Conditions: Hepatitis C Virus (HCV) Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 117
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy of 8 and 12 weeks of treatment with a fixed dose combination (FDC) of elbasvir (EBR) 50 mg + grazoprevir (GZR) 100 mg (i.e., MK-5172A) as assessed by the percentage of participants with hepatitis C virus (HCV) genotype (GT) 4 infection that achieve sustained virologic response (HCV ribonucleic acid \[RNA\] \< Lower Limit of Quantification \[LLOQ\]) 12 weeks after the end of study therapy (SVR12). This study also evaluated the safety and tolerability of EBR/GZR.

Detailed description:

Arms:
arm 1: Treatment-naïve participants with stage 0-2 fibrosis (F0-F2) receive FDC of EBR/GZR (50 mg/100 mg) for 8 weeks, with 24 weeks of follow-up. arm 2: Treatment-naïve participants with F0-F2 stage fibrosis, treatment-naïve participants with F3-F4 stage fibrosis, and treatment-experienced participants with F0-F4 stage fibrosis receive FDC of EBR/GZR (50 mg/100 mg) for 12 weeks, with 24 weeks of follow-up.

Interventions: intervention 1: EBR/GZR (50 mg/100 mg) FDC
Intervention descriptions: intervention 1: One FDC tablet taken once daily by mouth for 8 or 12 weeks depending upon randomization.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03111108
Document Date: 
01-Feb-2018
A Multi-Site, Open-Label, Partially-Randomized Trial of the 
Efficacy and Safety of Fixed Dose Elbasvir/Grazoprevir (EBR/
GZR) Based Regimens in French Subjects with Chronic Hepatitis C 
Virus (HCV) Genotype 4 Infection


Product:  MK-5172 
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Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK &
CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Multi-Site, Open-Label, Partially-Randomized Trial of the Efficacy and Safety of Fixed 
Dose Elbasvir/Grazoprevir (EBR/GZR) Based Regimens in French Subjects with Chronic 
Hepatitis C Virus (HCV) Genotype 4 Infection
EudraCT NUMBER:  2016-001159-37
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
2.1
Trial Diagram........................................................................................................ 15
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 15
Primary Objective(s) & Hypothesis(es) .............................................................. 15
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 15
3.2
Exploratory Objectives......................................................................................... 16
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 16
Background ........................................................................................................... 16
4.1
Pharmaceutical and Therapeutic Background .................................................... 16
4.1.1
4.1.1.1
Natural 
History 
of 
Hepatitis C 
Virus 
(HCV) 
Infection 
and 
Epidemiology of HCV Genotype 4 (GT4) Infection................................... 16
4.1.1.2
General Overview of HCV Therapy and Treatment of HCV GT4 
Infection....................................................................................................... 17
4.1.1.3
EBR/GZR in HCV Genotype 4 Infection .................................................... 19
4.1.1.4
Current French Treatment Guidelines for HCV GT4.................................. 20
Background of Elbasvir/Grazoprevir.................................................................. 21
4.1.2
Ongoing Clinical Trials....................................................................................... 21
4.1.3
Rationale................................................................................................................ 21
4.2
Rationale for the Trial and Selected Subject Population .................................... 21
4.2.1
4.2.1.1
Rationale for Study Population (GT4 Infection) ......................................... 22
4.2.1.2
Rationale for Study Population (F0-F2 Fibrosis, TN, and TE subjects)...... 22
4.2.1.3
Rationale for Study Population (SOF + RBV and SOF + peg-IFN/RBV 
failures) ........................................................................................................ 22
4.2.1.4
Rationale for Study Population (Compensated Cirrhotic Patients) ............. 23
4.2.1.5
Rationale for Study Population (HIV Co-infection).................................... 23
4.2.1.6
Rationale for Sample Size............................................................................ 23
 
 
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Rationale for Dose Selection/Regimen/Modification ......................................... 24
4.2.2
4.2.2.1
Rationale for 8-week Regimen of EBR/GZR in TN GT4 Subjects with 
F0-F2 Fibrosis (Arm 1)................................................................................ 24
4.2.2.2
Rationale for 12-week Regimen of EBR/GZR in TN GT4 (F3-F4)............ 26
4.2.2.3
Rationale for 12-week Regimen of EBR/GZR in TE GT4 (F0-F4) ............ 26
Rationale for Endpoints ...................................................................................... 26
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 26
4.2.3.1.1
Measurement of HCV RNA ................................................................. 27
Definition of Efficacy Endpoints ................................................... 27
4.2.3.1.1.1
Definition of Virologic Failure:  Non-Response, Rebound, 
4.2.3.1.1.2
Virologic Breakthrough and Relapse...................................................... 28
4.2.3.1.2
Viral Resistance Measurements............................................................ 28
4.2.3.2
Safety Endpoints .......................................................................................... 29
4.2.3.3
Planned Exploratory Biomarker Research................................................... 29
4.2.3.4
Future Biomedical Research........................................................................ 29
Benefit/Risk ........................................................................................................... 30
4.3
5.0
METHODOLOGY ................................................................................................... 30
Entry Criteria........................................................................................................ 30
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 30
5.1.1
Subject Inclusion Criteria.................................................................................... 30
5.1.2
Subject Exclusion Criteria .................................................................................. 33
5.1.3
Trial Treatment(s) ................................................................................................ 35
5.2
Dose Selection/Modification .............................................................................. 35
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 35
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 35
Timing of Dose Administration .......................................................................... 36
5.2.2
Trial Blinding...................................................................................................... 36
5.2.3
Randomization or Treatment Allocation............................................................ 36
5.3
Stratification.......................................................................................................... 36
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 36
5.5
Rescue Medications & Supportive Care............................................................. 39
5.6
Diet/Activity/Other Considerations..................................................................... 39
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 40
5.8
 
 
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Discontinuation of Treatment ............................................................................. 40
5.8.1
Withdrawal from the Trial .................................................................................. 41
5.8.2
Subject Replacement Strategy............................................................................. 41
5.9
Beginning and End of the Trial ........................................................................... 41
5.10
Clinical Criteria for Early Trial Termination ................................................... 41
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 42
7.0
TRIAL PROCEDURES ........................................................................................... 46
Trial Procedures ................................................................................................... 46
7.1
Administrative Procedures.................................................................................. 46
7.1.1
7.1.1.1
Informed Consent......................................................................................... 46
7.1.1.1.1
General Informed Consent.................................................................... 46
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 47
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 47
7.1.1.3
Subject Identification Card .......................................................................... 47
7.1.1.4
Medical History ........................................................................................... 47
7.1.1.5
Prior and Concomitant Medications Review ............................................... 47
7.1.1.5.1
Prior Medications.................................................................................. 47
7.1.1.5.2
Concomitant Medications..................................................................... 47
7.1.1.6
Assignment of Screening Number............................................................... 48
7.1.1.7
Assignment of Treatment/Randomization Number ..................................... 48
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other) ................................... 48
Clinical Procedures/Assessments........................................................................ 49
7.1.2
7.1.2.1
Physical Examination................................................................................... 49
7.1.2.2
Weight and Height Assessment ................................................................... 49
7.1.2.3
Vital Signs.................................................................................................... 49
7.1.2.4
Birth Control Confirmation.......................................................................... 49
7.1.2.5
Adverse Events ............................................................................................ 49
7.1.2.6
Noninvasive Methods of Cirrhosis Evaluation............................................ 50
Laboratory Procedures/Assessments .................................................................. 50
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 50
7.1.3.2
HCV Evaluation........................................................................................... 52
 
 
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7.1.3.3
HIV Evaluation ............................................................................................ 52
7.1.3.4
HBV Evaluation........................................................................................... 53
7.1.3.5
Planned Genetic Analysis Sample Collection.............................................. 53
7.1.3.6
Future Biomedical Research Sample Collection ......................................... 53
Other Procedures................................................................................................. 53
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 53
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 54
7.1.4.2
Blinding/Unblinding .................................................................................... 54
7.1.4.3
Calibration of Equipment............................................................................. 54
Visit Requirements.............................................................................................. 54
7.1.5
7.1.5.1
Screening...................................................................................................... 54
7.1.5.2
Rescreening.................................................................................................. 56
7.1.5.3
Treatment Period.......................................................................................... 56
7.1.5.4
Drug Administration .................................................................................... 57
7.1.5.5
Follow-Up Visits.......................................................................................... 57
7.1.5.6
Evaluation of Laboratory Safety Signals ..................................................... 58
Assessing and Recording Adverse Events .......................................................... 58
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 59
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 59
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 60
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 60
7.2.3.2
Events of Clinical Interest............................................................................ 60
Evaluating Adverse Events ................................................................................. 61
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 64
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 64
Statistical Analysis Plan Summary ..................................................................... 64
8.1
Responsibility for Analyses/In-House Blinding ................................................. 65
8.2
Hypotheses/Estimation ......................................................................................... 65
8.3
Analysis Endpoints ............................................................................................... 66
8.4
Efficacy/Pharmacokinetics Endpoints ................................................................ 66
8.4.1
8.4.1.1
Efficacy Endpoints....................................................................................... 66
 
 
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8.4.1.2
Exploratory Endpoints ................................................................................. 66
Safety Endpoints ................................................................................................. 66
8.4.2
Analysis Populations............................................................................................. 67
8.5
Efficacy Analysis Population.............................................................................. 67
8.5.1
Safety Analysis Population ................................................................................. 67
8.5.2
Statistical Methods................................................................................................ 68
8.6
Statistical Methods for Efficacy Analyses .......................................................... 68
8.6.1
Statistical Methods for Safety Analyses ............................................................. 70
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 71
8.6.3
Interim Analysis.................................................................................................... 72
8.7
Multiplicity ............................................................................................................ 72
8.8
Sample Size and Power Calculation.................................................................... 72
8.9
Sample Size and Power for Efficacy Analysis.................................................... 72
8.9.1
Sample Size and Power for Safety Analysis ....................................................... 73
8.9.2
Subgroup Analyses and Effect of Baseline Factors ........................................... 74
8.10
Compliance (Medication Adherence).................................................................. 75
8.11
Extent of Exposure................................................................................................ 75
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 75
Investigational Product ........................................................................................ 75
9.1
Packaging and Labeling Information ................................................................. 76
9.2
Clinical Supplies Disclosure................................................................................. 76
9.3
Storage and Handling Requirements.................................................................. 76
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 77
9.5
Standard Policies................................................................................................... 77
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 77
Confidentiality....................................................................................................... 77
10.1
Confidentiality of Data ....................................................................................... 77
10.1.1
Confidentiality of Subject Records..................................................................... 77
10.1.2
Confidentiality of Investigator Information........................................................ 78
10.1.3
Confidentiality of IRB/IEC Information............................................................. 78
10.1.4
Compliance with Financial Disclosure Requirements....................................... 78
10.2
 
 
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Compliance with Law, Audit and Debarment ................................................... 79
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 80
10.4
Quality Management System............................................................................... 81
10.5
Data Management................................................................................................. 81
10.6
Publications ........................................................................................................... 81
10.7
11.0
LIST OF REFERENCES......................................................................................... 82
12.0
APPENDICES........................................................................................................... 86
Merck Code of Conduct for Clinical Trials........................................................ 86
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 88
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff ...................................................................................... 92
List of Abbreviations and Definition of Terms ................................................ 103
12.4
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.5
by Sample Types ................................................................................................. 105
13.0
SIGNATURES......................................................................................................... 106
Sponsor's Representative ................................................................................... 106
13.1
Investigator.......................................................................................................... 106
13.2
 
 
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LIST OF TABLES
    
Table 1
Treatment Arms by Characteristics of the Target Subject Population ................... 14
Table 2
Summary of Published Studies Evaluating DAAs in GT4..................................... 18
Table 3
Results from Integrated Analysis of EBR/GZR Efficacy in GT4 [1]..................... 20
Table 4
Summary of French National Treatment Guidelines.............................................. 21
Table 5
EBR and GZR In Vitro Susceptibility Data for All GT4 Subtypes Identified 
from French Patients .............................................................................................. 24
Table 6
EBR and GZR In Vitro Susceptibility Data for All GT4 Subtypes Among 
81 Isolates Identified from French Patients............................................................ 25
Table 7
Treatment Response Rates After 12 Weeks of EBR/GZR in Treatment-Naïve 
Subjects .................................................................................................................. 25
Table 8
Treatment 
Response 
Rates 
after 
12 Weeks 
of 
EBR/GZR 
in 
Treatment-Experienced Subjects............................................................................ 26
Table 9
Nomenclature for Describing HCV RNA Levels................................................... 27
Table 10 Laboratory Exclusion Criteria ................................................................................ 35
Table 11 Trial Treatment ....................................................................................................... 35
Table 12 Laboratory Tests ..................................................................................................... 51
Table 13 Evaluating Adverse Events..................................................................................... 62
Table 14 Analysis Strategy for Efficacy Variables................................................................ 70
Table 15 Analysis Populations, Criteria for Response, Non-Response, and Exclusion 
from Analysis Population....................................................................................... 70
Table 16 Analysis Strategy for Safety Parameters ................................................................ 71
Table 17 Two-Sided 95% Confidence Intervals for SVR12 ................................................. 73
Table 18 Estimate of Incidence of a Specific Adverse Event and 95% Upper Confidence 
Bound Based on a Hypothetical Number of Subjects with that Specific 
Adverse Event ........................................................................................................ 74
Table 19 Product Descriptions............................................................................................... 76
 
 
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LIST OF FIGURES
Figure 1
Trial Design ........................................................................................................ 15
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
1.0
2.1
8.1
Trial Summary
(Treatment Groups)
Trial Design
Statistical Analysis Plan 
Summary
For Study Arm 2, the target number of 
treatment-naïve (TN) subjects with 
fibrosis stage F3-F4 in bullet #2 was 
changed from “0-15” to “25 (min 15)”.
For Treatment Arm 2, the target 
number of TN subjects with fibrosis 
stage F3-F4 in the last column of Table 
1 was changed from “0-15” to “25 (min 
15)”.
Under Study Arm 2, the target number 
of TN subjects with fibrosis stage F3-
F4 has been changed from “0-15” to 
“25 (min 15)”.
Due to the diminishing pool of 
treatment-experienced (TE) genotype 
(GT) 4 subjects in France, further 
subject enrollment will shift from TE 
(F0-F4) to TN (F3-F4) in order to 
maintain the overall enrollment target 
of 70 subjects in Arm 2.
The new 
target minimum for the TN group is 
intended to match what is encountered 
in clinical practice in France. The 
original no minimum number for TN 
F3-F4 subjects was specified when the 
protocol was written 1.5 years ago. In 
the interim, expanded availability and 
access to direct acting antiviral (DAA) 
treatment in France (which prioritized 
treatment of patients with advanced 
fibrosis) has resulted in a significantly 
lower number of TE patients. As a 
result, the target enrollment minimum 
in Arm 2 was raised for TN subjects 
(F3-F4).
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
1.0
2.1
8.1
Trial Summary
(Treatment Groups)
Trial Design
Statistical Analysis Plan 
Summary
For Study Arm 2, the minimum number 
of TE subjects with fibrosis stage F0-
F4 in bullet #3 has been changed from 
“45 (min 30)” to “20 (min 15)” and the 
requirement for 10 subjects with stage 
F4 has been removed.
For Treatment Arm 2, the target 
number of TE subjects with fibrosis 
stage F0-F4 in the last column of Table 
1 was changed from “45 (min 30)” to 
“20 (min 15)” and the requirement for 
10 subjects with stage F4 has been 
removed from the table footnote.
For Study Arm 2, the minimum number 
of TE subjects with fibrosis stage F0-
F4 has been changed from “45 (min 
30)” to “20 (min 15)” and the 
requirement for 10 subjects with stage 
F4 has been removed.
Changes to the total number of TE 
subjects, and specifically the removal 
of a minimum of TE F4 subjects, were 
made to account for the changing 
epidemiology of GT4 infections in 
France (i.e., the GT4 TE population in 
France received prioritized treatment, 
thereby limiting subjects who are 
eligible for recruitment into the current 
trial). The new target minimum for the 
TE group is intended to match what is 
encountered in clinical practice in 
France. The original minimum number 
of 30 TE F0-F4 subjects was specified 
when the protocol was written 1.5 years 
ago. 
In 
the 
interim, 
expanded 
availability 
and 
access 
to 
DAA 
treatment in France (which prioritized 
treatment of patients with advanced 
fibrosis) has resulted in a significantly 
lower number of TE patients. As a 
result, the target enrollment minimum 
in Arm 2 was lowered for TE subjects.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
7.1.4.3
Calibration of Equipment
Removal of text referring to critical 
equipment.
Textual revisions were applied to 
clarify investigator responsibility for 
calibration and maintenance of trial 
equipment.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
EBR/GZR in TN/TE French Subjects with HCV GT4 infection
Sponsor Product Identifiers
MK-5172A (also termed MK-8742/MK-5172)
elbasvir/grazoprevir (EBR/GZR)
Trial Phase
IV
Clinical Indication
Treatment of hepatitis C virus (HCV) infection
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Oral
Trial Blinding
Unblinded Open-label
Treatment Groups
There are 2 treatment arms in this partially randomized study.  
Approximately 75 (minimum of 60) treatment-naïve (TN) subjects with 
stage 0-2 fibrosis will be randomized using a 2:1 ratio to Arms 1 or 2 to 
receive either 8 weeks or 12 weeks of EBR/GZR, respectively.  TN 
subjects with stage 3-4 fibrosis and treatment-experienced (TE) subjects 
with stage 0-4 fibrosis will be assigned to Arm 2 to receive 12 weeks of 
EBR/GZR.  
The target enrollment in each group is:
Study Arm 1 (n=50): 8-week regimen of EBR/GZR

