will be described in detail in the supplementary statistical analysis plan 
(sSAP).
Interim Analyses
8.7
An assessment of safety for the first 50 subjects will be made when the last of these subjects 
reaches TW4. The criteria for assessing safety in this cohort of 50 subjects can be found in 
 
 
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Section 5.11.1.  Specifically, if >3 out of the first 50 subjects receiving MK-3682 + RZR
experience any of the listed criteria, study therapy will be discontinued in all subjects and no 
additional subjects will be allocated to treatment. 
In addition to the safety assessment for the first 50 subjects, criteria for early stopping at any 
point in the trial is given in Section 5.11.2 and for pausing treatment allocation is given in 
Section 5.11.3. 
An assessment of efficacy will be made when the first 10 per-protocol subjects within each 
GT (GT1-6) have reached FW4.  If ≥3 out of the first 10 subjects in the PP population for 
each GT (GT1-6) receiving 12 weeks of therapy experience virologic failure (non-response, 
rebound, breakthrough, or relapse) by FW4, no additional subjects for that particular GT will 
be allocated to treatment in the trial.  Additionally, if the majority of failures are due to 
relapses (i.e., >50%), the treatment regimen with MK-3682 + RZR for subjects with a 
particular GT will be extended to 16 weeks’ duration and RBV will be added for subjects 
with this GT who remain on treatment.
In addition, efficacy will continue to be monitored throughout the trial and if >5 of subjects 
in the PP population for GT1-4, and >3 subjects in the PP population for GT5-6, experience 
virologic failure at any point in the trial, no additional subjects for that particular GT will be 
allocated to treatment.  Additionally, if the majority of failures are due to relapses (i.e., 
>50%), the treatment regimen with MK-3682 + RZR for subjects with a particular GT will 
be extended to 16 weeks’ duration and RBV will be added for subjects with this GT who 
remain on treatment. 
Finally, throughout the course of this open-label study, efficacy and safety will be monitored 
for trends and programmatic decisions.
Multiplicity
8.8
No multiplicity adjustment is planned for the study.
Sample Size and Power Calculations
8.9
Efficacy Analysis
8.9.1
Approximately 250 subjects will be allocated to treatment with a target allocation of 35 
GT1a-, 15 GT1b-, 50 GT2-, 50 GT3-, 50 GT4-, 25 GT5-, and 25 GT6-infected subjects.   
These sample sizes were chosen to provide sufficient confidence of the estimated treatment 
response rate for the most prevalent GTs (Section 4.2.3)
Table 18 below shows the 2-sided 95% CIs for SVR12 under varying assumptions of the 
number of successes in the FAS population for each GT. Note that these intervals are not 
symmetric around the point estimate.  
 
 
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Table 18
Two-Sided 95% Confidence Intervals for SVR12 (FAS Population)
Number of 
subjects in FAS
population
Observed Number of Successes 
(%)
Two-Sided 95% Confidence 
Interval1
15
15 (100.0%)
(78.2, 100.0)
14 (93.3%)
(68.1, 99.8)
13 (86.7%)
(59.5, 98.3)
12 (80.0%)
(51.9, 95.7)
25
25 (100.0%)
(86.3, 100.0)
24 (96.0%)
(79.6, 99.9)
23 (92.0%)
(74.0, 99.0)
22 (88.0%)
(68.8, 97.5)
35
35 (100.0%)
(90.0, 100.0)
34 (97.1%)
(85.1, 99.9)
33 (94.3%)
(80.8, 99.3)
32 (91.4%)
(76.9, 98.2)
50
50 (100.0%)
(92.9, 100.0)
49 (98.0%)
(89.4, 99.9)
48 (96.0%)
(86.3, 99.5)
47 (94.0%)
(83.5, 98.7)
FAS = Full Analysis Set.
1
Based on the Clopper-Pearson method
Safety Analysis
8.9.2
The primary safety objective of this study will be addressed by a review of the accumulated 
safety data. Certain safety endpoints of special interest have been identified in Section 8.4.2.
The ASaT population will include approximately 250 subjects. The upper bound of the 95% 
CI for the underlying percentage of subjects with a specific AE given various hypothetical 
observed number of subjects with that specific AE within the study are provided in Table 19. 
These calculations are based on the exact binomial method proposed by Clopper and Pearson 
[42].
 
