A Phase II, Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-3682 + MK-8408 in Subjects With Chronic HCV Genotype 1, 2, 3, 4, 5 or 6 Infection
Phase: PHASE2
Conditions: Hepatitis C, Chronic
Sponsor: Merck Sharp & Dohme LLC

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Phase II, Open-Label Clinical Trial to Study the Efficacy and 
Safety of the Combination Regimen of MK-3682 + MK-8408 in 
Subjects with Chronic HCV Genotype 1, 2, 3, 4, 5 or 6 Infection 
NCT number: 
NCT02759315 
Document Date: 
26-Oct-2017 

Product:  MK-3682 
1
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
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 II, Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination 
Regimen of MK-3682 + MK-8408 in Subjects with Chronic HCV Genotype 1, 2, 3, 4, 5 or 6 
Infection
IND NUMBER:  123,749
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 12
2.0
TRIAL DESIGN........................................................................................................ 13
Trial Design ........................................................................................................... 13
2.1
Trial Diagram........................................................................................................ 14
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
Other Objectives (e.g., Tertiary, Exploratory, etc.)........................................... 15
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 HCV .......................................................................... 16
4.1.1.2
Pre-clinical and Clinical Trials ........................................................................... 18
4.1.2
Summary of Preclinical Data....................................................................... 18
4.1.2.1
Summary of Clinical Data ........................................................................... 20
4.1.2.2
4.1.2.2.1
Phase 1 Studies ..................................................................................... 20
4.1.2.2.2
Summary of Ongoing Phase 2 Clinical Trials ...................................... 21
Rationale................................................................................................................ 26
4.2
Rationale for the Trial and Selected Subject Population .................................... 26
4.2.1
Rationale for the Trial.................................................................................. 26
4.2.1.1
Rationale for the Selected Subject Population............................................. 27
4.2.1.2
Rationale for Study Design.......................................................................... 28
4.2.1.3
Rationale for Dose Selection/Regimen/Modification......................................... 30
4.2.2
Dose Selection for MK-3682....................................................................... 30
4.2.2.1
Dose Selection for MK-8408....................................................................... 30
4.2.2.2
Rationale for Endpoints ...................................................................................... 31
4.2.3
Efficacy Endpoints....................................................................................... 31
4.2.3.1
 
 
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4.2.3.1.1
Measurement of HCV RNA ................................................................. 31
Definition of Efficacy Endpoints ................................................... 32
4.2.3.1.1.1
Definition of Virologic Failure: Non-Response, 
4.2.3.1.1.2
Rebound, Virologic Breakthrough and Relapse ..................................... 32
4.2.3.1.2
Viral Resistance Measurements............................................................ 33
Safety Endpoints .......................................................................................... 33
4.2.3.2
Pharmacokinetic Endpoints ......................................................................... 33
4.2.3.3
Pharmacodynamic Endpoints....................................................................... 33
4.2.3.4
Planned Exploratory Biomarker Research................................................... 34
4.2.3.5
Future Biomedical Research........................................................................ 34
4.2.3.6
Benefit/Risk ........................................................................................................... 34
4.3
5.0
METHODOLOGY ................................................................................................... 36
Entry Criteria........................................................................................................ 36
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 36
5.1.1
Subject Inclusion Criteria.................................................................................... 36
5.1.2
Subject Exclusion Criteria .................................................................................. 39
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 (Escalation/Titration/Other).......................................... 42
5.2.1.2
Timing of Dose Administration .......................................................................... 42
5.2.2
Trial Blinding...................................................................................................... 43
5.2.3
Randomization or Treatment Allocation............................................................ 43
5.3
Stratification.......................................................................................................... 43
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 43
5.5
Rescue Medications & Supportive Care............................................................. 46
5.6
Diet/Activity/Other Considerations..................................................................... 46
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 46
5.8
Subject Replacement Strategy............................................................................. 49
5.9
Beginning and End of the Trial ........................................................................... 49
5.10
Clinical Criteria for Early Trial Termination ................................................... 49
5.11
Safety Criteria for Pausing Enrollment............................................................... 49
5.11.1
 
 
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Safety Criteria for Stopping Enrollment and Early Trial Termination ............... 49
5.11.2
Efficacy Criteria for Stopping Enrollment.......................................................... 50
5.11.3
Clinical Criteria for Trial Modification.............................................................. 50
5.12
Efficacy Criteria for Modification of Treatment Duration ................................. 50
5.12.1
6.0
TRIAL FLOW CHART ........................................................................................... 51
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............................................................... 57
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 58
7.1.1.7
Trial Compliance (Medication/Diet/Activity/Other) ................................... 58
7.1.1.8
Clinical Procedures/Assessments........................................................................ 58
7.1.2
Physical Examination................................................................................... 58
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.......................................................................... 59
7.1.2.5
Adverse Events ............................................................................................ 59
7.1.2.6
Non-Invasive Methods of Cirrhosis Evaluation .......................................... 59
7.1.2.7
Laboratory Procedures/Assessments .................................................................. 60
7.1.3
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 60
7.1.3.1
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 61
7.1.3.2
 
 
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7.1.3.2.1
Blood Collection for Plasma MK-3682 (and metabolites) and 
MK-8408............................................................................................... 62
7.1.3.2.2
Intensive Viral Kinetic Sub-Study........................................................ 63
HCV Evaluation........................................................................................... 64
7.1.3.3
HIV Evaluation ............................................................................................ 65
7.1.3.4
Planned Genetic Analysis Sample Collection.............................................. 65
7.1.3.5
Future Biomedical Research Sample Collection ......................................... 65
7.1.3.6
Other Procedures................................................................................................. 66
7.1.4
Withdrawal/Discontinuation........................................................................ 66
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 66
Subject Blinding/Unblinding ....................................................................... 66
7.1.4.2
Domiciling ................................................................................................... 66
7.1.4.3
Calibration of Critical Equipment................................................................ 67
7.1.4.4
Visit Requirements.............................................................................................. 67
7.1.5
Screening...................................................................................................... 67
7.1.5.1
Rescreening.................................................................................................. 67
7.1.5.2
Treatment Period.......................................................................................... 68
7.1.5.3
Discontinued Subjects Continuing to be Monitored in the Trial ................. 68
7.1.5.4
Post-Trial...................................................................................................... 70
7.1.5.5
Long-Term Follow-Up................................................................................. 70
7.1.5.6
Evaluation of Laboratory Safety Signals ..................................................... 70
7.1.5.7
Assessing and Recording Adverse Events .......................................................... 70
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 71
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 72
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 72
7.2.3
Serious Adverse Events ............................................................................... 72
7.2.3.1
Events of Clinical Interest............................................................................ 73
7.2.3.2
Evaluating Adverse Events ................................................................................. 74
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 77
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 77
7.3
Scientific Advisory Committee........................................................................... 77
7.3.1
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 77
 
 
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Statistical Analysis Plan Summary ..................................................................... 77
8.1
Responsibility for Analyses/In-House Blinding ................................................. 78
8.2
Hypotheses/Estimation ......................................................................................... 78
8.3
Analysis Endpoints ............................................................................................... 79
8.4
Efficacy /Pharmacokinetics Endpoints ............................................................... 79
8.4.1
Efficacy Endpoints....................................................................................... 79
8.4.1.1
Pharmacokinetics Endpoints........................................................................ 79
8.4.1.2
Exploratory Endpoints ................................................................................. 79
8.4.1.3
Safety Endpoints ................................................................................................. 80
8.4.2
Analysis Populations............................................................................................. 80
8.5
Efficacy Analysis Populations ............................................................................ 80
8.5.1
Safety Analysis Populations ............................................................................... 81
8.5.2
Statistical Methods................................................................................................ 81
8.6
Statistical Methods for Efficacy Analyses .......................................................... 81
8.6.1
Statistical Methods for Safety Analyses ............................................................. 84
8.6.2
Summaries of Baseline Characteristics, Demographics, and other Analyses..... 85
8.6.3
Interim Analyses ................................................................................................... 85
8.7
Multiplicity ............................................................................................................ 86
8.8
Sample Size and Power Calculations .................................................................. 86
8.9
Efficacy Analysis ................................................................................................ 86
8.9.1
Safety Analysis ................................................................................................... 87
8.9.2
Subgroup Analyses and Effects of Baseline Factors.......................................... 88
8.10
Compliance (Medication Adherence).................................................................. 89
8.11
Extent of Exposure................................................................................................ 89
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 89
Investigational Product ........................................................................................ 89
9.1
Packaging and Labeling Information ................................................................. 90
9.2
Clinical Supplies Disclosure................................................................................. 90
9.3
Storage and Handling Requirements.................................................................. 90
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 90
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 91
 
 
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Confidentiality....................................................................................................... 91
10.1
Confidentiality of Data ....................................................................................... 91
10.1.1
Confidentiality of Subject Records ..................................................................... 91
10.1.2
Confidentiality of Investigator Information........................................................ 91
10.1.3
Confidentiality of IRB/IEC Information............................................................. 92
10.1.4
Compliance with Financial Disclosure Requirements....................................... 92
10.2
Compliance with Law, Audit and Debarment ................................................... 92
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 94
10.4
Quality Management System............................................................................... 94
10.5
Data Management................................................................................................. 94
10.6
Publications ........................................................................................................... 95
10.7
11.0
LIST OF REFERENCES......................................................................................... 97
12.0
APPENDICES......................................................................................................... 100
Merck Code of Conduct for Clinical Trials...................................................... 100
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 102
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 106
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.4
by Sample Types ................................................................................................. 117
List of Abbreviations and Definition of Terms ................................................ 118
12.5
13.0
SIGNATURES......................................................................................................... 120
Sponsor's Representative ................................................................................... 120
13.1
Investigator.......................................................................................................... 120
13.2
 
 
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LIST OF TABLES
Table 1
Treatment Regimen and Subject Characteristics ................................................ 13
Table 2
Potency of MK-8408 versus First Generation NS5A Inhibitors in 
HCV GT1-GT6.................................................................................................. 19
Table 3
Potency of MK-8408 in Treatment-Emergent GT1a RAVs Selected 
by Approved NS5A Inhibitors in Transient Replication Assay ........................ 20
Table 4
Preliminary results for PN011 Part B for 8 and 12 weeks of 
MK-3682B in GT1-infected Treatment-Naïve Subjects With and 
Without Cirrhosis............................................................................................... 23
Table 5
Preliminary results for PN011 Part B for 8, 12 and 16 weeks of 
MK-3682B with or without RBV in GT2-infected Treatment-Naïve 
Subjects With and Without Cirrhosis; % of Subjects Achieving 
SVR4+ of Those Who Have Reached at least FW4........................................... 24
Table 6
Preliminary results for PN012 Part B for 8, 12 and 16 weeks of MK-
3682B 
in 
GT3-infected 
Treatment-Naïve 
and 
Treatment-
Experienced Subjects With and Without Cirrhosis; % of Subjects 
Achieving SVR4+ of Those Who Have Reached FW4 ..................................... 25
Table 7
Nomenclature for Describing HCV RNA Levels ............................................... 32
Table 8
Laboratory Exclusion Criteria............................................................................. 41
Table 9
Trial Treatment for Each Arm ............................................................................ 42
Table 10
Discontinuation Scenarios .................................................................................. 48
Table 11
Laboratory Tests ................................................................................................. 61
Table 12
Pharmacokinetic Sampling Timepoints .............................................................. 63
Table 13
Intensive Viral Kinetic Week 1 Sampling Timepoints....................................... 64
Table 14
Evaluating Adverse Events................................................................................. 75
Table 15
Analysis Strategy for Efficacy Variables............................................................ 83
Table 16
Analysis Populations, Criteria for Response, Non-Response, and 
Exclusion from Analysis Populations................................................................ 84
Table 17
Analysis Strategy for Safety Parameters............................................................. 85
Table 18
Probability of Observing 3 or More Subjects with Virologic Failure ................ 86
Table 19
Two-Sided 95% Confidence Intervals for SVR12 (PP Population) .................... 87
Table 20
Estimate of Incidence of a Specific AE and 95% Upper Confidence 
Bound Based on a Hypothetical Number of Subjects with that 
Specific AE........................................................................................................ 88
Table 21
Product Descriptions........................................................................................... 90
 
 
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LIST OF FIGURES
Figure 1
Trial Diagram...................................................................................................... 14
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
2.1; 6.0; 7.1.5.4; 7.1.5.6
Trial Design;Trial Flow Chart; 
Discontinued 
subjects 
continuing to be monitored in 
the trial; Long- Term Follow-
up
The 3-year long term follow up 
(LTFU) portion of the study is 
being discontinued.  Subjects 
that have enrolled in the LTFU 
will be discontinued via an 
unscheduled visit (telephone 
contact) and no further subjects 
will be enrolled in the LTFU 
period of the study.  
These changes were made to 
discontinue 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.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.2.3.3
Protocol-Specific Exceptions to 
Serious 
Adverse 
Event 
Reporting
The 
section 
heading 
was 
deleted
The 
section 
heading 
was 
deleted as there was no text 
content in this section
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-3682 + MK-8408 in Subjects with Chronic HCV GT1, 2, 3, 4, 5, 
or 6 Infection
Sponsor Product Identifiers
MK-3682 and MK-8408
Trial Phase
Phase II
Clinical Indication
Treatment of Hepatitis C virus infection
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Oral
Trial Blinding
Unblinded Open-label
Treatment Groups
Subjects will be assigned to receive MK-3682 (450mg) and MK-8408 
(60mg) once daily for 12 weeks.  Treatment-naïve and interferon-
based treatment-experienced subjects without cirrhosis or with 
compensated cirrhosis (target ~25-30% compensated cirrhotics), and 
HIV co-infection may be enrolled.  Subjects will be enrolled into one 
of six arms based on genotype:
Arm 1 (n=50): GT1-infected subjects (35 GT1a and 15 GT1b)
Arm 2 (n=50): GT2-infected subjects 
Arm 3 (n=50): GT3-infected subjects 
Arm 4 (n~50): GT4-infected subjects 
Arm 5 (n~25): GT5-infected subjects 
Arm 6 (n~25): GT6-infected subjects 
Number of trial subjects
Approximately 250 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 68 
weeks for the main study and up to a total of 200 weeks including 
long-term follow-up 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
Subjects 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 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.  Subjects 
who take at least 1 dose of study drug, experience virologic failure,
complete Follow-up Week (FW) 24, AND consent to long-term 
follow-up will be followed for 3 years after last study dose, for a total 
trial participation of up to approximately 175 weeks.
A list of abbreviations used in this document can be found in Section 12.5.
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This study will evaluate a novel two-drug combination regimen to treat hepatitis C virus 
(HCV) infection of all genotypes (GTs).  This is an open-label, multi-center trial in subjects 
with chronic HCV GT1, GT2, GT3, GT4, GT5 or GT6 infection. All subjects in this study 
will receive the same treatment regimen that consists of MK-3682 (450mg) + MK-8408 
(60mg) co-administered concomitantly as separate medications once daily for 12 weeks.  An 
estimated total of 250 subjects will be enrolled, with an overall target enrollment in six arms 
of 50 GT1, 50 GT2-, 50 GT3-, approximately 50 GT4-, approximately 25 GT5-, and 
approximately 25 GT6-infected subjects as displayed in Table 1.  Subjects who have prior 
treatment experience with interferon (IFN)-based therapy may be enrolled, but subjects may 
not have previously received treatment with HCV direct-acting antiviral (DAA) therapy.
Subjects may be HCV mono-infected or HCV/HIV-co-infected.  HCV/HIV co-infected 
subjects and IFN-treatment-experienced subjects may be enrolled with no minimum number
or caps.
Table 1
Treatment Regimen and Subject Characteristics
Treatment
Regimen
Treatment 
Arm
Group Characteristics
(N = 250)
Genotype (GT)
Target Enrollment
Target Cirrhotics
MK-3682 
450 mg + 
MK-8408 
60 mg for 
12 weeks
1
GT1a
n = 35
n ~10
GT1b
n = 15
n ~ 5
2
GT2
n = 50
n ~15
3
GT3
n = 50
n ~15
4
GT4
n ~ 50
n ~15
5
GT5
n ~ 25
N/A
6
GT6
n ~ 25
N/A
If a total of ≥3 out of the first 10 subjects in the per-protocol (PP) population of the 12-week 
treatment arm experience virologic relapse by Follow-up Week 4 (FW4), the treatment 
duration of any remaining subjects of that genotype still on treatment in the 12-week arms 
will be extended to 16 weeks.  
All subjects will be followed for 24 weeks after the end of treatment.  Any subject who has
taken at least one dose of study drug (either MK-3682 or MK-8408), experiences virologic 
failure, AND completes Follow-up Week (FW) 24 will be asked to extend follow-up for a 
total of 3 years after the end of treatment.  
Amendment 04 implemented the discontinuation of the LTFU period of the trial.  Subjects 
who already entered the LTFU period are to be discontinued (via an unscheduled visit).  No 
further subjects will be entered into the LTFU period.
Safety and tolerability will be carefully monitored throughout the study by the Sponsor in 
accordance with standard procedures.
 