TN subjects with fibrosis stage F0-F2 n=50 (min 40)
Study Arm 2 (n=70): 12-week regimen of EBR/GZR

TN subjects with fibrosis stage F0-F2 n=25 (min 20)

TN subjects with fibrosis stage F3-F4 n=25 (min 15)

TE subjects with fibrosis stage F0-F4 n=20 (min 15)
Number of trial subjects
Approximately 120 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
68 weeks from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 38 or 
42 weeks (depending on the treatment arm) from the time the subject 
signs the Informed Consent Form (ICF) through the final contact.  
After a screening phase of up to 6.5 weeks, each subject will be 
receiving assigned treatment for approximately 8 or 12 weeks.  All 
subjects will be followed for 24 weeks after completing study 
medication dosing.
A list of abbreviations used in this document can be found in Section 12.4.
Randomization Ratio
For TN subjects stage 0-2 fibrosis only: 2:1 into Arms 1 and 2
TN subjects stage 3-4 fibrosis and all TE subjects are not randomized.
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This is a multi-site, open-label, partially-randomized trial of a fixed dose combination (FDC) 
of elbasvir (50 mg) and grazoprevir (100 mg) (EBR/GZR or MK-5172A) in subjects with 
chronic hepatitis C virus (HCV) genotype (GT) 4 infection to be conducted in conformance 
with Good Clinical Practices.
Approximately 120 subjects with chronic HCV GT4 infection, with or without advanced 
fibrosis, and HCV treatment-naïve (TN) or treatment-experienced (TE) as defined in 
Section 7.1.5.1, will be enrolled.
Approximately 75 (minimum of 60) TN subjects with stage 0-2 fibrosis (F0-F2) will be
randomized using a 2:1 ratio to Arms 1 or 2, to receive either 8 weeks or 12 weeks of 
EBR/GZR, respectively.  TN subjects with stage 3-4 fibrosis (F3-F4) and TE subjects with 
stage 0-4 fibrosis (F0-F4) will be assigned to Arm 2 to receive 12 weeks of EBR/GZR.  The
target enrollment in each treatment arm is shown in Table 1.
Table 1
Treatment Arms by Characteristics of the Target Subject Population
Arm
Study Treatment 
Duration
GT4 HCV Subject Characteristics
Previous
Treatment
Fibrosis Stage
Target # of Subjects
1
(n=50)
8 weeks
TN
F0-F2
50†
(min 40)
2
(n=70)
12 weeks
TN
F0-F2
25†
(min 20)
TN
F3-F4
25
(min 15)
TE
F0-F4
20
(min 15)
GT4 = genotype 4; HCV = hepatitis C virus; TN = treatment-naïve; TE = treatment-experienced
†: At least 60 TN F0-F2 subjects will be randomized 2:1 to Arm 1 or Arm 2.
All subjects will be followed for 24 weeks after the completion of study medication dosing.  
Safety and tolerability will be carefully monitored throughout the study by the Sponsor in 
accordance with standard procedures.
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.
 
 
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Trial Diagram
2.2
The trial design is depicted in Figure 1.
GT4 = genotype 4; TE = treatment-experienced; TN = treatment-naïve; EBR = elbasvir; GZR = grazoprevir; 
WK = week.
Figure 1
Trial Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
As this is an estimation study, there are no hypotheses.
The following objectives will be evaluated in individuals with chronic HCV GT4 infection 
with pre-treatment HCV RNA of at least 10,000 IU/mL.
Primary Objective(s) & Hypothesis(es)
3.1
(1) To evaluate the efficacy of each treatment arm of EBR/GZR as assessed by the 
proportion of subjects achieving SVR12 [sustained virologic response defined as 
HCV RNA <Lower Limit of Quantitation (LLOQ) 12 weeks after the end of all study 
therapy].
(2) To evaluate the safety and tolerability of EBR/GZR.
Secondary Objective(s) & Hypothesis(es)
3.2
(1) To evaluate the efficacy of each treatment arm of EBR/GZR as assessed by the 
proportion of the treatment naïve F0-F2 subjects achieving SVR12.
(2) To evaluate the efficacy of each treatment arm of EBR/GZR as assessed by the 
proportion of subjects achieving SVR24 (sustained virologic response defined as HCV 
RNA < LLOQ 24 weeks after the end of all study therapy).
 
 
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(3) To evaluate resistance-associated variants (RAVs) to EBR or GZR, including the 
association of baseline RAVs with treatment outcomes and the emergence of RAVs
in subjects who fail to achieve SVR.
Exploratory Objectives
3.3
(1) To explore the relationship between interleukin 28B (IL28B) genetic variation and:
-
SVR12
-
SVR24
(2) To explore the relationship between genetic variation and response to the treatment(s) 
administered. Variation across the human genome may be analyzed for association 
with clinical data collected in this study.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on EBR/GZR.
Pharmaceutical and Therapeutic Background
4.1.1
EBR: elbasvir (MK-8742) is an HCV NS5A inhibitor
GZR: grazoprevir (MK-5172) is an HCV NS3/4A protease inhibitor
EBR/GZR: elbasvir/grazoprevir (MK-5172A) is a fixed-dose combination of EBR (50 mg) 
and GZR (100 mg), per tablet.
4.1.1.1
Natural History of Hepatitis C Virus (HCV) Infection and Epidemiology of 
HCV Genotype 4 (GT4) Infection
Every year, 3 to 4 million people worldwide are newly infected with HCV [2] and 
approximately 80% of these will progress to chronic infection [3]. It is estimated that 
130 to 170 million people, or 2% to 3% of the world’s population, are chronically infected 
with HCV [4]. Long-term complications of chronic HCV infection develop in chronically 
infected individuals over the course of several years to decades. These complications include 
cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC) [5]. The rate of HCC 
development among those with chronic HCV has been estimated as 1% to 3% after 30 years 
[3], while over 40% of untreated individuals will develop cirrhosis within 30 years after 
infection [6].
HCV is genetically diverse and classified into 7 genotypes and multiple subtypes, which to 
date number around 70. This classification is based upon viral genome sequence homology 
which differs from 30% to 35% between genotypes while within each subtype there is <15% 
sequence variability. 
Some HCV genotypes, such as GT1a, 1b, 2a, and 3a are more 
widespread geographically, whereas others, such as GT4, have endemic foci of infection 
where the virus has been circulating for generations. HCV GT4 accounts for close to 20% of 
the 170 million HCV infections worldwide and about 85% of these infections are located in 
 
 
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Central Africa and the Middle East. Distribution of the remaining HCV GT4 infections 
mirror migration patterns from this endemic region, notably to western and southern Europe, 
where there are currently over 1.5 million cases [7] [8].
In France, which has an overall 
HCV seroprevalence of 0.6%, up to 10% of HCV infections are GT4 [4] [8].
There is 
considerable genetic diversity in terms of clinical isolates of GT4 that have been identified, 
as 17 subtypes have been confirmed to date [9].  The prevalence of these subtypes varies 
geographically, even within the endemic region. While GT4a predominates in Egypt, non-4a 
and non-4d subtypes are the most common strains isolated in Sub-Saharan Africa. 
Accordingly, there is a more heterogeneous distribution of GT4 subtypes in France and the 
rest of Europe perhaps reflecting the country of origin of the infected individual [10]. A 
phylogenetic analysis that combined patient derived GT4 specimens from daclatasvir late-
stage clinical trials with GT4 sequences from the European HCV database demonstrated that 
of 128 GT4 sequences from Europe, 54 (42%) were GT4a, and 46 (36%) were GT4d, while 
the remaining 28 (22%) were distributed across 11 GT4 subtypes. In this same study, of 81 
sequences from France, 41 (51%) were GT4a, 17 (21%) were GT4d, while the remaining 23 
(28%) GT4 sequences were distributed across 8 genotype 4 subtypes [9].
4.1.1.2
General Overview of HCV Therapy and Treatment of HCV GT4 Infection
The goal of therapy for chronic HCV infection is eradication of virus, as defined by a 
sustained virologic response (SVR), which is tantamount to virologic cure [8].
Until 
recently, SVR at 24 weeks after treatment (SVR24) has been considered the gold standard for 
treatment success as this end point is predictive of long term eradication of the virus and 
correlates with a reduction in symptoms and in the rate of negative clinical outcomes [11]. 
Specifically, SVR has been associated with improved outcomes including biochemical and 
histologic remission of liver disease as well as reduction in the incidence of long-term 
complications of HCV infection including hepatic decompensation, HCC, liver 
transplantation and overall mortality [12]. Given data confirming of the durability of SVR at 
earlier time points than SVR24 (such as SVR12); the US FDA has concluded that SVR12 is 
suitable as a primary end point for regulatory approval [13].
Due to treatment limiting toxicities and suboptimal responses associated with 
interferon-based treatment, which was the standard of care up until 2011, recent drug 
development has focused on all-oral, interferon (IFN) free regimens comprising agents that 
directly and specifically inhibit viral proteins (direct-acting antivirals [DAAs]). Four DAA 
classes have been developed: NS3/4A protease inhibitors (PIs), NS5A inhibitors (NS5AIs), 
nucleotide-mimetic NS5B polymerase inhibitors (NIs), and non-nucleoside NS5B 
polymerase inhibitors (NNIs). Candidate medicines within each of these categories can vary 
substantially in terms of potency across genotypes and against resistance-associated variants 
(RAVs) within each genotype and sub-genotype.
There is now clear evidence that IFN-free regimens consisting of combinations of DAAs that 
target unique proteins integral to completion of the HCV life cycle, can be highly effective in 
clearing chronic HCV infection and are well tolerated. Accordingly, standard of care of 
treatment for chronic HCV infection is rapidly evolving to all-oral IFN-sparing DAA 
regimens. However, availability of DAA-based therapy may be limited in certain regions 
and given that the disease burden of HCV GT4 infection primarily impacts resource-
constrained regions, data on the efficacy of DAA regimens in this population are limited to 
 
 
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pilot or single arm studies with small sample sizes. In general, DAA-based treatment 
responses in GT4 infection have been similar to those observed in GT1 infection; however,
the impact of GT4 subtype and baseline polymorphisms on treatment response is not well 
characterized. A summary of published studies evaluating DAAs in GT4 is included in 
Table 2.
Table 2
Summary of Published Studies Evaluating DAAs in GT4
Study and Reference
Population
Regimen
SVR12
NIAID SYNERGY GT4 [14]
(n=21)

8/21 TE (prior 
IFN-based regimens

7/21 compensated 
cirrhosis
SOF/LDV × 12 weeks
20/21 (95%) 
(overall)
TN: 12/13 (92.3%)
TE: 8/8 (100%) 
PEARL-1 [15] (n=44)

Non-cirrhotic TN 
OBV/PTV/r (no 
RBV) × 12 weeks
40/44 (91%)
PEARL-1 [15] (n=42)

Non-cirrhotic TN/TE
OBV/PTV/r + RBV ×
12 weeks
91/91 (100%) 
overall
TN: 42/42 (100%)
TE: 49/49 (100%) 
Egyptian Ancestry Trial 
(n=31) [16]

TN (n=14)

TE (n =17)

Cirrhotic (n=7)
SOF + RBV ×
12 weeks
21/31 (68%)
TN: 11/14 (79%)
TE: 10/17 (59%)
Egyptian Ancestry Trial 
(n=29) [16]

TN (n=14)

TE (n=15)

Cirrhotic (n=7)
SOF + RBV ×
24 weeks 
27/29 (93%)
TN: 14/14 (100%)
TE: 13/15 (87%) 
Egypt GT4 (n=52) [17]

TN (n=25)

TE (n=21)

Cirrhotic (n=8)
SOF + RBV ×
12 weeks
40/52 (77%)
TN: 21/25 (84%)
TE: 19/27 (70%)
Cirrhotic: 5/8 
(63%)
Egypt GT4 (n=51) [17]

TN (n=24)

TE (n=27)

Cirrhotic (n=9)
SOF + RBV ×
24 weeks
46/51 (90%)
TN: 22/24 (92%)
TE: 24/27 (89%)
Cirrhotic: 7/9 
(78%)
NEUTRINO (n=28) [18]

TN only

Cirrhotic and 
non-cirrhotic 
Peg-IFN + RBV 
+ SOF × 12 weeks 
27/28 (96%)
Study 1119: France Open 
Label GT4 (n=44) and 5 Study 
[19]

TN (n=22)

TE (n=22)

Cirrhotic (n=10)
SOF/LDV × 12 weeks 
41/44 (93%)
TN: 21/22 (96%)
TE: 20/22 (91%)
ION-4 (n=8) [20]

TN/TE

HIV co-infected

Cirrhotic and 
non-cirrhotic
SOF/LDV × 12 weeks
8/8 (100%) 
 
 
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Study and Reference
Population
Regimen
SVR12
French Observational Cohort: 
ANRS CO22 HEPATHER
[21] (prelim results)

TN

TE

Cirrhosis: > 80% for 
all arms evaluated
SOF/SIM × 12 weeks 
8/8 (100%)
French Observational Cohort: 
ANRS CO22 HEPATHER
[21] (prelim results)

TN

TE

Cirrhosis: > 80% for 
all arms evaluated
SOF/SIM × 24 weeks 
10/11 (91%)
French Observational Cohort: 
ANRS CO22 HEPATHER
[21] (prelim results)

TN

TE

Cirrhosis: > 80% for 
all arms evaluated
SOF/SIM/RBV ×
12 weeks 
1/1 (100%)
French Observational Cohort: 
ANRS CO22 HEPATHER
[21] (prelim results)

TN

TE

Cirrhosis: > 80% for 
all arms evaluated
SOF/SIM/RBV ×
24 weeks 
6/6 (100%) 
French Observational Cohort: 
ANRS CO22 HEPATHER
[21] (prelim results)

TN

TE

Cirrhosis: > 80% for 
all arms evaluated
SOF/DCV × 12 weeks 
16/18 (89%)
French Observational Cohort: 
ANRS CO22 HEPATHER
[21] (prelim results)

TN

TE

Cirrhosis: > 80% for 
all arms evaluated
SOF/DCV × 24 weeks 
4/4 (100%)
French Observational Cohort: 
ANRS CO22 HEPATHER
[21] (prelim results)

TN

TE

Cirrhosis: > 80% for 
all arms evaluated
SOF/DCV/RBV ×
12 weeks 
3/3 (100%)
French Observational Cohort: 
ANRS CO22 HEPATHER
[21] (prelim results)

TN

TE

Cirrhosis: > 80% for 
all arms evaluated
SOF/DCV/RBV × 
24 weeks 
6/6 (100%) 
DAA = direct-acting antiviral; DCV = daclatasvir; GT = genotype; HIV = human immunodeficiency; LDV = ledipasvir;
OBV = ombitasvir; PTR/r = paritaprevir/ritonavir; SOF = sofosbuvir; SIM=simeprevir; SVR = sustained virologic 
response; TE = treatment-experienced; TN = treatment-naïve.
4.1.1.3
EBR/GZR in HCV Genotype 4 Infection
The efficacy of the GZR 100 mg and EBR 50 mg with and without (±) RBV in GT4 infected 
subjects was evaluated in an integrated analysis of the phase 2/3 clinical program [1]. Two 
pooled datasets were analyzed: (1) treatment-naïve (TN) subjects who received 12 weeks of 
EBR/GZR ± RBV; and (2) treatment-experienced (TE) subjects, defined as those who had 
previously failed pegylated interferon (peg-IFN) + RBV (PR) who received 12, 16, or 
18 weeks of GZR/EBR ± RBV. 
A total of 103 GT4-infected subjects were evaluated 
including 66 subjects who were treatment-naïve and 27 subjects who were treatment-
experienced. Results from this analysis are summarized in Table 3.
 