 
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Table 19
Estimate of Incidence of a Specific AE and 95% Upper Confidence Bound Based 
on a Hypothetical Number of Subjects with that Specific AE
n
Hypothetical Number of 
Subjects with AE
Estimate of Incidence
95% Upper Confidence 
Bound1
250
0
0.0%
1.5%
1
0.4%
2.2%
5
2.0%
4.6%
10
4.0%
7.2%
20
8.0%
12.1%
30
12.0%
16.7%
40
16.0%
21.1%
50
20.0%
25.5%
AE = adverse event.
1
Based on the 2-tailed exact confidence interval of a binomial proportion (Clopper and Pearson, 1934)
Subgroup Analyses and Effects of Baseline Factors
8.10
The subgroup analyses detailed below will be performed within each GT.
To assess the consistency of the response across various subgroups, the SVR12 and SVR24 
rates and associated 95% CIs will be estimated within each category of the following 
baseline factors as classification variables:

Presence or absence of baseline RAVs to any of the 2 classes of drugs

Gender (female, male)

Age (≥65, <65)

Race (White, Black or African American, Asian, Other) 

Ethnicity (Hispanic or Latino, not Hispanic or Latino)

IL28B GT (CC versus non-CC GT)

HCV RNA at baseline, ≤800,000 IU/mL versus >800,000 IU/mL; ≤2 million IU/mL 
versus >2 million IU/mL; ≤10 million IU/mL versus > 10 million IU/mL

Stage of fibrosis (non-cirrhotic [F0-F3], cirrhotic [F4]) 

HIV co-infection status (HCV/HIV co-infected, HCV mono-infected)

Treatment-experienced and treatment-naïve 

For GT1 subjects: (GT1a vs. GT1b)

Geographical Region (US, Canada, European Union, Latin America, Asia Pacific, 
Middle East – note that regions may be collapsed depending on actual enrollment in 
the trial)
 
 
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Compliance (Medical Adherence)
8.11
In this study, as part of the routine recording of the amount of study treatment taken by each 
subject, the number of tablets remaining in study packaging will be counted, reviewed, and 
recorded at regular intervals.  These results will be used to calculate subject compliance.
A day within the study will be considered an “On-Therapy” day if the subject takes the 
assigned treatment MK-3682 (450 mg) + RZR (180 mg) as noted in Section 5.2.
For a subject who is followed for the entire study period, the “Number of Days Should be on 
Therapy” is the total number of days from allocation to the last scheduled day for treatment 
administration for that subject.  For a subject who discontinued from the study permanently, 
the “Number of Days Should be on Therapy” is the total number of days from allocation to 
the date of the last dose of study medication.
For each subject, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance for the FAS population.
Extent of Exposure
8.12
The Extent of Exposure to study treatment will be evaluated by summary statistics (N, mean,
and range) for the “Number of Days on Therapy” by dose for each study drug.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 20
Table 20
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
MK-3682 150 mg
Tablet
Provided Centrally
RZR 60 mg
Capsule
Provided Centrally
Ribavirin 
‒
Locally Sourced
 
 
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Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open-label bottles (2 bottles of MK-3682 and 2 bottles of RZR) every 4
weeks during the treatment duration.  Each bottle will contain a 2-week supply of study 
medication. No kitting is required.
If the duration of treatment with MK-3682 + RZR is extended to 16 weeks, sites should 
dispense RBV (locally sourced).
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.  Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with
anyone.
 