 
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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.
Note: Subjects who take at least 1 dose of study drug, experience virologic failure, complete FW24, AND 
consent to long-term follow-up will be followed for a total of 3 years after the last study dose (Section 7.1.5).
Figure 1
Trial Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
This is an estimation study; there are no formal hypotheses.
In subjects infected with each HCV genotype:
1) Objective:  To evaluate the efficacy of co-administered MK-3682 (450mg) + MK-
8408 (60mg) following 12 weeks of treatment as assessed by the proportion of 
subjects achieving SVR12 (Sustained Virologic Response 12 weeks after the end of all 
study therapy), defined as HCV RNA < LLOQ 12 weeks after the end of all study 
therapy.
2) Objective: To evaluate the safety and tolerability of co-administered MK-3682
(450mg) + MK-8408 (60mg).
Secondary Objective(s) & Hypothesis(es)
3.2
Objectives will be evaluated separately for each HCV GT.  
1) Objective:  To evaluate the efficacy of co-administered MK-3682 (450mg) + MK-
8408 (60mg) following 12 weeks of treatment, as assessed by the proportion of 
subjects achieving SVR24 (Sustained Virologic Response 24 weeks after the end of all 
study therapy), defined as HCV RNA < LLOQ 24 weeks after the end of all study 
therapy.
2) Objective: To evaluate the efficacy of 12 weeks of treatment with co-administered 
MK-3682 (450mg) + MK-8408 (60mg), as assessed by the proportion of subjects
 
 
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who experience virologic failure (either on-treatment failure or relapse post-
treatment) at Follow-up Week 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 
NS5A and/or NS5B on the efficacy of 12 weeks of treatment with co-administered 
MK-3682 (450mg) + MK-8408 (60mg), as assessed by the proportion of subjects 
with baseline RAVs achieving SVR12. 
Other Objectives (e.g., Tertiary, Exploratory, etc.)
3.3
1) Objective: To evaluate the pharmacokinetics (PK) of MK-3682 (including its 
metabolites) and MK-8408. 
2) Objective: To evaluate the emergence of RAVs in NS5A and/or NS5B in subjects 
with virologic failure.
3) Objective: To explore the relationship between genetic variation, such as IL-28B 
genetic variation and clinical endpoints, 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.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochures (IBs) for detailed background information on MK-3682
and MK-8408.
Pharmaceutical and Therapeutic Background
4.1.1
MK-3682 is an HCV NS5B polymerase nucleotide inhibitor (NI).
MK-8408 is an HCV NS5A replication complex inhibitor (NS5AI).
Overview
4.1.1.1
This study will evaluate a novel two-drug combination regimen to treat HCV infection of all 
genotypes.  Of the 6 HCV genotypes (GTs), GT1 and GT3 are the most common and account 
for approximately 46% and 22% of all global infections, respectively.  GT1 has a broad 
geographical distribution, being the most common genotype in most of North America, 
Northern and Western Europe, South America, Asia and Australia [1]. GT3 HCV infection is 
most prevalent in India, Pakistan, and Southeast Asia.  GT2 infection is the third most 
common genotype worldwide and has a broad geographical distribution.  GT4 infection is 
found predominantly in Africa and the Middle East [1], but is increasingly prevalent in 
France and Southern Europe due to increasing transmission through injection drug use [2].  
Although GT5 and GT6 have a more limited geographic distribution than the other 
genotypes, they predominate in certain regions and represent an unmet medical need in those 
areas with GT5 and GT6 found mostly in sub-Saharan Africa and in Asia, respectively [1].
 
 
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With the advent of oral DAAs, effective IFN and ribavirin (RBV)-free combination regimens 
are now available for subjects chronically infected with certain genotypes.  However, some 
subgroups of subjects, particularly treatment-experienced, cirrhotic subjects, do not achieve 
optimal rates of sustained virologic response (SVR) with existing, approved 12-week 
regimens.  In addition, the currently available dosing regimens are different for different 
HCV genotypes, with some regimens requiring prolonged treatment of up to 24 weeks with 
or without RBV, thus leading to complexity of treatment. Therefore, a regimen without the 
efficacy, safety, and convenience deficits of the existing regimens will be a substantial 
advance in the treatment of HCV infection.  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. MK-3682 and MK-8408 are potent, once-daily antiviral agents 
that inhibit the HCV NS5B RNA polymerase and NS5A replication complex, respectively. 
This study will evaluate the efficacy and safety profile of a novel combination regimen of 
MK-3682 and MK-8408 that simultaneously targets two key points in the viral life-cycle.
The preclinical and clinical profiles of MK-3682 and MK-8408 demonstrate high potency 
against GT1-6 in vitro, supporting the use of this two-drug combination in this trial. MK-
3682 is at least equipotent to sofosbuvir (SOF), an approved NI that anchors multiple current 
all-oral DAA therapies.
In in vitro replicon studies, MK-8408 is more potent against 
multiple HCV genotypes and resistant variants compared with other NS5AI, such as the 
approved drugs ledipasvir (LDV), daclatasvir (DCV), ombitasvir (OMB) and elbasvir (EBR), 
and velpatasvir (VEL). Therefore, a regimen that combines MK-3682 and MK-8408 may be 
sufficient to result in high efficacy in clearing HCV infection of all genotypes.  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 HCV
4.1.1.2
GT1: All oral, IFN-free regimens have demonstrated high degrees of efficacy in treating 
GT1–infected subjects. The highest efficacy rates have been observed in treatment-naïve 
patients.  An approved 12-week regimen of the fixed-dose combination (FDC) of SOF/LDV
resulted in SVR12 rates of 96% to 99% in treatment-naïve (TN), non-cirrhotic (NC) and 94% 
in cirrhotic (C) GT1-infected subjects [3, 4, 5, 6]. SOF/LDV also resulted in SVR12 rates of 
94% in TE NC and C GT1-infected subjects [7]. An approved 12-week regimen of 
ombitasvir/paritaprevir/dasabuvir/ritonavir with RBV achieved SVR12 rates of 96% in TN,
NC patients and 92% in cirrhotic GT1-infected subjects [8, 9, 10].  Without RBV, the 
corresponding SVR12 rate was 99.0% for GT1b and 90.2% for GT1a NC subjects [11].  
Ombitasvir/paritaprevir/dasabuvir/ritonavir with RBV also achieved SVR12 rates of >95% in 
TE GT1-infected subjects [12]. An approved 12-week regimen of grazoprevir (GZR)/ EBR
in TN, NC and cirrhotic GT1-infected subjects achieved SVR12 rates of 94.1% and 97.1%, 
respectively [13, 14], and SVR12 rates of 94.0% and 100.0% in TN NC and cirrhotic HIV co-
infected GT1- and 4-infected subjects, respectively [14, 15].  In the ASTRAL-1 Phase 3 
study, the investigational two-drug combination of SOF/VEL for 12 weeks in GT1-infected 
NC and C subjects with or without previous IFN-based treatment achieved an SVR12 of 98% 
to 99% (323/328) [16].
 
 
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GT2: Current all-oral therapy for GT2 infection consists of a 12-week regimen of SOF/RBV.  
A 12-week regimen of SOF/RBV for TN patients with HCV GT2 infection was studied in 3 
clinical trials: FISSION, POSITRON, and VALENCE [17, 18, 19, 20]. Across all 3 trials,
94% of subjects achieved SVR12.  Based on real-world data from Trio Health, lower response 
rates were seen in TN subjects with cirrhosis than in those without cirrhosis [21]. Longer 
treatment duration improves SVR in treatment-experienced subjects with cirrhosis [18]. In 
current treatment guidelines, longer duration of treatment is recommended in HCV GT2–
infected subjects with cirrhosis [22, 23].  In the ASTRAL-1 and -2 Phase 3 studies, the 
investigational two-drug combination of SOF/VEL for 12 weeks in GT2-infected NC and 
cirrhotic subjects with or without previous IFN-based treatment achieved an SVR12 of 99-
100% (104/104 in ASTRAL-1 and 133/134 in ASTRAL2) [16, 24].
GT3: In GT3-infected subjects, a 24-week regimen of SOF/RBV resulted in SVR12 rates of 
~80-85%, but showed reduced efficacy in prior pegylated-INF+RBV (PR)-treatment failures 
and cirrhotics [20].  More recent IFN-free studies have shown improved efficacy with a 12-
week regimen of SOF/DCV, but continue to show reduced efficacy in prior PR-treatment 
failures and cirrhotics.  SOF/DCV for 12 weeks resulted in SVR12 rates of 98% and 58% in 
TN NC and C subjects, respectively, and in 92% and 69% of TE NC and C subjects, 
respectively [25, 26, 27, 28].  In the ASTRAL-3 Phase 3 study, the investigational two-drug 
combination of SOF/VEL for 12 weeks in GT3-infected NC and cirrhotic subjects achieved 
an SVR12 of 97% (191/197) and 91% (73/80), respectively [24].  In this study, the SVR12 was 
97% (200/206) among those who were TN, 90% (67/71) among those who were treatment 
experienced, and 89% in subjects who had received previous treatment and who had 
evidence of cirrhosis.
GT4: A number of 12-week regimens have been demonstrated to be highly efficacious in 
GT4-infected subjects.  Currently approved all-oral regimens for treatment of GT4 include
SOF/LDV, SOF/DCV, paritaprevir/ritonavir/ombitasvir/ritonavir with RBV, and GZR/EBR.  
SOF/LDV for 12 weeks is approved in the United States (US) for non-cirrhotic and cirrhotic 
subjects, having achieved SVR12 rates of 93% (41/44) and 100% (8/8) in two studies [5].  
SOF/LDV is approved in the European Union (EU) for 12 weeks in non-cirrhotic subjects
and for 12 weeks with RBV or for 24 weeks without RBV for cirrhotic subjects [6]. 
SOF/DCV is approved in the EU for 12 weeks in non-cirrhotic subjects and for 24 weeks for 
cirrhotic subjects [28].  Paritaprevir/ritonavir/ombitasvir with RBV is approved in the EU 
and US for 12 weeks in non-cirrhotic subjects and in the EU for 24 weeks for cirrhotic 
subjects, based on the results of the PEARL-1 trial, in which treatment-naïve and treatment-
experienced subjects treated for 12 weeks achieved SVR12 in 100% (42/42) and 100% 
(49/49) of cases, respectively [10, 29, 30].  A 12-week regimen of GZR/EBR achieved a 96% 
(54/56) SVR12 rate in GT4-infected subjects treated for 12 weeks [13, 15, 14, 31]. In the 
ASTRAL-1 Phase 3 study, the investigational combination regimen of SOF/VEL for 12 
weeks in GT4-infected NC and cirrhotic subjects achieved an SVR12 of 100% (116/116) [16].  
GT5: SOF/LDV is currently the only US-approved all-oral regimen for treatment of GT5.  
SOF/LDV was administered for 12 weeks to 41 treatment-naive (n=21) or previously-treated 
subjects (n=20) with GT5 infection, with or without cirrhosis.  The overall SVR12 was 95% 
(39/41) [5, 32].  In the ASTRAL-1 Phase 3 study, the investigational combination of 
SOF/VEL for 12 weeks in GT5-infected NC and cirrhotic subjects achieved an SVR12 of 
97% (34/35) [16].
 
 
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GT6: SOF/LDV is currently the only US-approved all-oral regimen for treatment of GT6.  
SOF/LDV was administered for 12 weeks to 23 treatment-naive and 2 previously-treated 
subjects with GT6 infection, with or without cirrhosis. The overall SVR 12 was 96% (24/25) 
[5, 33]. In the ASTRAL-1 Phase 3 study, the investigational combination of SOF/VEL for 
12 weeks in GT6-infected NC and cirrhotic subjects achieved an SVR12 of 100% (41/41)
[16].
Pre-clinical and Clinical Trials
4.1.2
Summary of Preclinical Data
4.1.2.1
MK-3682
MK-3682 is a nucleotide prodrug inhibitor of the HCV NS5B RNA-dependent RNA 
polymerase.  The preclinical profile demonstrates that MK-3682 has high potency against 
genotypes 1-6 in vitro.  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).    
MK-3682 has low HCV replicon activity due to a lack of the activating enzyme CES-1 in 
human Huh-7 replicon cells.  Antiviral activity was therefore assessed using a closely related 
surrogate prodrug which shares the same active nucleoside triphosphate moiety as MK-3682.  
The surrogate prodrug had moderate activity against HCV replicons and did not demonstrate 
cross-resistance to several known resistance mutations in NS3, NS5A, and NS5B with the 
exception of NS5B S282T.  Resistance to the surrogate prodrug in the HCV replicon was low 
level and emerged slowly.  The in vitro data implicate S282T as the primary mutation 
responsible for surrogate prodrug resistance.  Overall, the pan-genotypic in vitro potency 
profile and the moderate potency shift against signature RAV S282T for MK-3682 is similar 
to those observed for sofosbuvir [34].
MK-3682 belongs to a class of uridine-based nucleotide analogs, like SOF, that have been 
well tolerated.  Certain purine (guanosine and adenosine) based nucleotide analogs utilizing a 
different prodrug platform have shown mitochondrial toxicities and have had clinical safety 
findings including liver toxicity, cardiomyopathy and hematologic toxicity.  Notably, BMS -
986094 (INX-189), a guanosine analog, showed myocardial degeneration in preclinical 
species and cardiomyopathy/heart failure in clinical trials and was discontinued.  The in vitro
and in vivo preclinical data demonstrate that MK-3682 and its predominant circulating 
metabolite have limited potential for mitochondrial toxicities at the exposures observed in 
clinical settings.
Comprehensive preclinical evaluations of MK-3682 and its predominant circulating 
metabolite have been performed to characterize thoroughly the safety of this compound prior 
to the conduct of clinical studies.  Results of the nonclinical safety program to date have 
demonstrated an acceptable safety profile which compares favorably to other NIs and 
supports the continued clinical development of MK-3682.  MK-3682 exhibited little or no in 
vitro cytotoxicity in a large number of proliferating and non-proliferating human and 
mammalian cell lines, showed no mitochondrial effects in highly proliferating hepatic and 
non-hepatic cells and exerted no measurable cytotoxicity in human cardiomyocytes.  The 
 
 
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toxicity potential of MK-3682 has also been well characterized in a battery of in vitro and in 
vivo genetic toxicity studies, safety pharmacology studies, as well as 2-week, 1-month, 3-
month, and 6-month repeat-dose oral toxicity studies in rats and monkeys.  Collectively, the 
toxicity studies identified minimal findings that were not considered adverse and identified 
the liver and kidney as potential target organs.  No observed adverse effect levels (NOAELs) 
in the rat and Cynomolgus monkey provide adequate margins of safety relative to anticipated 
human doses.  In summary, preclinical assessments have established that MK-3682 has 
promising characteristics as a clinically effective agent and support the use of MK-3682 in 
the treatment of GT1- to GT6-infection in the present study.  Please refer to the MK-3682 IB 
for more information on the preclinical background of MK-3682.
MK-8408
MK-8408 is a potent NS5A replication complex inhibitor.  NS5A is a pleiotropic protein 
with important roles in both HCV RNA replication and modulation of host cell physiology.  
MK-8408 has in vitro activity against replicons from all genotypes tested (Table 2).  It has 
broad genotype activity with an EC50 10 pM against sub-genomic replicons from GTs 1-6.  
The in vitro potency profile of MK-8408 is comparable or better than other NS5A inhibitors, 
such as ledipasvir, EBR, and velpatasvir (Table 2).  MK-8408 retains its potent activity in 
full-length infectious viruses from GT1a (H77Sv3) and GT2a (JFH-1), as well as against 
GT1a RAVs selected by previous NS5A inhibitors in the clinic (Table 3).  Its potency is also 
not affected by signature RAVs from other HCV DAA classes. 
MK-8408 interacts 
synergistically with replicon-active analogues of MK-3682.
Table 2
Potency of MK-8408 versus First Generation NS5A Inhibitors in HCV GT1-GT6
daclatasvirc
ledipasvird
ombitasvir
velpatasvir
elbasvir
MK-8408
Genotype
EC50 (pM)
1a (H77)
50
34
14
12
4
1
1b (con1)
9
4
5
15
3
2
2a (JFH1)
71
21000
12
9
3
1
2b_31Ma
n/a
n/a
4.3
8
3000
4
3a
146
35000
19
12
20
2
4ab
12
110
1.7
9
3
2
5aa
33
150
3.2
75
1
1
6aa
n/a
120
366
130
3
4
a NS5A chimeric replicons from gt2b, gt5 & gt6 were constructed in the background of JFH-1. 
b GT4a NS5A was in the con1 background.  Full-length NS5A was evaluated.
c [35]
d [36]
e [37]
n/a = not available 
 