 
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Table 3
Results from Integrated Analysis of EBR/GZR Efficacy in GT4 [1]
GT4 Subgroup
Regimen
Duration
(weeks)
SVR12 n/N (%) 
[CI] FAS1
Non-SVR Reason
Treatment-naïve Subjects
TN
EBR/GZR ± RBV
12
64/66 (97%) 
[89.4-99.6]
TN
EBR+GZR
12
54/56 (96%)
1 - Relapse
1 - Other2
TN
EBR+GZR + RBV
12
10/10 (100%)
TN with cirrhosis 
EBR/GZR
12
6/6 (100%)
Treatment-experienced Subjects
TE
EBR+GZR ± RBV
12-18
32/37 (86.5%) 
[71.2-95.4]
TE 
EBR+GZR
12
7/9 (77.8%)
1 - Relapse
1 - Discontinuation 
due to AE
TE with cirrhosis 
EBR+GZR
12
4/6 (67%)
1 - Relapse
1 - Discontinuation
due to AE
TE
EBR+GZR+RBV
12
14/15 (93.3%)
1 - Relapse
TE with cirrhosis 
EBR+GZR+RBV
12
4/5 (80%)
1 - Relapse 
TE
EBR+GZR
16-18
3/5 (60%)
1 - Rebound
1 - Breakthrough
TE with cirrhosis 
EBR+GZR
16-18
1/2 (50%)
1 - Rebound
TE
EBR+GZR+RBV
16-18
8/8 (100%)
TE with cirrhosis 
EBR+GZR+RBV
16-18
4/4 (100%)
AE = adverse event; CI = confidence interval; EBR = elbasvir; FAS = full analysis set; GZR = grazoprevir; 
OTF = on treatment virologic failure; RBV = ribavirin; TE = treatment-experienced; TN = treatment naive.
1
FAS: analysis includes all subjects who received at least one dose of study drug.
2
"Other" includes subjects who did not achieve SVR but did not meet virologic failure criteria (e.g., lost to 
follow-up, withdrew consent), nor discontinued due to an AE.
4.1.1.4
Current French Treatment Guidelines for HCV GT4
The June 2015 French national treatment guidelines [22] provide guidance on management 
of HCV GT4 infection based on the level of available evidence supporting each 
recommended regimen. These guidelines, summarized in Table 4, include recommendations 
for regimens that as of June 2015, were either available or in late stage development.
 
 
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Table 4
Summary of French National Treatment Guidelines
Population
Regimen
(Available in 
June 2015)
Duration
Level of Evidence
Non-cirrhotic TN/TE 
SOF+SIM
12 weeks
C
SOF+DCV
12 weeks
C
SOF+LDV
12 weeks
B
OBV/PTV/r + RBV
12 weeks
A
Compensated Cirrhotic TE/TN
SOF+SIM+RBV
12 weeks
C
SOF+SIM
24 weeks
C
SOF+DCV+RBV
12 weeks
C
SOF+DCV
24 weeks
C
SOF+LDV+RBV
12 weeks
EA
Non-cirrhotic TN: Late Stage Development Regimen
EBR/GZR
12 weeks
C
SOF/GS-5816
12 weeks
C
A = established scientific evidence; B = scientific assumption; C = low level of evidence; DCV = daclatasvir; 
EA = expert agreement; LDV = ledipasvir; OBV = ombitasvir; PTR/ r= paritaprevir/ritonavir; 
SIM=simeprevir; SOF = sofosbuvir; TE=treatment-experienced; TN=treatment-naïve.
Background of Elbasvir/Grazoprevir
4.1.2
Please refer to the EBR and GZR Investigator Brochures (IBs) for more information on the 
pre-clinical and clinical studies with EBR/GZR.
Ongoing Clinical Trials
4.1.3
Please refer to the respective IBs for details regarding the preliminary results of ongoing 
clinical studies.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Optimal management of HCV GT4 infection is not well defined as current treatment 
guidelines in France are based on efficacy data from smaller studies. Although regimens 
recommended in these guidelines offer improved safety and efficacy over peg-IFN based 
therapy, evaluation and availability of newer DAAs such as EBR/GZR may expand treatment 
options for those not optimally managed with currently available therapies.
 
 
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4.2.1.1
Rationale for Study Population (GT4 Infection)
The prevalence of HCV GT4 infection is 10% in France and increasing across all of western 
and southern Europe. With over 30 million cases worldwide, GT4 infection contributes 
significantly to the disease burden attributable to chronic HCV infection. Evaluation of 
strategies aimed at optimizing management of GT4 infection, such as treatment with shorter 
RBV-free regimens may eventually lead to expanded access to treatment in the resource 
limited settings where GT4 infection is endemic.
4.2.1.2
Rationale for Study Population (F0-F2 Fibrosis, TN, and TE subjects)
Although current French National HCV Treatment Guidelines imply that therapy should be 
proposed for almost all patients with HCV infection, including cirrhotic, non-cirrhotic, TN,
and TE patients, consideration of eligible candidate’s accounts for practical limitations to 
treatment access, including budgetary constraints. Accordingly, treatment recommendations 
outlined in these guidelines entail prioritizing treatment in those TN and TE patients with 
stage 2 or higher fibrosis, i.e., those who are at higher risk of developing complications from 
liver disease if untreated. However, the guideline authors do point out that universal access 
to HCV treatment for all patients in France is a goal by 2025 and that gradual extension of 
treatment indications will be considered by health authorities [22]. 
All currently 
recommended regimens for HCV GT4 patients are at least 12 weeks in duration and as seen 
in 
Table 4, 
the 
regimen 
with 
the 
most 
supporting 
evidence 
(ombitasvir 
[OBV]/PTV/r + RBV × 12 weeks) includes RBV. Thus evaluation of whether a shorter 
8-week RBV-free regimen is a viable option in subjects with F0-F2 fibrosis is important as 
treatment expansion strategies aimed at the goal of universal access are developed. 
Furthermore, this trial proposes to evaluate 2 unique treatment arms, thus inclusion of a 
broad spectrum of GT4 subjects can aid in understanding the merits of these regimens 
relative to specific patient subgroups.
4.2.1.3
Rationale for Study Population (SOF + RBV and SOF + peg-IFN/RBV failures)
TE subjects who have failed SOF with or without RBV are eligible for this study as it is 
highly unlikely they will respond any differently to EBR/GZR than other IFN/RBV 
failures. Given that SOF utilizes a mechanism of action distinct from either EBR or GZR, 
RAVs selected by SOF maintain full susceptibility to EBR and GZR. Furthermore, to date, 
identification of SOF RAVs in GT4 subjects failing either SOF/RBV or SOF/peg-IFN/RBV 
is exceedingly rare. Of the 17 patients who did not achieve a SVR12 in the Egyptian GT4 
study [17] and the one failure in the NEUTRINO study [18], none had the signature RAV for 
SOF, the S282T, suggesting that GT4 subjects who fail these SOF/RBV +/-peg-IFN will 
have future treatment options in the unlikely event they fail EBR/GZR. The rationale for 
excluding all other DAA-based failures is that treatment with any DAA-including regimen 
other than SOF + RBV or SOF + peg-IFN would have included either an NS5A or NS3 
inhibitor, thus those who failed these regimens are at increased risk for baseline resistance to 
either EBR and/or GZR. 
 
 
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4.2.1.4
Rationale for Study Population (Compensated Cirrhotic Patients)
Compensated cirrhotic patients are included given that they are at the highest risk of 
developing complications from liver disease [23] and are considered to be a high priority for 
treatment in the French guidelines.
SVR confers numerous clinical benefits including 
improvement in mortality, reduction in HCC and reduction in hepatic decompensation [12], 
hence the need to treat those who are at the greatest risk for developing these outcomes. 
Current treatment recommendations for GT4 cirrhotic patients (Table 4) include either 24-
week regimens or 12-week regimens that include RBV. There are no 12-week RBV free 
regimens included in the current French treatment guidelines for cirrhotic GT4 patients and 
this study proposes to evaluate such a regimen in both TE and TN cirrhotic patients. In 
addition to increasing pill burden, RBV is associated with toxicities such as anemia, its use 
typically requires additional monitoring, and administration may not be optimal in the setting 
of significant comorbidities such as cardiac and renal disease. An integrated analysis of 
402 compensated cirrhotic patients with HCV GT1, GT4, or GT6 infection treated with EBR 
and GZR ± RBV for 12 to 18 weeks demonstrated comparable efficacy to what is seen in 
non-cirrhotic subjects. A small number of GT4 subjects were included in this analysis and as 
seen in Table 3, 6/6 TN GT4 cirrhotics and 4/5 TE GT4 cirrhotics achieved SVR12. The 
overall efficacy of all compensated cirrhotic GT1, GT4 and GT6 (SVR12) TN and TE
subjects treated with 12 weeks of EBR/GZR was 98% (135/138) and 89% (48/54), 
respectively.
Among TE cirrhotics, 2 of the 6 subjects failed to attain a SVR due to 
administrative reasons [24]. These data support inclusion of compensated cirrhotic subjects 
in the proposed study Arm 2.
4.2.1.5
Rationale for Study Population (HIV Co-infection)
Subjects co-infected with human immunodeficiency virus (HIV) will not be excluded from 
this trial given that treatment outcomes with DAA-based regimens are no different in HCV 
mono-infected versus co-infected HCV/HIV patients with preserved immune function [20]. 
Similar conclusions have been observed in the EBR/GZR clinical program, wherein, HIV 
co-infected GT1- and GT4-infected subjects had similar high efficacy following EBR/GZR 
therapy in Phase 3 studies [25]. In the EBR/GZR Phase 3 program, Protocol PN061 treated 
GT1-, GT4-, and GT6-infected subjects co-infected with HIV with and without cirrhosis 
[26]. All were treated with a regimen of EBR/GZR without RBV for 12 weeks and the 
efficacy was 96% (210/218) and was 100% in the 16% of co-infected subjects with cirrhosis. 
The subject response rate across all demographics, including Black subjects, was similar to 
the mono-infected subjects. With similar efficacy achieved with EBR/GZR in mono- and 
co-infected subjects, this trial will co-enroll HIV infected subjects in all treatment arms.
4.2.1.6
Rationale for Sample Size
The sample size for each treatment group in this study (n = 50 in Arm 1 and n = 70 in Arm 2) 
was selected based on the knowledge of the epidemiology of HCV infection in France.  This 
is an exploratory study with no formal hypotheses thus the sample size is reflective of the 
number of subjects that are likely to be enrolled in each treatment arm.  The current sample 
size will be used to estimate efficacy and safety of these 2 treatment regimens (refer to 
Table 17 and Table 18 in Section 8.9).
 
 
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Rationale for Dose Selection/Regimen/Modification
4.2.2
Dose Selection for EBR
An EBR dose of 50 mg daily (QD) was selected based on a Phase 1b monotherapy study in 
HCV-infected subjects, EBR PN002, and a Phase 2a dose-ranging study (PN035 Part A), as 
well as the favorable efficacy and safety profile demonstrated in a large Phase 2/3 program in 
which approximately 2000 subjects were treated with a dose of EBR (50 mg) including 
subjects with cirrhosis, HIV co-infection, and prior treatment experience. 
For detailed 
information, please refer to the IB.
Dose Selection for GZR
A GZR dose of 100 mg QD was selected based on Phase 2 dose-ranging studies (PN003, 
PN038) as well as the favorable efficacy and safety profile demonstrated in a large Phase 2/3
program in which approximately 2000 subjects were treated with a dose of GZR (100 mg) 
including subjects with cirrhosis, HIV co-infection and prior treatment experience.
For 
detailed information, please refer to the IB.
4.2.2.1
Rationale for 8-week Regimen of EBR/GZR in TN GT4 Subjects with F0-F2 
Fibrosis (Arm 1) 
Preclinical studies demonstrate that the in vitro activity of both EBR and GZR against GT4 is 
similar to GT1b when assessed in HCV replicon cell-based assays.
This work included 
evaluation of most of the common GT4 subtypes that are associated with clinical disease. 
For reference, available EBR and GZR in vitro susceptibility data for all GT4 subtypes that 
were identified from French patients in the study discussed in Section 4.1.1.1 [9] are 
summarized in Table 5 and Table 6 with GT1b EC50 provided for comparison.
Table 5
EBR and GZR In Vitro Susceptibility Data for All GT4 Subtypes Identified from 
French Patients
GT4 Subtype
Frequency of GT4 
subtype among 81 
isolates from 
France sequenced 
in ref [9]
n (%)
Number of GT4 
subtype replicons 
assayed
Range of GZR 
EC50 (nM)
GZR EC50 for 
GT1b in Con 1 
replicon for 
reference 
(nM ± SD)
4a
41 (50.6%)
1
0.3
0.5 ± 0.3
4d
17 (21%)
1
0.6
0.5 ± 0.3
4f
10 (12.3 %)
0
n/a
0.5 ± 0.3
4k
3 (3.7%)
0
n/a
0.5 ± 0.3
4g
2 (2.5%)
2
0.15-0.33
0.5 ±-0.3
4c
2 (2.5%)
0
n/a
0.5 ±-0.3
4q
2 (2.5%)
0
n/a
0.5 ±-0.3
4t
2 (2.5%)
0
n/a
0.5 ±-0.3
4n
1 (1.2%)
0
n/a
0.5 ±-0.3
4p
1 (1.2%)
0
n/a
0.5 ±-0.3
 
 
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Table 6
EBR and GZR In Vitro Susceptibility Data for All GT4 Subtypes Among 
81 Isolates Identified from French Patients
GT Subtype
Frequency of GT Subtype 
among 81 isolates from 
France sequenced in ref [9]
n (%)
Number of GT4 
subtype 
replicons assayed
Range of EBR 
EC50 nM
GZR EC50 for 
GT1b in Con 1 
replicon for 
reference 
(nM ± SD)
4a
41 (50.6%)
3
.0002-.003
.003 ± .001
4d
17 (21%)
2
.0004-.0005
.003 ± .001
4f
10 (12.3 %)
1
.0019
.003 ± .001
4k
3 (3.7%)
0
n/a
.003 ± .001
4g
2 (2.5%)
2
.072-.0006
.003 ± .001
4c
2 (2.5%)
0
n/a
.003 ± .001
4q
2 (2.5%)
1
.0005
.003 ± .001
4t
2 (2.5%)
0
n/a
.003 ± .001
4n
1 (1.2%)
0
n/a
.003 ± .001
4p
1 (1.2%)
0
n/a
.003 ± .001
The activity of both EBR and GZR against GT4a and 4d, which appear to be the most 
prevalent subtypes in France, is comparable to what is seen against GT1b. This similar
potency in vitro does appear to correlate with in vivo efficacy. As demonstrated in Table 7, 
the treatment response rate of 12 weeks of EBR/GZR in the pooled TN GT4 dataset [10] was
similar to the response rate in the in the TN GT1b patients treated in PN035, a randomized, 
placebo-controlled study that included both cirrhotic and noncirrhotic subjects with HCV 
GT1, 4, and 6 infection [27]. 
Table 7
Treatment Response Rates After 12 Weeks of EBR/GZR in Treatment-Naïve 
Subjects
Regimen
Duration
SVR12 GT1b (PN035)
SVR12 GT4 (pooled analysis)
EBR/GZR
12 weeks
129/131 (99%)
54/56 (96%)
The comparable in vitro and clinical profiles of EBR and GZR in GT4 and GT1b infection 
suggest that efficacy of regimens not yet studied in TN GT4 patients may be similar to what 
was seen in GT1b infection. Accordingly, justification for the 8-week regimen proposed for 
TN GT4 subjects with F0-F2 fibrosis is based on the high efficacy observed when this same 
regimen was given to a similar GT1b population. In PN035, one of the treatment arms 
included an 8-week regimen of EBR and GZR in noncirrhotic TN subjects with GT1b 
infection and demonstrated that 28/29 TN GT1b subjects with F0-F2 fibrosis achieved 
SVR12.
 