 
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
 
 
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If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
 
 
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The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
 
 
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According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the Protocol/CSR 
CI during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones).  The 
Protocol CI must be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures
and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
 
 
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Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
 
 
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the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
[1]
Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG, et al. 
Global distribution and prevalence of hepatitis C virus genotypes. 
Hepatology. 2015 Jan;61(1):77-87.
[2]
Wiessing L, Ferri M, Grady B, Kantzanou M, Sperle I, Cullen KJ, et al. 
Hepatitis C virus infection epidemiology among people who inject drugs in 
Europe: a systematic review of data for scaling up treatment and prevention. 
PLoS One. 2014 Jul 28;9(7):e103345.
[3]
Feld JJ, Jacobson IM, Hezode C, Asselah T, Ruane PJ, Gruener N, et al. 
Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N 
Engl J Med. 2015 Nov 16. [Epub ahead of print].
[4]
Zeuzem S, Ghalib R, Reddy KR, Pockros PJ, Ben Ari Z, Zhao Y, et al. 
Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic 
and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 
Infection: A Randomized Trial. Ann Intern Med. 2015 Jul 7;163(1):1-13.
[5]
U.S. Prescribing Information: ZEPATIER (elbasvir and grazoprevir) tablets,
for oral use: 2016.
[6]
Rockstroh JK, Nelson M, Katlama C, Lalezari J, Mallolas J, Bloch M, et al. 
Effi cacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in 
patients with hepatitis C virus and HIV co-infection (C-EDGE CO-
INFECTION): a non-randomised, open-label trial. Lancet. Forthcoming 2015.
[7]
Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N, et al. 
All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with 
hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 
2015 Apr;61(4):1127-35.
[8]
Goossens N, Negro F. Is genotype 3 of the hepatitis C virus the new villain? 
Hepatology. 2014 Jun;59(6):2403-12.
 
 
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[9]
Buti M, Esteban R. Hepatitis C virus genotype 3: a genotype that is not 'easy-
to-treat'. Expert Rev Gastroenterol Hepatol. 2015 Mar;9(3):375-85.
[10]
U.S. Prescribing Information: DAKLINZA (daclatasvir) tablets: 2015.
[11]
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir 
and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014 
May 15;370(20):1889-98.
[12]
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et 
al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without 
cirrhosis. N Engl J Med 2014;370(20):1879-88.
[13]
U.S. Prescribing Information: HARVONI (ledipasvir and sofosbuvir) tablets, 
for oral use: 2014.
[14]
E.U. Product Circular: HARVONI 90 mg/400 mg Film-Coated Tablets: Oct 
2014.
[15]
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. 
Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. 
N Engl J Med. 2014 Apr 17;370(16):1483-93.
[16]
Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR, Crawford D, et al. 
Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. 
N Engl J Med. 2014 Apr 24;370(17):1594-603.
[17]
Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, et al. 
ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with 
cirrhosis. N Engl J Med. 2014 May 22;370(21):1973-82.
[18]
E.U. Product Circular: VIEKIRAX 12.5 mg/75 mg/50 mg Film-Coated 
Tablets: Jan 2015.
[19]
Gane E, Poordad F, Asatryan A, Lalezari J, Hassanein T, Aguilar H, et al. 
High efficacy and favourable safety of ABT-493 + ABT-530 co-
administration for 12 weeks in HCV genotype 1-infected patients with 
cirrhosis (SURVEYOR-I). Proceedings of the International Liver Congress; 
2016 Apr 13-17; Barcelona, ES. EASL; 2016.
 