 
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Table 3
Potency of MK-8408 in Treatment-Emergent GT1a RAVs Selected by Approved 
NS5A Inhibitors in Transient Replication Assay
ledipasvir
ombitasvir
elbasvir
MK-8408
EC50 (nM) Fold Shift EC50 (nM) Fold Shift EC50 (nM) Fold Shift EC50 (nM) Fold Shift
GT1a_H77 (WT)
0.068
1
0.12
1
0.013
1
0.016
1
M28A
17.367
257
40.33
330
0.486
39
0.016
1
M28T
2
30
210.5
1724
0.212
17
0.016
1
M28V
0.038
1
7
55
0.019
2
0.016
1
Q30E
65
962
41
336
0.516
41
0.019
1.2
Q30H
7
102
1.0
8
0.045
4
0.013
0.8
Q30K
32
478
21
175
0.469
37
0.016
1
Q30L
0.695
10
0.07
0.5
0.006
1
0.007
0.4
Q30R
9.5
141
80.5
659
0.229
18
0.02
1.2
L31M
10
150
0.25
2
0.118
9
0.018
1.1
L31V
19
276
6
48
0.821
65
0.076
4.7
H58D
26
380
15
124
0.072
6
0.017
1.1
H58P
0.098
1
0.12
1
0.012
1
0.014
0.9
Y93C
18
266
76
622
0.187
15
0.011
0.7
Y93N
342
5067
1421
11637
6.767
539
0.09
5.6
Y93H
98
1451
1138
9319
3.25
259
0.042
2.6
MK-8408 is highly selective; a selectivity factor of >106 was determined when profiled 
against a panel of 116 proteins comprising enzymes, receptors, ion channels and transcription 
factors.  MK-8408 is not cytotoxic up to 25 µM in replicon cells.  The toxicity potential of 
MK-8408 has also been well characterized in a battery of in vitro and in vivo genetic toxicity 
studies, safety pharmacology studies, as well as 2-week, 1-month, 3-month, 6-month, and 9-
month repeat-dose oral toxicity studies in rats and/or dogs.   Collectively, the toxicity studies 
identified minimal findings that were not considered adverse.  NOAELs in the rat and dogs
provide adequate margins of safety relative to anticipated human doses.  A 1-month oral 
combination toxicity study in rats co-administered MK-3682 with MK-8408 has also been 
completed and demonstrated no findings considered to be adverse or of toxicological 
significance.  In summary, preclinical assessments have established that MK-8408 has 
promising characteristics as a clinically effective agent and support the use of MK-8408 in 
the treatment of GT1- to GT6-infection in the present study.  Please refer to the MK-8408 IB 
for more information on the preclinical studies with MK-8408.
Summary of Clinical Data
4.1.2.2
4.1.2.2.1 Phase 1 Studies
MK-3682 and MK-8408 are currently being evaluated in multiple ongoing Phase 1 trials.  
Please refer to the MK-3682 and MK-8408 IBs for more detailed information on the Phase 1 
clinical studies with MK-3682 and MK-8408.  A brief summary of the relevant Phase 1 
results is provided below. 
MK-3682
 
 
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Single and multiple oral doses of MK-3682 have been well tolerated.  To date, there have 
been no safety signals identified for MK-3682 single doses of up to 900 mg of the tablet 
formulation and total daily doses of up to 300 mg of the capsule formulation for 14 days in 
healthy volunteers, as well as up to 450mg of the tablet formulation once-daily for 7 days in 
HCV-infected subjects.  At a total daily dose of 300 mg of the capsule formulation × 7 days, 
mean maximal HCV RNA reductions were approximately -4.2 and -4.3 log10 IU/mL in GT1 
and GT2 or GT3 HCV-infected subjects, respectively.  At a total daily dose of 450mg of the 
tablet formulation × 7 days, the mean maximal HCV RNA reduction was 
approximately -4.58 log10 IU/mL in GT1-infected subjects.  The magnitudes of viral load 
(VL) decline at 450mg of the MK-3682 tablet formulation are comparable to what was 
observed in the sofosbuvir monotherapy proof-of-concept study [38].  The rationale for dose 
selection in the current protocol is discussed in Section 4.2.2.1.
MK-8408
Single and multiple oral doses of MK-8408 have been well tolerated.  To date, there have 
been no safety signals identified at single doses up to 600 mg and multiple doses once-daily 
up to 100 mg for 10 days in healthy volunteers, as well as multiple doses up to 120 mg once-
daily for 5 days in HCV-infected subjects.  At a total daily dose of 60mg × 5 days, mean 
maximal HCV RNA reductions were at least -3 log10 reduction in VL from baseline in GT1, 
GT2, and GT3 HCV-infected subjects.  The magnitudes of viral load decline with MK-8408 
are comparable to what was observed with velpatasvir monotherapy proof-of-concept study 
[39]. The rationale for dose selection in the current protocol is discussed in Section 4.2.2.2.
4.1.2.2.2 Summary of Ongoing Phase 2 Clinical Trials
MK-3682 and MK-8408 are currently being evaluated in combination with MK-5172 
(grazoprevir or GZR, an HCV NS3/4A protease inhibitor).  GZR is approved in the US in 
combination with EBR, MK-8742, an HCV NS5A inhibitor, for the treatment of HCV 
infection genotypes 1 and 4 as EBR/GZR (ZepatierTM).  A FDC of MK-3682/GZR/MK-8408 
(MK-3682B) is currently being evaluated in three 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. A brief summary of the Phase 2 three-drug combination 
regimen studies containing MK-3682 and MK-8408 is provided. 
MK-3682 PN011 and PN012
MK-3682 PN011 and PN012 are two ongoing Phase 2 two-part, randomized, dose-ranging, 
parallel-group, multicenter, open-label trials to evaluate the safety and efficacy of three-drug 
regimens in subjects with chronic HCV GT1-GT6 infection. Subjects with GT1 and GT2 are 
being enrolled in PN011; subjects with GT3-GT6 are being enrolled in PN012.
In Part A of these studies, 93 GT1 (46 GT1a, 47 GT1b), 61 GT2, and 86 GT3-infected 
treatment-naïve, non-cirrhotic subjects with chronic HCV infection were dosed once-daily 
for 8 weeks duration with one of 4 regimens including MK-3682 (300 mg or 450mg), GZR 
(100 mg), and either EBR (50 mg) or MK-8408 (60mg).  
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 
 
 
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(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 (450mg)/GZR/MK-8408 regimen was highly 
effective (94%), but SVR rates were suboptimal among subjects who received the other 
regimens (60-71%).  The MK-3682 (450mg)/GZR/MK-8408 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 MK-8408 achieved 
SVR12.  The MK-3682 (300 or 450mg)/GZR/MK-8408 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) 
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 four 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× the 
upper limit of normal (ULN) at TW8 with a pattern consistent with the late ALT increases 
observed in the Phase 2 and 3 GZR studies, which rapidly resolved off study drug.  There 
were no drug-related serious adverse events (SAEs) and no subjects discontinued due to AEs.  
The results of Part A demonstrated that an 8-week regimen of MK-3682 (450mg)/GZR/MK-
8408 was highly effective and well tolerated in GT1-, GT2-, and GT3-infected treatment-
naïve, non-cirrhotic subjects, supporting the selection of this regimen from the four 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
(MK-3682B).  Each MK-3682B tablet contains GZR (50 mg), MK-3682 (225 mg), and MK-
8408 (30 mg), and is administered as two tablets once daily, for a total daily dose of 100 mg 
GZR, 450mg MK-3682, and 60mg MK-8408.  Non-cirrhotic and cirrhotic, treatment-naïve 
and pegylated-IFN/RBV (PR) treatment-experienced, GT1-GT6 subjects with or without 
HIV co-infection have received MK-3682B with or without RBV for 8, 12, or 16 weeks of 
therapy, depending on the treatment arm.
A total of 603 GT1, 2, and 3 subjects were enrolled in Part B: 153 GT1-infected (82 GT1a, 
71 GT1b) treatment naïve (TN) patients with or without compensated cirrhosis, 135 GT2 TN 
patients (99 non-cirrhotic, 36 cirrhotic), and 315 GT3-infected treatment-naïve or treatment 
experienced (PR) patients with or without compensated cirrhosis. All patients were treated 
with MK-3682B, with or without RBV, for 8, 12, or 16 weeks. Patients could be mono-
infected or HIV co-infected. Enrollment is underway for subjects infected with genotypes 4, 
5 and 6, but no results are yet available for these GTs.
 
 
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PPD

Product:  MK-3682 
24
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
Table 5
Preliminary results for PN011 Part B for 8, 12 and 16 weeks of MK-3682B with 
or without RBV in GT2-infected Treatment-Naïve Subjects With and Without 
Cirrhosis; % of Subjects Achieving SVR4+ of Those Who Have Reached at least 
FW4
Non-Cirrhotic†
n/N (%SVR)
Cirrhotic†
n/N (%SVR)
Total†
n/N (%SVR)
GT2 8 weeks (n=16)
14/16 (88%)
--
14/16 (88%)
GT2 8 weeks w/RBV (n=31)
25/29 (86%)
--
25/29 (86%)
GT2 12 weeks (n=31NC; 15C)
31/31 (100%)
10/10 (100%)
41/41 (100%)
GT2 12 weeks w/RBV (n=16)
--
10/10 (100%)
10/10 (100%)
GT2 16 weeks (n=26)
--
21/21 (100%)
21/21 (100%)
† SVR4/8/12 (last visit on record) in subjects with ≥4 weeks of post-therapy follow-up updated 5 June 2016
In the 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 MK-8408 in vitro.  Baseline next-generation sequencing (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). The 
results to date suggest that MK-3682B for 12 weeks is highly effective and well tolerated in 
GT2-infected treatment-naïve, non-cirrhotic and compensated cirrhotic subjects.  
Results to date are available for 283 GT3-infected patients who have reached at least FW4 
(Table 6).  All subjects had undetectable HCV RNA at the end of their assigned 8, 12, or 16 
weeks of treatment.  Of the 283 patients (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.  
 
 
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PPD

Product:  MK-3682 
27
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
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 MK-8408, both once-
daily medications, is suggested by their non-overlapping viral targets, the pangenotypic in 
vitro potencies of both MK-3682 and MK-8408, the proven success of other HCV NIs in 
combination with other NS5A inhibitors, and the high efficacy rates from the investigational 
three-drug regimen containing MK-3682, MK-8408, and GZR.
Rationale for the Selected Subject Population
4.2.1.2
The rationale for the patient populations selected for this trial is as follows:

Genotypes:  The efficacy of the two-drug regimen in HCV-infected subjects of all 
genotypes will be evaluated to allow for an initial assessment of the two-drug 
combination regimen of MK-3682 and MK-8408 as a pangenotypic therapy for HCV.  
The preclinical profiles of MK-3682 and MK-8408 demonstrate high potency against 
GT1-6 in vitro.  In addition, the preliminary data from Phase 2 studies of MK-
3682/GZR/MK-8408 demonstrate excellent tolerability and very high efficacy of this 
three-drug regimen when administered for 8 weeks or for 12 weeks in GT1- and GT3-
infected subjects (see Section 4.1.2.2.2, above).  In GT2-infected subjects there was 
excellent tolerability and the 12-week arm has had very high efficacy (100%), while 
the 8-week arm has shown sub-optimal efficacy (87%). Taken together, these data 
support the clinical evaluation of the combination of MK-3682 and MK-8408 as a 
pangenotypic therapy for HCV as a 12-week regimen in GTs 1-6.

Treatment-Naïve: Treatment-naïve subjects who have never received medical 
therapy for HCV and have no evidence of cirrhosis represents 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 IFN-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, 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 [4, 7, 12, 16, 18, 24, 40].  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 4.2.1.3 and 8.9.1, 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 evaluation of this 
two-drug regimen to better understand the ability of this regimen to effectively treat 
subjects with baseline resistant variants in the context of this study before proceeding 
to further studies to evaluate the ability of the two-drug regimen to treat prior DAA 
failures.
 
 
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
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 [13, 16, 24, 40].  Most 
recently, the ASTRAL-1 Phase 3 study of SOF/VEL demonstrated 100% SVR in 5/5 
GT5- and 6/6 GT6-infected cirrhotic subjects [16]. Given the comparable SVR12 rates 
observed following 12 weeks of all-oral IFN-free DAA regimens, including the 3-
drug regimen of MK-3682/GZR/MK-8408 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 4.2.1.3, 5.3 and 8.9.1, 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, since
HCV infection is a leading cause of morbidity and mortality among those with HIV-1 
[41].  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 [42].  Compared 
to subjects infected with HCV alone, HIV/HCV co-infected subjects have higher 
baseline HCV 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 [31].  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 
[15].  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.
Rationale for Study Design
4.2.1.3
The pangenotypic preclinical profiles of MK-3682 and MK-8408, as well as the preliminary
results from the three-drug, 8- and 12-week regimens of MK-3682/GZR/MK-8408 in GT1, 
GT2 and GT3 support the preliminary evaluation of the safety and efficacy of 12 weeks of 
MK-3682+MK-8408 in treatment-naïve or prior IFN-based treatment experienced, non-
cirrhotic and compensated cirrhotic GT1-, GT2-, GT3-, GT4-, GT-5, and GT-6-infected 
 
 
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subjects.  A treatment duration of 12-weeks for all genotypes using the MK-3682+MK-8408 
combination in this study is supported by the equipotent or superior in vitro potency profiles 
of MK-3682 and MK-8408 (Table 2 and Table 3) compared to other compounds of the same 
classes, such as the approved NI/NS5A SOF/LDV or SOF/VEL, that have demonstrated high 
efficacy rates against GT1-6 after 12 weeks of treatment as two-drug IFN-free DAA 
regimens.  RBV is not proposed to be evaluated in this study given the high efficacy rates 
observed with other two-drug all-oral DAA regimens without RBV, such as SOF/LDV and 
SOF/VEL, and the equipotent or superior in vitro potency profiles of MK-3682 and MK-
8408 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.  The target number of GT1-, GT2-,
GT3-, and GT4-infected subjects is specified in order to provide sufficient confidence of the 
estimated treatment response rate in these genotypes, since they are the most prevalent 
genotypes globally.  Since subjects with genotypes 5 and 6 are uncommon outside of certain 
geographic areas, the study will enroll approximately a targeted number of subjects with the 
assumption that full enrollment of these genotypes may not be reached.    
If a total of ≥3 out of the first 10 subjects in the per-protocol population of the 12 week arms 
experience virologic relapse by FW4, all subjects already enrolled and on treatment for that 
GT will have their treatment duration extended to 16 weeks.  This treatment duration 
modification rule was chosen in order to stop a regimen that had a reasonable probability of 
being insufficiently effective (in this case because of insufficient duration), while not 
prematurely discontinuing a regimen that could be successful.  This choice was based on the 
following calculations to estimate the probability of observing a given number of subjects 
with virologic failure rates assuming a range of true SVR rates.  Assuming a protocol 
violation rate of 10%, the PP population will include approximately 9 subjects out of the first 
ten of each genotype. The probability of observing 3 or more subjects with virologic failure 
out of 9 subjects per arm is 53.7%, 39.9%, 26.2%, 14.1%, and 5.3% assuming the true SVR 
rates of 70, 75, 80, 85, and 90%, respectively.  Detailed information on these calculations is 
in Section 8.7.  This modification rule provides an approximately 40% probability of 
extending treatment duration of a given genotype in the study for a true SVR rate of 75% or 
less, but is unlikely to extend the treatment duration if the SVR rate is 90% or higher (which 
is the SVR rate expected from a competitive regimen).
Patients who fail the MK-3682+MK-8408 regimen will be followed long-term, as described 
in Sec. 7.1.5.6.  No rescue medications are included in this trial because it is not clear which
rescue regimen would be optimal for patients who fail MK-3682+MK-8408.  Subjects who 
experience virologic failure will be considered for future therapy once data are available to
guide selection of rescue regimens. The composition and duration of future retreatment will 
be informed not only by the efficacy and RAVs observed at baseline and at failure in this 
study, but also from results from ongoing Phase 2 studies of MK-3682B.  The efficacy of 
MK-3682B in cirrhotic and non-cirrhotic patients at different durations in GT1-6 is being 
evaluated in Part B of MK-3682 PN011 and PN012.  In addition, results from Part C of MK-
3682 PN011 and PN012, in which subjects who failed 8-week regimens of MK-3682+ GZR
+ either MK-8408 or EBR, are being retreated with a regimen consisting of 16 weeks of MK-
3682B plus RBV, may provide insights into the optimal treatment for these patients.  MK-
3682 PN021 is evaluating retreatment of GT1-infected patients who have previously failed 
 