 
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4.2.2.2
Rationale for 12-week Regimen of EBR/GZR in TN GT4 (F3-F4)
As seen in Table 3, the efficacy of EBR/GZR was over 96% when given for 12 weeks in TN 
GT4 subjects enrolled in the phase 2/3 clinical program and there was no difference in TN 
GT4 subjects with cirrhosis compared to those without cirrhosis supporting continued 
evaluation of this regimen for GT4 infected subjects in France.
4.2.2.3
Rationale for 12-week Regimen of EBR/GZR in TE GT4 (F0-F4) 
As discussed previously, EBR and GZR have comparable in vitro activity against GT4 and 
GT1b replicons and parallels in treatment response were noted between TN GT4 and GT1b 
subjects treated with 12 weeks of EBR/GZR. As seen in Table 8, in the pooled Phase 2/3 
dataset, TE GT1b subjects responded well to 12 weeks of EBR and GZR while the response 
rates were lower in a much smaller sample size of TE GT4 subjects. Among the 2 TE GT4 
subjects who did not achieve SVR12, one subject relapsed and a second discontinued due to 
an adverse event (AE) that was not drug related. Similar treatment responses to those 
observed in TE GT1b infection are expected in TE GT4 subjects and the difference noted 
above may be modulated by the small sample size of TE GT4 subjects making it difficult to 
assess the validity of this result. Accordingly, additional work to optimize management of TE 
GT4 infection, specifically by studying a 12-week RBV free regimen, is warranted. 
Table 8
Treatment 
Response 
Rates 
after
12 Weeks 
of 
EBR/GZR 
in 
Treatment-Experienced Subjects
Regimen
Duration
SVR12 GT1b
SVR12 GT4
EBR/GZR
12 weeks
54/56 (96%)
7/9 (78%)
Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
The primary measurement for efficacy in this study is the plasma HCV RNA level.  Long 
term suppression of HCV RNA, typically reported as sustained virologic response (SVR), 
has been associated with improved outcomes in patients with chronic hepatitis C 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 and improve survival [28].
The primary evaluation of efficacy in this trial is based on SVR 12 (sustained virologic 
response 12 weeks after the end of all study therapy), the current standard ever since first 
used for registration of simeprevir and sofosbuvir. Because there is a high degree of 
concordance between SVR12 and SVR24 [29], SVR12 is used as the primary endpoint for 
registration of DAAs [13].
Other secondary evaluations of efficacy are based on SVR24 (sustained virologic response 
24 weeks after the end of all study therapy).
Detailed definitions for evaluation for SVR are provided later in this section.
 
 
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4.2.3.1.1 Measurement of HCV RNA
HCV RNA levels in plasma will be measured on blood samples drawn from each subject at 
various time points prior to, during, and after dosing, as indicated in the Trial Flow Chart 
(Section 6.0).  Samples are collected and processed as per instructions provided by the 
central laboratory manual (assay type indicated in central laboratory manual).
Results from the sample collected at the screening visit are used to determine eligibility.  
Samples collected at other time points are used for efficacy analyses.  They are also used to 
identify subjects who meet virologic failure criteria.
The nomenclature detailed in Table 9 will be used when describing HCV RNA levels:
Table 9
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 time points during the trial. Specific endpoints are:

SVR12 (sustained virologic response 12 weeks after the end of all study therapy).  The 
subject has HCV RNA < LLOQ (either TD[u] or TND) 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 (either TD[u] or TND) 24 weeks after the end of all 
study therapy.
 
 
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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 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 (TD [q]) after 
being < LLOQ previously while on treatment. Confirmation is defined as an 
HCV RNA ≥LLOQ from a separate blood draw repeated within 2 weeks.

Relapse: Subject has a confirmed HCV RNA ≥LLOQ (TD [q]) following end of all 
study therapy, after becoming undetectable (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
HCV resistance measurements
Resistance-associated variants (RAVs) of the hepatitis C virus can lead to increased risk of 
failure to DAA therapy.  In addition, subjects with virologic failure may develop RAVs. 
Blood samples for viral resistance assays are collected on all subjects at Baseline (Day 1) to 
determine the impact of baseline RAVs on response to EBR and GZR.
To better understand the presence of RAVs after treatment with a regimen containing 
EBR/GZR, samples will be collected at virologic failure confirmation visits and all follow-up 
visits after virologic failure is confirmed. Samples will be tested for any subject meeting 
virologic failure criterion who has detectable virus >1000 IU/mL. These same subjects who 
meet any virologic failure criterion will have samples collected at all subsequent follow-up 
visits to be assessed for RAVs, if the virus is detectable and >1000 IU/mL.
Subjects who fail due to early discontinuation of study medication and continue in the trial 
will also have samples collected and tested for RAVs at each follow-up visit, if the virus is 
detectable and >1000 IU/mL.
Analysis of RAVs will entail a variety of techniques that may include population sequencing 
and/or next generation sequencing.  Additionally, genotypic and investigational assays may 
be employed to differentiate virologic failure from re-infection.  Resistance testing may also 
be performed on leftover HCV RNA plasma samples.
 
 
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4.2.3.2
Safety Endpoints
The safety and tolerability of the study regimens will be assessed by a clinical evaluation of 
AEs and inspection of other study parameters including vital signs, physical examinations, 
and standard laboratory safety tests at appropriate time points as specified in the Trial Flow 
Chart (Section 6.0).  Adverse events are graded and recorded according to Section 7.2.  
Subjects may be asked to return for unscheduled visits in order to perform additional safety 
monitoring.
4.2.3.3
Planned Exploratory Biomarker Research
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, IL28B genetic
variants will specifically be investigated for understanding variation in clinical endpoints for 
example, but not limited to, SVR and other efficacy and safety measurements.
4.2.3.4
Future Biomedical Research
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.
 
 
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Benefit/Risk
4.3
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Elbasvir/Grazoprevir
In Phase 1-3 studies, 1234 healthy volunteers, 66 non-HCV-infected persons with liver or 
kidney impairment, and 2704 HCV-infected subjects have been treated with any dose or 
regimen of EBR and/or GZR, with or without RBV. At a dose of EBR (50 mg) and GZR 
(100mg) in ~ 2000 subjects, high efficacy and a favorable safety profile has been 
demonstrated including subjects with cirrhosis, HIV co-infection, chronic kidney disease and 
history of prior HCV treatment failure.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with chronic HCV GT4 infection who are at least 18 years of age will 
be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. be ≥18 years of age on day of signing informed consent
2. be a current resident of France
3. have HCV RNA (≥10,000 IU/mL in peripheral blood) at the time of screening
4. have documented chronic HCV GT4 (with no evidence of non-typeable or mixed 
genotype) infection and meet the definition below:
a.
positive for anti-HCV antibody, HCV RNA, or HCV GT4 at least 6 months 
before screening, or
b. positive for anti-HCV antibody or HCV RNA at screening with a liver biopsy 
consistent with chronic HCV infection (or a liver biopsy performed before 
enrollment with evidence of CHC disease, such as the presence of fibrosis)
5. have one of the below liver staging assessments as follows:
a.
Liver biopsy performed within 24 months of Day 1 of this study (if subject 
has cirrhosis, there is no time restriction on biopsy)
 
 
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b. FibroScan® performed within 12 months of Day 1 of this study with 
interpretable result in kilopascals (kPa) as follows

Fibrosis score of F0-F2 = <8.0 kPa

Fibrosis score of F3 = 8.0 – 12.5 kPa

Cirrhosis (F4) = >12.5 kPa
c.
For cirrhotic (F4) subjects only: A FibroTest® (FibroSure®)* performed 
during Screening with a score of >0.75 and an aspartate aminotransferase 
(AST): platelet ratio index (APRI) of >2.  
APRI formula:  AST÷lab upper limit of normal (ULN) for AST x 100÷ 
(platelet count÷100) (APRI calculation to be provided by the central 
laboratory). 
*If FibroTest®/APRI results are not available or if the FibroTest®/APRI 
score is indeterminant then either a liver biopsy or interpretable FibroScan®
result, performed within timeframe above, must be obtained and reported for 
study entry and liver fibrosis staging.
NOTE: In cases where more than one liver fibrosis staging assessment is available, 
only one result may be used to determine fibrosis status. 
6. have a prior treatment history of either of the following (see Section 7.1.5 for 
definitions):
a.
HCV treatment-naïve (TN)
b. HCV treatment-experienced (TE) with IFN +/- RBV +/- SOF:
On-treatment Failure
Relapser
Other/intolerant
NOTE: When available, documentation of prior IFN +/- RBV +/- SOF
treatment history should include clinic notes or referral letter documenting 
regimen administered, approximate dates of treatment, approximate date of 
virologic failure, and a history of laboratory confirmed prior virologic failure 
or documented intolerance to allow for categorization of prior regimen.  If the 
subject was treated with a regimen more than once, the categorization must be 
based on the most recent round of treatment.
7. meet one of the following categories:
a.
the subject is a male.
b. the subject is a female who is not of reproductive potential, defined as a 
female who either: (1) is postmenopausal (defined as at least 12 months with 
no menses in women ≥45 years of age); (2) has had a hysterectomy and/or 
bilateral 
oophorectomy, 
bilateral 
salpingectomy, 
or 
bilateral 
tubal 
ligation/occlusion at least 6 weeks prior to screening; OR (3) has a congenital 
or acquired condition that prevents childbearing.
 
 
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c.
the subject is a female who is of reproductive potential and agrees to avoid 
becoming pregnant from Day 1 through 14 days after 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 her 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 2 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. understands the study procedures, alternative treatments available, risks involved with 
the study, and voluntarily agrees to participate by giving written informed consent.
9. provides written informed consent for the trial. The subject may also provide consent 
for future biomedical research (FBR). However, the subject may participate in the 
main trial without participating in FBR.
For HIV co-infected subjects, these additional criteria must also be met:
10. have HIV-1 infection documented at any time prior to screening by any licensed rapid 
HIV test or HIV enzyme or chemiluminescense immunoassay (E/CIA) test kit and 
confirmed by a licensed Western blot or a second antibody test by a method other 
than the initial rapid HIV and/or E/CIA, or by HIV-1 p24 antigen, or plasma HIV-1 
RNA viral load.
 
 
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11. meet one of the following criteria:
a.
If not currently on antiretroviral therapy (ART) and has no plan to initiate 
ART treatment while participating in this study:
i. Subjects not on ART must have CD4+ T-cell count > 500 cells/mm3 at 
screening.
b. have well controlled HIV on ART, defined as:
i. must have achieved and maintained virologic suppression (defined as 
confirmed HIV RNA level below the LLOQ of available assay) on 
HIV ART at least 8 weeks prior to study entry (Day 1).
a) ART regimen must contain only the following antiretroviral 
medications: tenofovir, abacavir, lamivudine, emtricitabine, 
raltegravir, dolutegravir, and rilpivirine.
b) Dose modifications or changes in drugs during the 4 weeks 
prior to study entry (Day 1) are not permitted.
ii. have HIV RNA < LLOQ at screening
iii. subjects on ART must have a CD4+ T-cell count > 200 cells/mm3 at 
screening.
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. had prior treatment (defined as 1 dose or more) with DAA therapy not listed in 
Section 7.1.5.1.
3. 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 active advanced liver disease.
4. is classified as Child-Pugh B or C or has a Child Pugh-Turcotte score (CPT) > 6:
NOTE: To calculate the Child-Pugh score, refer to the following website: 
http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality
5. 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 of Day 1 not available, imaging is required 
during screening.
 
 
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6. is hepatitis B surface antigen [HBsAg] positive at screening.
NOTE:  Subjects who are HBsAg negative at screening, but who are hepatitis B core 
antibody (anti-HBc) positive at screening may be included.  For all anti-HBc positive 
subjects, hepatitis B virus (HBV) deoxyribonucleic acid (DNA) will be assessed at 
screening, and both HBV DNA and HBsAg will be monitored during the trial.  
Additional details can be found in Section 7.1.3.4 ‒ HBV Evaluation and Section 7.2.3.2 
‒ Events of Clinical Interest.
7. is under evaluation for active or suspected malignancy, except for adequately treated 
basal cell or squamous cell skin cancer or in situ cervical cancer.
8. is taking or plans to take any of the prohibited medications listed in Section 5.5.
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 clinically-relevant drug or alcohol abuse within 12 months of screening, in the 
opinion of the investigator that would compromise the patient’s ability to participate in 
the trial.
11. is a female and is pregnant or breastfeeding, or expecting to conceive or donate eggs from 
Day 1 through 14 days after the last dose of study drug or longer if dictated by local 
regulations, OR a male subject who is expecting to donate sperm from Day 1 through 14 
days after the last dose of study drug or longer if dictated by local regulations.
12. has any clinically-significant illness (other than HCV) or any other major medical 
disorder that in the opinion of the investigator may interfere with subject treatment, 
assessment or compliance with the protocol or any medical/surgical conditions that may 
result in a need for hospitalization during the period of the study; subjects currently under 
evaluation for a potentially clinically-significant illness (other than HCV) are also 
excluded.
NOTE: Subjects with a 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 10
NOTE: If any of the laboratory exclusion criteria in Table 10 are met, the site may 
have the abnormal value retested once. No other tests may be repeated for 
determining study entry eligibility.
 
 
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Table 10
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Parameters
Hemoglobin
< 10 g/dL in females or < 11 g/dL in males
Platelets
< 40 × 103/μL 
Serum Albumin
< 3.0 g/dL 
INR
> 1.7 (unless subject has known hemophilia or is 
stable on an anticoagulant regimen affecting INR)
ALT
> 10 × ULN
AST
> 10 × ULN
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 treatments to be used in this trial are outlined below in Table 11.
Table 11
Trial Treatment
Drug
Weight
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
MK-5172A 
(fixed dose 
combination 
of 
EBR/GZR)
NA
50 mg/ 100 mg
QD
Oral
Arm 1: 
8 weeks
Arm 2: 
12 weeks
Experimental
The first dose of trial treatment will be administered at the trial site at Visit 2 (Day 1).  All 
other dosing will be performed by the subject (i.e., unsupervised at his/her home) at 
approximately the same time each day.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection (Preparation)
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 of EBR/GZR to each subject.  
5.2.1.2
Dose Modification (Escalation/Titration/Other)
Dose modification of EBR/GZR is not permitted.
 
 
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Timing of Dose Administration
5.2.2
EBR/GZR
Subjects will be instructed to take EBR/GZR without regard to food.
If a subject misses a dose of EBR/GZR and it is less than 8 hours before the next dose, the 
missed dose should be skipped and the normal dosing schedule resumed. Subjects should not 
double the next dose in order to compensate for what has been missed.
If for any reason EBR/GZR needs to be interrupted, it can be interrupted for up to 3 
consecutive days. If the interruption lasts for more than 3 consecutive 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
In this open-label, partially randomized study, approximately 120 subjects will be enrolled. 
Approximately 75 (minimum of 60) TN subjects with stage 0-2 fibrosis will be randomized 
2:1 to Arms 1 and 2, respectively.  A total of approximately 45 TN subjects with stage 3-4 
fibrosis and TE subjects with stage 0-4 fibrosis will be assigned (not randomized) to Arm 2.  
The treatment allocation (Table 1) will be implemented centrally using an interactive voice 
response system/integrated web response system (IVRS/IWRS).
Stratification
5.4
The randomized subjects will be stratified by baseline HCV RNA viral load:  less than or 
equal to 800,000 IU/mL and greater than 800,000 IU/mL.
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

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.
 
