Clinical trial NCT03379506
Conditions: HCV Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-01-25; Completion date: 2020-07-23
Enrollment: 57 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the pharmacokinetics (PK), safety, and efficacy of oral MK-5172 (a fixed dose combination \[FDC\] tablet containing elbasvir \[EBR\] 50 mg and grazoprevir \[GZR\] 100 mg) and EBR/GZR (varying doses) pediatric granules in pediatric hepatitis C virus (HCV)-infected participants who are 3 to \<18 years of age. Within each age cohort (Cohort 1: 12 to \<18 years of age; Cohort 2: 7 to \<12 years of age; and Cohort 3: 3 to \<7 years of age), a Mini Cohort of 7 participants will be enrolled first. For the oldest cohort (Cohort 1), the Mini Cohort will assess ability to swallow a placebo tablet prior to administering active FDC tablets; participants in Cohorts 2 and 3 will take pediatric granules instead of a tablet.

Detailed description:

Arms: arm 1: Pediatric participants receive EBR/GZR as either FDC tablets or oral granules once daily for 12 weeks. A 24-week follow-up period will follow the 12-week treatment regimen.
Interventions: intervention 1: EBR/GZR FDC Tablet intervention 2: Placebo intervention 3: Grazoprevir Oral Granules intervention 4: Elbasvir Oral Granules
Intervention descriptions: intervention 1: Participants who are 12 to \<18 years of age will receive oral FDC tablets with EBR 50 mg/GZR 100 mg once daily by mouth. intervention 2: Placebo tablet matched to EBR/GZR FDC tablet. intervention 3: Participants 3 to \<12 years of age take grazoprevir granules 0.5 mg by mouth in a soft food vehicle at a dose not to exceed 50 mg. intervention 4: Participants 3 to \<12 years of age take elbasvir oral granules 1 mg by mouth in a soft food vehicle at a dose not to exceed 100 mg.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03379506 
Document Date: 
16-Feb-2018
A Phase IIb Clinical Study to Assess the Pharmacokinetics, Safety, 
and Efficacy of the Combination Regimen of Elbasvir (EBR)/
Grazoprevir (GZR) in Participants Aged 3 to less than 18 Years with 
Chronic Hepatitis C Infection


Product:  MK-5172 
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Confidential
Title Page
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.
Protocol Title: A Phase IIb Clinical Study to Assess the Pharmacokinetics, Safety, and 
Efficacy of the Combination Regimen of Elbasvir (EBR)/Grazoprevir (GZR) in Participants 
Aged 3 to less than 18 Years with Chronic Hepatitis C Infection
Protocol Number: 079-02
Compound Number: MK-5172
Sponsor Name and Legal Registered Address: 
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.
Regulatory Agency Identifying Number(s):
IND NUMBER:   [110,261]
EudraCT NUMBER: [2015-003006-16]
Approval Date:  16-Feb-2018
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
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.
Typed Name:
Title:
Date
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 02
Overall Rationale for the Amendment:
This amendment incorporates a number of minor changes throughout to improve the clarity of the protocol and three major changes:
1. Ctrough at Week 4 was added as a primary endpoint.
2. Dosing by weight bands for Mini Age Cohort 3 and Expanded Age Cohorts 1 and 2/3.
3. Revised DILI and ECI language.
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
Main Changes
1 – Synopsis, 
Objectives/Hypotheses 
and Endpoints
4 – Objectives / 
Hypothesis and 
Endpoints
5.4.2.4 –
Pharmacokinetic 
Endpoints
10 – Statistical 
Analysis Plan
Drug concentration immediately pre-
dose (Ctrough) at Week 4 was added as a 
primary endpoint
Ctrough, a relevant pharmacokinetic (PK) endpoint, was raised to a 
primary endpoint to fully characterize the PK profile. Additional 
blood from participants will not need to be collected in order to 
analyze Ctrough.
 
 
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Section # and Name
Description of Change
Brief Rationale
5.1 – Overall Design
5.5.1 – Starting Dose 
for this Trial
5.5.1.3 – Dose in Mini 
Age Cohort 3 and 
Expanded Age 
Cohorts 1, 2, and 3
7.1 – Treatments 
Administered
10.6.2 – Modeling and 
Simulation for Dose 
Selection
10.10 – Subgroup 
Analyses
The text was updated to include the use 
of weight bands (which will be 
determined based on PK analyses) for 
dose recommendations in Mini Age 
Cohort 3 and the Expanded Age 
Cohorts. In Section 10.10, weight 
bands have been added as a category of 
subgroup analyses.
Added to improve the precision of pediatric dosing
recommendations made by the study.
9.3.7 – Events of 
Clinical Interest (ECI)
The following revisions were made to 
liver-related ECIs:

In ECI #2, “from the initiation of 
study therapy” was replaced with 
“after initiation of study therapy”

In ECI #3, “3X ULN from the 
initiation of study therapy” was 
replaced with “100 IU/L after
initiation of study therapy”
An ALT/AST threshold of >100 IU/L is a clinically meaningful 
threshold for evaluation of potential drug induced liver toxicity for 
pediatric participants. Using a numerical trigger for evaluation 
rather than fold ULN, ensures a uniform approach to evaluation of 
ALT and AST elevations. Use of the word “after” rather than 
“from initiation” ensures that the elevation being captured occurs 
after Day 1 of therapy.
 
 
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Section # and Name
Description of Change
Brief Rationale
Other Changes
2 – Schedule of 
Activities (SoA)
Removed heart rate and blood pressure 
as examples of vital signs that will be 
collected from the first column of the 
table.
These were removed to clarify that comprehensive vital sign data 
will be collected, not just heart rate and blood pressure.  Vital signs 
being collected were added to the “Notes” column.
3.3 – Benefit/Risk 
Assessment
Details of study procedures to monitor 
for elevations in alanine 
aminotransferase (ALT) were added.
Revisions made to allow investigators to more easily identify the 
benefit/risks to the participant and the protocol-defined procedures 
in place for monitoring potential risks
5.1 – Overall Design
Enrollment requirements for the mini 
and expanded age cohorts were 
removed from the text and summarized 
in a table.
Presentation of enrollment requirements revised to improve 
readability of section.
5.1.1 – Study Diagram
The diagram was updated to be 
consistent with Table 2.
Consistent with the enrollment requirements for each Age Cohort 
in Table 2.
5.4.2.3.2 – Late ALT 
Elevations and 
Hepatic ECI Resulting 
in a Pause in 
Enrollment
8.1 – Discontinuation 
of Study Treatment
Bulleted criterion in each section was 
revised to remove “Grade 4 laboratory 
abnormality”.
Grading of adverse events (AE), including laboratory AEs, are 
reported by the investigator as mild, moderate, or severe as 
described in Section 9.3 of the protocol and not as a numerical 
scoring system. Any Grade 4 event would be reported by this 
methodology.
 
 
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Section # and Name
Description of Change
Brief Rationale
6.1 – Inclusion 
Criteria
Inclusion criterion #5 (a) (iii) was 
revised to add that absence of cirrhosis 
can be determined by local clinical 
standards during screening as assessed 
by the investigator.
This change was made to clarify that absence of cirrhosis can be 
determined by local clinical standards that includes physical 
examination during screening in combination with laboratory 
evaluation during screening and/or imaging test within 6 months of 
screening, as assessed by the investigator.
Inclusion criterion #5 (b) (iii) was 
revised to add that cirrhosis can be 
determined by local clinical standards 
during screening as assessed by the 
investigator.
This change was made to clarify that the presence of cirrhosis can 
be determined by local clinical standards that includes physical 
examination during screening in combination with laboratory 
evaluation and/or imaging test as assessed by the investigator.
The following note was removed from 
inclusion criterion #5: Computed 
tomography or magnetic resonance 
imaging obtained as part of clinical 
care may be used in place of 
ultrasound, if available.
This change was made to remove an errant note from inclusion 
criterion #5.
The term “legally acceptable 
representative” in inclusion criterion 
#10 was revised to “legally acceptable 
representative(s)”.
This change was made to address potential site-specific 
requirements that both parents need to sign the informed consent 
before the child can participate in a clinical trial. 
 
 
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Section # and Name
Description of Change
Brief Rationale
6.2 – Exclusion 
Criteria
1. A note was added to criterion #2 to 
specify use of +1 for the bilirubin 
category of the Child-Pugh calculation 
for participants with Gilbert’s 
syndrome.
2. Criterion #7c was updated to specify 
that participants with “uncontrolled” 
celiac sprue disease are excluded.
3. “Failure to thrive” was added to the 
list of excluded medical conditions in 
criterion #7e.
1. Added to improve clarity of the protocol; mild bilirubin 
elevations are found in patients with Gilbert’s syndrome, which is 
common and not reflective of an underlying advanced liver 
disease.
2. Wording refined as patients with controlled disease do not have 
malabsorption.
3. This change was made to provide an additional medical 
exclusion of children with an unusually low weight that might 
impact PK.
6.3.1 – Meals and 
Dietary Restrictions
7.1 – Treatments 
Administered
9.1.8.1 – Timing of 
Dose Administration
The type of soft food dosing vehicle for 
the pediatric formulation was updated 
to applesauce, pudding, or yogurt.
This change was made to clarify the type of soft food acceptable 
for use in this study.
 
 
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Section # and Name
Description of Change
Brief Rationale
7.1 – Treatments 
Administered
A statement was added to specify that, 
following assignment of formulation, 
participants may not change from FDC 
tablets to pediatric formulation or from 
pediatric formulation to FDC tablets.
Added to improve clarity of the protocol. 
The description of the pediatric formula 
single entity packet was updated to 
clarify that the Sponsor’s product 
number (MK-8742 for EBR and MK-
5172 for GZR) will be included on the 
label.
This change was made to clarify that MK-8742 represents EBR 
and MK-5172 represents GZR on the label.
7.7 – Concomitant 
Therapy
1. The table containing prohibited 
medications was updated to reflect that 
all statins are prohibited during the 
dosing period of the study.
2. Text that repeated a prohibited 
medication (“modafinil”) was deleted 
from the table. 
1. Statins are excluded in order to minimize the number of 
variables that impact the PK of EBR/GZR.
2. Redundant content removed.
“Including but not limited to” was 
added to the list of prohibited strong 
CYP3A inhibitors by participants in the 
Mini Age Cohorts. 
To improve clarity of the protocol.
8.1 – Discontinuation 
of Study Treatment
Repeated bullet has been deleted.
Redundant content removed.
9.1.12 – 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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Section # and Name
Description of Change
Brief Rationale
9.6.1 – Blood 
Collection for Plasma 
EBR/GZR
1. Instructions were added for 
participants receiving pediatric 
formulation to record the following 
information in the Study Medication 
and Meal Diary (SMD) for all doses: 
a) the soft food that EBR/GZR granules 
were mixed into and b) the pediatric 
formulation food consumption 
timeframe (ie, the time from mixing of 
medication into the soft food vehicle to 
complete consumption of all granules 
that were mixed into the soft food).
Sites should also enter this information 
into the eCRF.
2. The text was revised to clarify that 
meal data entry for the pre-dose PK 
sample on Day 1 is not required. 
3. The timing for recording meal data 
on the day prior to the predose PK visit 
and on the day of the visit was updated.
1. Soft food vehicle information may be considered as part of the 
PK analyses in order to ascertain whether the type of food vehicle 
or the duration pediatric granules are dispersed within the food 
vehicle impact PK.
2. To improve clarity of the protocol.
3. The timeframe for collection of meal data around the dose was 
revised to represent the timeframe for which meals can impact PK 
results.
9.11.1 – Screening
An abnormal FibroScan result at 
Screening was deleted as an 
exclusionary criterion that could be 
retested
This change was made to correct an error.  Abnormal FibroScan 
results at screening may not be repeated.
 
 
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Section # and Name
Description of Change
Brief Rationale
9.11.2 – Treatment 
Period
1. The description of the packaging of 
open-label EBR/GZR FDC tablets was 
revised. “Blister card(s)” was replaced 
with “container(s)”.
2. A reference to the soft food 
information to be recorded in the SMD 
for participants on EBR/GZR pediatric 
formulation was added.
1. The final packaging may be in the form of “blister cards” or 
“bottles” depending on geographic region.  Therefore, the word 
“container” is inclusive for all packaging types.
2. Consistent with the soft food information instructions for the 
SMD added to Section 9.6.1.
9.11.4 – Discontinued 
Participants Continued 
to be Monitored in the 
Study
Participants who have met virologic 
failure criteria will also need to be 
identified as having a treatment-
emergent resistance associated 
substitution in order to be eligible for 
follow-up in protocol MK-5172-017
Updated to clearly define participants who require additional 
follow-up to assess persistence of resistance following DAA 
therapy.
10.4.1.1 –
Pharmacokinetic 
Endpoints
Included statement that the meal and 
soft food vehicle information may be 
considered in PK analyses.
This statement was added to improve clarity of the protocol 
regarding the purpose of meal and soft food information collection 
in this study.
Throughout
Minor editorial and document 
formatting revisions
Minor, therefore have not been summarized.
 