 
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all-oral DAA regimens with regimens of 16 weeks of MK-3682B plus RBV or 24 weeks of 
MK-3682B without RBV. The role of RAVs in virologic failures in these studies will be 
analyzed and results from other retreatment studies using currently available therapies will be 
considered in evaluating the optimal retreatment regimen for potential subjects who fail 
treatment in this study.
Additional stopping rules are described in Section 5.11.
Rationale for Dose Selection/Regimen/Modification
4.2.2
The regimen selected for administration in this trial is 450mg of MK-3682 + 60mg of MK-
8408 administered concomitantly once daily as separate medications.
Dose Selection for MK-3682
4.2.2.1
The 450mg dose of MK-3682 was chosen for this study based on the dose-response analysis 
generated by monotherapy data from MK-3682 PN001.  This analysis suggests that the 
450mg dose of the tablet formulation is on the plateau of the dose-response curve and would 
provide a greater margin to loss of efficacy than would the 300mg of the tablet formulation, 
while still maintaining margins to preclinical safety exposures.  Although the 300mg and 
450mg MK-3682 dose arms had comparable efficacy in GT3-infected subjects in PN012 Part 
A (SVR12 of 39/42 (93%) and 39/44 (89%), respectively), a slightly higher efficacy was 
observed in in GT2-infected subjects in MK-3682 PN011 Part A who were on the 450mg
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 
(450mg)/GZR/MK-8408 arm with an SVR12 rate of 94% (15/16), supporting the selection of 
this regimen for this study.  In addition, the 450mg dose of MK-3682 has demonstrated an 
acceptable safety profile in Part A of MK-3682B PN011 and PN012 when co-administered 
with GZR and MK-8408 or MK-8742.
Dose Selection for MK-8408
4.2.2.2
The 60mg dose of MK-8408 was chosen for the MK-3682B FDC regimen based on the 
available safety, tolerability, and pharmacokinetic data from the single and multiple dose and 
drug-interaction studies in healthy volunteers and the pharmacokinetic, pharmacodynamic 
(PD)
and safety profiles of MK-8408 in HCV infected subjects.  Preliminary 
pharmacodynamic data from PN003 are available for doses up to 120 mg in HCV GT3 
subjects and demonstrate that following once daily fasted dosing of 10, 30, 60, and 120 mg 
MK-8408 for 5 days, the mean maximum reduction in HCV VL was -2.83, -3.03, -3.35 and -
1.75 log10 IU/mL, respectively.  The anomalous fall in VL decline at 120 mg dose of MK-
8408 was explained by sequencing of the HCV subjects’ isolates that revealed that all 3 
subjects in this panel had either baseline or treatment-emergent resistance-associated variant 
viruses.  One subject had the resistant variants S62L/Y93H at baseline and following 
treatment; this subject had a maximal VL reduction of -0.34 log 10 IU/mL.  One subject had 
no detectable RAVs at baseline but had both S62L and Y93H emerge during treatment; this 
subject had a -1.85log10 IU/mL VL reduction.  The third subject had A30K at baseline with 
emergence of Y93H/Y during treatment; this subject had a -3.06log10 IU/mL VL reduction.  
These VL results demonstrate that 30 mg and 60mg of MK-8408 are associated with a 
substantial and rapid initial VL decline of GT3, but that MK-8408 may not exhibit full 
 
 
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efficacy against some GT3 RAVs in the setting of monotherapy administration.  Following a 
single dose of 60mg MK-8408 once-daily × 5 days the mean maximum reduction in HCV 
VL in GT1a subjects was -3.86 log10 IU/mL, and the mean maximum reduction in HCV VL 
in GT2b subjects was -3.62 log10 IU/mL.  For detailed information, please refer to the MK-
8408 IB.
The fit-for-purpose capsule formulation of MK-8408 demonstrates 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.  Study drugs should be taken with 
water, but without food.  Drug-drug interaction studies with MK-3682 and MK-8408 (MK-
3682 PN007 and MK-3682 PN008) demonstrated no clinically significant drug interactions, 
thus supporting the coadministration of these drugs without need for dose adjustment.
Rationale for Endpoints
4.2.3
Efficacy Endpoints
4.2.3.1
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 [43].
The primary evaluation of efficacy in this trial is based on SVR12, the same endpoint used for 
all investigational and approved DAAs (e.g., simeprevir, SOF).  Since a high degree of 
concordance has been observed between SVR12 and SVR24 [44], SVR12 is now being used as 
the primary endpoint for registration of DAAs.  A secondary evaluation of efficacy is based 
on SVR24 (Sustained Virologic Response 24 weeks after the end of all study therapy), and for 
this study this will be a secondary endpoint [45].
4.2.3.1.1 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 Study 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.
 
 
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The nomenclature detailed in Table 7 will be used when describing HCV RNA levels:
Table 7
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
Definition of Efficacy Endpoints
4.2.3.1.1.1
Efficacy will be defined at different timepoints during the trial. 
Specific primary and 
secondary endpoints are:

SVR4 (Sustained Virologic Response 4 weeks after the end of all study therapy).  The 
subject has HCV RNA < LLOQ 4 weeks after the end of all study therapy.

SVR8 (Sustained Virologic Response 8 weeks after the end of all study therapy).  The 
subject has HCV RNA < LLOQ 8 weeks after the end of all study therapy.

SVR12 (Sustained Virologic Response 12 weeks after the end of all study therapy).  
The subject has HCV RNA < LLOQ 12 weeks after the end of all study therapy.

SVR24 (Sustained Virologic Response 24 weeks after the end of all study therapy). 
The subject has HCV RNA < LLOQ 24 weeks after the end of all study therapy.

Virologic failure rate among subjects who do not discontinue study for non-
treatment-related reasons at FW12.
Definition of Virologic Failure: Non-Response, Rebound, Virologic 
4.2.3.1.1.2
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 captured 
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.

Virologic breakthrough:
Subject has a confirmed HCV RNA ≥ LLOQ after being < LLOQ previously 
while on treatment. Confirmation is defined as an HCV RNA ≥ LLOQ from a 
separate blood draw repeated within 2 weeks.
 
 
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
Relapse:
Subject has a confirmed HCV RNA ≥ LLOQ following end of all study therapy, 
after becoming undetectable (TND) at end of treatment. Confirmation is defined 
as an HCV RNA ≥ LLOQ from a separate blood draw repeated within 2 weeks.
4.2.3.1.2 Viral Resistance Measurements
Resistance associated variants (RAVs) in the hepatitis C virus 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+MK-
8408, blood samples for viral resistance assays are collected at Baseline (Day 1) to determine 
pre-existing RAVs to MK-3682 and MK-8408.  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 MK-8408 following treatment initiation. RAVs will be assessed for any subject who 
has detectable virus above 1000 IU/mL and has met a virologic failure criteria.  
Safety Endpoints
4.2.3.2
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 electrocardiograms (ECGs), and standard laboratory safety tests at appropriate time 
points as specified in the Study 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
4.2.3.3
The primary pharmacokinetic (PK) endpoint for MK-3682 (and metabolites) and MK-8408 is
Ctrough.  PK samples will be collected from all subjects on each visit as described in the Study 
Flow Chart (Section 6.0) and in Table 12 (Pharmacokinetic Sampling Timepoints).  These 
samples will be used to evaluate not only PK concentrations, but also PK/PD and PK/AE 
relationships of MK-3682 (and metabolites) and MK-8408, as appropriate.  The pre-dose 
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 post-dose 
time points, in conjunction with the other samples, will be used for PK-safety and PK-
efficacy modeling.
Pharmacodynamic Endpoints
4.2.3.4
As described in Section 7.1.3.2.2, 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 which may
be efficacious with various treatment durations.
These subjects will have HCV RNA samples collected during Week 1 as described in the
Study Flow Chart (Section 6.0) and in Table 13 (Intensive Viral Kinetic Week 1 Sampling
 
 
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Timepoints). In addition, PK samples will be collected as described in Table 12
(Pharmacokinetic Sampling Timepoints).  These samples will be used to evaluate the PK/PD 
relationships of MK-3682 (and metabolites) and MK-8408, as appropriate.
Planned Exploratory Biomarker Research
4.2.3.5
Planned Genetic Analysis 
Understanding genetic determinants of drug response 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. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
In addition to studying variation across the human genome, for example IL28, genetic 
variants [46] will specifically be investigated for understanding variation in clinical 
endpoints for example, but not limited to, SVR and other efficacy safety and measurements.
Future Biomedical Research
4.2.3.6
The Sponsor will conduct Future Biomedical Research on specimens collected 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.
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 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.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination 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 to address deficiencies in current 
therapy, including lower than optimal efficacy rates in select patient populations, drug 
resistance, and a lack of convenience. The two-drug, once-daily combination regimen 
containing MK-3682 (an HCV NS5B NI) and MK-8408 (an HCV NS5A complex inhibitor) 
has the potential to simplify treatment paradigms and reduce the need for pretreatment testing 
by providing a well-tolerated and efficacious regimen for multiple genotypes and diverse 
patient populations.  
 
 
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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. 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 
750 mg per day for 10 days, and in Phase 2a trials of 300 mg or 450mg 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 (450mg)/GZR/MK-8408 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.
MK-8408
MK 8408 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 MK-8408 against 
RAVs observed with earlier generation NS5A inhibitors suggests that MK-8408 will have 
 
 
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improved efficacy in individuals who have experienced treatment failures with other anti-
HCV regimens and/or have NS5A RAVs at baseline. 
MK-8408 has favorable safety findings in safety assessment toxicity studies and ancillary 
pharmacology studies, supporting the continued evaluation of MK-8408 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. MK-8408 has been given to approximately 217 subjects and subjects in 8 MK-8408 
Phase 1 trials and in over 800 subjects in ongoing Phase 2a trials (MK-8408 in combination 
with MK-3682 and GZR in HCV GT1, 2, and 3-infected subjects). MK-8408 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.  No serious adverse experiences 
have been reported in any individual receiving MK-8408. There were no consistent 
treatment-related changes in labs, vital signs, or ECG safety parameter values.  Adverse 
experiences in subjects receiving MK-8408 monotherapy have been mild to moderate in 
intensity and transient in duration.  The totality of the safety data indicates that MK-8408 is 
well-tolerated.
Definitive embryo-fetal developmental toxicity studies conducted in concordance with the 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) M3 (R2) guidance have been completed in rats and 
rabbits for MK-3682 and MK-8408.  Data support the inclusion of women of childbearing 
potential in clinical trials with MK-3682 and MK-8408.  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 two-drug combination of MK-3682+MK-8408.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (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 of at least 18 years of age with chronic HCV infection 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 genotype) infection and meet the definition below:
 
 
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
Positive for anti-HCV antibody, HCV RNA, or HCV GT1, GT2, GT3, GT4, 
GT5, or GT6 at least 6 months before Day 1
OR

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. be otherwise healthy as determined by the medical history, physical examination, 
ECG, and clinical laboratory measurements performed at the time of screening.
5. have liver disease staging assessment as follows:
Absence of cirrhosis is defined as any one of the following:

Liver biopsy performed within 24 months of Day 1 of this study showing 
absence of cirrhosis

Fibroscan performed within 12 months of Day 1 of this study with a result of 
≤12.5 kPa

A Fibrosure® (Fibrotest®) score of ≤0.48 and aspartate aminotransferase 
(AST) to Platelet Ratio Index (APRI) of ≤1 during Screening
Compensated cirrhosis is defined as any one of the following:

A liver biopsy performed prior to Day 1 of this study showing cirrhosis (F4)

Fibroscan performed within 12 calendar months of Day 1 of this study with a 
result >12.5 kPa 

A FibroSure® (Fibrotest®) performed during Screening with a score of >0.75 
and an aspartate aminotransferase (AST): platelet ratio index (APRI) of >2.  
APRI formula:  AST÷lab ULN for AST × 100÷ (platelet count÷100) (APRI 
calculation to be provided by the central laboratory)
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®
6. be HCV treatment-naïve (defined as no prior exposure to any IFN, RBV, or other 
approved or experimental HCV-specific direct-acting antiviral agent) OR be HCV 
treatment-experienced (defined as prior virologic failure after treatment with an IFN-
containing regimen, with or without ribavirin, or intolerance to an IFN-containing 
regimen).  Subjects may not have previously received treatment with HCV direct-
acting antiviral agents
7. meet one of the following criteria:
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 
 
 
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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 through 14 days after taking the last 
dose of study drug (or longer if dictated by local regulations) by complying with one 
of the following:  (1) practice abstinence† from heterosexual activity OR (2) use (or 
have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
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.
8. understand the study procedures, alternative treatments available, risks involved with 
the study, and voluntarily agrees to participate by giving written informed consent.
9. provide written informed consent for the trial.  The subject may also provide consent 
for Future Biomedical Research.  However, the subject may participate in the main 
trial without participating in Future Biomedical Research.
For HIV co-infected subjects these additional criteria must also be met:
10. have HIV-1 infection documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
 
 
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(Day 1) 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.
11. meet one of the following criteria:
a.
not currently be on antiretroviral therapy (ART) and have no plans to initiate 
ART treatment while participating in this study. 
i. subjects not on ART must have CD4+ T-cell count >500 cells/mm3 at 
time of screening
b. have well controlled HIV on ART, defined as:
i. subjects on ART must have a CD4+ T-cell count >200 cells/mm3 at 
time of screening
ii. subjects on ART must have achieved and maintained virologic 
suppression (defined as confirmed HIV RNA level below the LLOQ of 
available assay at the time of screening) for at least 8 weeks prior to 
screening
iii. subjects on ART 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)
iv. the combination ART regimen must not contain any antiretroviral 
medications other than: tenofovir, abacavir, lamivudine, emtricitabine, 
raltegravir, dolutegravir or rilpivirine
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. For cirrhotics: subjects that are Child-Pugh Class B or C, or who have a Pugh-
Turcotte (CPT) score >6, must be excluded.
NOTE: To calculate the Child-Pugh score, refer to the following website: 
http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality.
4. is coinfected with hepatitis B virus (e.g. HBsAg positive).
5. For subjects with HIV, has a history of opportunistic infection in the preceding 6 
months prior to screening.  A list of these events may be found in Appendix B of the 
following document: http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm
 
 
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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 Section 5.5 of the 
protocol 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.
10. Has, in the opinion of the investigator, clinically-relevant drug or alcohol abuse 
within 12 months of screening.
11. is a female and is pregnant or breast-feeding, or expecting to conceive or donate eggs 
from at least 2 weeks prior to Day 1 through at least 14 days after the last dose of 
study drug, or longer if dictated by local regulations, OR is a male subject who is 
expecting to donate sperm or planning to impregnate female partner(s) from at least 2 
weeks prior to Day 1 through 14 days after the last dose of study drug, or longer if 
dictated by local regulations.
NOTE: After treatment allocation, female subjects should avoid conceiving or 
donating eggs and male subjects should avoid impregnating a partner or donating 
sperm for at least 14 days after taking the last dose of study drug.
12. has any of the following conditions:
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. Any clinically significant cardiac abnormalities/dysfunction, including but not 
limited to: unstable angina, unstable congestive heart failure, and unstable
arrhythmia.
e.
History of a medical/surgical condition that resulted in hospitalization within 
the 3 months prior to enrollment, other than for minor elective procedures.
f.
Medical/surgical conditions that may result in a need for hospitalization 
during the period of the study.
 