 
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
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.nij.gov website.
Listed below are specific restrictions for concomitant therapy or vaccination during the 
course of the trial.
The following medications/therapies are prohibited during the dosing period and for 14 
days before and after the dosing period:
Known hepatotoxic drugs, including but not limited to:

Etifoxine 

Isoniazid 

Nitrofurantoin 

Phenytoin 

Oral Ketoconazole
Strong and moderate CYP3A/P-gp inducers, including but not limited to:

antibiotics:  nafcillin

antimycobacterials: rifampin

anticonvulsants:  carbamazepine, phenytoin

endothelin Antagonists:  bosentan

Herbal Products: St. John’s wort

HIV Medications: efavirenz, etravirine

Wakefulness-Promoting Agents:  modafinil
OATP inhibitors, including but not limited to:

immunosuppressants:  cyclosporine

antimycobacterials:  rifampin

HIV Medications: atazanavir, darunavir, lopinavir, saquinavir, tipranavir
HIV medications:

Cobicistat-containing regimens - elvitegravir/ cobicistat/emtricitabine/ tenofovir 
(disoproxil fumarate or alafenamide)

atazanavir,

darunavir

lopinavir

saquinavir
 
 
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
tipranavir

efavirenz

etravirine
HMG-CoA reductase inhibitors (statins):

atorvastatin greater than 20 mg (see Allowed Medications, below)

rosuvastatin greater than 10 mg (see Allowed Medications, below)

fluvastatin, lovastatin, simvastatin (see Allowed Medications, below): The dose of 
fluvastatin, lovastatin, or simvastatin should not exceed a daily dose of 20 mg when 
co-administered with ZEPATIER. Statin-associated adverse events such as myopathy 
should be closely monitored.
The following medications/therapies may require dose adjustment or monitoring 
during the dosing period and for 14 days before and after the dosing period:
Co-administration with systemic tacrolimus increases the concentrations of tacrolimus. 
Therefore, frequent monitoring of tacrolimus whole blood concentrations, changes in renal 
function, and tacrolimus-associated adverse events upon the initiation of co-administration is 
recommended.
Other CYP3A4 substrates with narrow therapeutic ranges (e.g., alfentanil, astemizole, 
cisapride, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, terfenadine) are not 
prohibited, but their concentrations have the potential to be increased by approximately 30-
40%.  Therefore, subjects taking these medications should be monitored closely or dose 
adjusted appropriately.
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.
Concomitant medications and therapies discontinued or dose adjusted during the dosing 
period may be restarted 2 weeks after the last dose of study drug is administered and may 
continue during the follow-up period.
The following medications/therapies are allowed in this study:
Antihypertensives:

Angiotension-converting enzyme (ACE) inhibitors/angiotensin receptor blockers 
(ARB):  enalapril, captopril, lisinopril, ramipril, valsartan, losartan, telmisartan

Beta blockers:  atenolol, metoprolol, propranolol 
Note:  for other beta blockers, please consult with the Sponsor
 
 
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
Calcium-channel blockers: verapamil, diltiazem, amlodipine
Note:  for other calcium-channel blockers, please consult with the Sponsor

hydralazine, clonidine, minoxidil, isosorbide nitrates
Anemia:  erythropoietin
Anticoagulants:  warfarin, heparin, low molecular weight heparin, aspirin, fondaparinux, 
desirudin, acenocoumarol
Diuretics:  HCTZ, furosemide, spironolactone, triamterene
Hypoglycemic agents:  insulin, sitagliptin, glipizide, metformin
Contraceptives:  oral contraceptive pills, progesterone injects, intrauterine devices
Antidepressants/anxiolytics:  citalopram, paroxetine, duloxetine, escitalopram, fluoxetine, 
bupropion, trazodone, diazepam, clonazepam, temazepam, lorazepam
Acid reflux:  H2 blockers, proton pump inhibitors, antacids
HMG-CoA reductase inhibitors (statins):

pravastatin and pitavastatin:  may be coadministered without dose adjustment

rosuvastatin:  the dose of rosuvastatin should not exceed a daily dose of 10 mg

atorvastatin:  the dose of atorvastatin should not exceed the daily dose of 20 mg

fluvastatin, lovastatin, simvastatin:  The dose of fluvastatin, lovastatin, or simvastatin 
should not exceed a daily dose of 20 mg when co-administered with ZEPATIER.

HIV/HBV medications:  abacavir, dolutegravir, emtricitabine,  entecavir, lamivudine, 
raltegravir, rilpivirine, tenofovir disoproxil fumarate
Immunosuppressants:  prednisone, mycophenolate mofetil
Opiate substitution therapy:  buprenorphine/naloxone, methadone
Antiarrhythmics:  digoxin
Phosphate Binders
Note:  For other medications not listed here, please 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
EBR/GZR can be taken with or without food.
Considerations for Study Visits
Procedure visits should be scheduled as close to the indicated study days and study weeks as 
possible. See the Trial Flow Chart (Section 6.0) for a complete listing of study procedures 
required at each visit.
 
 
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Subjects should complete study therapy as defined by the length of the assigned treatment 
regimen. If dosing is missed or interrupted (see Section 5.2.2), the assigned study therapy 
regimens should still be completed.
Subject Withdrawal/Discontinuation Criteria
5.8
Discontinuation of Treatment
5.8.1
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment will still continue to participate in the trial as specified in 
Section 6.0 - Trial Flow Chart and Section 7.1.5 – Trial Procedures.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:

The subject or legal representative (such as parent or legal representative) withdraws 
consent.

Subject meets any HCV virologic failure criteria (see Section 4.2.3.1.1.2).

Subject becomes pregnant during the trial.

The investigator feels that it is in the best interest of the subject to discontinue.

The subject’s ALT or AST increases to >500 IU/L and is confirmed with repeat test 
within one week.

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).

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.
Clinical management of HIV-1 virologic failure will be handled by site investigators 
according to current HIV treatment guidelines and local standard of care. Subjects with HIV 
virologic failure may continue in the trial unless treatment with a prohibited concomitant 
medication (see Section 5.5) is required to construct a new HIV treatment regimen.
 
 
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For subjects who are discontinued from treatment but continue to be monitored in the trial, 
see Section 6.0 - Trial Flow Chart and Section 7.1.5 – Trial Procedures for those procedures 
to be completed at each specified visit.
Subjects may be allowed to begin treatment again if deemed medically appropriate.
Withdrawal from the Trial
5.8.2
Subjects may withdraw from the trial at any time for any reason.  If a subject withdraws from 
the trial, they will no longer receive treatment or be followed at scheduled protocol visits.
A subject must be withdrawn from the trial if:
○
The subject or legal representative (such as parent or legal representative) withdraws 
consent from the trial.
○
The subject is lost to follow-up
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 7.1.4 – Other Procedures.
Subject Replacement Strategy
5.9
A subject who discontinues from 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
There are no pre-specified criteria for terminating the trial early.
 
 
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6.0 TRIAL FLOW CHART
Treatment Arm
Screen
Treatment Period
Follow Up Period
Unscheduled Visits
Day
Week
Arm 1: 8 weeks
SCR
11
4
8
NA
FU4
FU12
FU24
HCV VFC 
Visit
Early DC
Visit
Arm 2: 12 weeks
SCR
11
4
8
12
FU4
FU12
FU24
Visit Number
1
2
3
4
5
6
7
8
9
10
Visit Window
-45 d
NA
-7 to +7 d
-7 to +14 d
-7 to +14 d
-1 to +2 w
-2 to +2 w
-2 to +2 w
NA
NA
Administrative Procedures
Informed consent
X
Informed consent for FBR
X
Inclusion/exclusion criteria
X
X
Subject identification card
X
Medical history
X
Prior and concomitant medication 
review
X
X
X
X
X
X
X
Treatment
randomization/allocation
X
Review study medication diary
X
X
X
X
X
Clinical Procedures/Assessments
PE
X2
X2
X2
X2
X2
X2
X2
Height
X
Weight
X
X
Vital signs 
X
X
X
X
X
X
X
Subject confirmation of birth 
control
X
X
X
X
X
X
X
X
Review AEs3
X
X
X
X
X
X
X
X
X
X
 
 
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Treatment Arm
Screen
Treatment Period
Follow Up Period
Unscheduled Visits
Day
Week
Arm 1: 8 weeks
SCR
11
4
8
NA
FU4
FU12
FU24
HCV VFC 
Visit
Early DC
Visit
Arm 2: 12 weeks
SCR
11
4
8
12
FU4
FU12
FU24
Visit Number
1
2
3
4
5
6
7
8
9
10
Visit Window
-45 d
NA
-7 to +7 d
-7 to +14 d
-7 to +14 d
-1 to +2 w
-2 to +2 w
-2 to +2 w
NA
NA
Laboratory Procedures/Assessments
Coagulation
X
X
X
X
X
X
X
X
X
X
Chemistry & hematology
X
X
X
X
X
X
X
X
X
X
FSH4
X
Urinalysis
X
Urine pregnancy test5 (female of 
childbearing potential only)
X
X
X
X
X
X5
X
X
HBV Evaluations6
HBsAg
X
X
X
X
X
X
X
X
Anti-HBc
X
Anti-HBs
X
HBV DNA
X
X
X
X
X
X
X
X
HCV Evaluations
HCV genotype determination
X
Liver imaging
X7
HCV RNA level8
X
X
X
X
X
X
X
X
X
X9
Plasma for HCV viral resistance
and biomarkers10
X
X
X
X
X
X9
Blood for genetic analysis11
X
 
 
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Treatment Arm
Screen
Treatment Period
Follow Up Period
Unscheduled Visits
Day
Week
Arm 1: 8 weeks
SCR
11
4
8
NA
FU4
FU12
FU24
HCV VFC 
Visit
Early DC
Visit
Arm 2: 12 weeks
SCR
11
4
8
12
FU4
FU12
FU24
Visit Number
1
2
3
4
5
6
7
8
9
10
Visit Window
-45 d
NA
-7 to +7 d
-7 to +14 d
-7 to +14 d
-1 to +2 w
-2 to +2 w
-2 to +2 w
NA
NA
HIV Evaluations
HIV-1 serology
X
HIV RNA and CD4+ T-Cell 
Counts (all subjects)12
X
Drug Administration13
EBR/GZR (open label)
X
X
X14
X14
AE = adverse event; anti-HBc = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; DC = discontinuation; DNA = deoxyribonucleic acid; EBR = elbasvir; EOT = end 
of treatment; FBR = future biomedical research; FSH = follicle-stimulating hormone; FU = follow-up; GZR = grazoprevir; HBsAg = hepatitis B surface antigen; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus; IEC = independent ethics committee; IRB = institutional review committee; NA = not applicable; PE = physical examination; 
RNA = ribonucleic acid; SCR = screening; TW = treatment week; VFC = virologic failure confirmation
1
Procedures on Day 1 should be performed prior to the first morning dose unless otherwise specified.
2
A comprehensive PE will be performed at screening and baseline (Day 1). For all other visits, a focused PE will be conducted when clinically indicated.
3
All AEs that occur after the consent form is signed but before randomization/allocation must be reported by the investigator if they cause the subject to be excluded from the 
trial, or are the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. From 
the time of randomization/allocation through 14 days following discontinuation of study treatment, all AEs must be reported by the investigator.  The reporting timeframe for 
AEs meeting any serious criteria is described in Section 7.2.3.1.
4
For postmenopausal women only, defined as at least 12 months with no menses in women ≥45 years of age.
5
Urine pregnancy test kits will be dispensed to female subjects of childbearing potential so that a pregnancy test can be performed 2 weeks after completing treatment.  The test 
results must be provided to the investigator and/or site personnel at FU4.  Subjects should be instructed to contact the investigator and/or site personnel immediately if the result 
of the self-pregnancy test is positive.  A serum pregnancy test will be performed whenever a urine pregnancy test yields a positive result.
6
HBsAg, anti-HBc, and anti-HBs will be assessed at screening in all subjects.  For all anti-HBc positive subjects, HBV DNA will also be assessed at screening, and both HBV 
DNA and HBsAg will be monitored during the trial.
7
For cirrhotic subjects only, imaging is required within 6 months of randomization to evaluate for hepatocellular carcinoma. If liver imaging within 6 months prior to Day 1 is not 
available, imaging is required during screening.
8
Leftover main study plasma will be stored at the end of the study for future biomedical research if the subject consents to FBR.
9
If a subject is a confirmed virologic failure during therapy (i.e., rebound, breakthrough), then the sample collection for HCV RNA and viral resistance/biomarker is not needed 
for the early discontinuation visit.
 
 
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10
Blood samples will be collected for HCV viral resistance testing at baseline, virologic failure confirmation visits, and all FU visits after virologic failure confirmation or after 
early study medication discontinuation if the subject has quantifiable HCV RNA. 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 future biomedical research if the subject consents to future biomedical research.  
11
This sample will be drawn for IL28B 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 variations 
and drug response.  Leftover extracted DNA will be stored for future biomedical research if the subject signs the optional FBR consent.
12
Blood samples will be collected for HIV RNA and CD4+ T cell counts as part of the screening visit for all subjects; however, these samples will only be processed if the HIV-1 serology result is 
positive. 
13
Sites should dispense 3 open-label EBR/GZR blister cards at the Day 1 visit and 2 open-label EBR/GZR blister cards at each remaining dispensing visit. 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 drug as defined 
by the length of the assigned treatment regimen.  If dosing is missed or interrupted (see Section 5.2.2), the assigned study therapy regimen should still be completed. 
14
Subjects in Arm 1 (8-week treatment arm) will proceed to FU4 as TW8 is their EOT visit. Subjects in Arm 2 (12-week treatment arm) will proceed to FU4 as TW12 is their 
EOT visit.
 
 
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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
7.1.1.1
Informed Consent
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.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria (see Section 5.1) will be reviewed by the investigator or 
qualified designee to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
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.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
7.1.1.5
Prior and Concomitant Medications Review
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.
The investigator or qualified designee will discuss with the subject the necessity of not taking 
any concomitant medications or herbal preparations with known suspected hepatotoxic 
potential.  All medications with known hepatotoxicity must be discontinued from 2 weeks 
prior to dosing through 2 weeks after dosing. If medications with potential hepatotoxicity 
cannot be discontinued in a subject, the principal investigator must discuss the inclusion of 
the subject with the Merck clinical director who must approve the use of the medication prior 
to inclusion of the subject in the trial.
 
 
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7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be either randomly allocated or assigned (in accordance with the 
trial design described in Section 2.1) and will receive a treatment/randomization number.  
The treatment/randomization number identifies the subject for all procedures occurring after 
treatment allocation/randomization.  Once a treatment/randomization number is assigned to a 
subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
The investigator/study coordinator will give the subject a Study Medication Diary (SMD) to 
be completed during the study period. The investigation/study coordinator will be responsible 
for entering the subject’s identification (treatment/randomization number), treatment period, 
and other pertinent subjection information before giving the SMD to the subject. The subject 
will be instructed to record dates/times and the number of tablets of study drug doses on the 
SMD for the entire time period. Only the subject should enter information on the SMD. The 
subject is to return the completed SMD at each scheduled visit. At visits when used/unused 
study drugs are returned, site personnel must verify the accuracy of the SMD by comparing 
entries with amounts of return study drugs. If a discrepancy is noted, the investigator/study 
coordinator must discuss the discrepancy with the subject, and the explanation must be 
documented. Only the subject shall make any changes to the entries on the SMD. The subject 
will initial the SMD to confirm that the information accurate. The investigator/study 
coordinator will be responsible for transferring the appropriate information from the diary 
card onto the appropriate case report form (CRF).
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 should be witnessed by the investigator and/or trial staff at 
the Day 1 visit.
 