 
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Table of Contents
PROTOCOL AMENDMENT SUMMARY OF CHANGES ...............................................3
1.
Synopsis.......................................................................................................................20
2.
Schedule of Activities (SoA) ......................................................................................23
3.
Introduction................................................................................................................29
Study Rationale .......................................................................................................29
3.1
Background..............................................................................................................29
3.2
Pharmaceutical and Therapeutic Background .....................................................29
3.2.1
Overview.......................................................................................................30
3.2.1.1
Summary of Clinical Experience with EBR/GZR ...............................................31
3.2.2
Summary of Clinical Experience with EBR/GZR in Adults ........................31
3.2.2.1
PK Background and Strategy...............................................................................33
3.2.3
EBR/GZR Metabolism..................................................................................33
3.2.3.1
Modeling and Simulation in Adults..............................................................33
3.2.3.2
Preclinical Trials Supporting a Pediatric Clinical Study .....................................35
3.2.4
Benefit/Risk Assessment.........................................................................................35
3.3
4.
Objectives/Hypotheses and Endpoints.....................................................................36
5.
Study Design...............................................................................................................37
Overall Design .........................................................................................................37
5.1
Study Diagram .....................................................................................................40
5.1.1
Number of Participants ..........................................................................................40
5.2
Beginning and End of Study Definition ................................................................40
5.3
Clinical Criteria for Early Study Termination .....................................................40
5.3.1
Scientific Rationale for Study Design....................................................................41
5.4
Rationale for Study Population............................................................................41
5.4.1
Rationale for Endpoints .......................................................................................41
5.4.2
Efficacy Endpoints........................................................................................41
5.4.2.1
Measurement of HCV RNA ..................................................................41
5.4.2.1.1
Viral Resistance Measurements.............................................................42
5.4.2.1.2
 
 
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Palatability and Acceptance Assessment Endpoint ......................................43
5.4.2.2
Safety Endpoints ...........................................................................................43
5.4.2.3
General Safety........................................................................................43
5.4.2.3.1
Late ALT Elevations and Hepatic ECI Resulting in a Pause in 
5.4.2.3.2
Enrollment .............................................................................................43
Growth ...................................................................................................44
5.4.2.3.3
Pharmacokinetic Endpoints ..........................................................................44
5.4.2.4
Future Biomedical Research.........................................................................44
5.4.2.5
Rationale for the Use of Comparator/Placebo .....................................................45
5.4.3
Justification for Dose ..............................................................................................45
5.5
Starting Dose for This Trial .................................................................................45
5.5.1
Dose Justifications ........................................................................................45
5.5.1.1
Dose in Mini Age Cohort 1 and 2.................................................................46
5.5.1.2
Dose in Mini Age Cohort 3 and Expanded Age Cohorts 1, 2, and 3............46
5.5.1.3
Maximum Dose/Exposure for This Trial .............................................................46
5.5.2
6.
Study Population........................................................................................................47
Inclusion Criteria ....................................................................................................47
6.1
Exclusion Criteria ...................................................................................................49
6.2
Lifestyle Restrictions...............................................................................................51
6.3
Meals and Dietary Restrictions............................................................................52
6.3.1
Screen Failures ........................................................................................................52
6.4
Participant Replacement Strategy.........................................................................52
6.5
7.
Treatments..................................................................................................................52
Treatments Administered.......................................................................................52
7.1
Dose Modification (Escalation/Titration/Other)..................................................54
7.2
Method of Treatment Assignment.........................................................................54
7.3
Stratification.........................................................................................................54
7.3.1
Blinding....................................................................................................................54
7.4
Preparation/Handling/Storage/Accountability ....................................................54
7.5
Dose Preparation..................................................................................................54
7.5.1
Handling, Storage and Accountability.................................................................55
7.5.2
Treatment Compliance...........................................................................................55
7.6
 
 
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Concomitant Therapy.............................................................................................56
7.7
Rescue Medications & Supportive Care ..............................................................58
7.7.1
Treatment After the End of the Study ..................................................................58
7.8
Clinical Supplies Disclosure ...................................................................................59
7.9
8.
Discontinuation/Withdrawal Criteria......................................................................59
Discontinuation of Study Treatment .....................................................................59
8.1
Withdrawal from the Study ...................................................................................60
8.2
Lost to Follow Up ....................................................................................................60
8.3
9.
Study Assessments and Procedures..........................................................................61
Administrative and General Procedures ..............................................................62
9.1
Informed Consent/Assent.....................................................................................62
9.1.1
General Informed Consent............................................................................62
9.1.1.1
Consent/Assent and Collection of Specimens for Future 
9.1.1.2
Biomedical Research ....................................................................................62
Parental Consent to Use and Disclose Personal Data ...................................63
9.1.1.3
Inclusion/Exclusion Criteria ................................................................................63
9.1.2
Participant Identification Card.............................................................................63
9.1.3
Medical History ...................................................................................................63
9.1.4
Prior and Concomitant Medications Review .......................................................63
9.1.5
Prior Medications..........................................................................................63
9.1.5.1
Concomitant Medications .............................................................................63
9.1.5.2
Assignment of Screening Number .......................................................................64
9.1.6
Assignment of Treatment/Randomization Number .............................................64
9.1.7
Treatment Administration....................................................................................64
9.1.8
Timing of Dose Administration....................................................................65
9.1.8.1
Withdrawal/Discontinuation................................................................................65
9.1.9
Withdrawal From Future Biomedical Research ...........................................65
9.1.9.1
Participant Blinding/Unblinding..........................................................................65
9.1.10
Domiciling ...........................................................................................................66
9.1.11
Calibration of Equipment.....................................................................................66
9.1.12
Efficacy Assessments...............................................................................................66
9.2
HCV RNA Measurements ...................................................................................66
9.2.1
 
 
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Viral Resistance Measurements...........................................................................66
9.2.2
Adverse Events, Serious Adverse Events and Other Reportable Safety 
9.3
Events.......................................................................................................................67
Time Period and Frequency for Collecting AE, SAE and Other 
9.3.1
Reportable Safety Event Information ..................................................................67
Method of Detecting AE, SAE and Other Reportable Safety Events..................69
9.3.2
Follow-up of AE, SAE and Other Reportable Safety Event Information............69
9.3.3
Regulatory Reporting Requirements for SAE .....................................................69
9.3.4
Disease-Related Events and/or Disease-Related Outcomes Not 
9.3.5
Qualifying as AEs or SAEs..................................................................................69
Pregnancy and Exposure During Breastfeeding ..................................................69
9.3.6
Events of Clinical Interest (ECI)..........................................................................70
9.3.7
Treatment of Overdose...........................................................................................70
9.4
Safety........................................................................................................................70
9.5
Physical Examinations .........................................................................................71
9.5.1
Height of Biological Parent(s) ......................................................................71
9.5.1.1
Vital Signs............................................................................................................71
9.5.2
Electrocardiograms ..............................................................................................71
9.5.3
Date of Menarche.................................................................................................72
9.5.4
Contraception Confirmation ................................................................................72
9.5.5
Clinical Safety Laboratory Assessments..............................................................72
9.5.6
Fibroscan®.....................................................................................................72
9.5.6.1
Pregnancy Testing.........................................................................................73
9.5.6.2
HIV Evaluation .............................................................................................73
9.5.6.3
Hepatitis B Virus Evaluation ........................................................................73
9.5.6.4
Pharmacokinetics....................................................................................................73
9.6
Blood Collection for Plasma EBR/GZR ..............................................................73
9.6.1
Pharmacodynamics.................................................................................................75
9.7
Future Biomedical Research Sample Collection ..................................................75
9.8
Biomarkers ..............................................................................................................76
9.9
Palatability and Acceptance Assessment ..............................................................76
9.10
Visit Requirements..................................................................................................76
9.11
Screening..............................................................................................................76
9.11.1
 
 
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Treatment Period..................................................................................................77
9.11.2
Follow-Up Period.................................................................................................78
9.11.3
Discontinued Participants Continuing to be Monitored in the Study ..................78
9.11.4
10.
Statistical Analysis Plan ............................................................................................79
Statistical Analysis Plan Summary........................................................................80
10.1
Responsibility for Analyses/In-House Blinding....................................................81
10.2
Hypotheses/Estimation ...........................................................................................81
10.3
Analysis Endpoints..................................................................................................81
10.4
Efficacy/Immunogenicity/Pharmacokinetics Endpoints......................................81
10.4.1
Pharmacokinetic Endpoints ..........................................................................81
10.4.1.1
Efficacy Endpoints........................................................................................81
10.4.1.2
Safety Endpoints ..................................................................................................82
10.4.2
Analysis Populations...............................................................................................82
10.5
PK Analysis Population .......................................................................................82
10.5.1
Efficacy Analysis Populations .............................................................................82
10.5.2
Safety Analysis Populations ................................................................................82
10.5.3
Statistical Methods..................................................................................................83
10.6
Statistical Methods for Pharmacokinetic Analyses..............................................83
10.6.1
Modeling and Simulation for Dose Selection......................................................83
10.6.2
Statistical Methods for Efficacy Analyses...........................................................83
10.6.3
Statistical Methods for Safety Analyses ..............................................................85
10.6.4
Summaries of Baseline Characteristics, Demographics, and Other 
10.6.5
Analyses...............................................................................................................86
Demographic and Baseline Characteristics ..................................................86
10.6.5.1
Growth ..........................................................................................................87
10.6.5.2
Viral Resistance Measurements....................................................................87
10.6.5.3
Palatability and Acceptance Assessment ......................................................87
10.6.5.4
Interim Analyses .....................................................................................................87
10.7
Multiplicity ..............................................................................................................87
10.8
Sample Size and Power Calculations ....................................................................87
10.9
Sample Size and Power for PK Analyses ............................................................87
10.9.1
Sample Size and Power for Efficacy Analyses ....................................................88
10.9.2
 
 
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Sample Size and Power for Safety Analyses .......................................................89
10.9.3
Subgroup Analyses..................................................................................................90
10.10
Compliance (Medication Adherence)....................................................................91
10.11
Extent of Exposure..................................................................................................91
10.12
11.
References...................................................................................................................91
12.
Appendices..................................................................................................................96
Appendix 1: Abbreviations and Trademarks.......................................................96
12.1
Appendix 2: Clinical Laboratory Tests.................................................................98
12.2
Appendix 3: Study Governance Considerations ................................................101
12.3
Merck Code of Conduct for Clinical Trials ...................................................................101
Financial Disclosure.......................................................................................................103
Data Protection...............................................................................................................103
Confidentiality of Data ..................................................................................................103
Confidentiality of Participant Records...........................................................................103
Confidentiality of IRB/IEC Information........................................................................104
Committees Structure.....................................................................................................104
Executive Oversight Committee................................................................................104
Data Monitoring Committee......................................................................................104
Publication Policy......................................................................................................104
Compliance with Trial Registration and Results Posting Requirements .......................105
Compliance with Law, Audit and Debarment ...............................................................105
Data Quality Assurance .................................................................................................106
Source Documents .........................................................................................................107
Study and Site Closure...................................................................................................107
Appendix 4: Adverse Events: Definitions and Procedures for 
12.4
Recording, Evaluating, Follow-up, and Reporting ............................................108
Definition of AE ............................................................................................................108
Definition of SAE ..........................................................................................................109
Recording AE and SAE .................................................................................................110
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor ................113
Appendix 5: Contraceptive Guidance and Pregnancy Testing.........................115
12.5
Contraception Requirements..........................................................................................115
 
 
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Pregnancy Testing..........................................................................................................117
Appendix 6: Collection and Management of Specimens for Future 
12.6
Biomedical Research.............................................................................................118
Appendix 7: Palatability and Acceptance Assessment Form............................122
12.7
 
 
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LIST OF TABLES
    
Table 1
SVR12 of EBR/GZR (50 mg/100 mg) – MK-5172 Protocols 035, 048, 
052, 060, 061, and 068..........................................................................................32
Table 2
Enrollment Requirements for Each Age Cohort...................................................38
Table 3
Nomenclature for Describing HCV RNA Levels.................................................41
Table 4
Laboratory Exclusion Criteria ..............................................................................51
Table 5
Study Treatments..................................................................................................53
Table 6
List of Prohibited Medications .............................................................................57
Table 7
List of Allowed Medications ................................................................................58
Table 8
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events......................................................................................68
Table 9
Pharmacokinetic Sampling Timepoints for All Age Cohorts...............................75
Table 10
Analysis Strategy for Key Efficacy Variables......................................................85
Table 11
Analysis Strategy for Safety Parameters ..............................................................86
Table 12
Expected Precision (80% Likely) for Estimates of GZR and EBR 
AUC0-24.................................................................................................................88
Table 13
Two-Sided 95% Confidence Intervals for SVR12 (FAS Population) ...................89
Table 14
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based 
on Hypothetical Numbers of Participants with AEs.............................................90
Table 15
Protocol-Required Safety Laboratory Assessments .............................................98
Table 16
Approximate Blood Volumes Collected.............................................................100
Table 17
Contraceptive Methods.......................................................................................116
 
 
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LIST OF FIGURES
Figure 1
Impact of Intrinsic Factors on the AUC of EBR and GZR...................................34
Figure 2
Trial Design ..........................................................................................................40
 
 
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1. Synopsis
Protocol Title:  
A Phase IIb Clinical Study to Assess the Pharmacokinetics, Safety, and Efficacy of the 
Combination Regimen of Elbasvir (EBR)/Grazoprevir (GZR) in Participants Aged 3 to less 
than 18 Years with Chronic Hepatitis C Infection
Short Title: 
The Combination Regimen of Elbasvir (EBR)/Grazoprevir (GZR) in Pediatric Participants
with Chronic Hepatitis C Infection
Objectives/Hypotheses and Endpoints:
In pediatric participants (aged 3 to 18 years) with chronic hepatitis C genotype (GT) 1 or 
GT4 infection with or without compensated cirrhosis. 