 
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g. Any medical condition requiring, or likely to require, chronic systemic 
administration 
of 
corticosteroids, 
TNF 
antagonists, 
or 
other 
immunosuppressant drugs during the course of the trial.
h. Any condition, pre-study laboratory or ECG abnormality or history of any 
illness, which, in the opinion of the investigator, might confound the results of 
the study or pose additional risk in administering the study drugs to the 
subject.
i.
A life-threatening SAE during the screening period.
j.
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.
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 8.
NOTE:  If any of the laboratory exclusion criteria below in Table 8 are met, 
the site may have the abnormal value retested one time.
Table 8
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
Total Bilirubin
>2.0 mg/dL unless history of Gilbert's disease (If Gilbert’s disease is the proposed 
etiology, this must be documented in the subject’s chart)
Serum Albumin
<3.0 g/dL
INR
>1.7 unless subject has a stable INR on an anticoagulant regimen
ALT
>10× ULN
AST
>10× ULN
1 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
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 in Table 9.  
 
 
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Table 9
Trial Treatment for Each Arm
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
MK-3682
450mg
(3 x 150mg 
tablet)
QD
Oral
12 weeks
Experimental
MK-8408
60mg
(6 x 10mg 
capsule)
QD
Oral
12 weeks
Experimental
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.  All other dosing will be performed by the subject (i.e., 
unsupervised at his/her home) in the morning at approximately the same time each day for 
MK-3682 and MK-8408.
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.
Dose Modification (Escalation/Titration/Other)
5.2.1.2
Dose modification of MK-3682 or MK-8408 is not permitted. See Section 5.2.2 for 
instructions if for any reason MK-3682 or MK-8408 needs to be interrupted.  For any other 
dose modifications that occur, consult the Sponsor Protocol team.
Timing of Dose Administration
5.2.2
All doses of MK-3682 and MK-8408 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;
PK samples will still be collected during these visits.
If a subject misses a dose of MK-3682 or MK-8408 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. 
 
 
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If a subject misses a dose of MK-3682 or MK-8408 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 MK-8408 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.  
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
All subjects will receive a treatment regimen of MK-3682 (450mg) + MK-8408 (60mg) co-
administered concomitantly as separate medications once-daily for 12 weeks.  Subjects will 
be assigned to treatment arms based on genotype.
Documentation of treatment period entry will occur centrally using a computer generated 
allocation schedule to assign a treatment/allocation number.
Stratification
5.4
Although there is no randomization, subjects are classified (stratified) by genotype to 
determine assignment to treatment arm by design.  No other stratification based on age, sex, 
or other characteristics will be used in this trial.
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.
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. 

At each visit, subjects should be questioned about any new drug they are taking or 
have taken since the last visit. 

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. 

Drugs known to be hepatotoxic (i.e., drugs with a warning of hepatotoxicity in the 
package insert) should be avoided during the dosing period. Investigators are 
encouraged to review each medication for potential hepatotoxicity by searching the 
www.livertox.nih.gov website.
 
 
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Specific restrictions for concomitant therapy during the course of the trial are listed.  These 
are based on the current known metabolism of the drugs as described.
Restrictions may be removed if indicated by emergent data from drug-drug interaction trials.  
Any medications/therapies no longer contraindicated will be communicated to the site by an 
administrative letter.
The following medications/therapies are not permitted from 2 weeks prior to Day 1 through 
2 weeks after the study treatment period.
Known hepatotoxic drugs, including but not limited to: 

etifoxine

isoniazid

nitrofurantoin
Herbal supplements
Antiarrhythmic agents (including but not limited to amiodarone, quinidine, bepridil, 
disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone)
Strong inhibitors of CYP3A, including but not limited to:

clarithromycin

telithromycin

itraconazole

ketoconazole

nefazodone
Strong and moderate CYP3A inducers, including but not limited to: 

anti-infectives: nafcillin, rifampin

anticonvulsants: carbamazepine, phenytoin, phenobarbital

bosentan

modafinil

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 MK-8408 (see Allowed Medication 
below)
 
 
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HIV medications (note that not all prohibited HIV medications are listed): 

efavirenz

etravirine

nevirapine

ritonavir

all boosted and unboosted HIV protease inhibitors
Note: the only permitted HIV medications are tenofovir, abacavir, lamivudine, 
emtricitabine, raltegravir, dolutegravir and rilpivirine
HMG-CoA reductase inhibitors (statins):  

rosuvastatin greater than 10 mg (see Allowed Medications below)

atorvastatin, simvastatin, lovastatin, or fluvastatin greater than 20 mg (see 
Allowed Medications below)
In general, P-gp 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.
Investigational agents are not permitted.
Systemic corticosteroids (dose equivalent to ≥10 mg prednisone per day, except in the case 
of rapid steroid tapers <1 week in duration) are not permitted.
Allowed Medications:
The following concomitant medications are allowed in this study: 
Antihypertensives:

ACE inhibitors/ARB: 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: erythropoetin
Diuretics: hydrocholorothiazide, 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
 
 
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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 MK-8408
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  
Anti-coagulants: warfarin, heparin, low molecular weight heparin, aspirin, fondaparinux, 
desirudin, acenocoumarol
Opiate 
substitution 
therapy: 
Subjects
on 
stable 
doses 
of 
methadone 
or 
buprenorphine/naloxone may be enrolled in this study, if not excluded under Exclusion 
Criterion 10 in Section 5.1.3.
Given that this list is 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.
Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
5.7
MK-3682 and MK-8408 should be taken on an empty stomach after an overnight fast and at 
least 1 hour before the morning meal.  Study medication should be taken with water but 
without food.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
A subject must be discontinued from the trial if:
○
The subject or legal representative (such as parent or legal representative) withdraws 
consent.
 
 
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A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
Table 10 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 10
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 
<30 mL/min/1.73 m2, confirmed with repeat test within 1 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 to be a study drug-related 
laboratory or clinical AE.
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 study unless there is a requirement 
for prohibited concomitant medications (see Section 5.5) to construct a new HIV treatment 
regimen.
 
 
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Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall
not be allowed to restart treatment.
Subject Replacement Strategy
5.9
A subject who discontinues 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,
discontinues 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 as follows.
Safety Criteria for Pausing Enrollment
5.11.1
If ≥3 subjects receiving MK-3682 and MK-8408 experience any of the following, assignment 
of new subjects into that arm will be paused. Subjects that are tolerating treatment may 
continue to receive study therapy, but no additional subjects will be enrolled into that arm 
until the Sponsor has reviewed all safety data on subjects, including:

Life threatening clinical AEs, or an event that results in or prolongs an existing in-
subject hospitalization, or deaths that are assessed to be study drug-related

Grade 4 laboratory AEs that are assessed to be study drug-related laboratory AEs
Safety Criteria for Stopping Enrollment and Early Trial Termination
5.11.2
If a total of ≥12 subjects (~5%) in the 12-week arms of MK-3682+MK-8408 experiences any 
of the following, the trial will terminate.

ALT or AST increases to >500 IU/L and is assessed to be study drug related

The subject’s serum creatinine increases to Grade 3 or higher (>1.8× upper limit of 
normal), confirmed with repeat test within 1 week

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, or death, that is 
assessed to be study drug-related

The subject’s creatinine clearance decreases to <30 mL/min/1.73 m 2, confirmed with 
repeat test within 1 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
 
 
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Efficacy Criteria for Stopping Enrollment
5.11.3

If a total of ≥2 out of the first 10 HIV-infected subjects in the PP population across all 
arms experience confirmed loss of HIV-1 virologic suppression, then no additional 
HIV/HCV 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 would continue HCV treatment 
regimen while their HIV regimen is being reassessed.

If a total of ≥3 out of the first 10 subjects in the PP population enrolled in a 12-week 
dosing duration arm experience virologic non-response, rebound, breakthrough or 
relapse by FW4, no further subjects will be enrolled in that 12-week treatment arm.
Clinical Criteria for Trial Modification
5.12
Efficacy Criteria for Modification of Treatment Duration
5.12.1

If a total of ≥3 out of the first 10 subjects in the PP population enrolled in a 12-week 
dosing duration arm experience virologic relapse by FW4, the treatment duration of 
any remaining subjects of that genotype in that arm will be extended to 16 weeks and 
no further subjects will be enrolled in that 12 week treatment arm. 
 
 
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6.0 TRIAL FLOW CHART
1st Week
Treatment Weeks
Follow-Up Weeks
Unscheduled
Main Study Population
12-week Treatment 
Screening
Day 18
NA
NA
NA
Day 7
2
4
6
8
10
12
1413
1613
FW4
FW8
FW
12
FW
1614
FW
2014
FW
24
HCV/HIV Viral 
Failure 
Confirmation 
Visit 9,10
Early 
Discontinuation 
Visit 9, 11
Intensive Viral Kinetic subgroup
Day 2 12
Day 312
Day512
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Visit Windows
NA
NA
NA
+2d
-1 to 
+2d
-2 to 
+2d
-4 to 
+7d
-7 to 
+7d
-7 to 
+7d
-7 to 
+14d
-7 to 
+14d
-7 to 
+14d
-7 to 
+14d
-7 to 
+14d
-1 to +2 weeks
NA
NA
ADMINISTRATIVE PROCEDURES
Informed Consent
x
Informed Consent for Future Biomedical 
Research (FBR)
x
Inclusion/Exclusion Criteria
x
Subject Identification Card
x
Medical History
x
Prior and Con-med Review
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Treatment Allocation
x
Review Study Medication Diary
x
x
x
x
x
x
x
x
x
x
x
Distribute Study Medication Diary
x
x
x
x
x
x
x15
x
CLINICAL SAFETY EVALUATIONS
Physical Examination1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
x1
Weight
x
x
x
Height
x
 
 
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1st Week
Treatment Weeks
Follow-Up Weeks
Unscheduled
Main Study Population
12-week Treatment 
Screening
Day 18
NA
NA
NA
Day 7
2
4
6
8
10
12
1413
1613
FW4
FW8
FW
12
FW
1614
FW
2014
FW
24
HCV/HIV Viral 
Failure 
Confirmation 
Visit 9,10
Early 
Discontinuation 
Visit 9, 11
Intensive Viral Kinetic subgroup
Day 2 12
Day 312
Day512
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Visit Windows
NA
NA
NA
+2d
-1 to 
+2d
-2 to 
+2d
-4 to 
+7d
-7 to 
+7d
-7 to 
+7d
-7 to 
+14d
-7 to 
+14d
-7 to 
+14d
-7 to 
+14d
-7 to 
+14d
-1 to +2 weeks
NA
NA
12-Lead ECG
x
x
x
x
x
x
x
x
Vital Signs
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
x
x
x
Review SAEs
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Telephone contact
x
x
LABORATORY SAFETY EVALUATIONS
Coagulation (PT & INR)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Chemistry & Hematology
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
HBsAg
x
HIV-1 Serology
x
Urinalysis
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine Pregnancy Test (females of child 
bearing potential only)
x
x
x
x
x
x
x
x
x
x
x
x
PHARMACOKINETICS
MK 8408 PK 
x
x12
x
x
x
x
x
x
x
x
x
x9
x9
MK-3682 and metabolites PK
x
x12
x
x
x
x
x
x
x
x
x
x9
x9
Meal Information for PK
x
x12
x
x
x
x
x
x
x
x
x
x9
x9
 
 
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1st Week
Treatment Weeks
Follow-Up Weeks
Unscheduled
Main Study Population
12-week Treatment 
Screening
Day 18
NA
NA
NA
Day 7
2
4
6
8
10
12
1413
1613
FW4
FW8
FW
12
FW
1614
FW
2014
FW
24
HCV/HIV Viral 
Failure 
Confirmation 
Visit 9,10
Early 
Discontinuation 
Visit 9, 11
Intensive Viral Kinetic subgroup
Day 2 12
Day 312
Day512
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Visit Windows
NA
NA
NA
+2d
-1 to 
+2d
-2 to 
+2d
-4 to 
+7d
-7 to 
+7d
-7 to 
+7d
-7 to 
+14d
-7 to 
+14d
-7 to 
+14d
-7 to 
+14d
-7 to 
+14d
-1 to +2 weeks
NA
NA
HCV EVALUATIONS
HCV Genotype Determination
x
Liver imaging2
x
HCV RNA Level3
x
x
x12
x12
x12
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x11
Plasma for HCV Viral Resistance and 
Biomarkers4
x
x
x
x
x
x
x11
Blood for genetic analysis4
x
HIV EVALUATION5
HIV RNA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Plasma for HIV Viral Resistance
x10
CD4+ T-Cell Counts
x
x
x
x
x
x
x
x
x
x
x
DRUG ADMINISTRATION16
MK-3682 (open-label)
x6
x
x
x
x
x6
x6
x6
x6
x6
x6,7
x6
x7
MK-8408 (open-label)
x6
x
x
x
x
x6
x6
x6
x6
x6
x6,7
x6
x7
1
A comprehensive PE will be done at screening.  For all other visits a focused PE will be conducted when clinically indicated.
2
For cirrhotic subjects imaging must be performed within 6 months prior to treatment allocation to rule out hepatocellular carcinoma. 
3
Blood samples will be collected for HCV viral resistance testing at baseline, viral failure confirmation visits, and follow-up visits.  At the same time points, samples will be collected for 
proteomics, and metabolomics and other exploratory analysis.  Leftover main study plasma will be stored at the end of the study for FBR if the subject signs the FBR consent.
 
 
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4
Blood sample will be collected for IL28 genotyping and for planned analysis of the association between genetic variants in DNA and drug response.  Data analysis will be limited to 
IL28B genotyping if the IRB/IEC does not approve of, or if there is a documented law or regulation prohibiting, the planned analysis of the association between DNA variation and drug 
response.  Leftover extracted DNA will be stored at the end of the study for FBR if the subject consents to FBR.
5
Blood samples will be collected for HIV RNA and CD4+ T-cell counts as part of the screening visit for all subjects.  HIV evaluations will only be performed at subsequent visits in 
subjects that are HIV co-infected.
6
Study drug is to be dispensed at Day 1, Week 2, Week 4, Week 6, Week 8 and Week 10 visits for all subjects receiving 12 weeks of treatment. If it is determined that the treatment 
duration will be 16 weeks, study drug will also be dispensed at Week 12 and Week 14 visits.
7
After the last dosing visit, subjects proceed to the follow up visit schedule.
8
Procedures at visit 2, Day 1 should be performed prior to the first dose unless specified otherwise.
9
Pharmacokinetic 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.
10 In subjects that are HIV co-infected, blood samples will be collected for HIV viral resistance at the time of HIV RNA failure confirmation visit.
11 If a subject is confirmed viral failure during therapy (i.e., break through), then sample collection for HCV RNA and Viral Resistance/Biomarker is not needed for the early 
discontinuation visit.
12 Visits on Day 2, Day 3 and Day 5 are applicable to intensive viral kinetic subgroup only.
13 Treatment week 14 and 16 are only applicable if it is determined during the study that the treatment duration needs to be extended to 16 weeks.
14 FW16 and FW20 visits are virtual visits.  The study nurse will have telephone contact with the subject to make sure that he/she is doing well and provide a reminder for the FW24 visit.
15 If it is determined that the treatment duration needs to be extended to 16 weeks, Study Medication Diaries will be distributed at the treatment week 12 visit for subjects that will receive 
16 weeks of treatment.
16 MK-3682 and MK-8408 open-label bottles provided by the SPONSOR cover a maximum of 18 days of dosing (2w + 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.  Subjects should complete study therapy for all study drugs as defined by the length of the assigned treatment 
regimen.
 
 
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Long Term Follow-Up 
Subjects with Virologic Failure
Follow-up Period
Month
M12
M18
M24
M30
M36
Unscheduled 
Visit
Visit Number
23
24
25
26
27
28
Visit Window
-3 to +3 months
NA
ADMINISTRATIVE PROCEDURES
Long-Term Follow-Up Informed Consent1
x
Review HCV Medications/Therapies
x
x
x
x
x
x
CLINICAL EVALUATIONS
Focused Physical Examination (PE)2
x
x
x
Vital Signs (heart rate, blood pressure, temperature)
x
x
x
Review Serious Adverse Events3
x
x
x
x
x
x
LABORATORY SAFETY EVALUATIONS
Coagulation (PT & INR)
x
x
x
Chemistry & Hematology
x
x
x
HCV EVALUATIONS
HCV RNA4
x
x
x
x
x
Plasma for HCV Viral Resistance4
x
x
x
x
x
HCV = hepatitis C virus, INR = international normalized ratio, M = long-term follow-up month, PT = prothrombin time, SAE =Serious adverse event
1
Subjects who take at least 1 dose of study drug, experience virologic failure, complete FW24, AND agree to participate in the long-term follow-up period of the study must sign a separate 
Informed Consent.  This must occur prior to performing any procedures in the long-term follow-up period.
2
A focused PE will be conducted when clinically indicated at the subject’s annual visits. 
3
Serious Adverse Events will be collected per requirements in Section 7.2; the reporting timeframe for serious adverse events is described in Section 7.2.3.1.
4
Blood samples will be collected for HCV viral resistance testing if the subject has quantifiable HCV RNA.
 