 
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Clinical Procedures/Assessments
7.1.2
7.1.2.1
Physical Examination
All physical examination 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 and on Day 1 includes the 
following assessments: general appearance, head, eyes, ears/nose/throat, neck, lymph nodes, 
skin, lungs, heart, abdomen, musculoskeletal, and neurologic evaluations. Breast, rectal, and 
genitourinary/pelvic examinations should be performed when clinically indicated. For all 
other visits, a focused examination will be performed when clinically indicated. Any 
significant changes between the Screening visit and Day 1 should be noted in the Medical 
History electronic CRF (eCRF). Any significant changes after receiving study drug at Day 1 
must be reported as AEs and entered on the AE eCRF. If a subject is discontinued for any 
reasons during the treatment period, every attempt should be made to perform a final 
physical examination.
7.1.2.2
Weight and Height Assessment
The subject’s weight should be assessed as mentioned in the Trial Flow Chart (Section 6.0). 
Clinically significant changes from Day 1 should also be captured as AEs in the eCRF.
7.1.2.3
Vital Signs
Vital signs will include heart rate, blood pressure, and oral temperature. Subjects should be 
resting in a semi-recumbent or sitting position for at least 10 minutes prior to having vital 
sign measurements obtained.
NOTE: Oral temperatures should be taken, but if oral is not possible, a tympanic, rectal, or 
axillary temperature 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 AE.
7.1.2.4
Birth Control Confirmation
Extreme care must be taken to avoid pregnancy in female subjects of childbearing potential.
Confirmation must be obtained by site personnel that subjects 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.
7.1.2.5
Adverse Events
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 13. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 13 for instructions in evaluating adverse events.
 
 
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7.1.2.6
Noninvasive Methods of Cirrhosis Evaluation
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 [30], a population of 
patients with chronic hepatitis C, a cutoff of 12.5 kPa was selected for cirrhotics. At this 
cutoff, the sensitivity and specificity of the test for cirrhosis were 87% and 91%, respectively 
and the negative predictive value was 95%. Since this analysis was assessed specifically in 
patients with chronic hepatitis C, the cutoff value > 12.5 kPa used by Castera was selected to 
include cirrhotics in the current study.
FibroTest® + APRI: Various methodologies have been developed in order to improve the 
sensitivity and specificity of blood tests used to diagnose cirrhosis in patients with chronic 
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 [31]. For cirrhosis, the 
SAFE for F4 algorithm provides a diagnostic accuracy of 89.5% with a negative predictive 
value of 94.6%. Using this algorithm, it is estimated that only 6.2% of the patients would 
need a liver biopsy to confirm the diagnosis of cirrhosis. The cutoff values for excluding 
cirrhotics using the 2 tests, without the use of liver biopsy, are ≤1 and ≤0.48 for FibroTest®
and APRI when the SAFE for F4 is used. This study uses this method with one variation 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 cutoff values that will differentiate cirrhotic from non-cirrhotic 
patients 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 as follows. 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 12.5.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 12.  
All screening laboratory results must be reviewed and approved before a subject can be 
assigned or randomly assigned to study medication.  Sample collection, storage and shipment 
instructions will be provided in the operations/laboratory manual.
 
 
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Table 12
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Bilirubin
Hemoglobin
ALP
Blood
HCV genotype
Platelet count
ALT
Glucose
FSH
WBC count (total and 
differential)
AST
Ketones
Prothrombin time (PT)
Erythrocytes 
(RBC count)
Creatinine
Leukocyte esterase
INR
Creatine kinase
Nitrite
Choriogonadotropin beta 
(urine pregnancy test kits to 
sites)
GGT
pH
Serum 
human 
chorionic 
gonadotropin (reflex when 
urine 
pregnancy 
test 
is 
“positive”)
Glucose (serum glucose)
Protein
Plasma HCV RNA
Amylase
Specific gravity
FibroSure®
(FibroTest®) as 
requested by site for entry 
criteria [may be performed 
locally]) 
Lipase
WBC
APRI calculation (screening 
only)
Potassium
Bacteria
HIV-1 and HIV-2 serology 
(screening only)
Sodium
CD4 T-cell count
(HIV positive subjects)
Total bilirubin
Squamous epithelial 
cells
HIV RNA viral load
(HIV positive subjects)
Direct bilirubin
RBC
HBsAg (at screening in all 
subjects, 
then 
at 
certain 
subsequent visits for subjects 
who are anti-HBc positive)
Indirect bilirubin
Anti-HBc (screening only)
Total protein
Anti-HBs (screening only)
BUN
HBV DNA (for subjects who 
are anti-HBc positive, at 
screening 
and 
at 
certain 
subsequent visits)
ALP = alkaline phosphatase; ALT = alanine aminotransferase; Anti-HBc = hepatitis B core antibody; Anti-HBs = hepatitis 
B surface antibody; APRI = AST-to-platelet ratio index; AST = aspartate aminotransferase; BUN = blood, urea, nitrogen; 
FSH = follicle-stimulating 
hormone; 
GGT = gamma-glutamyltransferase; 
HBsAg = hepatitis B 
surface 
antigen; 
HBV DNA = hepatitis B virus deoxyribonucleic acid; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
INR = International Normalized Ratio; PT = prothrombin time; RBC = red blood cell; RNA = ribonucleic acid; 
WBC = white blood cell.
 
 
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7.1.3.2
HCV Evaluation
The following specimens are to be obtained for HCV evaluation 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 Abbot HCV Real 
Time Genotype II assay that 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 
PT-PCR assay. The RT-PCR reaction uses 3 sets of HCV-specific amplification 
primers targeting the 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 5; 89% for GT5, and 
83% for GT6; with 100% specificity in HCV serologically negative plasma samples.

Blood must be drawn from each subject to assess HCV RNA plasma levels at various 
time points as shown in the Trial Flow Chart (Section 6.0). HCV RNA in plasma will 
be measured using a COBAS™
AmpliPrep/COBAS™
Taqman HCV Test, 
version 2.0® assay with 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 FBR only if the subject signed for FBR consent.

Blood must be drawn from each subject to assess viral resistance mutation and 
processed as instructed by the central laboratory manual. Leftover plasma may be 
used for FBR only if the subject signed for FBR consent.

Protein and metabolites may be measured from blood samples to compare biomarkers 
measured prior to treatment, to biomarkers measured at several time points during 
treatment that correlate with subject response to treatment (e.g., sustained viral 
response).

Samples collected for genetic analysis are obtained at Day 1. Any leftover 
deoxyribonucleic acid (DNA) may be used for FBR only if the subject sign for FBR 
consent.
NOTE: Samples may also be used for future assay development and validation if the subject 
signed for FBR consent.
7.1.3.3
HIV Evaluation
The following specimens are to be obtained for HIV evaluation:

Blood must be drawn from each subject to assess HIV RNA plasma levels at 
screening as shown in the Trial Flow Chart (Section 6.0). HIV RNA in plasma will be 
measured using a COBAS™AmpliPrep/COBAS™TaqMan HIV-1 Test, version 2.0®
assay with a LLOQ of 20 IU/mL.

Blood must be drawn from each subject to assess immunologic status. CD4+ T-cell 
counts will be obtained at screening as shown in the Trial Flow Chart (Section 6.0).
 
 
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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 IU/mL
7.1.3.4
HBV Evaluation

Blood must be drawn from each subject to assess HBsAg, anti-HBc, and anti-HBs at 
screening.

For subjects who are anti-HBc positive, HBV DNA will be assessed at screening, and 
both HBV DNA and HBsAg will be monitored during the trial.  The results of these 
assessments will be used to determine HBV reactivation, which will be reported as an 
Event of Clinical Interest as specified in Section 7.2.3.2.  

Subjects who develop HBV reactivation will be managed by site investigators 
according to current treatment guidelines and/or local standard of care.  

Subjects who develop HBV reactivation may continue in the trial at the discretion of 
the site investigators
7.1.3.5
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the operations/laboratory manual.
7.1.3.6
Future Biomedical Research Sample Collection
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; and 
leftover plasma from viral resistance and biomarkers for future research.
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
 
 
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7.1.4.1.1 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 mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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.
7.1.5.1
Screening
Up to 45 days prior to randomization/treatment 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.
Documentation of prior IFN +/- RBV +/- SOF treatment history must include clinic notes or 
referral letter documenting regimen administered, approximate dates of treatment, 
approximate date of virologic failure, and a history of laboratory confirmed prior virologic 
 
 
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failure or documented intolerance to allow for one of the following categorizations (if the 
subject was treated with a PR regimen more than once, the categorization must be based on 
the most recent round of treatment):
1. HCV Treatment-Naïve: defined as no prior exposure to any interferon, ribavirin, or 
other approved or experimental HCV-specific direct-acting antiviral agent.
2. HCV Treatment-experienced: defined as any prior treatment with an IFN regimen 
(IFN or peg-IFN +/- RBV) or sofosbuvir (SOF) + RBV or SOF + peg-IFN + RBV 
that did not result in a sustained virologic response (SVR)
All TE patients will be classified into one of the following categories:
I.
Prior On-Treatment Failures (may be one or more of the following):
i. Non-Responder: Subject has HCV RNA detected at end of prior 
treatment without HCV RNA <LLOQ on treatment.
ii. Null Responder: <2 log10 IU/mL reduction in HCV RNA after at least
12 weeks of a IFN regimen OR <1 log10 IU/mL reduction in HCV 
RNA after 4 weeks and discontinued therapy prior to treatment-week 
12.
iii. Breakthrough: Subject has a confirmed HCV RNA ≥LLOQ [TD(q)] 
while on prior treatment after being <LLOQ previously.
iv. Partial Responder: ≥2 log10 IU/mL reduction in HCV RNA after at
least 12 weeks of treatment, but not achieving HCV RNA target not 
detected at end-of-treatment, with prior regimen.
II.
Relapser: HCV RNA target not detected at end-of-treatment after prior 
regimen, but HCV RNA quantifiable (≥LLOQ) during follow-up.
III.
Intolerant to Prior Regimen: ≥ 4 weeks of prior regimen and no more than 
80% of treatment duration:
1. ≤ 20 weeks for a 24 week treatment regimen
2. ≤ 40 weeks for a 48 week treatment duration
IV.
Otherwise not Classified/Unknown response to Prior Regimen: Subject 
received at least one dose of prior regimen and stopped for any other reason 
not listed above
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 14 days after the last dose of study medication, or longer if dictated by local 
regulations, for women and men, respectively.
 
 
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Subjects will be instructed about the restrictions for concomitant medications, as noted in 
Section 5.5.
All screening procedures listed for Visit 1 in the Trial Flow Chart must be completed and 
subject 
eligibility 
confirmed 
by 
the 
investigator 
prior 
to 
the 
subject’s 
randomization/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.
7.1.5.2
Rescreening
Subjects who have previously completed the Screening visit (Visit 1) and were deemed 
eligible for randomization/allocation into this study, but failed to be randomized or allocated 
within the 45-day window, may be rescreened to re-evaluate study eligibility.  To reconfirm 
the subject's eligibility, all pre-study evaluations should be repeated after approval from the 
Sponsor, except for the following:

HCV GT determination

Hepatitis B virus screening

HIV-1 serology

Liver biopsy/FibroScan®/ FibroSure® (FibroTest®)

Liver imaging
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.
7.1.5.3
Treatment Period
Day 1 procedures listed on the Trial 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 randomization/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/allocated to study medication.
Blood and urine will be collected for assay of safety evaluations, plasma HCV RNA, plasma 
HIV RNA. These samples will be sent to the appropriate central laboratory 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 EBR/GZR (as appropriate) therapy.
 
 
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Subjects should complete study therapy for all study drugs as defined by the length of the 
assigned treatment regimen.  If dosing is missed or interrupted (see Section 5.2.2), the 
assigned study therapy regimen should still be completed.
7.1.5.4
Drug Administration
Following completion of the Day 1 procedures and confirmation of eligibility, the site 
pharmacist or study coordinator will contact the IVRS for assignment of the drug regimen to 
be administered and duration of treatment. Sites should not call IVRS for drug administration 
until the subject has met all criteria for the study and are ready to receive the first dose of 
study medication on Day 1. 
The first dose of prescribed study medications should be administered at the Day 1 visit.
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, collect the following information when a subject discontinues:

The reason the subject discontinued

The date of the last dose of study medications from the trial

The date of the last assessment and/or contact. A follow-up contact (telephone or 
visit) will be arranged as appropriate

(Serious) Adverse events
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.
7.1.5.5
Follow-Up Visits
At the completion of study therapy subjects will return to the study site for follow-up visits at 
4, 12, and 24 weeks after the last dose of study drug.
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, 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, 12, and 24 weeks) as outlined in the 
Trial Flow Chart (Section 6.0).
Subjects who discontinue for reasons other than virologic failure should complete an Early 
Discontinuation Visit as outlined in the Trial Flow Chart and return to the study site for 
follow-up visits at 4, 12, and 24 weeks following the discontinuation of treatment.
 
 
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7.1.5.6
Evaluation of Laboratory Safety Signals
Laboratory safety measurements will be evaluated throughout the study to assess potential 
liver safety signals as outlined in the Trial Flow Chart (Section 6.0).
If a subject has one or more of the laboratory ECI criteria (see Section 7.2.3.2) at the last 
dosing visit, then the subject should return to the site weekly for additional monitoring until 
the values normalize.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
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).
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is any dose higher than the prescribed dose of EBR/GZR per 
calendar day.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations 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.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  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).
 
 
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Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
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 13 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
 
 
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For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. first instance of ALT or AST >500 IU/L from the initiation of study therapy through 14 
days following treatment.*
3. first instance of ALT or AST >3X nadir AND >3X ULN from the initiation of study 
therapy through 14 days following treatment. *
*Note:  The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require 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).
4.  HBV reactivation defined as either:
a.
sero-reversion from HBsAg negative to HBsAg positive, OR
b. detectable HBV DNA in subjects who were previously undetectable or ≥1 log increase 
in HBV DNA from baseline.
Note:  As detailed in Section 7.1.3.4, subjects who develop HBV reactivation will be 
managed by site investigators according to current treatment guidelines and/or local 
standard of care.  Subjects who develop HBV reactivation may continue in the trial at 
the discretion of the site investigators.  
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 13. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 13 for instructions in evaluating adverse events.
 
 
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Table 13
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.   (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a supplemental SAP 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
This section contains a brief summary of the statistical analyses for this trial. Full detail is 
provided in 8.2-8.12.
Study Design Overview
A Multi-Site, Open-Label, Partially-Randomized Trial of the Efficacy 
and Safety of Fixed Dose Elbasvir/Grazoprevir (EBR/GZR) Based 
Regimens in French Subjects with Chronic Hepatitis C Virus (HCV) 
Genotype 4 Infection
Treatment Assignment
This study will enroll approximately 120 genotype 4 (GT4) HCV 
subjects with or without advanced fibrosis.  
There are 2 treatment arms in this study.  Approximately 75 (minimum 
of 60) TN subjects with stage 0-2 fibrosis will be randomized using a 
2:1 ratio to receive either 8 weeks of EBR/GZR (Arm 1) or 12 weeks of 
EBR/GZR (Arm 2).  TN subjects with stage 3-4 fibrosis and TE 
subjects with stage 0-4 fibrosis will be assigned to Arm 2 to receive 12 
weeks of EBR/GZR.  
The target enrollment in each group is:
Study Arm 1: 8-week regimen of EBR/GZR
TN subjects with fibrosis stage F0-F2 n=50 (min 40)
Study Arm 2: 12-week regimen of EBR/GZR
TN subjects with fibrosis stage F0-F2 n=25 (min 20)
TN subjects with fibrosis stage F3-F4 n=25 (min 15)
TE subjects with fibrosis stage F0-F4 n=20 (min 15)
Analysis Populations
Efficacy: The Full Analysis Set (FAS) population will serve as the 
primary population for the analysis of efficacy data in this study. The 
FAS population consists of all subjects who were assigned to a 
treatment arm and received at least one dose of study treatment.
A supportive analysis using the modified Full Analysis Set (mFAS) 
population will be performed for the primary efficacy and secondary 
endpoints. The mFAS population is a subset of the FAS, with subjects 
excluded for study discontinuation (lost to follow-up) with reasons 
unrelated to the treatment regimen.
Safety: 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 subjects who received at least one dose of study treatment, 
classified according to the study treatment duration they actually 
received. 
 