GT1-infected participants who are treatment-naïve (TN) or treatment-experienced (TE).  

GT4-infected participants who are TN and have hepatitis C virus (HCV) ribonucleic acid 
(RNA) 800,000 IU/mL.
Objective/Hypothesis
Endpoint
There are no hypotheses to be tested in this trial.
Primary

Objective:  To evaluate the steady-state 
EBR and GZR pharmacokinetics (PK)
in children and adolescents grouped by 
age.

Week 4 AUC0-24, maximum observed drug 
concentration (Cmax), drug concentration 
immediately pre-dose (Ctrough), and apparent 
clearance (CL/F).
Secondary

Objective:  To evaluate the safety and 
tolerability of 12 weeks of treatment 
with EBR/GZR in children and 
adolescents grouped by age.

Number of participants experiencing 
adverse events (AEs).

Number of participants discontinuing study 
drug due to AEs.

Objective:  To evaluate the efficacy of 
12 weeks of treatment with EBR/GZR 
in children and adolescents grouped by 
age, as assessed by the proportion of 
participants achieving sustained 
virologic response 12 weeks after the 
end of all study therapy (SVR12).

SVR12: defined as HCV RNA <lower limit 
of quantification (LLOQ) (either target 
detected, but unquantifiable [TD(u)] or 
target not detected [TND]) 12 weeks after 
the end of all study therapy.
 
 
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Overall Design:
Study Phase
Phase IIb
Clinical Indication
Treatment of HCV infection
Population
Pediatric participants aged 3 to less than 18 years of age 
with chronic Hepatitis C GT1 or GT4 infection.
Study Type
Interventional
Type of Design
Non-randomized, single arm, multiple cohort, uncontrolled
Type of Control
No active control
Study Blinding
Unblinded Open-label
Estimated Duration 
of Trial
The Sponsor estimates that the trial will require 
approximately 112 weeks from the time the first participant 
signs the informed consent/assent until the last participant’s 
last study-related phone call or visit.
Number of Participants:
Approximately 56 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
Pediatric participants with HCV GT1a without baseline 
NS5A resistance associated substitution (RAS) at position 
28, 30, 31, and/or 93 or GT1b/1-other infected TN or 
pegylated-interferon/ribavirin (PR) TE cirrhotic or 
noncirrhotic (NC). Pediatric participants infected with GT4 
(with HCV RNA 800,000 IU/mL) who are TN can also be 
enrolled.  Participants will receive EBR/GZR for 12 weeks
with 24 weeks of follow-up.  The trial will enroll 
participants into three Age Cohorts:
Age Cohort 1:  aged 12 years to less than 18 years
Age Cohort 2:  aged 7 years to less than 12 years
Age Cohort 3:  aged 3 years to less than 7 years
Age Cohort 1 will initially be administered Fixed Dose 
Combination (FDC) tablets (EBR 50 mg/GZR 100 mg).  
Age Cohort 2 and 3 will be administered pediatric 
formulation product (dosage to be informed by trial).  
 
 
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Participants in Mini Age Cohort 1 will receive a single 
placebo to EBR/GZR FDC tablet prior to allocation in order 
to demonstrate the ability to swallow a tablet the size and 
shape of the FDC.  This will also apply to participants in 
Expanded Age Cohort 1 if it is determined by PK analysis 
that Expanded Age Cohort 1 will also receive the adult FDC 
dose.
Duration of 
Participation
Each participant will participate in the trial for 
approximately 42.5 weeks from the time the participant 
signs the Informed Consent/Assent Form through the final 
contact.  After a screening phase of up to 45 days 
(6.5 weeks), each participant will receive the assigned 
treatment for approximately 12 weeks followed by 24 weeks 
of standard follow-up.  
A list of abbreviations used in this document can be found in Appendix 1. Study governance 
considerations are outlined in Appendix 3.
 
 
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2. Schedule of Activities (SoA)
Trial Period
Screening
Treatment
Follow-up
Unscheduled
Notes
Day 1
TW 2
TW 4
TW 6
TW 8
TW 10
TW 12
FW 4
FW 8
FW 12
FW 16
FW 20
FW 24
Unsched/
HCV VF 
Conf 
Visit
Early 
Discon 
Visit
Visit Number/Title
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Day 1 procedures to be performed prior to 1st morning 
dose unless otherwise specified. FW8, FW16, & FW20 
are via phone contact w/the participant or the 
participant’s legally acceptable representative to make 
sure he/she is doing well and FW24 visit reminder
Scheduled Hour, Day, 
Week, etc., and Window:
-45
NA
TW4: -3 to +3 days
All other TW: -7 to +7 days
-2 to +2 weeks
NA
Participants should be allocated within a 45 day 
screening window
Administrative Procedures
Informed Consent/assent
X
ICF: Each legally minor participant who assented at the 
beginning of the trial and become legally adult by the 
local/country law, during the trial period, will have to 
consent again. Study coordinator will check the 
participant’s age periodically.
Informed Consent for Future 
Biomedical Research (FBR)
X
Participation in FBR is voluntary and is not required in 
order to participate in the study.
Biological Parental Consent to 
Use and Disclose Personal 
Data
X
The height of the biological parents will be collected 
between screening and Day 1.  If biological parents are 
unable to be reached during that period the participant may 
continue in the trial.  Later attempts during the trial will be 
made to collect these data. Biological parental consent 
must be signed prior to obtaining, using, and disclosing 
their personal data.  The participant may continue in the 
study without these data and/or consent to obtain, use, and 
disclose parental personal data.
Inclusion/Exclusion Criteria
X
Participant Identification Card X
Medical History
X
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Only non-study HCV medications will be queried during 
Follow-up weeks
Treatment Allocation
X
Distribute Study Medication 
and Meal Diary (SMD) and 
review instructions
X
X
X
X
X
X
Review SMD
X
X
X
X
X
X
X
 
 
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Trial Period
Screening
Treatment
Follow-up
Unscheduled
Notes
Day 1
TW 2
TW 4
TW 6
TW 8
TW 10
TW 12
FW 4
FW 8
FW 12
FW 16
FW 20
FW 24
Unsched/
HCV VF 
Conf 
Visit
Early 
Discon 
Visit
Visit Number/Title
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Day 1 procedures to be performed prior to 1st morning 
dose unless otherwise specified. FW8, FW16, & FW20 
are via phone contact w/the participant or the 
participant’s legally acceptable representative to make 
sure he/she is doing well and FW24 visit reminder
Scheduled Hour, Day, 
Week, etc., and Window:
-45
NA
TW4: -3 to +3 days
All other TW: -7 to +7 days
-2 to +2 weeks
NA
Participants should be allocated within a 45 day 
screening window
Reconcile Study 
Medication/Assess 
Compliance with EBR/GZR
X
X
X
X
X
X
X
Drug Administration
Placebo to EBR/GZR (FDC) 
Administration
X
Placebo is given once prior to allocation to participants in 
Mini Age Cohort 1 to test whether the participant can 
swallow the tablet.  If it is determined by PK analysis that 
Expanded Age Cohort 1 will also receive the adult FDC 
dose, then placebo will be given once prior to allocation to 
participants in Expanded Age Cohort 1.  If the participant
cannot swallow the placebo tablet then they cannot be 
allocated into the trial.
Placebo tablets are different in color but identical in size 
and shape to the active EBR/GZR FDC tablets.
Dispense EBR/GZR (open 
label)
X
X
X
X
X
X
HCV Evaluations
HCV Genotype Determination X
Liver imaging
X
For cirrhotic participants only, imaging (eg, ultrasound) is 
required within 6 months prior to allocation to rule out 
HCC.
HCV RNA Level
X
X
X
X
X
X
X
X
X
If a participant is confirmed HCV viral failure during 
therapy (ie, break through), then the sample collection for 
HCV RNA is not needed for the early discontinuation 
visit. Leftover main study plasma from HCV RNA will be 
stored for FBR if the participant/legally acceptable rep 
consents to FBR.
 
 
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Trial Period
Screening
Treatment
Follow-up
Unscheduled
Notes
Day 1
TW 2
TW 4
TW 6
TW 8
TW 10
TW 12
FW 4
FW 8
FW 12
FW 16
FW 20
FW 24
Unsched/
HCV VF 
Conf 
Visit
Early 
Discon 
Visit
Visit Number/Title
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Day 1 procedures to be performed prior to 1st morning 
dose unless otherwise specified. FW8, FW16, & FW20 
are via phone contact w/the participant or the 
participant’s legally acceptable representative to make 
sure he/she is doing well and FW24 visit reminder
Scheduled Hour, Day, 
Week, etc., and Window:
-45
NA
TW4: -3 to +3 days
All other TW: -7 to +7 days
-2 to +2 weeks
NA
Participants should be allocated within a 45 day 
screening window
Plasma for HCV Viral 
Resistance/Resistance 
Associated Substitutions 
(RAS) 
X
X
X
X
X
X
Blood samples will be collected for HCV RAS testing at 
screening (to assess NS5A polymorphisms at amino acid 
positions 28, 30, 31, or 93); results for GT1a participants
must be available prior to allocation.  Viral resistance 
testing will be performed at screening to determine pre-
existing RASs to EBR and GZR.  Samples for resistance 
testing are also collected at follow-up visits and at the 
virologic failure confirmation visit (should this occur).  If 
a participant is confirmed HCV viral failure during therapy 
(ie, break through), then the sample collection for HCV 
RAS is not needed for the early discontinuation visit.  
Leftover main study plasma from HCV Resistance may be 
used for FBR only if the participant/legally acceptable 
representative signed for FBR consent.
Safety Procedures
Comprehensive Physical 
Examination
X
X
A comprehensive PE will be done at screening and 
baseline (Day 1). For all other visits a focused PE will be 
conducted when clinically indicated.
Focused Physical 
Examination
X
X
X
X
X
X
A comprehensive PE will be done at screening and 
baseline (Day 1). For all other visits a focused PE will be 
conducted when clinically indicated.
Height
X
X
X
X
X
Weight
X
X
X
X
X
X
X
12-Lead ECG
X
Vital Signs 
X
X
X
X
X
X
X
X
X
Includes pulse, blood pressure, respiratory rate, and body 
temperature.
 