 
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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 
during the trial.
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 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.
 
 
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Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
Assignment of Treatment/Randomization Number
7.1.1.7
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation.   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/Diet/Activity/Other)
7.1.1.8
The investigator/study coordinator will give the subject a Study Medication Diary to be 
completed during the study period.  The investigator/study coordinator will be responsible 
for entering the subject’s identification (allocation number), visit number, and the dates
before giving the diary to the subject.  The subject will be instructed to record dates/times 
and the number of tablets or capsules of study drug doses in the diary for the entire time 
period.  Only the subject should enter information into the diary.  The subject is to return the 
completed diary at each scheduled visit.  At visits when used/unused study medications are 
returned, site personnel must verify the accuracy of the dosing diary by comparing entries 
with amounts of returned study medication.  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 diary. The 
investigator/study coordinator will be responsible for transferring the appropriate information 
from the diary card onto the appropriate case report form.
Interruptions from the protocol specified treatment plan 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 and on all PK visits during which a pre-dose sample will be collected.
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 exams should be performed when clinically indicated. For all other 
visits, a focused exam will be performed when clinically indicated. Any significant changes 
between the screening visit and Day 1 should be noted in the Medical History electronic case 
report form (eCRF). Any significant changes after receiving study therapy at Day 1 must be 
reported as adverse events and entered on the adverse event eCRF.  If the subject is 
 
 
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discontinued for any reason during the treatment phase, every attempt should be made to 
perform a final physical examination.
Weight and Height Assessment
7.1.2.2
The subject's weight should be assessed as mentioned in the flow chart. Clinically significant 
changes from Day 1 should also be captured as adverse events 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 adverse events.
Vital Signs
7.1.2.4
Vital signs will include heart rate, blood pressure, and oral temperature.  
Note:  Oral temperatures should be taken, but if oral is not possible, tympanic, rectal, and 
axillary temperatures may be taken.
After the screening visit, the site should indicate whether or not the result is clinically 
significant and if any subsequent changes constitute an adverse event.
Birth Control Confirmation
7.1.2.5
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.
Adverse Events
7.1.2.6
For details on assessing and recording adverse events please refer to Section 7.2.
Non-Invasive 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 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. [47] in a population of 
subjects with chronic hepatitis C, a cut-off of 12.5 kPa was selected for cirrhotics. At this 
cut-off, 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 hepatitis C, the cut-off value ≤12.5 kPa used by Castera 
was selected to exclude cirrhotics in the current study.
 
 
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FibroTest® + APRI: – Various methodologies have been developed in order to improve the 
sensitivity and specificity of blood tests used to diagnose cirrhosis in subjects with chronic 
hepatitis C infections.  One such algorithm, the Sequential Algorithm for Fibrosis Evaluation 
(SAFE), which uses a combination of Fibrotest and the aspartate aminotransferase-to-platelet 
ratio index (APRI), is very accurate for diagnosing cirrhosis [48].  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 subjects would need a liver 
biopsy to confirm the diagnosis of cirrhosis. The cut-off values for excluding cirrhotics using 
the two 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 and that 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.  Accordingly, the Sponsor is confident 
these cut-off values will differentiate cirrhotic from non-cirrhotic subjects with reasonable 
accuracy in this study.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 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 volumes 
drawn/collected by visit and by sample type per subject can be found in Section 12.4.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
7.1.3.1
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 11.
 
 
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Table 11
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Bilirubin
Hepatitis C Virus Genotype
Hemoglobin
Alkaline phosphatase
Blood
HBsAg (screening only)
Platelet count
Alanine aminotransferase 
(ALT)
Glucose
HIV-1 serology (screening 
only)
WBC (total and 
differential)
Aspartate 
aminotransferase (AST)
Ketone
Prothrombin time
Erythrocytes (RBC 
count)
Creatinine
Leukocyte Esterase
International Normalized 
Ratio (INR)
Creatinine Clearance 
(estimated glomerular 
filtration rate, GFR)
Nitrites
Choriogonadotropin Beta  
(Urine pregnancy test kits to 
sites)
Creatine Kinase
pH
Serum human chorionic 
gonadotropin (reflex when 
urine pregnancy test is 
“positive”)
Gamma-
glutamyltransferase
Protein
Plasma HCV RNA
Glucose (serum glucose) 
Specific Gravity
Fibrosure® (Fibrotest) as 
requested by site for entry 
criteria (may be performed 
locally)
Amylase
Bacteria
APRI calculation (screening 
only)
Lipase
Squamous Epithelial Cells
CD4+ T-cell count (at 
screening in all subjects, 
then in co-infected subjects 
only at subsequent visits) 
Potassium
RBC
Plasma HIV-1 RNA (at 
screening in all subjects, 
then at subsequent visits in 
coinfected subjects only) 
Sodium
WBC
Total Bilirubin 
Direct Bilirubin
Indirect Bilirubin
Total protein
Blood Urea Nitrogen
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2
The decision as to which plasma samples collected will be assayed for evaluation of 
pharmacokinetics will be collaboratively determined by the Departments of Quantitative 
Pharmacology and Pharmacometrics and the appropriate department within Clinical 
 
 
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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.
7.1.3.2.1 Blood Collection for Plasma MK-3682 (and metabolites) and MK-8408
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual. 
Pharmacokinetic samples will be collected from all enrolled subjects according to the PK 
sampling schemes shown in Table 12.  Subjects participating in an intensive viral kinetic 
sub-study will be providing additional PK samples on Days 3 and 7 that are not being 
collected from the other subjects in the study. The intensive viral kinetic substudy will 
include the first 10 GT1, 10 GT2, 10 GT3 and up to the first 5 GT4, 5 GT5 and 5 GT6 
subjects who consent to participate.
On all PK visits where a pre-dose sample will be collected, the subject must withhold their 
dose on the day of the PK visit; the dose will be administered at the site after collection of the 
pre-dose PK sample.  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 (in 
accordance with Section 5.2.2 Timing of Dose Administration) and PK samples will still be 
collected during these afternoon visits. 
All PK samples will be used to evaluate not only PK exposures but also to assess the PK/PD 
and PK/AE relationships of MK-3682 (and metabolites) and MK-8408.  The date and time of 
each PK sample as well as the date and time of the last dose of MK-3682 and MK-8408 prior 
to the PK sample will be recorded.
When predose PK samples are collected, information regarding meal qualitative fat content 
and time of the meal consumed within 5 hr before and 2 hr after the subject’s last dose of 
MK-3682 and MK-8408 prior to the PK samples will be recorded; when postdose PK 
samples are collected, information regarding meal qualitative fat content and time of the meal 
consumed within 5 hr before and 2 hr after the subject’s last dose of MK-3682 and MK-
8408, as appropriate, which is administered at the study site will be recorded also. 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 recorded.
 
 
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Table 12
Pharmacokinetic Sampling Timepoints
Visit Number
Study Day/Week
Time Relative to Dose of
MK-3682/MK-84083, 4
PK Timepoints 
for
Non-Intensive 
Viral Kinetic 
Subjects
PK Timepoints for 
Intensive Viral 
Kinetic Subjects
2 
Day 1
Pre-dose
x
x
4
Day 3
Pre-dose
x
6
Day 7
Pre-dose
x
x
0.5-, 2-, and 4-hour5 post-
dose
x
7 
Week 2
Pre-dose
x
x
8
Week 4
Pre-dose
x
x
0.5- and 2-hour post-dose5
x
x
9
Week 6
Pre-dose
x
x
10
Week 8
Pre-dose
x
x
11
Week 10
Pre-dose
x
x
12
Week 12
Pre-dose
x
x
131
Week 14
Pre-dose
x
x
141
Week 16
Pre-dose
x
x
21
HCV/HIV
Viral Failure 
Confirmation Visit3
NA
x2
x2
22
Early Discontinuation 
Visit3
NA
x3
x3
1 If the treatment duration is increased to 16 weeks, Visit 13 (Week 14) and Visit 14 (Week 16) PK samples will be collected.  
2 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.
3 Time relative to last dose of MK-3682 and MK-8408 must be recorded in the electronic case report form.
4 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 afternoon visits.
5 0.5 hour samples may be taken ± 5 minutes, 2 hour and 4 hour post-dose samples may be taken ± 15 minutes.
Note:   ~4 mL of blood will be collected at each specified time point for plasma PK assessment of MK-3682 (and metabolites).
  ~4 mL of blood will be collected at each specified time point for plasma PK assessment of MK-8742 or MK-8408.
Note: The date and time of the PK sample collection for all MK-3682 (and metabolites) and MK-8408 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 MK-8408 dose prior to the PK sample collection. (This can also be obtained by referencing the subject's study medication diary).
7.1.3.2.2
Intensive Viral Kinetic Sub-Study
A subgroup of the study population will be included in an intensive viral kinetic sub-study.  
Approximately ten subjects who are GT1-infected (two of whom are cirrhotics), ten GT2, ten 
GT3 (two of whom are cirrhotics) and up to five subjects each who are GT4, GT5 or GT6-
infected, will be asked to participate in order of allocation until we have reached the targeted 
numbers per genotype.  The data from this sub-study will be used to validate the existing 
viral dynamics model for MK-3682 and MK-8408.
 
 
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These subjects will have HCV RNA samples collected during Week 1 as shown in Table 13:
Table 13
Intensive Viral Kinetic Week 1 Sampling Timepoints
Visit 
Number
Study Day
Time Relative to Dose of MK-3682/MK-8408
2 and 3
Starting on Day 1
and completing on Day 2
Pre-dose and 2, 4, 8, 12, 24, and 32 hours post-dose*
4
Day 3
Pre-dose
5
Day 5
Pre-dose
6
Day 7
Pre-dose
*Post-dose samples may be taken ±15 minutes for each time point.
HCV RNA samples also will be collected at the Week 2, 4, 6, 8, 10 and 12 visits. If the 
treatment duration is extended to 16 weeks, HCV RNA samples will be collected at the 
Weeks 14 and 16 visits during treatment.
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the laboratory manual. 
HCV Evaluation
7.1.3.3
The following specimens are to be obtained as part of Efficacy/Pharmacogenetic 
Measurements:

Samples for HCV Genotype evaluation must be obtained for inclusion in the study.  
All baseline samples will be genotyped using the FDA approved Abbott HCV Real 
Time Genotype II assay which detects HCV genotypes 1a, 1b, 2, 3, 4, 5, and 6 
through the use of genotype-specific fluorescent-labeled oligonucleotide probes in a 
real-time RT-PCR assay.
The RT-PCR reaction uses 3 sets of HCV specific 
amplification primers targeting the conserved 5’UTR (for all genotypes) and NS5B 
regions from GT1a and 1b. The assay has accuracy of >96% for GT1, 1a, 1b, 2, 3 
and 4, 89% for GT5 and 83% for GT6 with 100% specificity in HCV serologically 
negative plasma samples.  Phylogenetic analyses will be performed using sequences 
for NS3, NS5A and NS5B to ensure accurate assignment of sample 
genotype/subtype.

Blood must be drawn from each subject to assess HCV RNA plasma levels at various 
time points as shown in the study flow chart.  HCV RNA in plasma will be measured 
using a COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay with a 
lower limit of quantification (LLOQ) of 15 IU/mL.  Leftover plasma may be used for 
viral resistance testing if needed.  Also, leftover plasma may be used for future 
biomedical research only if the subject signed for future biomedical 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 future biomedical research only if the subject signed for future biomedical 
consent. 
 
 
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
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 future biomedical research only if the subject signed for future biomedical 
research consent.
Note: Samples may also be used for future assay development and validation if the subject 
signed for future biomedical research consent.
HIV Evaluation
7.1.3.4
The following specimens are to be obtained:

Blood must be drawn from each subject to assess HIV RNA plasma levels at 
various time points as shown in the study flow chart (Section 6).  HIV RNA in 
plasma will be measured using a COBAS® AmpliPrep/COBAS® TaqMan® 
HIV-1 Test, version 2. 0 assay with a lower limit of quantification of 
20 IU/mL.

Blood must be drawn from each subject at HIV RNA viral failure 
confirmation visit (in case of potential failure, defined as HIV-1 RNA ≥ 200 
copies/mL, confirmed on 2 consecutive tests at least 2 weeks apart in subjects 
compliant with their HIV ART) to assess viral resistance mutations, and 
processed as instructed by the central laboratory manual. HIV-1 drug 
resistance will be assessed using the PhenoSense GT™ HIV Assay, and the 
Genosure Prime Assay.

Blood must be drawn from each subject to assess immunologic status.  CD4+ 
T-cell counts will be obtained at screening and at various time points as 
shown in the flow chart.
The following nomenclature will be used when describing HIV RNA levels:

HIV-1 RNA <LLOQ, Target Not Detected

HIV-1 RNA <LLOQ, Target Detected

HIV-1 RNA copies/mL
Planned Genetic Analysis Sample Collection
7.1.3.5
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the laboratory manual.
Future Biomedical Research Sample Collection
7.1.3.6
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future research

Leftover plasma from HCV RNA for future research
 
 
04S4N9

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Confidential
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 
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
Up to 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 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 Study 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 
 
 
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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

HbsAg

HIV-1 serology

Liver biopsy/Fibroscan/ FibroSure® (Fibrotest®)

Liver imaging

12-Lead ECG
If any of the laboratory exclusion criteria are met, the site may have the abnormal value 
retested one time, except as prohibited in exclusion criterion #13.
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 Study Flow Chart should be performed prior to dosing unless 
specified otherwise.  For female subjects, 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, plasma HCV RNA, plasma 
HIV RNA, 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 MK-8408.
Discontinued Subjects Continuing to be Monitored in the Trial
7.1.5.4
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
 
 
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
The date of the last assessment and/or contact. A follow-up contact (telephone or 
visit) will be arranged as appropriate

(Serious) Adverse events
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 4.2.3.1.1.2) 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).
All subjects who take at least 1 dose of study drug, experience virologic failure, and 
complete FW24 should be offered long-term follow-up (see Section 7.1.5.6).
Discontinuation during Follow-Up Period(s)
Subjects who discontinue during the follow-up period (e.g. follow-up visits at 4 through 24 
weeks after EOT) for reasons other than virologic failure should complete an Early 
Discontinuation Visit as outlined in the Trial Flow Chart.  Subjects who discontinue from the 
long-term follow-up period (e.g. through 3 years after EOT) should complete an 
Unscheduled Visit as outlined in the Long-Term Follow up section of 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)
Discontinuation of Long Term Follow-Up
Amendment 04 implemented the discontinuation of the LTFU period.  Subjects who already 
entered the LTFU section of the trial are to be discontinued (via an unscheduled visit).  No 
further subjects will be entered into the LTFU period.
 
 
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Post-Trial
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.  Virtual visits by telephone will occur 
at follow-up weeks 16 and 20.
Long-Term Follow-Up
7.1.5.6
To assess the persistence of RAVs over time, follow-up in this study will be extended to a 
total of 3 years and offered to any subject who meets all of the following:

Has taken at least 1 dose of study drug (MK-3682 or MK-8408) 

Experienced virologic failure 

Completed the FW24 visit  
Subjects must read and sign a separate informed consent before being allowed to participate 
in the long-term follow-up. There are a total of 5 additional study visits at Long-term Follow-
up Month 12, 18, 24, 30, and 36 after end-of-treatment.  Subjects who complete treatment, 
experience virologic failure, and complete long-term follow-up of this trial can expect to 
participate for a total of approximately 175 weeks.
As of amendment 04, the long term follow up period is being discontinued.  Any subject who 
has consented to participate in the Long Term Follow Up will be discontinued via an 
unscheduled visit.  
Monitoring during these long-term follow-up visits will include assaying HCV RNA and 
resistance testing.  For safety assessments, SAEs will be collected in accordance with the 
safety requirements outlined in Section 7.2, along with a yearly directed physical 
examination and laboratory testing.  Subjects participating in the long-term follow-up will be 
discontinued from the study if they receive HCV treatment at any time during the long-term 
follow-up.
Evaluation of Laboratory Safety Signals
7.1.5.7
Laboratory safety measurements will be made after the first week of treatment, followed by 
every 2 weeks for the entire treatment period, and during the follow-up period to assess 
potential liver and renal safety signals as outlined in the flow chart.
If a subject has one or more of the laboratory events of clinical interest (ECI)
(refer to 
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-
 
 
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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
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 defined as any intake in excess of the prescribed dose of 
MK-3682 or MK-8408.
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).
 