 
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[20]
Poordad F, Felizarta F, Asatryan A, Hassanein T, Aguilar H, Lalezari J, et al. 
SURVEYOR-I: 98% - 100% SVR4 in HCV genotype 1 non-cirrhotic 
treatment-naive or pegylated interferon/ribavirin null-responders with the 
combination of the next generation NS3/4A protease inhibitor ABT-493 and 
NS5A inhibitor ABT-530. Proceedings of 66th Annual Meeting of the 
American Association for the Study of Liver Diseases 2015; 2015 Nov 13-17; 
Boston, MA. 2015.
[21]
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon 
SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N 
Engl J Med 2013;368(20):1878-87.
[22]
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski  MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients 
without treatment options. N Engl J Med 2013;368(20):1867-77.
[23]
Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, et al. 
Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014 May 
22;370(21):1993-2001.
[24]
U.S. Prescribing Information: SOVALDI (sofosbuvir) Tablets: 2013.
[25]
Foster GR, Afdhal N, Roberts SK, Brau N, Gane EJ, Pianko S, et al. 
Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J 
Med. 2015 Dec 31;373(27):2608-17.
[26]
Abergel A, LoustaudRatti V, Metivier S, Jiang D, Kersey K, Knox SJ. 
Ledipasvir/Sofosbuvir for the treatment of patients with chronic genotype 4 or 
5 HCV infection. Proceedings of the 50th annual meeting of the European 
association for the Study of the Liver; 2015 Apr 22-26; Vienna, AT. EASL; 
2015.
[27]
U.S. Prescribing Information: TECHNIVIE (ombitasvir, paritaprevir and 
ritonavir) tablets, for oral use: 2016.
[28]
Hezode C, Asselah T, Reddy KR, Hassanein T, Berenguer M, Fleischer-
Stepniewska K, et al. Ombitasvir plus paritaprevir plus ritonavir with or 
without ribavirin in treatment-naive and treatment-experienced patients with 
genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, 
open-label trial. Lancet. 2015 Jun 20;385(9986):2502-9.
 
 
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[29]
Brown A, Hezode E, Zukerman E, Foster G, Zekry A, Roberts S, et al. C-
SCAPE: Efficacy and safety of 12 weeks of grazoprevir +/- elbasvir +/-
ribavirin in patients with HCV GT2, 4, 5 or 6 infection [abstract]. J Hepatol. 
2015 Apr;62(2Suppl):S619. Abstract no. P0771.
[30]
Gane E, Lalezari J, Asatryan A, Greenbloom S, Hassanein T, Ng TI, et al. 
100% SVR4 and favorable safety of ABT-493 + ABT-530 administered for 
12 Weeks in non-cirrhotic patients with genotypes 4, 5, or 6 infection 
(SURVEYOR-I). Proceedings of the International Liver Congress; 2016 Apr 
13-17; Barcelona, ES. EASL; 2016.
[31]
Abergel A, Asselah T, Metivier S, Kersey K, Jiang D, Mo H, et al. 
Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: 
an open-label, multicentre, single-arm, phase 2 study. Lancet Infect Dis. 2016 
Jan 20. [Epub ahead of print].
[32]
Gane EJ, Hyland RH, An D, Svarovskaia E, Pang PS, Brainard D, et al. 
Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks 
in patients with HCV genotype 3 or 6 infection. Gastroenterology. 2015 
Nov;149(6):1454-1461. e1.
[33]
Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F, Bourliere M, et 
al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with 
ribavirin. N Engl J Med. 2014 Apr 24;370(17):1604-14.
[34]
Kwo P, Gane E, Peng C, Pearlman B, Vireling J, Serfaty L, et al. Efficacy and 
safety of grazoprevir/elbasvir +/− RBV for 12 weeks in patients with HCV 
G1 or G4 infection who previously failed peginterferon/RBV: C-edge 
treatment-experienced trial [abstract]. J Hepatol. 2015;62:S674: P0886.
[35]
Taylor LE, Swan T, Mayer KH. HIV coinfection with hepatitis C virus: 
evolving epidemiology and treatment paradigms. Clin Infect Dis 
2012;55(Suppl 1):S33-42.
[36]
Pol S, Soriano V. Management of chronic hepatitis C virus infection in HIV-
infected patients. Clin Infect Dis 2008;47:94-101.
[37]
Alberti A. Impact of a sustained virological response on the long-term 
outcome of hepatitis C. Liver Int 2011:18-22.
 