 
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Trial Period
Screening
Treatment
Follow-up
Unscheduled
Notes
Day 1
TW 2
TW 4
TW 6
TW 8
TW 10
TW 12
FW 4
FW 8
FW 12
FW 16
FW 20
FW 24
Unsched/
HCV VF 
Conf 
Visit
Early 
Discon 
Visit
Visit Number/Title
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Day 1 procedures to be performed prior to 1st morning 
dose unless otherwise specified. FW8, FW16, & FW20 
are via phone contact w/the participant or the 
participant’s legally acceptable representative to make 
sure he/she is doing well and FW24 visit reminder
Scheduled Hour, Day, 
Week, etc., and Window:
-45
NA
TW4: -3 to +3 days
All other TW: -7 to +7 days
-2 to +2 weeks
NA
Participants should be allocated within a 45 day 
screening window
Height of Biological Parent
X
The height of the biological parents will be collected 
between screening and baseline.  If biological parents are 
unable to be reached during that period the participant may 
continue in the trial.  Later attempts will be made to collect 
these data. Biological parental consent must be signed 
prior to obtaining, using, and disclosing their personal 
data.  The participant may continue in the study without 
these data and/or consent to obtain, use, and disclose 
parental personal data.
Date of menarche (females 
only)
X
X
X
X
X
X
X
X
Review at each visit as appropriate in prepubescent female 
participants.  Once a date of menarche has been confirmed, 
the participant is considered to be a woman of childbearing 
potential (WOCBP) and the next 2 procedures 
(confirmation of birth control and urine pregnancy test) 
will apply.
Participant confirmation of 
birth control (WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
Urine Pregnancy Test 
(WOCBP only)
X
X
X
X
X
X
X
X
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
All AEs that occur after the consent/assent form is signed 
but before allocation must be reported by the investigator 
if they cause the participant 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 allocation through 14 days following cessation 
of treatment, all AEs must be reported by the investigator. 
The reporting timeframe for AEs meeting any serious 
criteria is described in Section 9.3.4. All protocol specified  
ECIs will be collected throughout the trial as listed in 
Section 9.3.7.
Coagulation
X
X
X
X
X
X
X
X
 
 
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Trial Period
Screening
Treatment
Follow-up
Unscheduled
Notes
Day 1
TW 2
TW 4
TW 6
TW 8
TW 10
TW 12
FW 4
FW 8
FW 12
FW 16
FW 20
FW 24
Unsched/
HCV VF 
Conf 
Visit
Early 
Discon 
Visit
Visit Number/Title
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Day 1 procedures to be performed prior to 1st morning 
dose unless otherwise specified. FW8, FW16, & FW20 
are via phone contact w/the participant or the 
participant’s legally acceptable representative to make 
sure he/she is doing well and FW24 visit reminder
Scheduled Hour, Day, 
Week, etc., and Window:
-45
NA
TW4: -3 to +3 days
All other TW: -7 to +7 days
-2 to +2 weeks
NA
Participants should be allocated within a 45 day 
screening window
Chemistry (complete)
X
X
X
X
X
X
X
X
X
Chemistry (abbreviated)
X
X
X
X
Abbreviated blood chemistry includes only ALT, AST, 
Alkaline phosphatase, T. Bili, Albumin, GGT, CPK
Hematology
X
X
X
X
X
X
X
X
X
X
HIV Serology
X
Urinalysis
X
X
X
X
X
X
Hepatitis B Virus
Evaluations
HBsAg
X
Anti-HBc
X
Patient-reported Outcome
Palatability and Acceptance 
Assessment
X
X
 
 
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Trial Period
Screening
Treatment
Follow-up
Unscheduled
Notes
Day 1
TW 2
TW 4
TW 6
TW 8
TW 10
TW 12
FW 4
FW 8
FW 12
FW 16
FW 20
FW 24
Unsched/
HCV VF 
Conf 
Visit
Early 
Discon 
Visit
Visit Number/Title
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Day 1 procedures to be performed prior to 1st morning 
dose unless otherwise specified. FW8, FW16, & FW20 
are via phone contact w/the participant or the 
participant’s legally acceptable representative to make 
sure he/she is doing well and FW24 visit reminder
Scheduled Hour, Day, 
Week, etc., and Window:
-45
NA
TW4: -3 to +3 days
All other TW: -7 to +7 days
-2 to +2 weeks
NA
Participants should be allocated within a 45 day 
screening window
Pharmacokinetics (PK)
EBR/GZR PK
X
X
X
X
X
Refer to Section 9.6.1 for details of PK sample collection 
timepoints for individual Age Cohorts. 
At Day 1 (Mini Age Cohort 1 only) and TW4 (all 
participants), an overnight stay is recommended to obtain 
PK samples over a 24-hour period (intensive PK).  
On all PK visits where a predose sample will be collected, 
the visit should occur prior to the participant’s regular time 
for taking their study medication and the participant should 
withhold their dose until after the visit.  For predose PK 
visits (ie, Day 1, Week 4, Week 8), if it is not feasible to 
schedule the visit prior to the participant’s regular time for 
taking their study medication, the participant should 
withhold their dose until reporting to the clinic.  The 
predose PK sample will be obtained and the dose will be 
administered at the clinic.
If HCV viral failure confirmation visit is after the end of 
therapy, do not collect the PK sample at this visit.
Meal Information for PK
X
X
X
 
 
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3. Introduction
MK-5172 is a fixed dose combination (FDC) of elbasvir (EBR:  an NS5A inhibitor) and 
grazoprevir (GZR:  an NS3/4A protease inhibitor) which has been approved for the treatment 
of chronic hepatitis C virus (HCV) infection in adults.
Study Rationale 
3.1
The purpose of this protocol is to assess pharmacokinetics (PK), safety, and efficacy of EBR 
and GZR in a population of pediatric HCV-infected participants aged 3 years up to 18 years. 
These data will be used to support dosing recommendations in the pediatric population.
EBR/GZR with and without ribavirin (RBV) has been developed and approved for adults 
with chronic hepatitis C genotype (GT) 1 or 4. Diverse adult populations have been studied 
including those with cirrhosis, human immunodeficiency virus type 1 (HIV-1) co-infection, 
end stage renal disease, and prior treatment failure. Efficacy rates exceed 90% regardless of 
these underlying co-morbidities or patient characteristics. 
Historically, children treated for HCV have had similar response rates as adults when given a 
similar regimen at the appropriate dose. The adult EBR/GZR PK model is highly predictive 
of clinical response (safety and efficacy in adults). Therefore pediatric patients are 
anticipated to have a similar safety and efficacy profile when given doses that achieve a 
similar exposure as that seen in adult patients. The intensive PK obtained at Treatment Week 
(TW) 4 will be used to update the adult population PK model to support dosing 
recommendations in the pediatric population. 
Background
3.2
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information including preclinical and clinical trial data for EBR/GZR.
Pharmaceutical and Therapeutic Background
3.2.1
MK-5172 is comprised of the following 2 direct-acting antiviral (DAA) HCV agents:

EBR (elbasvir, MK-8742) is an HCV NS5A inhibitor.

GZR (grazoprevir, MK-5172) is an HCV NS3/4A protease inhibitor.
Each MK-5172 FDC tablet contains EBR (50 mg) and GZR (100 mg) and is administered 
once daily (QD).  Participants in Mini Age Cohort 1 (oldest Age Cohort) will receive the 
FDC tablet.  This will also apply to participants in Expanded Age Cohort 1 if it is determined 
by PK analysis that Expanded Age Cohort 1 will also receive the adult FDC dose.  The two 
younger age cohorts will receive EBR pediatric formulation and GZR pediatric formulation.  
See Section 7.1 for a description and dosing instructions of the EBR/GZR pediatric 
formulation.
 
 
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Overview
3.2.1.1
Children with chronic hepatitis C are vulnerable to the same long-term health consequences 
as adults, including progressive liver damage, cirrhosis, and hepatocellular carcinoma (HCC). 
Developing an age appropriate, all-oral, well tolerated, short duration treatment regimen for 
HCV infected children is highly desirable for a population that is currently restricted to the 
current pediatric standard of care, pegylated-interferon with RBV (PR). In contrast to the 
current safe and convenient therapies available to adults, PR most commonly requires 48 
weeks of therapy, with weekly injections. The therapy has many adverse events (AEs),
including flu-like symptoms, anemia, and impairment of growth, while achieving a sustained 
virologic response (SVR) of only ~50%.
Epidemiology of Chronic Hepatitis C
Worldwide it is estimated that 3 to 4 million people are newly infected with HCV annually 
and 170 million are chronically infected [Hanafiah, K. M., et al 2013]. For those who are 
chronically infected, there is a lifetime risk of developing progressive liver damage, cirrhosis,
and liver cancer. In the United States (US), approximately 2.2 to 3.2 million persons are 
estimated to have chronic HCV infection based on a national survey of the civilian, non-
institutionalized population [Denniston, M. M., et al 2014].
Of the patients infected with HCV, many are children.  Seroprevalence data for children aged 
1 to 15 years in the US and in Western Europe are 0.6% and 0.8-1.3%, respectively. The 
prevalence is similar to the 20-30 year old population in each of these regions [Hanafiah, K. 
M., et al 2013]. Most studies that have investigated the seroprevalence of HCV in childhood
fail to investigate whether HCV antibody-positive children are also HCV viremic. 
Extrapolating from adult studies, it is estimated that approximately 50-80% of those with 
positive HCV antibody are chronically infected and viremic [Aach, R. D., et al 2000] [Vogt, 
M., et al 1999].
Modes of Transmission of HCV in Pediatrics:  Vertical transmission of HCV infection is the 
most common route of acquiring HCV infection in infants and children. In the US, there are 
approximately 7500 new cases per year from vertical transmission [Mack, C. L., et al 2012].
Mother to child transmission among HCV mono-infected women is approximately 5%. 
Although the risk is low for an individual, HCV infection is common, and thus accounting 
for a significant number of new infections in newborns annually. Among HIV-1/HCV co-
infected women, vertical transmission can be as high as 25%. Other modes of transmission 
in pediatrics, include household contacts and most importantly, especially among 
adolescents, acquisition due to high risk behaviors such as injection drug use, tattoos, and 
piercings.  For children younger than the age of 3 years, results from a prospective study 
following a birth cohort have shown that 17% had spontaneous viral clearance by age 2 and 
24% had clearance by age 3 [England, K., et al 2005] [Narkewicz, M. R., et al 2007]. It is 
because of this early predilection for spontaneous clearance that treatment trials for children 
with chronic HCV do not include the age group from birth to age 3 years.
Therapy for Chronic Hepatitis C
The therapeutic goal of treatment of hepatitis C is the eradication of the virus with a halt in 
the progression of liver damage. Similarities in the treatment response characteristics of 
 
 
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chronic HCV in adult and pediatric populations support the premise that therapeutic advances 
demonstrated in adults will likely be applicable to children. Historically, children have 
benefited from a similar approach to treatment of chronic HCV as adults [Kelly, D. A., et al 
2011] [Wirth, S., et al 2010]. As of 2017, high efficacy was observed in a Phase II trial and 
supported approval in children aged 12 to 18 of an all-oral DAA regimen of
sofosbuvir/ledipasvir [Balistreri, W. F., et al 2016]. The observed efficacy in the pediatric 
population in this study was similar to that seen among adults treated with the same regimen. 
Children should benefit from the new generation of HCV treatments that are all oral, safe,
and effective. These advances are substantial improvements compared to the current
standard of care for children, which is 24 to 48 weeks of PR.
It is anticipated that EBR/GZR dosed to provide the same PK exposures achieved in the adult 
population will be an effective and safe pediatric HCV therapy for GT1 and GT4 infection, 
as indicated in adults.
Summary of Clinical Experience with EBR/GZR
3.2.2
Summary of Clinical Experience with EBR/GZR in Adults
3.2.2.1
EBR/GZR (50 mg/100 mg) ± RBV has demonstrated a favorable safety and efficacy profile 
in a diverse adult (≥18 years of age) population that included patients with compensated 
cirrhosis, chronic kidney disease, and HIV-1/HCV co-infection [Ferrante, S., et al 2015] 
[Lawitz, E., et al 2014] [Sulkowski, M., et al 2014] [Zeuzem, S., et al 2015] [Rockstroh, J. 
K., et al 2015] [Forns, X., et al 2015] [Buti, M., et al 2016] [Roth, D., et al 2015].
The data below provides an overview of the primary efficacy endpoint, sustained virologic 
response 12 weeks after the end of all study therapy (SVR12), supporting final adult dosing 
and administration guidance. 

High response rates in GT1 and GT4 treatment-naïve (TN) subjects (SVR12 of 94-
96%) treated with a 12-week, RBV free regimen.  

High response rates in GT1, and GT4 PR-treatment-experienced (TE) relapsers 
(SVR12 of 100%) treated with a 12-week, RBV free regimen. 

High response rates in GT1b PR-TE subjects who failed prior PR therapy due to 
either null or partial response (SVR12 100%) when treated with a 12-week, RBV free 
regimen.

High response rates in all GT1 and GT4 subjects treated for 16 weeks with a regimen 
of EBR/GZR with RBV.