 
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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) that occurs during the trial.
Pregnancies and lactations of 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 that occur from the time of 
treatment allocation/randomization through 14 days following cessation of Sponsor’s product 
(or longer if dictated by local regulations) 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.
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 
 
 
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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.
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 Upper Limit of Normal (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 an additional evaluation for an underlying etiology. The trial site guidance 
for assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
 
 
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Additional events of clinical interest for this trial include:
1. first instance of eGFR < 30 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 MDRD equation:
eGFR (mL/min/1.73 m2) = 175 x (Scr, std)-1.154 x (Age)-0.203 x (0.742 if female) x 
(1.212 if black)
Scr, std: serum creatinine measured with a standardized assay
2. first instance of serum creatinine Grade 2 or higher (> 1.3x ULN) and elevated from 
baseline from the initiation of study therapy through 14 days following treatment.
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.
 
 
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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.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Scientific Advisory Committee
7.3.1
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
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 are summarized below; the comprehensive plan 
is provided in Sections 8.2 through 8.11.  
Study Design Overview
A Phase II, open-label, multicenter, multi-arm trial to study the 
efficacy and safety of the combination regimen of MK-3682+MK-
8408 in cirrhotic or non-cirrhotic subjects with chronic HCV GT1, 
GT2, GT3, GT4, GT5 or GT6 infection. Subjects will receive the 
combination regimen of MK-3682+MK-8408 for 12 weeks.  Subjects 
may be HCV mono-infected or HIV-co-infected, treatment-naïve or 
treatment-experienced with a prior interferon-based therapy.
Treatment Assignment
Approximately 250 subjects will be enrolled into six cohorts receiving 
MK-3682 + MK-8408 for 12 weeks based on the genotype of their 
HCV infections. Although within six cohorts subjects will receive the 
same treatment regimen, i.e., MK-3682 + MK-8408 for 12 weeks, 
these cohorts are designated as six “treatment arms” in the study. 
Analysis Populations
Efficacy:  Per Protocol (PP), modified Full Analysis Set (mFAS) and 
Full Analysis Set (FAS)
Safety:  All Subjects as Treated (ASaT)
Primary Endpoint(s)
Proportion of subjects achieving SVR12 after 12 weeks of treatment 
Key Secondary Endpoints
Proportion of subjects achieving SVR24 after 12 weeks of treatment, 
respectively; 
Proportion of subjects experiencing virologic failure at FW12 among 
all subjects who do not discontinue study for non-treatment-related 
reasons after 12 weeks of treatment, respectively.
Statistical Methods for Key 
Efficacy Analyses
For the primary efficacy analysis based on the PP population, the 
proportions of subjects achieving SVR12 will be estimated in each
 
 
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treatment arm, and 95% confidence intervals (CIs) for these rates will 
be calculated using the Clopper-Pearson method [49]. The missing 
data 
approach 
of 
Treatment-Related 
Discontinuation=Failure 
(TRD=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 for each treatment arm with TRD=F as the 
missing data approach and based on the FAS population for each 
treatment arm with Missing=Failure (M=F) as the missing data 
approach.  
Statistical Methods for Key 
Safety Analyses
The All-Subjects-as-Treated population will be employed for safety 
analyses. The proportion of subjects with adverse experiences of 
elevated laboratory values that are reported as ECIs described in 
section 7.2.3.2 during the study therapy period are prespecified as 
events of clinical interest and 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, a 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
Sentinel cohorts (i.e. first 10 subjects) in each treatment arm for GT1, 
GT2, GT3, and GT4 subjects will be assessed to determine the 
treatment duration for the main cohorts (i.e. the remaining subjects 
still on treatment). 
Multiplicity
No multiplicity adjustment is planned for the study.
Sample Size and Power 
Approximately 250 subjects will be allocated into one of the six
treatment arms of combination of MK-3682 (450mg) and MK-8408
(60mg) for 12 weeks with 50 GT1-, 50 GT2-, 50 GT3-, 50 GT4-, 25
GT5- and 25 GT6-infected subjects in Arms 1, 2, 3, 4, 5 and 6, 
respectively Assuming a protocol violation rate of 10%, the PP 
population will include approximately 45 subjects in each of Arms 1, 
2, 3 and 4. If the SVR12 rate is approximately 96% (43 successes out 
of 45), the exact 95% CI is (84.9%, 99.5%). The PP population will 
include approximately 22 subjects in Arms 5 and 6. If the SVR12 rate 
is approximately 91% (20 successes out of 22), the exact 95% CI is 
(70.8%, 98.9%). Detailed information 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. Through the course of this open-label study, efficacy and safety 
analyses may be performed by the Sponsor to monitor trends and facilitate programmatic 
decisions.  In particular, when at least half of the subjects have reached FW4 and/or FW8, 
initial assessment of SVR4 and/or SVR8 may be performed.
Hypotheses/Estimation
8.3
Objectives of the study are stated in Section 3.0.
 
 
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Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated are listed in the following sections.
Efficacy /Pharmacokinetics Endpoints
8.4.1
Efficacy Endpoints
8.4.1.1
An initial description of efficacy measures is provided in Section 4.2.3.1.
The primary efficacy endpoint is the proportion of subjects achieving SVR12 after 12 weeks 
of treatment. 
The secondary efficacy endpoints are:
1)  the proportion of subjects achieving SVR24 after 12 weeks of treatment.
2) the proportion of subjects experiencing virologic failure (either on-treatment failure or 
relapse post-treatment) at Follow-up Week 12 after 12 weeks of treatment,  among all 
subjects who do not discontinue the study for non-treatment-related reasons.
Pharmacokinetics Endpoints
8.4.1.2
Additional details are in Section 4.2.3.3. 
The primary PK endpoint for MK-3682 (and metabolites) and MK-8408 is Ctrough.
Exploratory Endpoints
8.4.1.3
1. The emergence of RAVs to MK-3682 or MK-8408 when administered as part of a 
combination regimen. 
2. The proportion of subjects with HCV RNA <LLOQ (either TD(u) or TND) at TW2, 
TW4, TW8, end of treatment, FW4, and FW8 after 12 weeks of treatment,.  
3. The viral kinetics in the first 32 hours of treatment and Days 3 and 7 in the first 10 
GT1-infected (two of whom are cirrhotics), 10 GT2, 10 GT3 (two of whom are 
cirrhotics) and up to five subjects each who are GT4, GT5 or GT6-infected who 
consent to participate. The collection of the viral kinetics in this subset of subjects
will be used to explore the impact of early viral load decline on sustained viral 
response in each treatment arm as stated in the exploratory objective. The viral 
kinetics will be summarized, and the relationship of viral kinetics and likelihood of 
achieving SVR12 response may be explored in the future after appropriately 
combining subjects with viral kinetic measurements from other studies.
4. The association between genetic variation (such as IL28 genetic variation) and the 
clinical response to the treatment(s) administered.
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.
 
 
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Safety Endpoints
8.4.2
An initial description of safety measures is provided in Section 4.2.3.2 and ECIs are defined 
in Section 7.2.3.2.  
Analysis Populations
8.5
Efficacy Analysis Populations
8.5.1
Per Protocol (PP)
The PP population will serve as the primary population for the analysis of SVR12 and SVR24
in this study, since it provides a more accurate assessment of the virological efficacy in 
subjects who are reasonably compliant in this Phase 2 trial. 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 reasons will be excluded.  Potential violations that may result in the 
exclusion of a patient from the PP population include:

The subject did not meet specific inclusion/exclusion criteria (for example, the 
subject is infected with a mixed GT infection or non-typeable genotype).

The subject received concomitant medications that are prohibited due to their 
potential to result in a clinically significant lowering of the MK-3682 or MK-8408 
concentrations 
(see 
Section 
5.5
for 
specific 
details 
of 
prohibited 
medications). Further, any co-administered medication currently unidentified, but for 
which subsequent clinical DDI data indicate that co-administration with MKs leads to 
a clinically significant lowering of MK concentrations. 

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.  
Full Analysis Set (FAS) 
The FAS population will serve as a supportive analysis of efficacy data in this study.  The 
FAS population consists of all subjects who are assigned to a treatment arm and receive at 
least one dose of study treatment in this study.  
Modified Full Analysis Set (mFAS)
The mFAS population will be used for the efficacy endpoints of SVR12 and SVR24 as a 
supportive analysis and 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.
 
 
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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.  
Subjects will be included in the treatment arm to which they are allocated for the analysis of 
efficacy data using the FAS, mFAS, and PP populations.  Details on the approach to handling 
missing data are provided in Section 8.6, Statistical Methods.
Safety Analysis Populations
8.5.2
The All Subjects as Treated (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 one 
dose of study treatment. Subjects will be included in the treatment group corresponding to 
the study treatment (i.e., treatment duration, if applicable) they actually received for the 
analysis of safety data using the ASaT population.  
At least one laboratory or vital sign measurement obtained subsequent to at least one 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
The approach to handling missing data for efficacy analyses is described in Section 8.6.1. A 
summary of the analysis strategy for efficacy variables is shown in Table 15.
Nominal p-values may be computed for some efficacy analyses as a measure of strength but 
no formal tests of hypotheses are planned in this study.
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.
 
 
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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 (MAR) assumption is 
reasonable.
The following two 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 after 12 weeks 
of treatment in each treatment arm will be provided and 95% confidence intervals for these 
rates will be calculated using the Clopper-Pearson method [49]. The same method will be 
used to analyze all binary endpoints including SVR24 after 12 weeks of treatment.
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 in these two populations, a subject will 
be considered to have achieved a particular endpoint if the HCV RNA levels for the infection 
he/she had at baseline are < LLOQ. In other words, 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 genotype 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. 
Sensitivity analyses that use the FAS population will utilize the M=F missing data approach.  
Also, in the FAS 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.  
 
 
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To estimate the secondary efficacy endpoint of proportion of subjects experiencing virologic 
failure at FW12 for each treatment arm, 95% CIs for these rates will be calculated based on 
the mFAS analysis population using the Clopper-Pearson method [49]. 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 after 
12 weeks of treatment) and secondary endpoints (SVR24 and proportion of subjects 
experiencing virologic failure at FW12 after 12 weeks of treatment, respectively). 
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 in each 
treatment arm after 12 
weeks of treatment
P
95% Confidence
Interval (Clopper-
Pearson)
PP
TRD=F‡
Proportion of subjects
achieving SVR12 in each 
treatment arm after 12 
weeks of treatment
S
95% Confidence
Interval (Clopper-
Pearson)
mFAS
TRD=
F‡
Proportion of subjects
achieving SVR12 in each 
treatment arm after 12 
weeks of treatment
S
95% Confidence
Interval (Clopper-
Pearson)
FAS
M=F*
Secondary
Proportion of subjects
achieving SVR24 in each 
treatment arm after 12 
weeks of treatment
P
95% Confidence
Interval (Clopper-
Pearson)
PP
TRD=F‡
Proportion of subjects
achieving SVR24 in each 
treatment arm after 12 
weeks of treatment
S
95% Confidence
Interval (Clopper-
Pearson)
mFAS
TRD=
F
‡
Proportion of subjects
achieving SVR24 in each 
treatment arm after 12 
weeks of treatment
S
95% Confidence
Interval (Clopper-
Pearson)
FAS
M=F *
Proportion of subjects 
experiencing virologic 
failure at FW12 in each 
treatment arm after 12 
weeks of treatment
P
95% Confidence
Interval
(Clopper-
Pearson)
mFAS
TRD=
F
‡
mFAS = modified Full Analysis Set
FAS = Full Analysis Set
PP = Per Protocol  
†  P=Primary approach; S=Secondary approach.
‡ TRD=F = Treatment-Related Discontinuation=Failure.
* M=F = Missing=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
PP (Primary for 
SVR12 and SVR24)
HCV RNA < LLOQ
for
baseline infection
HCV RNA ≥LLOQ
demonstrated to be due
to reinfection (after
clearance of baseline
infection)
HCV RNA ≥ LLOQ for
baseline infection*
Subject with important 
deviations from the protocol 
including subject discontinued 
from the study for non-
treatment related reasons and 
other violations such as 
violation of I/E criteria, use of 
prohibited concomitant 
medications (see Section 8.5.1)
mFAS (Supportive
for SVR12, SVR24; 
Primary for 
proportion of 
subjects 
experiencing 
virologic failure at 
FW12)
HCV RNA < LLOQ
for
baseline infection
HCV RNA ≥LLOQ
demonstrated to be due
to reinfection (after
clearance of baseline
infection)
HCV RNA ≥ LLOQ for
baseline infection*
Subject discontinued from the
study for non-treatment related
reasons.
FAS (Supportive for 
SVR12 and SVR24)
HCV RNA < LLOQ
HCV RNA ≥ LLOQ
Subject did not receive at least  
one dose of study medication
mFAS = modified Full Analysis Set
FAS = Full Analysis Set
PP = Per Protocol
LLOQ = Lower limit of quantification
*Baseline infection: Genotype(s) and subtype(s) present at baseline based on population 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 4.2.3.1.1.2. Reinfection will be 
defined as having detectable virus of a different genotype 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 the baseline infection was achieved HCV RNA < 
LLOQ.  
Statistical Methods for Safety Analyses 
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences and laboratory parameters. The primary safety analysis will summarize 
the safety data for subjects during the treatment period plus 14 days of follow-up. The 95% 
CIs for the safety parameters will be estimated using the Clopper-Pearson method [49],
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.  
 
 
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The first tier includes the following safety parameters or adverse experiences of special 
interest that will be assessed via point estimates with 95% confidence intervals for each 
treatment arm for GT1, GT2, GT3, GT4, GT5 and GT6 subjects and combined across 
genotypes after 12 weeks of treatment: (1) AEs of elevated laboratory values that are 
reported as ECIs described in Section 7.2.3.2; (2) at least one AE; (3) a drug-related AE; (4) 
an SAE; (5) a serious and drug-related AE, and (6) an AE leading to discontinuation.  
All other safety parameters will be included in the second tier with point estimates to be 
provided for each treatment arm for GT1, GT2, GT3, GT4, GT5 and GT6 subjects and 
combined across genotypes after 12 weeks of treatment for the following safety parameters: 
specific AEs by System Organ Class (SOC), vital signs, 12-lead ECGs, and standard 
laboratory safety tests at time points specified in the Trial Flow Chart (Section 6.0).
Missing safety laboratory, vital signs, or ECG values will be handled using the Data-As-
Observed (DAO) 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.
Table 17
Analysis Strategy for Safety Parameters
Safety Endpoint†
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
†  Adverse Experience references refer to both Clinical and Laboratory AEs.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be provided.
Summaries of Baseline Characteristics, Demographics, and other Analyses
8.6.3
Summaries of demographic and baseline characteristics, pharmacokinetic analyses, analyses 
of data from the long-term follow-up in this study (as described in Section 7.1.5.6), and 
analyses for the exploratory endpoints will be described in detail in the supplementary 
statistical analysis plan (sSAP). 
Interim Analyses
8.7
Interim assessments will include the following to evaluate the need to extend the treatment 
duration from 12 weeks to 16 weeks. If a total of ≥3 out of the first 10 subjects in the PP
population in a 12-week arm experience virologic relapse by FW4, all subjects already 
enrolled and on treatment in an 12- week dosing duration arm for that GT will have their 
treatment duration extended to 16 weeks, and no further subjects will be enrolled. 
The probability of observing 3 or more subjects with virologic failure can be computed using 
the binomial distribution and is a function of the actual total sample size per arm (n) and the 
assumed proportion of virologic failure (p = 1 – true SVR rate).  These probabilities 
 
 
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(expressed as a percent) are displayed in Table 18 for sample sizes (n) of 9 and 10 subjects 
and true SVR rates of 70, 75, 80, 85, and 90%.
Table 18
Probability of Observing 3 or More Subjects with Virologic Failure
Sample Size Per Arm (n)
True SVR Rate
9
10
0.70
53.7%
61.7%
0.75
39.9%
47.4%
0.80
26.2%
32.2%
0.85
14.1%
18.0%
0.90
5.3%
7.0%
0.95
0.8%
1.2%
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 receive treatment with MK-3682 (450mg) 
and MK-8408 (60mg) for 12 weeks with a target enrollment of 50 GT1-, 50 GT2-, 50 GT3-, 
50 GT4-, 25 GT5- and 25 GT6-infected subjects in Arms 1, 2, 3, 4, 5 and 6, respectively.  
Assuming a protocol violation rate of 10%, the PP population will include approximately 45 
subjects in each of Arms 1, 2, 3 and 4. The PP population will include approximately 22
subjects in Arms 5 and 6. 
Table 19 below shows the two-sided 95% CIs for SVR12 under varying assumptions of the 
number of successes for the PP population. Note that these intervals are not symmetric 
around the point estimate.  
 