 
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Primary Endpoint(s)
Proportion of subjects achieving SVR12 (Sustained Virologic Response 
12 weeks after the end of all study therapy).
Key Secondary Endpoints
Proportion of subjects achieving SVR24 (Sustained Virologic Response 
24 weeks after the end of all study therapy).
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
A 2-sided 95% confidence interval (CI) based on Clopper-Pearson 
method will be constructed for the proportion of subjects achieving
arm-specific SVR12 and SVR24, and for treatment naïve F0-F2 subjects 
achieving arm-specific SVR12. 
There will be no efficacy hypothesis testing conducted in this 
estimation study.
Statistical Methods for Key 
Safety Analyses
The proportion of subjects who experienced adverse events of elevated 
laboratory values that are reported as ECIs during the study therapy 
period will be estimated along with the corresponding 95% confidence 
intervals based on Clopper-Pearson method. In addition, the broad 
clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, a drug related AE, a serious AE, an AE which is 
both drug-related and serious, and who discontinued due to an AE will 
be summarized.
Interim Analyses
No interim analyses are planned for this study.
Multiplicity
There will be no multiplicity adjustments in the final analysis of this 
estimation study.
Sample Size and Power 
Approximately 120 subjects will be enrolled with approximately 50 in 
Arm 1 (8 week treatment) and 70 in Arm 2 (12 week treatment). The 
95% CI and half-width of the 95% CI for SVR12, under various 
scenarios, is presented in Table 17. 
For example, when the sample size is 25, if the SVR12 rate is 92.0% (23 
successes out of 25), the exact 95% CI is (74.0%, 99.0%).  When the 
sample size is 50, if the SVR12 rate is 90.0% (45 successes out of 50), 
the exact 95% CI is (78.2%, 96.7%).  When the sample size is 70, if the 
SVR12 rate is 90.0% (63 successes out of 70), the exact 95% CI is 
(80.5%, 95.9%).  
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 of the Sponsor. Certain specific analyses such as resistance will be the 
responsibility of the appropriate department of the Sponsor.
This study will be conducted as a partially randomized and open-label study; therefore, the 
subjects, the study site personnel, and the Sponsor will be aware of subject treatment 
assignments after each subject is enrolled.
Throughout the course of this partially randomized and open-label study, efficacy and safety 
analyses may be performed by the Clinical Biostatistics department of the Sponsor to 
monitor trends and facilitate programmatic decisions.
Hypotheses/Estimation 
8.3
Objectives of the study are stated in Section 3. There will be no efficacy hypothesis testing 
conducted in this estimation study.
 
 
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Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated are listed as follows.
Efficacy/Pharmacokinetics Endpoints
8.4.1
8.4.1.1
Efficacy Endpoints
An initial description of efficacy measures is provided in Section 4.2.3.1.
The primary efficacy endpoint is the proportion of subjects achieving SVR 12 (sustained 
virologic response 12 weeks after the end of all study therapy), defined as HCV RNA 
<LLOQ (either TD[u] or TND).
The secondary efficacy endpoints are:

The proportion of subjects achieving SVR12, defined as HCV RNA < LLOQ (either 
TD[u] or TND) in the treatment-naïve F0-F2 subjects.

The proportion of subjects achieving SVR24 (sustained virologic response 24 weeks 
after the end of all study therapy), defined as HCV RNA < LLOQ (either TD[u] or 
TND).

The viral resistance-associated variants (RAVs) resistant to EBR or GZR, including 
the association of baseline RAVs with treatment outcomes (SVR12 and SVR24) and 
the emergence of RAVs in subjects who fail to achieve SVR.
8.4.1.2
Exploratory Endpoints
The exploratory efficacy endpoints are:

To explore the relationship between IL28B genetic variation and:
-
SVR12
-
SVR24

The relationship between genetic variation and the clinical response to the treatments 
administered.

The proportion of anti-HBc positive subjects at screening who develop HBV 
reactivation (see Section 7.2.3.2).
Safety Endpoints
8.4.2
An initial description of safety measures is provided in Section 4.2.3.2 and events of clinical
interest (ECIs) are defined in Section 7.2.3.2. The proportion of subjects who experience AEs 
of elevated laboratory values that are reported as ECIs described in Section 7.2.3.2 during the 
study therapy period will be estimated.
The following events will also be investigated: the proportion of subjects with adverse events
of the following types at any time during the study therapy period: (1) at least one adverse 
event; (2) a drug-related adverse event; (3) a serious adverse event; (4) a serious and drug-
related adverse event and (5) an adverse event leading to discontinuation.
 
 
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Other safety parameters include vital signs, physical examinations, and standard laboratory
safety tests at time points specified in the Trial Flow Chart (Section 6.0).
Drug related serious adverse events will continue to be collected throughout the study.
Analysis Populations
8.5
Efficacy Analysis Population
8.5.1
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study. The FAS population consists of all subjects who were assigned
to a treatment arm and received at least one dose of study treatment.
A supportive analysis using the modified Full Analysis Set (mFAS) population will be 
performed for the primary (SVR12) and key secondary efficacy endpoint (SVR24). The mFAS 
population is a subset of the FAS, with subjects excluded for study discontinuation (lost to 
follow-up) with reasons unrelated to the treatment regimen. Examples of reasons for the 
exclusion of a subject include: failure to receive at least one dose of study treatment; loss to 
follow-up; missing data due to death with reasons unrelated to the study drug; 
discontinuation due to non-drug related AEs; informed consent and withdrawal.
Resistance Analysis (RA) Population will be used for resistance-associated variants (RAVs)
analysis. The RA population is a subset of FAS, who either achieved SVR12 or met criteria 
for virologic failure (see Section 4).  The RA does not include any subject who discontinued 
the study for reasons other than virologic failure. Baseline RAV analyses will be conducted 
in subjects for whom baseline sequencing data was available. Post-baseline RAV analyses 
will be limited to subjects who had both baseline and post-failure sequence data.
Details on the approach to handling missing data are provided in Section 8.6.1.
Safety Analysis Population
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 subjects who received at least one dose of 
study treatment. Subjects will be included in the treatment arm corresponding to the study 
treatment durations they actually received for the analysis of safety data using the ASaT 
population. The subjects who receive 9 weeks of treatment or less will be summarized in 
Arm 1 and subjects who receive longer than 9 weeks of treatment will be summarized in Arm 
2 for the purposes of safety. Subjects who withdraw study drug early during the treatment 
period will be included in the treatment arm based on the study treatment duration they 
actually received.
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 8.6.2 Statistical Methods for Safety Analyses.
 
 
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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 14. Nominal p-
values may be computed for some efficacy analyses as a measure of strength of the 
association but no tests of hypotheses are planned in this estimation study. The analysis 
strategy for safety is described in Section 8.6.2.
Statistical Methods for Efficacy Analyses
8.6.1
This section describes the statistical methods that address the primary and secondary
objectives.
Missing Values
A missing data point for a given study visit may be due to any 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 (Target not detected), TD(u) (Target 
detected but unquantifiable), and TD(q) (Target detected, quantifiable). There are 3 types of 
missing data handled by different approaches.
Type 1 is intermittent missing:

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 2 TNDs, then 
the missing value would be imputed as TND.
Type 2 and 3 are both non-intermittent missing, but differ regarding their relationship to the 
study drug:

Type 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.

Type 3 – Non-intermittent missing 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 violation, 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 
approaches to address this type of missing data depend on the analytical strategy, and 
these are described as follows.
 
 
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The following 2 approaches will be used to handle non-intermittent missing data (Type 2 and 
3) due to premature discontinuations, depending on the analytical strategy, as described in 
the following section and Table 14 Analysis Strategy for Efficacy Variables. 

Treatment-Related Discontinuation = Failure (TRD=F) approach: The treatment 
related type 2 missing will be considered as failure; whereas the subjects who have 
the type 3 missing value and 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.

Missing=Failure (M=F) approach: Any non-intermittent missing (i.e., type 2 and 3 
missing) will be imputed as failure, regardless of the reason for study discontinuation.
In addition, a missing baseline/Day 1 HCV RNA result will be replaced with a screening 
result throughout all analyses, if available. 
Proportion of Subjects With Virologic Responses
For the primary efficacy analysis based on the FAS population to estimate the proportions of 
subjects achieving SVR12, 95% confidence intervals for these rates will be calculated using 
the Clopper-Pearson method [32] within treatment arms with no stratification. The missing 
data approach of M=F described above will be utilized for the primary analysis. The same 
method will be used to analyze all binary endpoints based on the FAS population.  
The SVR12 rates and confidence intervals for the randomized treatment-naïve F0-F2 subjects 
who received either 8 weeks of treatment or 12 weeks of treatment will be interpreted in the 
context of the historical clinical experience with EBR/GZR.
Sensitivity analyses will be performed for the primary endpoint and key secondary endpoint 
using the mFAS population with the TRD=F missing data approach.  Under the assumption 
of missing completely at random (MCAR), the mFAS population excludes subjects who did 
not experience virologic failure, but prematurely withdraw from study due to reasons not 
related to the study drug (i.e., the subjects with the type 3 missing value). 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 included in the mFAS 
population and classified as failures. 
Table 14 summarizes the key efficacy analyses and Table 15 includes additional information 
on criteria to assess the primary endpoint (SVR12) and key secondary endpoint (SVR24).
 
 
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Table 14
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
P
95% CI 
(Clopper-Pearson)
FAS
M=F
Proportion of subjects 
achieving 
SVR12
in 
each treatment arm
S
95% CI 
(Clopper-Pearson)
mFAS
TRD=F
Secondary
Proportion of subjects 
achieving 
SVR24
in 
each treatment arm
P
95% CI
(Clopper-Pearson)
FAS
M=F
Proportion of subjects 
achieving 
SVR24
in 
each treatment arm
S
95% CI 
(Clopper-Pearson)
mFAS
TRD=F
CI = confidence interval; M=F = Missing=Failure; P = Primary approach; S = Secondary approach; 
TRD=F = Treatment-Related Discontinuation=Failure.
Table 15
Analysis Populations, Criteria for Response, Non-Response, and Exclusion from 
Analysis Population
Analysis 
Population
Criteria for Response
Criteria for 
Non-Response
Criteria for Exclusion From 
Analysis Population
FAS
HCV RNA < LLOQ
HCV RNA ≥LLOQ
Subject did not receive at least 
one dose of study medication
mFAS
HCV RNA < LLOQ for 
baseline infection†
HCV RNA ≥LLOQ for 
baseline infection
Subject discontinued from the 
study for non-treatment related 
reasons. Examples include: Loss 
to follow-up; d/c due non-drug 
related AEs; informed consent 
withdrawal.
FAS = full analysis set; HCV = hepatitis C virus; LLOQ = lower limit of quantification; mFAS = modified 
full analysis set; RNA = ribonucleic acid.
† This includes the case where HCV RNA ≥LLOQ but is demonstrated to be due to reinfection (after 
clearance of baseline infection)
Subject Virologic Failure: Non-response, Rebound, Virologic Breakthrough and 
Relapse
Summary statistics will be provided to describe the rates of occurrence of subject non-
response, rebound, virologic breakthrough, and relapse. Definitions for subject virologic non-
response, rebound, breakthrough, and relapse are in Section 4.2.3.1.1.2.
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 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.
 
 
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In addition, the broad clinical and laboratory AE categories consisting of the percentage of
subjects with any AE, a drug related AE, a serious AE, an AE which is both drug-related and
serious, and who discontinued due to an AE will be summarized in the same manner
(Table 16). Laboratory parameters will be summarized by pre-defined limits of change, 
laboratory grade shift summaries, and for selected laboratory parameters, change from 
baseline summaries.  
In this estimation study, rates of events of clinical interest (as defined in Section 7.2.3.2) as 
well as broad categories of adverse events will be reported along with 95% confidence 
intervals for safety monitoring. Rates will also be shown for all specific AEs reported and 
pre-determined limits of change in laboratory results.
Missing safety parameter values will be handled using the Data-As-Observed (DAO) 
approach, that is, any missing value will be excluded from the analysis.  For lab shift 
summaries, change from baseline summaries and certain pre-defined limits of change 
summaries require a baseline value.  If a baseline value is missing, the latest pre-treatment 
value will be used instead.  If no pre-treatment result is available, that subject will not be 
included in the summary.  The safety summarization of results will be presented by treatment 
arm (Arm 1 and Arm 2) unless otherwise specified.
Table 16
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
Any SAE
Any drug-related AE
Any serious and drug-related AE
Discontinuation due to AE
X
X
X
X
X
X
X
X
X
X
Specific AEs, SOCs, or PDLCs
Change from baseline results (laboratory 
results, vital signs)
X
X
AE = adverse event; CI = confidence interval; ECI = clinical event of interest; PDLC = pre-defined limit of 
change; SOC = system organ class; X = results will be provided.
† Adverse experience references refer to both clinical and laboratory AEs.
‡ 95% CIs are provided for selected endpoints in this estimation study for safety monitoring.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
Demographic and Baseline Characteristics
No statistical hypothesis tests will be performed on these characteristics. The number and 
percentage of subjects screened, enrolled, the primary reasons for screen failure, and the 
primary reason for discontinuation will be displayed. Demographic variables (e.g., age, 
gender, and genotype subtype), primary and secondary diagnoses, and prior and concomitant 
therapies will be summarized using descriptive statistics for continuous or categorical 
variables, as appropriate. Summary statistics for the baseline efficacy measure (HCV RNA)
will also be provided.
 
 
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Viral Resistance Measurements
Viral resistance testing will focus on the entire NS3/4A and NS5A regions for all subjects 
and for those who meet the subject virologic failure criteria (see Section 4.2.3.1.1.2). 
Interim Analysis
8.7
No interim analyses are planned for this study.
Multiplicity
8.8
There will be no multiplicity adjustments in the analyses of this study.
Sample Size and Power Calculation
8.9
An initial description of sample size is provided in Section 4.2.1.6.
The expected sample size for each treatment arm in this study (N=50, and 70) was selected 
based on the knowledge of the epidemiology of HCV infection in France.  This is an 
exploratory study and the samples sizes are reflective of the number of patients that are likely 
to be enrolled in each treatment arm and are not driven by statistical consideration.
Sample Size and Power for Efficacy Analysis
8.9.1
This is an estimation study; no statistical testing will be performed for the efficacy endpoints. 
In this study, approximately 120 subjects will be enrolled with expected 50 subjects
(minimum of 40) in Arm 1, and 70 in Arm 2.  
Because of the differing subject populations and treatment regimens being administered in 
each study arm, differing response rates may be expected in each group.  Table 17 shows 2-
sided 95% CIs for SVR12 under varying assumptions of the number of observed successes for 
the FAS population corresponding to the different expected response rates for a group. 
Confidence intervals are based on the expected sample size. If the actual sample size is 
smaller, the CI for a given observed rate will be wider.  Note that the intervals are not 
symmetric around the point estimate.  The width of the 95% CIs are also provided to give an 
estimate of the precision of each estimated SVR12 rate.  
 
 
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Table 17
Two-Sided 95% Confidence Intervals for SVR12
N
Expected 
Response 
Rate
Observed Number of 
Subjects Achieving 
SVR12 (%)
95% CI†
Width of 95% CI 
(percentage points)
25
88%
22 (88.0%)
( 68.8,  97.5)
28.7
92%
23 (92.0%)
( 74.0,  99.0)
25.0
96%
24 (96.0%)
( 79.6,  99.9)
20.3
50
90%
45 (90.0%)
( 78.2,  96.7)
18.5
92%
46 (92.0%)
( 80.8,  97.8)
17.0
94%
47 (94.0%)
( 83.5,  98.7)
15.2
96%
48 (96.0%)
( 86.3,  99.5)
13.2
98%
49 (98.0%)
( 89.4,  99.9)
10.5
70
90%
63 (90.0%)
( 80.5,  95.9)
15.4
92%
65 (92.9%)
( 84.1,  97.6)
13.5
95%
67 (95.7%)
( 88.0,  99.1)
11.1
97%
68 (97.1%)
( 90.1,  99.7)
9.6
98%
69 (98.6%)
( 92.3, 100.0)
7.7
†Confidence intervals are based on the expected sample size. If the actual sample size is smaller, the CI 
for a given observed rate will be wider.
Sample Size and Power for 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 estimate of the upper bound of the 95% confidence interval for the underlying 
percentage of subjects with a specific adverse event given various hypothetical observed 
number of subjects with that specific adverse event within any of the treatment groups is
provided in Table 18. These calculations are based on the exact binomial method proposed 
by Clopper and Pearson (1934) [32]. 
 