Response rates that are comparable in Childs-Pugh A cirrhotics and noncirrhotics.
In addition to the data above, a secondary analysis has been performed that demonstrates that 
incorporation of resistance testing for GT1a-infected participants can be used to optimize 
efficacy outcomes in the minority of GT1a-infected patients with baseline NS5A resistance-
associated substitutions (RASs) who may have suboptimal efficacy with a 12-week 
EBR/GZR regimen.  These data are shown below in Table 1 shows the integrated data and 
observed efficacy from the adult Phase II/III EBR/GZR development program when RAS 
 
 
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testing is incorporated into dosing and administration guidance for the GT1a population.  The 
populations included in these integrated data include TN and TE patients with compensated 
cirrhosis, advanced chronic kidney disease, and both mono HCV infected and HIV-1/HCV 
co-infected patients.
Table 1
SVR12 of EBR/GZR (50 mg/100 mg) – MK-5172 Protocols 035, 048, 052, 060, 
061, and 068
Regimen
SVR12
OVERALL
Study Population
N
n
%
12 wks no RBV
1a TN or PR-TE
Without BL RASs 28, 
30, 31, 93†
450
441
98.0%
1b TN or PR-TE
301
297
98.7%
4 TN
55
54
98.2%
16 wks + RBV
1a TN or PR-TE
With BL RASs 28, 30, 
31, 93†
6
6
100%
4 PR-TE
8
8
100%
Based on the modified Full Analysis Set population that excludes subjects who discontinued 
from the study for non-treatment-related reasons.
† In GT1a subjects, subjects without baseline NS5A sequencing information are excluded.
N: Number of subjects in population.
n: Number of subjects who achieved SVR12.
BL = baseline; GT = genotype; PR = pegylated-interferon with RBV; RAS = resistance-
associated substitution; RBV = ribavirin; SVR12 = sustained virologic response 12 weeks after 
the end of all study therapy; TE = treatment-experienced; TN = treatment-naïve.
Recommendations for dosing and administration of EBR/GZR have incorporated viral load, 
GT, treatment history, and GT/subtype and presence of baseline NS5A RASs. The 
recommendations adopted vary by region (eg, US vs European Union [EU]), in part due to 
the regional variability in availability of commercial RAS testing. In the US, the addition of 
RBV and lengthening the treatment duration to 16 weeks are recommended for the small 
subset of GT1a-infected patients with baseline RASs. In the EU, the addition of RBV and 
lengthening the treatment duration to 16 weeks are recommended for GT1a-infected patients 
with high viral load at baseline.
In this trial, in order to provide a simple regimen of 12 weeks without RBV (and applicable 
to both the EU and US prescribing information), only participants with HCV GT1 or with 
GT4 and HCV ribonucleic acid (RNA) 800,000 IU/mL will be enrolled. In addition, for 
those with GT1a infection, RAS testing will be used and only those without a baseline NS5A 
RAS at position 28, 30, 31, and/or 93 will be enrolled. 
 
 
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PK Background and Strategy
3.2.3
In the Phase II/III EBR/GZR development program, population PK, PK/pharmacodynamics 
(PD), and physiologically based pharmacokinetic (PBPK) modeling supported the proper 
dosing for a safe and efficacious adult regimen. The PK/PD modeling for safety and efficacy 
were used to define the clinical comparability bounds, based on an area under the time-
concentration curve (AUC) of [0.4, 5.0] for GZR and [0.5, 2.0] for EBR. Application of 
these models and clinical bounds will be applied to this pediatric trial to support dosing of 
children aged 3 years up to 18 years.
EBR/GZR Metabolism
3.2.3.1
EBR elimination in humans is via a combination of excretion of parent compound as well as 
oxidative metabolism (mediated via cytochrome P4503A [CYP3A]) into feces, with minimal 
elimination into urine. EBR is a substrate of CYP3A and P-glycoprotein (P-gp) (minor 
contribution). EBR exhibits linear and dose-proportional PK across the 10-100 mg dose 
range. HCV patients and healthy participants receiving 50-100 mg QD have comparable 
plasma exposures at steady-state. Following administration of EBR 50 mg QD to HCV 
patients, the geometric mean (GM) apparent terminal half-life is ~24 hours and steady-state 
is achieved within 5 days. EBR exhibits moderate bioavailability (32%), with a time to 
maximum concentration (Tmax) of ~3 hours. 
GZR is eliminated via biliary excretion in the form of oxidative metabolism (mediated via 
CYP3A4) and as GZR (likely via biliary efflux transport) in humans. GZR is a substrate of 
CYP3A4, P-gp (minor contribution), and the liver uptake transporters organic anion-
transporting polypeptide (OATP) 1B1/3. GZR has non-linear and greater than dose-
proportional plasma PK in humans, likely attributed to saturation of CYP3A metabolism and 
OATP1B uptake at higher doses/exposures. Steady-state GZR plasma PK is ~2-fold greater 
in HCV patients than in healthy participants. Following administration of GZR 100 mg QD 
to HCV patients, the GM apparent terminal half-life is ~31 hours. In HCV patients, the HCV 
viral load decline associated with the first few weeks of administration of EBR/GZR results 
in decreased GZR exposure (likely due to improved liver function); therefore, steady-state in 
patients is achieved by about TW4. GZR exhibits moderate bioavailability (10-40%), with a 
Tmax of ~2 hours.
Modeling and Simulation in Adults
3.2.3.2
Population PK, PK/PD, and PBPK models have been developed for EBR and GZR in support 
of the adult filings.
GZR is associated with exposure-dependent alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) elevations that typically occur around TW 8-10.  The efficacy 
endpoint for EBR and GZR of SVR12 is also exposure-dependent.  Logistic regression 
PK/PD models for safety and efficacy have been established using adult data.  During PK/PD 
model development, AUC was found to be the most predictive PK parameter for both safety 
and efficacy.  Using the PK/PD models, the therapeutic bounds, based on AUC, were defined 
for EBR [0.5, 2.0] and GZR [0.4, 5.0].  
 
 
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Based on the EBR and GZR population PK models (N=3214 total patients and healthy 
participants), the impact of various intrinsic factors on the plasma PK of EBR and GZR were 
determined and are demonstrated in the forest plot in Figure 1. Several intrinsic factors 
affected EBR and/or GZR PK, but most changes were within the clinical comparability
bounds, and therefore not clinically relevant. For example, low body weight (~37-66 kg) had 
an ~20% increase in AUC for both EBR and GZR, but the increase was well within the 
therapeutic window for both compounds. EBR/GZR are contraindicated in patients with 
Child-Pugh B and C cirrhosis.
PBPK models for EBR and GZR were previously developed, which incorporated the key 
absorption, distribution, metabolism, and excretion (ADME) and PK properties for both 
compounds (eg, OATP1B saturation for GZR) [M&S Analysis Rpt 2015][M&S Analysis Rpt 
2015]. This modeling provided supportive mechanistic evidence and interpretation for the 
effect of intrinsic factors (eg, HCV infection, cirrhosis, Asian ethnicity) on the PK of EBR 
and GZR.
These data and models supported the approval of EBR/GZR in adults infected with HCV 
GT1 and/or 4 and will be updated and used to select appropriate doses for the pediatric 
population.
Figure 1
Impact of Intrinsic Factors on the AUC of EBR and GZR
The shaded area of Figure 1 represents the region of no clinically relevant effect.
 
 
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Preclinical Trials Supporting a Pediatric Clinical Study
3.2.4
Prior to initiation of the pediatric clinical trial, pre- and postnatal developmental EBR and 
GZR monotherapy studies have been conducted and have not identified findings of concern 
in rats, rabbits, and dogs. In rats, dosing did not result in any effects on development, 
growth, behavior, reproductive performance, or fertility following oral administration to 
female rats from Gestation Day 6 through Lactation Day 20. In these studies, the highest 
maternal GZR exposure, area under the time-concentration curve over 24 hours (AUC0-24) = 
155 μM•hr represents approximately 31-fold the GZR clinical target AUC0-24 of 5 μM•hr in 
humans, and the highest maternal EBR exposure, AUC0-24 = 21.8 μM•hr (measured in 
pregnant females in the embryofetal developmental and toxicokinetic [TK] study in rats) 
represents approximately 16-fold the EBR clinical target AUC0-24 of 1.35 μM•hr in humans. 
Additionally, EBR and GZR placental and lactational transfer studies in rats and EBR and 
GZR placental transfer studies in rabbits showed distribution of EBR or GZR into rat and 
rabbit fetal plasma and rat milk. TK parameters obtained at different animal ages in the 
repeat-dose EBR and GZR monotherapy studies in rats and dogs did not indicate age-related 
differences in plasma systemic exposures. In rats, the first TK evaluation was performed in 
7-week old animals (which corresponds to an approximate human age of 12 years), and the 
last TK evaluation was performed in 18-week old animals (adult animals). In dogs, the first 
TK evaluation was performed in 26- (EBR) or 32-week old (GZR) animals (which 
corresponds to an approximate human age of 15-17 years), and the last TK evaluation was 
performed in 56- (EBR) or 78-week old (GZR) animals (adult animals). 
In conclusion, pre-clinical animal studies support the use of EBR and GZR in children.
Benefit/Risk Assessment
3.3
It cannot be guaranteed that participants 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 I-III studies, 1,234 healthy volunteers, 66 non-HCV-infected persons with liver or 
kidney impairment, and 2,704 HCV-infected participants 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 
(100 mg), high efficacy and a favorable safety profile have been demonstrated in 
approximately 2,000 participants, including participants with cirrhosis, HIV-1/HCV-
coinfection, chronic kidney disease, and history of prior HCV treatment failure.
ALT elevation is a safety signal associated with increased GZR exposures.  Because of this, a 
plan has been developed to monitor for the signal.  This protocol includes predefined 
monitoring of Events of Clinical Interest (ECI) (Section 9.3.7), specification of ALT levels 
that would require discontinuation of study treatment (Section 8.1), and predefined criteria 
for late ALT elevations and hepatic ECI which will result in a pause in enrollment 
(Section 5.4.2.3.2).  
 
 
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Additional details regarding specific benefits and risks for participants participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
4. Objectives/Hypotheses and Endpoints
In pediatric participants (aged 3 to 18 years) with chronic hepatitis C GT1 or GT4 infection 
with or without compensated cirrhosis.

GT1-infected participants who are TN or TE.

GT4-infected participants who are TN and have HCV RNA 800,000 IU/mL.
Objective/Hypothesis
Endpoint
There are no hypotheses to be tested in this trial.
Primary

Objective:  To evaluate the steady-
state EBR and GZR PK in children and 
adolescents grouped by age. 

Week 4 AUC0-24, maximum observed 
drug concentration (Cmax), drug 
concentration immediately pre-dose 
(Ctrough), and apparent clearance 
(CL/F).
Secondary

Objective:  To evaluate the safety and 
tolerability of 12 weeks of treatment 
with EBR/GZR in children and 
adolescents grouped by age.

Number of participants experiencing 
AEs.

Number of participants discontinuing 
study drug due to AEs.

Objective:  To evaluate the efficacy of 
12 weeks of treatment with EBR/GZR 
in children and adolescents grouped by 
age, as assessed by the proportion of 
participants achieving SVR12.

SVR12:  defined as HCV RNA <lower 
limit of quantification (LLOQ) (either 
target detected, but unquantifiable 
[TD(u)] or target not detected [TND]) 
12 weeks after the end of all study 
therapy.
Exploratory

Objective:  To evaluate the efficacy of 
12 weeks of treatment with EBR/GZR 
in children and adolescents grouped by 
age, as assessed by the proportion of 
participants achieving sustained 
virologic response 24 weeks after the 
end of all study therapy (SVR24).

SVR24:  defined as HCV RNA <LLOQ 
(either TD[u] or TND) 24 weeks after 
the end of all study therapy.
 
 
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Objective/Hypothesis
Endpoint

Objective:  To evaluate the emergence 
of NS3 and NS5A RASs in participants 
with virologic failure.

Treatment-emergent RASs to 
EBR/GZR.

Objective:  To evaluate the palatability 
and acceptability of treatment with 
EBR/GZR.

Score on a palatability scale.

Objective:  To evaluate growth in 
children treated with EBR/GZR.