 
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[38]
Martinot-Peignoux M, Stern C, Maylin S, Ripault M-P, Boyer N, Leclere L, 
et al. Twelve weeks posttreatment follow-up is as relevant as 24 weeks to 
determine the sustained virologic response in patients with hepatitis C virus 
receiving pegylated interferon and ribavirin. Hepatology 2010;51(4):1122-6.
[39]
Chen J, Florian J, Carter W, Fleischer RD, Hammerstrom TS, Jadhav PR, et 
al. Earlier sustained virologic response end points for regulatory approval and 
dose selection of hepatitis C therapies. Gastroenterology 2013;144(7):1450-
5e2.
[40]
Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using 
transient elastography. J Hepatol 2008;48:835-47.
[41]
Boursier J, de Ledinghen V, Zarski J-P, Fouchard-Hubert I, Gallois Y, Oberti 
F, et al. Comparison of eight diagnostic algorithms for liver fibrosis in 
hepatitis C: new algorithms are more precise and entirely noninvasive. 
Hepatology 2012;55(1):58-67.
[42]
Clopper CJ, Pearson ES. The use of confidence or Fiducial limits illustrated 
in the case of the binomial. Biometrika 1934;26(4):404-13.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 7.1.3.7 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on the visit designated in the 
trial flow chart.  If delayed, present consent at next possible Subject Visit.  Consent 
forms signed by the subject will be kept at the clinical trial site under secure storage 
for regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between subject identifiers 
and this unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  Subjects may withdraw 
consent at any time by contacting the principal investigator for the main trial. If medical 
records for the main trial are still available, the investigator will contact the Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@merck.com). 
 
 
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Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically 
for Future Biomedical Research, these specimens will be removed from the biorepository 
and destroyed. Documentation will be sent to the investigator confirming withdrawal 
and/or destruction, if applicable. It is the responsibility of the investigator to inform the 
subject of completion of the withdrawal and/or destruction, if applicable.  Any analyses 
in progress at the time of request for withdrawal/destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and subjects.  Subjects will not be identified by 
 
 
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name in any published reports about this study or in any other scientific publication or 
presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by Sample Types
12.3
Screening
Day 1
Day 1-2
Day 3
Day 5
Day 7
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
Week 141
Weekj 161
FW 4
FW 8
FW 12
FW 24
Total
Volume
Total
Volume (if 
treatment 
duration 
extended)
Test
Approximate Blood Volume (mL)
Coagulation 
(PT, INR)
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
58.5
67.5
HBV
Evaluations  
(HBsAg, Anti-
HBc, Anti-
HBs, HBV 
DNA)3
10
10
10
10
10
10
10
10
10
80
90
HIV-1/HIV-2
Serology
6
6
6
Chemistry
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
130
150
Hematology
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
39
45
HCV GT 
Determination
4
4
4
HCV Viral 
Resistance and 
biomarkers
6
6
6
6
6
30
30
MK-3682 PK
4
42
4/162
4
12
4
4
4
4
36/522
40/562
RZR PK
4
42
4/162
4
12
4
4
4
4
36/522
40/562
HCV RNA
6
6
242
62
62
6
6
6
6
6
6
6
6
6
6
6
6
6
78/1142
90/1262
HIV RNA
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
78
90
CD4+ T-cell 
count
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
78
90
Blood for 
Genetic 
Analysis
8.5
8.5
8.5
Expected 
Total (mL)
Main Study 
Population
55.5
68
242
142
62
43.5/
67.52
43.5
69.5
43.5
53.5
35.5
53.5
35.5
53.5
51.5
41.5
51.5
51.5
662/
7302
751/
8192
Anti-HBc=hepatitis B core antibody; anti HBs=hepatitis B surface antibody; GT = genotype; HBsAg=hepatitis B surface antigen; HBV DNA=hepatitis B virus deoxyribonucleic acid; HCV=hepatitis C 
virus; HIV=Human immunodeficiency virus; INR=international normalized ratio; PK=pharmacokinetic; PT=prothrombin time; RZR = ruzasvir .
1 TW14 and TW16 will only occur for those subjects whose treatment duration may be extended.
2 Total blood taken from Intensive Evaluation Group.
3 HBsAg, anti-HBc, and anti-HBs will be assessed at screening in all subjects.  For all anti-HBc positive subjects, HBV DNA will also be assessed at screening, and both HBV DNA and HBsAg will be 
monitored during the trial.
 