 
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Table 18
Estimate of Incidence of a Specific Adverse Event and 95% Upper Confidence 
Bound Based on a Hypothetical Number of Subjects with that Specific Adverse 
Event
n
Hypothetical Number of 
Subjects with Adverse 
Event
Observed Estimate of 
Incidence Rate
95% Upper Confidence 
Bound†‡
50
0
0.0%
7.1%
1
2.0%
10.6%
2
4.0%
13.7%
3
6.0%
16.5%
4
8.0%
19.2%
5
10.0%
21.8%
6
12.0%
24.3%
70
0
0.00%
  5.1%
1
1.43%
  7.7%
2
2.86%
  9.9%
3
4.29%
12.0%
4
5.71%
14.0%
5
7.14%
15.9%
6
8.57%
17.7%
7
10.00%
19.5%
† Based on the Clopper-Pearson method
‡ The 95% upper confidence bounds are based on the expected sample size. If the actual sample size is 
smaller, the upper bound for a given observed rate will be larger.
Subgroup Analyses and Effect of Baseline Factors
8.10
To assess the consistency of the response across various subgroups, the SVR12 rate with 95% 
CIs will be estimated within each category of the following classification variables listed 
below.  The subgroups will be presented within each treatment arm (Arm 1 and Arm 2).

Race (White, Black, Asian, Other)

Sex (Female, Male)

Age (≥65 years, < 65 years)

IL28B genotype (CC vs. non-CC)

HCV RNA at baseline:
o
≤800,000 IU/mL versus >800,000 IU/mL
o
≤2 million IU/mL versus >2 million IU/mL
o
≤10 million IU/mL versus >10 million IU/mL

Presence or absence of baseline NS3 and NS5A or both RAVs to any of the class of 
drugs used

Cirrhosis status (Non-cirrhotic [fibrosis stage F0-F3] versus cirrhotic [F4])

Fibrosis stage (F0-F2 vs F3-F4) by prior treatment history (TN or TE)
 
 
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
Prior treatment history (see Section 7.1.5 for definitions):
o
treatment-naïve (TN) versus treatment-experienced (TE)
o
Among treatment-experienced (TE): 

Relapse versus non-relapse

Genotype 4 subgroup (4a, 4d, Other)
In addition, for the randomized subjects, SVR12 rates by HCV RNA at baseline 
(≤800,000 IU/mL versus >800,000 IU/mL) will be presented by treatment arm.  Additional 
subgroup analysis summaries for the randomized subjects with regard to other factors may 
be considered as needed. 
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 (EBR/GZR± RBV) 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 the date of the first to the date of the last dose of 
study medication for that subject. Note, the date of the last dose of study medication would 
be the last scheduled day of treatment administration for subjects who completed the 
assigned treatment.
For each subject, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance for the FAS population.
Extent of Exposure
8.12
The Extent of Exposure to study treatment will be evaluated by summary statistics (N, mean 
and range) for the “Number of Days on Therapy” by treatment group.
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.
 
 
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Clinical Supplies will be provided by the Sponsor as summarized in Table 19.  
Table 19
Product Descriptions
Product Name 
& Potency
Dosage Form
Source/Additional Information
MK-5172A 
(elbasvir/grazoprevir, EBR/GZR) 
50 mg/100 mg
Tablet
Provided Centrally
All supplies indicated in Table 19 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 19 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial site is responsible for recording the lot number, 
manufacturer, and expiry date for any locally purchased product as per local guidelines 
unless otherwise instructed by the Sponsor.
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 MK-5172A (EBR/GZR, 50 mg/100 mg) blister cards every 
4 weeks. Each blister card will contain a 14 day supply. Two blister cards will support dosing 
requirements for a 28 day span between visits. At the day 1 visit 3 blister cards will be 
dispensed. The third blister card will cover the days between visits where the subject does not 
return for their visit on the 28th day. 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.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
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.
 
 
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Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
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.
 
 
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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.
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.
 
 
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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.
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 
 
 
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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.
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 Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  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 FDAMA/FDAAA 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.    
 
 
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
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.
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, 
 
 
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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 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
[1]
Asselah T, Reesink H, Gerstoft J, de Ledinghen V, Pockros P, Robertson M, et al. 
High efficacy of elbasvir and grazoprevir with or without ribavirin in 103 
treatment-naive and experienced patients with HCV genotype 4 infection: a pooled 
analysis. Oral Presentation at 66th Annual Meeting of the American Association 
for Study of Liver Diseases (AASLD); 2015 Nov 13-17; San Francisco (CA).
[2]
Report of a WHO Consultation organized in collaboration with the Viral Hepatitis 
Prevention Board (Antwerp B. Global surveillance and control of hepatitis C. J 
Viral Hepat 1999;6:35-47.
[3]
Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 
2011;17(2):107-15.
[4]
Hajarizadeh B, Grebely J, Dore GJ. Epidemiology and natural history of HCV 
infection. Nat Rev Gastroenterol Hepatol 2013;10:553-62.
[5]
Maasoumy B, Wedemeyer H. Natural history of acute and chronic hepatitis C. 
Best Pract Res Clin Gastroenterol 2012;26:401-12.
 
 
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[6]
Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis 
progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-
regression. Hepatology. 2008 Aug;48(2):418-31.
[7]
Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG, et al. 
Global distribution and prevalence of hepatitis C virus genotypes. Hepatology. 
2015 Jan;61(1):77-87.
[8]
Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology 
and genotype distribution of the hepatitis C virus infection. J Hepatol. 2014 
Nov;61(1S):S45-S57.
[9]
Zhou N, Hernandez D, Ueland J, Yang X, Yu F, Sims K, et al. NS5A sequence 
heterogeneity and mechanisms of Daclatasvir resistance in hepatitis C virus 
genotype 4 infection. J Infect Dis. 2016 Jan 15;213(2):206-15.
[10]
Asselah T, Bourliere M. Hepatitis C virus: current and evolving treatments for 
genotype 4. Gastroenterol Clin North Am. 2015 Dec;44(4):859-70.
[11]
Pearlman BL, Traub N. Sustained virologic response to antiviral therapy for 
chronic hepatitis C virus infection: a cure and so much more. Clin Infect Dis 
2011;52(7):889-900.
[12]
Hill AM, Saleem J, Heath KA, Simmons B. Effects of sustained virological 
response (SVR) on the risk of liver transplant, hepatocellular carcinoma, death and 
re-infection: meta-analysis of 129 studies in 23,309 patients with hepatitis C 
infection [abstract]. Hepatology. 2014 Oct;60(4):218A-9A. Abstract no. 44.
[13]
Chen J, Florian J, Carter W, Fleischer RD, Hammerstrom TS, Jadhav PR, et al. 
Earlier sustained virologic response end points for regulatory approval and dose 
selection of hepatitis C therapies. Gastroenterology 2013;144(7):1450-5e2.
[14]
Kohli A, Kapoor R, Sims Z, Nelson A, Sidharthan S, Lam B, et al. Ledipasvir and 
sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-
label phase 2a cohort study. Lancet Infect Dis. 2015 Sep;15(9):1049-54.
[15]
Hezode C, Asselah T, Reddy KR, Hassanein T, Berenguer M, Fleischer-
Stepniewska K, et al. Ombitasvir plus paritaprevir plus ritonavir with or without 
ribavirin in treatment-naive and treatment-experienced patients with genotype 4 
chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. 
Lancet. 2015 Jun 20;385(9986):2502-9.
[16]
Ruane PJ, Ain D, Stryker R, Meshrekey R, Soliman M, Wolfe PR, et al. 
Sofosbuvir plus ribavirin for the treatment of chronic genotype 4 hepatitis C virus 
infection in patients of Egyptian ancestry. J Hepatol. 2015 May;62(5):1040-6.
[17]
Esmat GE, Shiha G, Omar RF, Hassany M, Hammad R, Khairy M, et al. 
Sofosbuvir plus Ribavirin in the treatment of Egyptian patients with chronic 
genotype 4 HCV infection. Poster session presented at: AASLD The Liver 
Meeting; 2014 Nov 7-11; Boston, MA.
 
 
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[18]
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 
2013;368(20):1878-87.
[19]
Abergel A, Loustaud-Ratti V, Metivier S, Jiang D, Kersey K, Knox SJ, et al. 
Ledipasvir/Sofosbuvir treatment results in high SVR rates in patients with chronic 
genotype 4 and 5 HCV infection [abstract]. J Hepatol. 2015;62:S219-20. Abstract
no. O056.
[20]
Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, et al. 
Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J 
Med. 2015 Aug 20;373(8):705-13.
[21]
Fontaine H, Hezode C, Zoulim F, Samuel D, Bourliere M, Haour G, et al. Efficacy 
of the oral Sofosbuvir-based combination in HCV genotype 4-monoinfected 
patients from the French observational cohort ANRS CO22 HEPATHER. Poster 
session presented at: 50th annual Meeting of the European Association for the 
Study of the Liver - The International Liver Congress; 2015 Apr 22-26; Vienna.
[22]
French Association for Liver Studies (AFEF). AFEF guidelines: management of 
hepatitis C virus infection [Internet]. Paris: French Association for Liver Studies 
(AFEF); 
2015. 
Available 
from: 
http://www.afef.asso.fr/communication/afef/news.phtml?id=rc%2Forg%2Fafef%2
Fnws%2FNews%2F2015%2F20150629-190435-489.
[23]
Westbrook RH, Dusheiko G. Natural history of hepatitis C. J Hepatol. 2014 
Nov;61(1 Suppl):S58-68.
[24]
Jacobson I, Lawitz E, Kwo P, Hezode C, Peng C -Y, Howe A, et al. An integrated 
analysis of 402 compensated cirrhotic patients with HCV patients (GT) 1, 4 or 6 
infection treated with elbasvir/grazoprevir. Oral Presentation at 66th Annual 
Meeting of the American Association for Study of Liver Diseases (AASLD); 2015 
Nov 13-17; San Francisco (CA).
[25]
Rockstroh JK, Nelson M, Katlama C, Lalezari J, Mallolas J, Bloch M, et al. C-
edge co-infected: phase 3 study of Grazoprevir/Elbasvir in patients with 
HCV/HIV. Poster session presented at: The International Liver Congress 2015. 
50th annual meeting of the European Association for the Study of the Liver; 2015 
April 22-26; Vienna, Austria.
[26]
Rockstroh JK, Nelson M, Katlama C, Lalezari J, Mallolas J, Bloch M, et al. Effi 
cacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients 
with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-
randomised, open-label trial. Lancet. Forthcoming 2015.
[27]
Zeuzem S, Ghalib R, Reddy KR, Pockros PJ, Ari ZB, Zhao Y, et al. Grazoprevir-
Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic 
Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A 
Randomized Trial. Ann Intern Med. 2015 Jul 7;163(1):1-13.
[28]
Alberti A. Impact of a sustained virological response on the long-term outcome of 
hepatitis C. Liver Int 2011:18-22.
 
 
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[29]
Martinot-Peignoux M, Stern C, Maylin S, Ripault M-P, Boyer N, Leclere L, et al. 
Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the 
sustained virologic response in patients with hepatitis C virus receiving pegylated 
interferon and ribavirin. Hepatology 2010;51(4):1122-6.
[30]
Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using 
transient elastography. J Hepatol 2008;48:835-47.
[31]
Boursier J, de Ledinghen V, Zarski J-P, Fouchard-Hubert I, Gallois Y, Oberti F, et 
al. Comparison of eight diagnostic algorithms for liver fibrosis in hepatitis C: new 
algorithms are more precise and entirely noninvasive. Hepatology 2012;55(1):58-
67.
[32]
Clopper CJ, Pearson ES. The use of confidence or Fiducial limits illustrated in the 
case of the binomial. Biometrika 1934;26(4):404-13.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law,
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.5 – 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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mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
 
 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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List of Abbreviations and Definition of Terms
12.4
Term
Definition
AE
Adverse event
ART
Antiretroviral therapy
ASaT
All Subjects as Treated (population)
CFR
Code of Federal Regulations
CI
Confidence interval
CRF
Case report form
CSR
Clinical study report
DAA
Direct-acting antiviral
DNA
Deoxyribonucleic acid
EBR
Elbasvir
ECI
Events of Clinical Interest
eCRF
Electronic case report form
EDC 
Electronic Data Capture
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration, USA
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FDC
Fixed-dose combination
FU
Follow-up
FW
Follow-up Week
GCP
Good Clinical Practice
GCS
Global Clinical Supplies
GZR
Grazoprevir
HCC
Hepatocellular carcinoma
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
IL28B
Interleukin-28B (Interferon-lambda 3)
IRB
Institutional Review Board
IVRS
Interactive voice response system
IWRS
Integrated web response system
LLOQ
Lower Limit of Quantification
mFAS
Modified full analysis set
NA, N/A
Not applicable
NI
Nucleotide-Mimetic NS5B Polymerase Inhibitor
NNI
Non-Nucleoside NS5B Polymerase Inhibitor
OBV
Ombitasvir
Peg-IFN
Pegylated Interferon alfa-2b
PGx
Pharmacogenomics
PI
Protease Inhibitor
RAV
Resistance-associated variants
RBC
Red Blood Cell
RBV
Ribavirin
 
 
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Term
Definition
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SMD
Study Medication Diary
SOP
Standard Operating Procedure
SVR
Sustained Virologic Response
SVR12
(Sustained Virologic Response 12 weeks after the end of all 
study therapy): The subject has HCV RNA <25 IU/mL 
(either TD(u) or TND) 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 <25 IU/mL 
(either TD(u) or TND) 24 weeks after the end of all study 
therapy
TE
Treatment-experienced
TN
Treatment-naïve
TND
Target Not Detected (HCV RNA not detected)
TD (u)
Target detected but unquantifiable
TD (q)
Target Detected, quantifiable
TW
Treatment Week
US
United States
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
12.5
Sample Types
Screening
Day 1
Week 4
Week 8
Week 12
FW 4
FW 12
FW 24
Total
Volume
Test
Approximate Blood Volume (mL)
Coagulation 
(PT, INR)
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
36
HBV
Evaluations  
(HBsAg, Anti-
HBc, Anti-HBs, 
HBV DNA)1
10
10
10
10
10
10
10
10
80
HIV-1 
Serology
6
6
Chemistry
10
10
10
10
10
10
10
80
Hematology
3
3
3
3
3
3
3
3
24
Follicle 
Stimulating 
Hormone 
(FSH)
2
2
HCV 
Genotype 
Determination
4
4
HCV Viral 
Resistance 
and 
biomarkers
6
6
6
6
24
HCV RNA
10
10
10
10
10
10
10
10
80
HIV RNA
6
6
CD4+ T-cell 
count
6
6
Blood for 
Genetic 
Analysis
8.5
8.5
Expected 
Total (mL)
Main Study 
Population
61.5
52
37.5
37.5
37.5
43.5
43.5
43.5
356.5
Anti-HBc=hepatitis B core antibody; anti HBs=hepatitis B surface antibody; GT = genotype; HBsAg=hepatitis B surface 
antigen; HBV DNA=hepatitis B virus deoxyribonucleic acid; HCV=hepatitis C virus; HIV=Human immunodeficiency virus; 
INR=international normalized ratio; PT=prothrombin time.
1 HBsAg, anti-HBc, and anti-HBs will be assessed at screening in all subjects.  For all anti-HBc positive subjects, HBV DNA 
will also be assessed at screening, and both HBV DNA and HBsAg will be monitored during the trial.
 
 
04TYMT


Product:  MK-5172 
106
Protocol/Amendment No.: 096-03 
MK-5172-096-03 Final Protocol
1-Feb-2018
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
 
 
04TYMT