Changes from baseline for height and 
weight by age.
5. Study Design 
Overall Design 
5.1
This is a non-randomized, single arm, multiple cohort, multi-site, open-label Phase IIb trial 
of EBR/GZR in pediatric participants aged 3 to less than 18 years with chronic HCV
infection GT1b/1-other; GT1a without baseline NS5A RAS at positions 28, 30, 31, and/or 
93; or GT4, to be conducted in conformance with Good Clinical Practice.
The goals of this Phase IIb trial are: 1) to define doses for EBR/GZR in children by 
assessing plasma PK concentrations that target a similar PK to that seen in adults receiving 
EBR 50 mg and GZR 100 mg. The PK target has been defined by the clinical PK 
comparability bounds, within which there were no clinically important differences for safety 
and efficacy; 2) to establish the tolerability, safety, and efficacy of the combination therapy 
in the pediatric HCV-infected population.  All participants will receive EBR/GZR without 
RBV for 12 weeks.
The trial will enroll participants into three Age Cohorts:
1. Age Cohort 1 (aged 12 years to less than 18 years) 
2. Age Cohort 2 (aged 7 years to less than 12 years)
3. Age Cohort 3 (aged 3 years to less than 7 years)
Each Age Cohort starts with a Mini Age Cohort of 7 participants before enrolling additional 
participants into the Expanded Age Cohort. The enrollment requirements for the Mini and 
Expanded Age Cohorts are shown in Table 2.
 
 
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Table 2
Enrollment Requirements for Each Age Cohort
Age
Cohort
Age
Range
Enrollment Requirements
Mini Cohort
Expanded Cohort
1
12 to 18 
years

N=7 (to ensure at least 6 participants
with evaluable PK)

At least 2 participants aged 14 
years

N=~15

At least 3 participants aged 12 to 14 
years

At least 3 participants aged 16 to 18 
years
2
7 to 12 years

N=7 (to ensure at least 6 participants
with evaluable PK)

At least 2 participants aged 9 years

N=~20

At least 5 participants aged 7 to 12 years

At least 5 participants aged 3 to 7 years
o
At least 2 participants aged 5 years
3
3 to 7 years

N=7 (to ensure at least 6 participants
with evaluable PK)

At least 2 participants aged 5 years
The enrollment of participants will occur as follows:
1. Mini cohorts of the two oldest Age Cohorts will enroll in the first wave of participants.
a.
Mini Age Cohort 1
b. Mini Age Cohort 2
Enrollment into Mini Age Cohort 2 will follow Mini Age Cohort 1 by 2 to 3 weeks to allow 
time to review Day 1 PK (AUC) in a minimum of 6 participants of Mini Age Cohort 1 before 
enrolling Mini Age Cohort 2. The Week 4 intensive PK from the first two Mini Age Cohorts 
(N=~14), in addition to the Day 1 and Week 8 sparse PK, will be used to update the 
population PK and PBPK models to select optimal doses for Mini Age Cohort 3 and 
Expanded Age Cohort 1.
2. Mini Age Cohort 3 and Expanded Age Cohort 1 will enroll in the second wave of 
participants after optimal doses have been selected based on PK modeling results from 
the first wave of participants. 
a.
Expanded Age Cohort 1 will enroll following completion of the PK modeling
analyses; dosing will use the proposed dose for each component, EBR and GZR,
and dose recommendation by weight bands will be used.
b. Mini Age Cohort 3:  PK modeling and simulation will be used to propose dosing 
for each component, EBR and GZR. Dose recommendation by weight bands will 
be used for Mini Age Cohort 3.
 
 
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Data from the three Mini Age Cohorts and from Expanded Age Cohort 1 will be used to 
update the population PK and PBPK models in order to propose doses for Expanded Age 
Cohorts 2 and 3.
3. Expanded Age Cohorts 2 and 3 (Expanded Age Cohort 2/3)
a.
Expanded Age Cohorts 2 and 3 are combined as a single group Age Cohort 2/3. 
This age cohort will enroll following completion of the updated PK modeling
analyses that incorporates PK data from all previous cohorts, including all 21
participants from the three Mini Age Cohorts and all 15 participants from 
Expanded Age Cohort 1. Dosing of Expanded Age Cohort 2/3 will use the 
modeling and simulation proposed dose for each component, EBR and GZR.
While age cohorts are used for the purposes of enrollment, dose recommendations by weight 
bands will be used for Mini Age Cohort 3 and the Expanded Age Cohorts. Weight bands will 
be determined based on the PK analyses.
Following the conclusion of this study and the Clinical Study Report (CSR) for the study, a
final PK model will be developed that includes all PK data from participants aged 3 years up 
to 18 years, in addition to relevant adult data previously collected in the program.  The final 
model and proposed pediatric dosing regimen will be summarized in a separate report.
PK samples will be collected in all pediatric participants according to the sampling scheme in 
Table 9.  At Day 1 (Mini Age Cohort 1 only) and TW4 (all participants), an overnight stay is 
recommended to obtain PK samples over a 24-hour period (intensive PK).
In order to reduce PK variability, enrollment in the Mini Age Cohorts will be limited to 
noncirrhotic participants of non-Asian Race who are not currently taking methadone or 
strong CYP3A inhibitors.  The Mini Age Cohorts will also exclude participants below a 
weight as described in the inclusion/exclusion criteria; the Expanded Age Cohorts will enroll 
a broader population as described in the inclusion/exclusion criteria.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure 
are provided in Section 9 – Study Assessments and Procedures.
This trial will use an independent, external Data Monitoring Committee (eDMC) to monitor 
safety.  Periodic safety analyses will be conducted and reviewed by the eDMC at regular 
intervals as outlined in the eDMC Charter.
The eDMC will make recommendations to the Sponsor to continue, modify, or end the trial 
according to Section 10 - Statistical Analysis Plan (SAP).
 
 
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Study Diagram
5.1.1
The trial design is depicted in Figure 2.
Figure 2
Trial Design
Number of Participants
5.2
Approximately 56 participants will be allocated as described in Section 10.1.
Beginning and End of Study Definition
5.3
The overall study begins when the first participant (or the participant’s legally acceptable 
representative) signs the informed consent/assent form (ICF).  The overall study ends when 
the last participant completes the last study-related phone-call or visit, withdraws from the 
study or is lost to follow-up (i.e. the participant is unable to be contacted by the investigator).
Clinical Criteria for Early Study Termination
5.3.1
1. The eDMC recommends termination of the trial and the Executive Oversight 
Committee (EOC) agrees per Appendix 3 – Committee Structure - Data Monitoring 
Committee, Appendix 3 – Study and Site Closure, or as stated in the DMC charter.
2. The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial
population as a whole is unacceptable.  
 
 
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Scientific Rationale for Study Design 
5.4
Rationale for Study Population
5.4.1
Participants in this trial will include noncirrhotic or compensated cirrhotic pediatric 
participants who are either TN or PR-TE and infected with HCV GT1b/1-other; or with HCV 
GT1a without a baseline NS5A RAS at position 28, 30, 31, and/or 93; or TN and infected 
with GT4 and HCV RNA 800,000 IU/mL; and who meet other inclusion/exclusion criteria 
as described in Section 6.  Because PK exposure is independent of GT, the information 
obtained and doses proposed in this trial can be extrapolated to other GTs for final dosing 
and administration guidance. The final administration recommendations with regards to 
duration and need for RBV will be similar to the adult recommendations. Children enrolled 
in this trial will all be eligible for a 12-week RBV-free regimen, ie, this trial will enroll 
participants who are HCV GT1b/1-other; HCV GT1a without a baseline NS5A RAS at 
position 28, 30, 31, and/or 93; or are HCV GT4 with HCV RNA 800,000 IU/mL. 
Rationale for Endpoints
5.4.2
Efficacy Endpoints
5.4.2.1
The measurement for efficacy in this trial is the plasma HCV RNA level.  Long-term 
suppression of HCV RNA, typically reported as SVR, has been associated with improved 
outcomes in subjects with chronic 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 [Alberti, A. 2011].
The evaluation of efficacy in this trial is based on SVR12, the same endpoint used for all 
investigational and approved DAAs.  Since a high degree of concordance has been observed 
between SVR12 and SVR24 [Martinot-Peignoux, M., et al 2010], SVR12 is used as the primary 
endpoint for registration of DAAs.  For this trial, an evaluation of efficacy based on SVR24
will be an exploratory analysis [Chen, J., et al 2013].
Measurement of HCV RNA
5.4.2.1.1
HCV RNA plasma levels will be measured using the Roche COBAS® AmpliPrep/COBAS®
TaqMan® HCV Test, v2.0 on blood samples drawn from each participant at various time 
points prior to, during, and after dosing, as indicated in the SoA (Section 2).  
They are also used to identify participants who meet HCV virologic failure criteria.  HCV 
RNA levels are described as detailed in Table 3.
Table 3
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
 
 
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Definition of Efficacy Endpoints
Efficacy will be defined at different timepoints during the trial. Specific endpoints are:

SVR12 :  Participant has HCV RNA <LLOQ (either TD[u] or TND) 12 weeks after the 
end of all study therapy.

SVR24 : Participant has HCV RNA <LLOQ (either TD[u] or TND) 24 weeks after the 
end of all study therapy.
Definition of Virologic Failure
Lack of efficacy at different timepoints in the trial will be categorized as:

Non-response:  Participant has HCV RNA detected at end of treatment without HCV 
RNA <LLOQ having been achieved while on treatment (note that breakthrough is 
captured below).

Rebound:  Participant 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:  Participant 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:  Participant 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.
Viral Resistance Measurements
5.4.2.1.2
In this trial, RASs are defined as specific genetic substitutions that generate viral proteins 
that maintain function, but have reduced susceptibility to a DAA. As the presence of certain 
HCV RASs can lead to treatment failure, they are one of the most important considerations 
when treating with a DAA. Those genetic substitutions that impact efficacy outcomes may 
be present at baseline (ie, prior to therapy), or they may be treatment-emergent (ie, not 
detected at baseline, but which emerge and are selected over the course of therapy).
Blood samples for viral resistance assays are collected at:

Screening: Testing will be done to assess for the presence of NS5A and NS3 RASs that 
have been associated with reduced efficacy for NS5A compounds (eg, ledipasvir, 
daclatasvir, EBR) or protease inhibitors (eg, simeprevir, boceprevir, telaprevir, GZR). In
GT1a-infected participants, presence of NS5A RAS at amino acid position 28, 30, 31,
and/or 93 will be used for enrollment criteria as outlined in inclusion/exclusion.

Virologic failure and/or selected follow-up visits:  To better understand the emergence 
and natural history of RASs in association with virologic failure, samples will be 
obtained at virologic failure confirmation visits, Follow-up Week (FW) 4, FW12, and 
FW24.  RASs will be assessed for any participant who has detectable virus above
1000 IU/mL and has met an HCV virologic failure criteria.  Blood samples for resistance 
testing are also collected at all visits following confirmation of virologic failure to the end 
 
 
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of the trial.  To limit the risk of RASs, participants are not allowed to have monotherapy 
with EBR or GZR in this protocol.
Participants who have met virologic failure criteria, will be offered follow-up in a 3-year 
long-term follow-up protocol, MK-5172 Protocol 017, to determine the persistence of RASs 
and to determine time course of reversion to wild-type.
Palatability and Acceptance Assessment Endpoint
5.4.2.2
Adherence to treatment for chronic HCV infection is necessary for participants to achieve 
SVR.  Palatability may play an important role in adherence to HCV treatment in the pediatric 
population.  Palatability is an important element in the determination of acceptability, and 
encompasses a product’s smell, taste, aftertaste, and texture. Acceptability, including 
palatability, of EBR/GZR will be assessed in all participants using the Palatability 
Acceptance Assessment (PAA).  In previous studies, the most commonly reported 
assessment measured palatability preference using a visual analog scale that was modified by 
including a facial hedonic scale (FHS; facial expression scale depicting various degrees of 
pleasure) [Thompson, C., et al 2015]. The five-point FHS for taste is one of the most 
frequently reported types of palatability assessments used in pediatric clinical trials.
Safety Endpoints
5.4.2.3
General Safety
5.4.2.3.1
The safety and tolerability of EBR in combination with GZR are 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 SoA.  Adverse events are graded and recorded according to Section 9.3.  Participants may 
be asked to return for unscheduled visits in order to perform additional safety monitoring.
Late ALT Elevations and Hepatic ECI Resulting in a Pause in Enrollment
5.4.2.3.2
As discussed in Section 3.2.3.2, ALT elevation is a safety signal associated with increased 
GZR exposures. In this trial, it is expected that the safety profile should match adults. 
Therefore, safety of an Age Cohort will be based on the following criteria.
If ≥3 participants receiving a given EBR/GZR dose in an Age Cohort experience any of the 
following, allocation of new participants into the Age Cohort will be paused. Participants
that are tolerating treatment with that study drug combination may continue to receive study 
therapy, but no additional participants will be enrolled until the Sponsor has reviewed all 
safety and PK data of participants receiving the drug combination.

ALT or AST increases to >500 IU/L and is confirmed with repeat test immediately.