 
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Product:  MK-3682 
109
Protocol/Amendment No.: 041-05 
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26-Oct-2017
Confidential
List of Abbreviations and Definition of Terms
12.4
Term
Definition
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase 
AMA
American Medical Association
Anti-HBc
Hepatitis B core antibody
Anti-HBs
Hepatitis B surface antibody
APRI
Aspartate aminotransferase to platelet ratio index
ART
Antiretroviral therapy
ASaT
All subjects as treated
AST
Aspartate aminotransferase 
Cmax
Maximum plasma concentration
Ctrough
Trough plasma concentration
CFR
Code of Federal Regulations
CI
Confidence interval
CRF
Case report form
CRU
Clinical research unit
CSR
Clinical study report
CYP
Cytochrome P450
DAA
Direct-acting antiviral therapy
DAO
Data-as-observed
DCV
Daclatasvir
DNA
Deoxyribonucleic acid
EBR
Elbasvir
ECG
Electrocardiogram
ECI
Event of clinical interest
E/CIA
Enzyme or chemiluminescence immunoassay
eCRF
Electronic case report form
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
ERC
Ethics committee
EU
European Union
FAS
Full analysis set
FBR
Future biomedical research
FDAAA
Food and Drug Administration Amendments Act
FDA
Food and Drug Administration
FDC
Fixed-dose combination
FU
Follow-up
FW
Follow-up Week
GCP
Good Clinical Practice
GT
Genotype
GZR
Grazoprevir
HBsAg
Hepatitis B surface antigen
HBV 
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
 
 
04S4YM
 
 
04YJRT


Product:  MK-3682 
110
Protocol/Amendment No.: 041-05 
MK-3682-041-05 Final Protocol
26-Oct-2017
Confidential
Term
Definition
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use
IEC
Independent ethics committee
IFN
Interferon
INR
International normalized ratio
IRB
Institutional review board
IUD
Intrauterine device
IVRS/
IWRS
Interactive voice response system/interactive web response 
system
LDV
Ledipasvir
LLOQ
Lower limit of quantification
MDRD
Modification of diet in renal disease
mFAS
Modified full analysis set
NGS
Next-generation sequencing
NI
Nucleotide inhibitor
NOAEL
No observed adverse effect level
NS
Nonstructural protein
OMB
Ombitasvir
PD
Pharmacodynamics
PN
Protocol Number
PK
Pharmacokinetics
PP
Per-protocol
PR
Pegylated interferon/ribavirin
QPP
Quantitative pharmacology and pharmacometrics
RAV
Resistance-associated variant
RBV
Ribavirin
RNA
Ribonucleic acid
RT-PCR
Real-time polymerase chain reaction
RZR
Ruzasvir 
SAE
Serious adverse event
(S)AE
All adverse events, including serious adverse events
SAFE
Sequential algorithm for fibrosis evaluation
SAP
Statistical analysis plan
Scr, std
Serum creatinine measured with a standardized assay
SMD
Study medication diary
SOC
System organ class
SOF
Sofosbuvir
SOP
Standard operating procedure
sSAP
Supplemental statistical analysis plan
SVR
Sustained virologic response
SVR4
Sustained virologic response 4 weeks post-treatment 
SVR8
Sustained virologic response 8 weeks post-treatment 
SVR12
Sustained virologic response 12 weeks post-treatment
SVR24
Sustained virologic response 24 weeks post-treatment 
 
 
04S4YM
 
 
04YJRT


Product:  MK-3682 
111
Protocol/Amendment No.: 041-05 
MK-3682-041-05 Final Protocol
26-Oct-2017
Confidential
Term
Definition
TD(q)
Target detected, quantifiable
TD(u)
Target detected, unquantifiable
TE
Treatment experienced
TF
Treatment failure
TN
Treatment naïve
TND
Target NOT detected (HCV RNA not detected)
TRD
Treatment-related discontinuation
TW
Treatment week
ULN
Upper limit of normal
US
United States (of America)
VEL
Velpatasvir
VL
Viral load
 
 
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04YJRT


Product:  MK-3682 
112
Protocol/Amendment No.: 041-05 
MK-3682-041-05 Final Protocol
26-Oct-2017
Confidential
13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
04S4YM
 
 
04YJRT