 
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Table 19
Two-Sided 95% Confidence Intervals for SVR12 (PP Population)   
Number of subjects 
in PP population
Observed Number of Successes (%)
Two-Sided 95% Confidence Interval‡
21 (95.5%)
(77.2, 99.9)
22
20 (90.9%)
(70.8, 98.9)
19 (86.4%)
(65.1, 97.1)
18 (81.8%)
(59.7, 94.8)
45
43 (95.6%)
(84.9, 99.5)
41 (91.1%)
(78.8, 97.5)
39 (86.7%)
(73.2, 94.9)
37 (82.2%)
(67.9, 92.0)
‡  Based on the Clopper-Pearson method
Safety Analysis
8.9.2
The primary safety objective of this study will be assessed 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 25 or 50 subjects in each of the 6 treatment 
arms. When combined across genotypes, the ASaT population will include approximately
250 subjects for combined treatment arm of 12 weeks. The estimate of and the upper bound 
of the 95% confidence interval 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 20. These calculations are based on the exact binomial method 
proposed by Clopper and Pearson [49].
 
 
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Table 20
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 
Bound†
25
0
0.0%
13.7%
2
8.0%
26.0%
5
20.0%
40.7%
8
32.0%
53.5%
10
40.0%
61.3%
50
0
0.0%
7.1%
2
4.0%
13.7%
4
8.0%
19.2%
8
16.0%
29.1%
10
20.0%
33.7%
250
0
0.0%
1.5%
10
4.0%
7.2%
25
10.0%
14.4%
35
14.0%
18.9%
50
20.0%
25.5%
†Based on the two-tailed exact confidence interval of a binomial proportion (Clopper and Pearson, 1934)
Subgroup Analyses and Effects of Baseline Factors
8.10
To assess the consistency of the response across various subgroups, the SVR 12 and SVR24 
rate 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 two classes of drugs

Sex (female, male)

Age (≥65, <65)

Race (White, Black or African American, Asian, Other) 

Ethnicity (Hispanic or Latino, not Hispanic or Latino, Other)

IL28B genotype (CC vs. non-CC)

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, cirrhotic) 

HIV co-infection status (HCV/HIV co-infected, HCV mono-infected)

Treatment-experienced and treatment-naïve 

For Arm 1: GT1 subjects (GT1a vs. GT1b)
 
 
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The subgroup analyses will be performed within each treatment arm and based on pooled 
treatment arm across genotypes, as appropriate.  
Compliance (Medication 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 (450mg) + MK-8408 (60mg) 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 by treatment group 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 21.
 
 
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Table 21
Product Descriptions
Product Name & Potency
Dosage Form
MK-3682, 150 mg
Tablet
MK-8408, 10 mg
Capsule
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 (1 bottle of MK-3682 and 1 bottle of MK-8408)
every 2 weeks during the treatment duration. Each bottle will contain a 2-week supply of 
study medication. No kitting is required.
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.
 
 
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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 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.
 
 
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11.0 LIST OF REFERENCES
1. Messina JP, Humphreys I, Flaxman A, et al. Global distribution and prevalence of 
hepatitis C virus genotypes. Hepatology 2015; 61: 77-87.
2. Wiessing L, Ferri M, Grady B, 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. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV 
genotype 1 infection. N Engl J Med. 2014 May 15;370(20):1889-98.
4. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks 
for chronic HCV without cirrhosis. N Engl J Med. 2014 May 15;370(20):1879-88.
5. Harvoni USPI (11/2015)
6. Harvoni EU SPC (22Dec15)
7. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated 
HCV genotype 1 infection. N Engl J Med. 2014 April 17;370(16):1483-93.
8. Feld JJ, Kowdley KV, Coakley E, 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.
9. Poordad F, Hezode C, Trinh R, 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.
10. Viekirax EU SPC (20Nov15)
11. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or 
without ribavirin for HCV. N Engl J Med. 2014 May 22;370(21):1983-92.
12. Zeuzem S, Jacobson IM, Baykal T, 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.
13. Zeuzem S, Ghalib R, Reddy KR, et al.  Grazoprevir-elbasvir combination therapy for 
treatment-naive cirrhotic and noncirrhotic patients with chronic HCV genotype 1, 4, or 6
infection: a randomized trial. Ann Intern Med 2015;163(1):1-13. doi:10.7326/M15-0785.
14. Zepatier USPI (1/2016)
15. Rockstroh JK, Nelson M, Katlama C, et al. Efficacy 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 HIV. 2015 Aug;2(8):e319-
27. doi: 10.1016/S2352-3018(15)00114-9.
16. Feld JJ, Jacobson IM, Hézode C, et al.  ASTRAL-1: Sofosbuvir and velpatasvir for HCV 
genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015; 373:2599-2607.
17. Lawitz E, Mangia A, Wyles D, et al.  Sofosbuvir for previously untreated chronic 
hepatitis C infection. N. Engl. J. Med. 2013 May 16;368(20):1878-87.
18. Jacobson IM, Gordon SC, Kowdley KV, et al.  Sofosbuvir for hepatitis C genotype 2 or 3 
in patients without treatment options.  N Engl J Med. 2013 May 16;368(20):1867-77.
 
 
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19. Zeuzem S, Dusheiko GM, Salupere R, et al.  Sofosbuvir and ribavirin in HCV genotypes 
2 and 3. N Engl J Med. 2014 May 22; 370(21):1993-2001.
20. SOVALDI (sofosbuvir) USPI (12/2013)
21. Younossi ZM, Bacon BR, Dieterich DT, et al. Disparate access to treatment regimens in 
chronic hepatitis C patients: data from the TRIO network. J Viral Hepat 2016 
Jun;23(6):447–454. doi: 10.1111/jvh.12506.
22. http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infection
23. http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C/index.html#p=2
24. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV genotype 2 
and 3 infection. N Engl J Med 2015; 373(27):2608-2617.
25. Nelson DR, Cooper JN, Lalezari JP, et al.  All-oral, 12-week treatment with daclatasvir 
plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase 3 
study.  Hepatology. 2015;61(4):1127-1135. doi: 10.1002/hep.27726.
26. Goossens N, and Negro F. Is genotype 3 of the hepatitis C virus the new villain?. 
Hepatology 2014;59:2403-2412.
27. Buti M and Esteban R. Hepatitis C virus genotype 3: a genotype that is not ‘easy-to-
treat’. Expert Review of Gastroenterology & Hepatology 2015;9(3):375-385. doi:
10.1586/17474124.2015.960396.
28. Daklinza EU SPC (11May15)
29. Technivie USPI (10/2015)
30. Hezode C, Asselah T, Reddy KR, et al. Ombitasvir and ABT-450/r with or without 
ribavirin in patients with HCV genotype 4 infection (PEARL-I): a randomised open-label 
trial. Lancet 2015;385:2502-09. doi.org/10.1016/S0140-6736(15)60159-3.
31. Brown A, Hezode C, Zuckerman E, et al.  C-SCAPE: efficacy and safety of 12 weeks of 
grazoprevir +/−elbasvir +/−ribavirin in patients with HCV GT2, 4, 5 or 6 infection.  
Hepatology. 2015; 62(S2):S619. doi:10.1016/S0168-8278(15)30974.
32. Abergel A, Asselah T, Metivier S, 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 20:1-6. doi: 10.1016/S1473-3099(15)00529-0.
33. Gane EJ, Hyland RH, An 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;149:1454–1461.
34. Sofia MJ, Bao D, Chang W, et al. Discovery of a β-d-2’-deoxy-2′-α-fluoro-2′-β-C-
methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med 
Chem 2010;53:7202-18.
35. Gao M, Nettles RE, Belema M, et al. Chemical genetics strategy identifies an HCV 
NS5A inhibitor with a potent clinical effect. Nature 2010;465(7294):96-100. doi: 
10.1038/nature08960.
 
 
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36. Cheng X, Yang B, Liu D, et al. Genetic engineering of bacteria that can produce urate 
oxidase. Intern Med 2012;2(4):1-4. doi:10.4172/2165-8048.1000114.
37. Krishnan P, Beyer J, Mistry N, et al. In vitro and in vivo antiviral activity and resistance 
profile of ombitasvir, an inhibitor of Hepatitis C Virus NS5A. AAC 2014;59(2):979-987.
38. Lawitz E, Rodriguez-Torres M, Denning J, et al. Once daily dual-nucleotide combination 
PSI-938 plus PSI-7977 provides 94% HCV RNA <LOD at day 14: first 
purine/pyrimidine clinical combination data (NUCLEAR Study). J Hepatol 2011;54: 
Suppl:S543.
39. Lawitz E, Freilich B, Link J, et al.  A phase 1, randomized, dose-ranging study of GS-
5816, a once-daily NS5A inhibitor, in patients with genotype 1–4 hepatitis C virus. J 
Viral Hepat 2015; 22: 1011-9. doi:10.1111/jvh.12435.
40. Kwo P, Gane E, Peng C-Y, 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.  50th Annual Meeting of the 
European Association for the Study of the Liver (EASL).  Vienna, Austria, April 22-26, 
2015.  Abstract P0886.
41. Taylor LE, Swan T, and Mayer KH. HIV coinfection with hepatitis C virus: evolving 
epidemiology and treatment paradigms. Clin Infect Dis 2012;55(Suppl 1):S33-42.
42. Pol S and Soriano V. Management of chronic hepatitis C virus infection in HIV-infected 
patients. Clin Infect Dis 2008;47:94-101.
43. Alberti A. Impact of a sustained virological response on the long-term outcome of 
hepatitis C. Liver Int. 2011 Jan;31 Suppl 1:18-22. 
44. Martinot-Peignoux M, Stern C, Maylin S, 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 
Apr;51(4):1122-6.
45. Chen J, Florian J, Carter W, et al. Earlier sustained virologic response end points for 
regulatory approval and dose selection of hepatitis C therapies. Gastroenterology 
2013;144(7):1450-5e2.
46. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C 
treatment-induced viral clearance. Nature 2009;461:399-401.
47. Castera L, Forns X, and Alberti A. Non-Invasive evaluation of liver fibrosis using 
transient elastography. Journal of Hepatology 2008; 48: 835-847.
48. Boursier J, de Ledinghen V, Zarski J-P, 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.
49. Clopper C and Pearson E.  The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika 1934 Dec;26(4): 404-413.
 
 
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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 collected in this trial as outlined in Section 7.1.3.6 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects 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 Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  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. Each consent will be assessed for appropriate 
specimen permissions.  
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 Collections
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 for transfer to the storage facility.  This first 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 first 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 Merck Biorepository 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 have their 
specimens and all derivatives destroyed.   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 
 
 
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PPD

Product:  MK-3682 
106
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
04S4N9

Product:  MK-3682 
107
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
 
 
04S4N9

Product:  MK-3682 
108
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
 
 
04S4N9

Product:  MK-3682 
109
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
 
 
04S4N9

Product:  MK-3682 
110
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
 
 
04S4N9

Product:  MK-3682 
111
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
 
 
04S4N9

Product:  MK-3682 
112
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
 
 
04S4N9

Product:  MK-3682 
113
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
 
 
04S4N9

Product:  MK-3682 
114
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
 
 
04S4N9

Product:  MK-3682 
115
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
 
 
04S4N9

Product:  MK-3682 
116
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
 
 
04S4N9

Product:  MK-3682 
117
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by Sample Types
12.4
Screening
Day 1
Day 21
Day 31
Day 51
Day 7
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
Week 142
Week 162
FW 4
FW 8
FW 12
FW 24
Total Volume
Test
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
63
HBsAg
6
6
HIV-1 Serology
6
6
Chemistry
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
150
Hematology
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
45
MK-3682 PK
4
41
4/161
4
4/121
4
4
4
4
4
4
40/681
MK-8408 PK 
4
41
4/161
4
4/121
4
4
4
4
4
4
40/681
HCV Genotype 
Determination
4
4
HCV RNA Level
10
10/50
1
201
101
101
10
10
10
10
10
10
10
10
10
10
10
10
10
150/2401
HCV Viral 
Resistance and 
biomarkers
6
6
6
6
6
30
Blood for genetic 
analysis 
8.5
8.5
HIV  RNA
6
6
6
6
6
6
6
6
6
6
6
6
6
6
84
HIV Viral 
Resistance
10
10
CD4+ T-cell 
count
6
6
6
6
6
6
6
6
6
6
60
Expected Total 
(mL)
Study Population
64
67.5
0
0
0
39.5
39.5
51.5
45.5
51.5
45.5
51.5
51.5
51.5
45.5
35
45.5
45.5
627.5/
730.52
1 Applicable to Intensive Viral Kinetic Sub-study population only.
2 Applicable only if the treatment duration is extended to 16 weeks.
 
 
04S4N9

Product:  MK-3682 
118
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
List of Abbreviations and Definition of Terms
12.5
Term
Definition
AE
Adverse Event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
APRI
Aspartate Aminotransferase to Platelet Ratio Index
ART
Antiretroviral therapy
ASaT
All Subjects as Treated
AST
Aspartate aminotransferase
Ctrough
Trough plasma concentration
C
Cirrhotic
CFR
Code of Federal Regulations
CI
Confidence Interval
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CSM
Clinical Specimen Management
DAA
Direct-acting antiviral therapy
DAO
Data-As-Observed
DCV
Daclatasvir
DNA
Deoxyribonucleic Acid
EBR
Elbasvir
EC50
Half-maximal effective concentration
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
mFAS
Modified full analysis set
FBR
Future Biomedical Research
FDAAA
Food and Drug Administration Amendments Act
FDA
Food and Drug Administration, USA
FDC
Fixed dose combination
FW
Follow-up Week
GCP
Good Clinical Practice
GT
Genotype
GZR
Grazoprevir
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IFN
Interferon
IND
Investigational New Drug Application; legal instrument in the USA that allows trial of 
unapproved, investigational new drugs in human subjects
INR
International normalized ratio
Investigational 
Product
The drug, biologic, and/or device being investigated in the current trial
IRB
Institutional Review Board
LDV
Ledipasvir
LloQ
Lower limit of quantification
 
 
04S4N9

Product:  MK-3682 
119
Protocol/Amendment No.: 035-04 
MK-3682-035-04 Final Protocol
26-Oct-2017
Confidential
Term
Definition
MDRD
Modification of diet in renal disease
NC
Non-cirrhotic
OMB
Ombitasvir
PD
Pharmacodynamics
PDLC
Pre-Defined Limit of Change
PGx
Pharmacogenomics
PK
Pharmacokinetics
PP
Per-protocol
RAV
Resistance-Associated Variant 
RBC
Red Blood Cell
RBV
Ribavirin
RNA
Ribonucleic Acid
Scr, std
Serum creatinine measured with a standardized assay
SAE
Serious Adverse Event
SAFE
Sequential Algorithm for Fibrosis Evaluation
sSAP
Supplemental statistical analysis plan
SOC
System Organ Class
SOF
Sofosbuvir
SOP
Standard Operating Procedure
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 
TE
Treatment Experienced
TF
Treatment Failure
TN
Treatment Naïve
TND
Target NOT Detected (HCV RNA not detected)
TD (u)
Target detected but unquantifiable
TD (q)
Target Detected, quantifiable
TRD
Treatment-Related Discontinuation
TW
Treatment Week
ULN
Upper limit of normal
USA
United States
VEL
Velpatasvir
VL
Viral load
WBC
White Blood Cell
WK
Week
 
 
04S4N9

Product:  MK-3682 
120
Protocol/Amendment No.: 035-04 
MK-3682-035-04 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
 
 
04S4N9