ALT or AST increases to 3× baseline and/or nadir, is >100 IU/L, and there is a 
simultaneous increase in total bilirubin >2× upper limit of normal (ULN) and/or 
international normalized ratio (INR) is increased from the baseline value and is >1.5 
(unless the participant is on anticoagulation).
 
 
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
ALT or AST increases to 3× baseline and/or nadir, is >100 IU/L, and there is a 
simultaneous increase in total bilirubin >2× ULN and/or INR is increased from the 
baseline value and is >1.5 (unless the participant is on anticoagulation).

The participant’s alkaline phosphatase increases to >3× ULN, there is a simultaneous 
increase in total bilirubin >2× ULN and other causes of elevated alkaline phosphatase are 
excluded.

The participant’s alkaline phosphatase increases to >5× ULN and other causes of 
elevated alkaline phosphatase are excluded.

The participant has a life-threatening clinical or laboratory AE or an AE that results in or 
prolongs an existing inpatient hospitalization, or death, that is assessed to be study drug-
related.
In the event this pause criterion is met, the eDMC will be notified and enrollment into the 
Age Cohort will be paused and PK-PD analysis will be performed to re-assess and identify 
an appropriate safety boundary for the pediatric population.
Growth
5.4.2.3.3
Growth assessments will include height and weight measurements of each participant
outlined in the SoA. The height of both biological parents will be obtained to determine the 
participant’s growth potential.  The participant may continue in the study without these data 
and/or consent to obtain, use, and disclose parental personal data.
Pharmacokinetic Endpoints
5.4.2.4
The primary PK endpoints for GZR and EBR are steady-state plasma AUC0-24, Cmax, Ctrough, 
and CL/F. Additional steady-state PK parameters such as plasma concentration immediately 
predose (Ctrough) and Tmax will also be estimated.
Future Biomedical Research
5.4.2.5
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
Future Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants 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 Appendix 6  –
Collection and Management of Specimens for Future Biomedical Research.
 
 
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Rationale for the Use of Comparator/Placebo
5.4.3
This is an open-label trial of the safety and efficacy of the combination of EBR and GZR.
The current pediatric standard of care is PR. Comparisons will be made to historic efficacy 
rates and safety profile in pediatric PR clinical trials [Kelly, D. A., et al 2011] [Wirth, S., et 
al 2010] [McHutchison, J. G., et al 2009].
As discussed in Section 3.2.2.1, the response rates for HCV in children are comparable to 
response rates in adults. With an all-oral DAA regimen, the medications directly interact 
with the virus and are not impacted significantly by host response. This is most clearly 
demonstrated by the minimal impact of race, gender, and IL28B status on efficacy of 
EBR/GZR in the adult program (see IB). Safety profile will be established without a 
comparator. PR has a well characterized safety profile in both adults and children. 
Justification for Dose 
5.5
Starting Dose for This Trial
5.5.1
Mini Age Cohort 1 (aged 12 to less than 18 years) will start with the adult FDC EBR/GZR 
(50 mg/100 mg) dose.  Mini Age Cohort 2 (aged 7 to less than 12 years) is planned to start 
with the pediatric formulation of EBR/GZR (30 mg/60 mg).  Based on the PK analyses from 
Mini Age Cohort 1 and 2, dosing recommendations will be provided by weight bands for 
Mini Age Cohort 3 and Expanded Age Cohort 1.  Similarly, as described below, dosing 
regimens for Expanded Age Cohorts 2/3 will be developed based on the population PK
model and dosing recommendations will be provided by weight bands.  Weight bands for 
Mini Age Cohort 3 and the Expanded Age Cohorts will be determined by PK analyses. See 
Section 7.1 for a description of EBR/GZR adult FDC dose versus the pediatric formulation.
Dose Justifications 
5.5.1.1
Since the relationship between exposure and safety and efficacy is well-established for EBR 
and GZR in adults, achieving AUC exposures in pediatric patients that is similar to adults is 
anticipated to result in similar safety and efficacy profile as adults. Therefore, the target dose 
in each pediatric age group is one that yields AUC exposures similar to that obtained in 
adults who receive EBR (50 mg) and GZR (100 mg). 
Similarity between pediatric and adult AUC will be assessed based on the GM AUC values. 
The pediatric GM AUC should be approximately within 2-fold that estimated in adults for 
EBR and GZR. Additionally, the pediatric GM AUC range should fall within the defined 
clinical bounds for EBR [0.5, 2.0] and GZR [0.4, 5.0]. Therefore, the pediatric GM AUC for 
each age group should fall within ~0.81-8.6 µM*hr for GZR and ~1.1-4.4 µM*hr for EBR, 
which corresponds to the AUC associated with the lower and upper clinical bounds. 
Otherwise, the dose will be adjusted for the Expanded Age Cohorts so that the AUC falls 
within the clinical bounds.
For EBR and GZR, CYP3A, P-gp, and OATP1B1/3 are the known enzymes/transporters to 
consider when thinking about potential age-related PK changes in the pediatric population.  
Children >7 years of age have mature CYP3A enzymes that are comparable to those of adults 
[Ince, I., et al 2013], with minor incremental maturation of CYP3A in children 3-7 years of 
 
 
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age [Johnson, T. N., et al 2006].  OATP1B1 protein expression is not age dependent in the 
range of 9 days to 12 years [Thomson, M. M., et al 2016], or in the range of 7 to 70 years 
[Prasad, B., et al 2014], and OATP1B3 protein expression was also not age dependent in the 
range of 2 to 12 years [Thomson, M. M., et al 2016]. These observations indicate that 
minimal to no age-related changes related to enzyme/transporter expression or maturation for 
EBR and GZR are anticipated in the age range of 3-18 years compared to adults.
Dose in Mini Age Cohort 1 and 2
5.5.1.2
The adult Phase II/III clinical program included patients with body weight down to 37 kg, 
who demonstrated favorable PK, safety, and efficacy. Based on the comparable body weight 
and CYP3A and OATP1B maturation in participants aged 12 years up to 18 years, 
participants in Mini Cohort 1 will be administered the adult FDC dose of EBR/GZR (50 
mg/100 mg), which is anticipated to result in comparable exposures to adults. 
The EBR and GZR PBPK models developed for the adult program were used to estimate 
exposures in pediatric HCV patients from 12 to 18 years of age. The pediatric simulations 
assumed the same OATP1B/3 factor for hepatic uptake as estimated for adult patients. The 
simCYPTM program used for the PBPK model accounts effects of physiology (eg, body 
weight, liver size) age-related CYP3A abundance, and HCV infection in these pediatric 
participants on PK.  The PBPK model suggests that the adult dose of EBR/GZR (50 mg/100 
mg) would result in comparable plasma exposures in 12-18 year olds as in adults.
The EBR and GZR PBPK models were also used to estimate exposures in pediatric HCV 
patients from 7 to 12 years of age. A dose of 30 mg and 60 mg for EBR and GZR, 
respectively, in pediatric HCV patients from 7 to 12 years of age is estimated to result in 
comparable AUC exposures as adult HCV patients that are administered the FDC. The 
starting dose for Mini Age Cohort 2 may be refined, if needed, based on the estimated Day 1 
AUC from Mini Age Cohort 1.  
Dose in Mini Age Cohort 3 and Expanded Age Cohorts 1, 2, and 3
5.5.1.3
The doses in these cohorts will be determined based on cumulative pediatric PK data and 
population PK and PBPK modeling and simulation. The Day 1 and TW4 PK data from Mini 
Age Cohorts 1 and 2 will be used to estimate the AUC for these participants and will be
incorporated in the population PK and PBPK models. 
The models will then be used to estimate the anticipated exposure and select optimal doses 
for Mini Age Cohort 3 and Expanded Age Cohort 1.  PK data from these cohorts will in turn 
be used to update the model, and select the dose for Expanded Age Cohort 2/3.  Dosing 
recommendations for Mini Age Cohort 3 and the Expanded Age Cohorts will be provided by 
weight bands, which will be determined by PK analyses. At each step, the goal of model-
based simulations will be to derive a dosing regimen expected to provide similar exposures in 
pediatric patients as in adults.  
Maximum Dose/Exposure for This Trial
5.5.2
The maximum dose in this trial will not exceed EBR 50 mg and GZR 100 mg.
 
 
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6. Study Population
Male/Female participants with chronic hepatitis C GT1 or GT4 virus infection from the age 
of 3 years up to <18 years will be enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
6.1
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. The participant has HCV RNA (≥1,000 IU/mL in peripheral blood) at the time of 
screening.
2. The participant has documented chronic HCV GT1 or GT4 infection as follows:
a) positive for anti-HCV antibody, HCV RNA, or HCV GT1 or GT4 at least 
6 months before Day 1; or 
b) positive for anti-HCV antibody or HCV RNA with a liver biopsy consistent 
with chronic HCV infection (such as the presence of fibrosis) before Day 1.
3. For participants with GT4, HCV RNA 800,000 IU/mL at the time of screening.
4. For participants with GT1a, no evidence of NS5A RASs detected at screening at 
positions 28, 30, 31, and/or 93.
5. The participant has liver disease staging assessment as follows:
a) Absence of cirrhosis (F0 to F3) defined as any one of the following:
i. Liver biopsy performed within 24 months of Day 1 showing absence 
of cirrhosis, or
ii. FibroScan® performed within 12 months of Day 1 with a result ≤12.5 
kPa (only for participants aged 12 years up to 18 years), or
iii. In the absence of criterion i. or ii. above, absence of cirrhosis can be 
determined by the investigator according to local clinical standards 
that includes physical examination during screening in combination 
with laboratory evaluation during screening and/or imaging test within 
6 months of screening.
b) Compensated Cirrhosis (F4) defined as any one of the following:
i. Liver biopsy performed prior to Day 1 showing cirrhosis, or
ii. FibroScan® performed within 12 months of Day 1 with a result >12.5 
kPa (only for participants aged 12 years up to 18 years), or
 
 
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iii. In the absence of criterion i. or ii. above, cirrhosis can be determined 
by the investigator according to local clinical standards that includes 
physical examination during screening in combination with historical 
or current laboratory evaluation and/or imaging with findings 
consistent with cirrhosis (such as firm or enlarged liver, 
splenomegaly).
NOTE: Enrollment in the Mini Age Cohorts will be limited to non-cirrhotic 
participants.
6. The participant has an HCV treatment status that is one of the following:
a) GT1 and GT4:  HCV TN (defined as no prior exposure to any interferon 
[IFN]-containing regimen, RBV, or other HCV-specific DAA agent).
b) GT1 only:  HCV TE (defined as prior virologic failure during or after 
treatment with an IFN or pegylated-IFN with or without RBV; or intolerance 
to IFN or pegylated-IFN with or without RBV). Participants cannot have 
previously received treatment with HCV specific DAA agents (NOTE:  GT4-
infected participants cannot be HCV TE).
Demographics
7. The participant is male or female between 3 years to less than 18 years of age on day 
of signing informed consent/assent.
8. For participants in the Mini Age Cohorts only (these restrictions do not apply for the 
Expanded Age Cohorts):
a) Weight:
i.
Age Cohort 1:  ≥32 kg 
ii.
Age Cohort 2:  ≥19 kg
iii.
Age Cohort 3:  ≥12 kg
b) Race:  Participants of non-Asian Race.
Female participants:
9. A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies: 
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR 
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during 
the treatment period and for at least 14 days after the last dose of study treatment.
 
 
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Informed Consent/Assent
10. The participant’s legally acceptable representative(s) provides written informed 
consent for the study and, when applicable, the participant provides written informed 
assent. 
NOTE:  The participant’s legally acceptable representative(s) may also provide 
consent for Future Biomedical Research (FBR); however, the participant may 
participate in the main study without participating in FBR.
Other Inclusion Criterion
11. The participant must be able to swallow the placebo to EBR/GZR (FDC) prior to
allocation.  This is applicable only to participants in Mini Age Cohort 1 and, if it is 
determined by PK analysis that Expanded Age Cohort 1 will also receive the adult 
FDC dose, to participants in Expanded Age Cohort 1.
Exclusion Criteria 
6.2
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions 
1. The participant has evidence of decompensated liver disease manifested by the 
presence of or history of ascites, esophageal or gastric variceal bleeding, hepatic 
encephalopathy, or other signs or symptoms of advanced liver disease.
2. The participant is cirrhotic AND has a Child-Turcotte-Pugh score >6, corresponding 
to a Child Class B or C.
NOTE:  To calculate the Child-Turcotte-Pugh score and classification, refer to the 
following website: http://www.mdcalc.com/child-pugh-score-cirrhosis-mortality/.
NOTE:  For participants with documented Gilbert’s syndrome, use +1 for the 
bilirubin category of the Child-Pugh calculation.
3. The participant is co-infected with HIV.
4. Has evidence of past or present hepatitis B infection (either hepatitis B core antibody 
[anti-HBc] positive and/or hepatitis B surface antigen [HBsAg] positive) at screening.
5. The participant has a history of malignancy ≤5 years prior to signing informed 
consent or is under evaluation for other active or suspected malignancy including 
HCC.
6. A WOCBP is expecting to conceive or donate eggs from Day 1 through at least 
14 days after the last dose of study treatment or longer if dictated by local regulations.
7. The participant has any of the following conditions:
a) organ transplants (including hematopoietic stem cell transplants) other than 
cornea and hair.
b) poor venous access that precludes routine peripheral blood sampling required 
for this study.
 
 
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c) history of gastric surgery (eg, stapling, bypass) or malabsorption disorders (eg, 
uncontrolled celiac sprue disease).
d) any clinically significant cardiac abnormalities/dysfunction that may interfere 
with participant treatment, assessment, or compliance with the protocol, 
including but not limited to: unstable angina, unstable congestive heart failure, 
unstable arrhythmia; participants currently under evaluation for a potentially 
clinically significant cardiac abnormality/dysfunction are also excluded.
e) any major medical condition, clinically significant illness (other than HCV), 
pre study laboratory or electrocardiogram (ECG) abnormality, or history of any 
illness, including failure to thrive, which, in the opinion of the investigator, 
might interfere with participant treatment, assessment, compliance with the 
protocol, or confound the results of the study or pose additional risk in 
administering the study drug to the participant.
f)
history of a medical/surgical condition that resulted in hospitalization within 
the 3 months prior to enrollment, other than for minor elective procedures.
g) medical/surgical conditions that may result in a need for hospitalization during 
the study duration.
NOTE:  Elective procedures will be permitted following 14 days after taking 
the last dose of study drug.
h) any medical condition requiring, or likely to require, chronic systemic 
administration of corticosteroids, tumor necrosis factor antagonists, or other 
immunosuppressant drugs through FW24.
i)
life-threatening serious adverse event (SAE) during the screening period.
j)
Evidence of history of chronic hepatitis not caused by HCV, including but not 
limited to, drug-induced hepatitis, hemochromatosis, Wilson’s disease, α1 
antitrypsin deficiency, alcoholic liver disease, and autoimmune hepatitis (See 
Exclusion Criterion #4 regarding evidence of history of hepatitis B).
NOTE:  Participants with history of acute non-HCV-related hepatitis, which 
resolved >6 months before study entry, can be enrolled.
8. A WOCBP who has a positive urine pregnancy test within 24 hours before the first 
dose of study treatment (see Appendix 5).  If the urine test cannot be confirmed as 
negative, a serum pregnancy test is required.  In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive.
Prior/Concomitant Therapy
9. The participant is taking or plans to take any of the prohibited medications listed in 
the protocol (see Section 7.7 – Concomitant Therapy) or is taking herbal supplements, 
including but not limited to St. John’s Wort (Hypericum perforatum), from 2 weeks 
prior to Day 1 through 2 weeks after the study treatment period.
NOTE:  For the Mini Age Cohorts only, the participant is taking or plans to take 
methadone or strong CYP3A inhibitors.
 
 
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10. The participant has had previous HCV DAA treatment.
Prior/Concurrent Clinical Study Experience
11. The participant is currently participating or has participated in a study with an 
investigational compound within 30 days of signing informed consent/assent and is 
not willing to refrain from participating in another such study through 24 weeks after 
the study treatment period (FW24).
Diagnostic assessments
12. The participant has exclusionary laboratory values at the screening visit as listed in 
Table 4 below.
NOTE: If any of the laboratory exclusion criteria below in Table 4 are met, the site 
may have the abnormal value retested one time.
Table 4
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Values
Creatinine clearance (eGFR)a
<50 mL/min/1.73 m2
Hemoglobin
<10 g/dL
Platelets
<100 × 103/μL
Serum Albumin
<3.0 g/dL
INR
>1.7 (unless participant has a stable INR on an anticoagulant regimen)
ALT
>10 × ULN
AST
>10 × ULN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; eGFR = estimated glomerular filtration rate; 
INR = international normalized ratio; ULN = upper limit of normal
a Creatinine clearance will be evaluated as eGFR based on the modification of diet in renal disease equation:
eGFR (mL/min/1.73 m2) = 175 × (Scr, std)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if black)
Scr, std: serum creatinine measured with a standardized assay
Other Exclusions
13. The participant has significant emotional problems or a clinically significant 
psychiatric disorder that may interfere with participant treatment, assessment, or 
compliance with the protocol.
14. The participant has clinically relevant drug or alcohol abuse within 12 months of 
screening that may interfere with participant treatment, assessment, or compliance 
with the protocol.
15. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this study.
Lifestyle Restrictions
6.3
Based on the number of PK sampling timepoints, an overnight stay in the clinic is
recommended for the Day 1 (Mini Age Cohort 1 only) and Week 4 visits (all participants).  
 
 
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Meals and Dietary Restrictions
6.3.1
EBR/GZR (FDC) can be taken without regard to food; however, intake of EBR/GZR 
pediatric formulation must be mixed in a soft food dosing vehicle (applesauce, pudding, or 
yogurt).
Screen Failures
6.4
Screen failures are defined as participants who consent/assent to participate in the clinical 
study but are not subsequently entered in the study.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the entry guidelines.
Participant Replacement Strategy
6.5
If a participant discontinues from trial treatment prior to intensive PK sampling at TW4, a 
replacement participant may be enrolled if deemed appropriate by the Sponsor.  The 
replacement participant will be matched to the same cohort and receive the same treatment as 
the participant being replaced. The replacement participant will be assigned a unique 
treatment/allocation number. The trial site should contact the Sponsor for the replacement 
participant’s treatment/allocation number.
7. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment as required.  Clinical supplies will be affixed with a clinical label in accordance 
with regulatory requirements.
Treatments Administered
7.1
The study treatments to be used in this trial are outlined below in Table 5.
 
 
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Table 5
Study Treatments
Study Treatment 
Name:
EBR/GZR 
FDC
Placebo to 
match MK-
5172A 
(EBR/GZR) 
FDC*
MK-8742 (EBR) 
Pediatric 
Formulation
MK-5172 (GZR) 
Pediatric 
Formulation
Dosage 
Formulation:
Tablet
Tablet
Oral granules***
Oral granules***
Unit Dose 
Strength(s):
50 mg/100 mg
0 mg/0 mg
0.5 mg
1 mg
Dosage Level(s):
1 tablet QD
1 tablet given 
prior to 
allocation**
TBD – dose will 
not exceed 50 mg
TBD – dose will 
not exceed 
100 mg
Route of 
Administration:
Oral
Oral
Oral
Oral
Sourcing:
Sponsor
Sponsor
Sponsor
Sponsor
*Placebo tablets are different in color but identical in size and shape to the active EBR/GZR FDC tablets.
**Placebo to EBR/GZR (FDC) tablet is given once prior to allocation to participants in Mini Age Cohort 1.  
This will also apply to participants in Expanded Age Cohort 1 if it is determined by PK analysis that 
Expanded Age Cohort 1 will also receive the adult FDC dose.
***Pediatric formulation supplied as single entity packets.
EBR = elbasvir; FDC = fixed dose combination; GZR = grazoprevir; PK = pharmacokinetics; QD = once-
daily; TBD = to be determined.
As PK data becomes available, the dose proposed for participants will be adjusted to meet the 
scientific goals and study objectives.
Mini Age Cohort 1 will be administered FDC tablets (EBR 50 mg/GZR 100 mg). Expanded 
Age Cohort 1 is expected to receive FDC tablets but alternatively may receive pediatric 
formulation, if PK data suggests a lower dose (dosage to be informed by trial).   Age Cohorts
2 and 3 will be administered pediatric formulation product (dosage to be informed by trial).
Following assignment of formulation, participants may not change from FDC tablets to 
pediatric formulation or from pediatric formulation to FDC tablets during the course of the 
trial.  
The pediatric formulation in this study allows for flexibility of dosing. EBR 0.5 mg and 
GZR 1.0 mg are packaged as single entity packets, which contain oral granules. The foil 
packets are opened and the contents (oral granules) are mixed into a soft food vehicle 
(applesauce, pudding, or yogurt) prior to consumption.
Each single entity packet is individually labeled with the Sponsor’s product number
(MK-8742 is EBR; MK-5172 is GZR) and contains 10 oral granules of either EBR or GZR.

EBR packets have 5 mg per unit package and

GZR packets have 10 mg per unit package
 
 
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The recommended dosing for each Age Cohort will be detailed by the Sponsor in a memo to 
the Study File.  Dosing recommendations for Mini Age Cohort 3 and all Expanded Age 
Cohort(s) will be by weight bands, which will be determined based on PK analyses. This 
memo will be communicated to the site personnel. The memo should be forwarded to the 
Institutional Review Board/Ethics Review Committee (IRB/ERC) by the Investigator, as 
appropriate per IRB/ERC guidelines.
All placebos were created by the Sponsor to match the active product.
All supplies indicated in Table 5 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  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.
Refer to section 9.1.8 for details regarding administration of the study treatment.
Dose Modification (Escalation/Titration/Other) 
7.2
Dose modification of EBR/GZR is not permitted by the site personnel.  For more information 
on dose modification during the course of the trial, see Section 5.5.1.1.
Method of Treatment Assignment 
7.3
Participants will be allocated to treatment via an interactive voice response system/interactive 
web response system (IVRS/IWRS) by non-random assignment.
Stratification
7.3.1
Treatment allocation/randomization will be stratified according to the following factors:
By design, participants will be stratified by Age Cohorts (3 years to 7 years, 7 years to 
12 years, 12 years to 18 years).
Blinding 
7.4
This is an open-label trial; therefore, the Sponsor, investigator and participant will know the 
treatment administered.
Preparation/Handling/Storage/Accountability
7.5
Dose Preparation
7.5.1
The study is designed with staged enrollment.  PK data from earlier enrolled cohorts within 
the study will inform the recommended daily dose of EBR and GZR for subsequently 
enrolled cohorts.  Details are provided in Section 5.5 – Justification for Dose.
Once the Sponsor has determined and communicated recommended dosing for subsequent 
cohorts receiving the pediatric formulation of EBR/GZR, site personnel will count and 
package the appropriate number of EBR and GZR single entity packets for each participant’s 
daily dose. Daily dosage preparation will be multiples of individually labeled unopened 
packets.
 
 
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Handling, Storage and Accountability
7.5.2
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
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.
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
7.6
The participant/legally acceptable representative will be provided a Study Medication and 
Meal Diary (SMD) to record the number of FDC tablets or EBR/GZR pediatric formulation 
packets taken during the treatment period (Section 9.11.2).  At all visits during the treatment 
period, site personnel must verify the accuracy of the dosing SMD by comparing entries with 
amounts of unused study medication.  If a discrepancy is noted, investigator/study 
coordinator must discuss the discrepancy with the participant/legally acceptable 
representative and the explanation must be documented.
Administration of trial medication will be witnessed by the investigator and/or trial staff at 
the Day 1, TW4, and TW8 (visits where the predose PK samples will be collected).
Missed Doses
If a participant misses a dose (or any part thereof) of EBR/GZR, the next dose should not be
doubled in order to compensate for what has been missed.  The participant should be 
instructed as follows:

If the next dose is in more than 8 hours, the missed dose should be taken as soon as 
possible and the normal dosing schedule resumed.
 
 
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
If the next dose is less than 8 hours, the missed dose should be skipped and the 
normal dosing schedule resumed.
Treatment Interruptions
Treatment interruptions should be avoided, but if for any reason EBR/GZR needs to be 
interrupted, it can be interrupted for up to 3 consecutive days.
Interruptions from the protocol specified treatment for 3 consecutive days require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
Concomitant Therapy
7.7
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the dosing period.  If there is a clinical indication for any medication or vaccination 
specifically prohibited, 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 participant's primary physician.  However, the decision to continue 
the participant on study treatment requires the mutual agreement of the investigator, the 
Sponsor and the participant or the participant’s legally acceptable representative.
It is important for investigators to review each medication (prescription and non-prescription) 
the participant is taking before starting the study and at each study visit.

All concomitant medications should be reviewed and data collected through 2 weeks 
after the study treatment period.  Participants or the participant’s legally acceptable 
representative should be asked about any new drugs/vaccines they are taking/have 
taken or changes to any previously reported drugs/vaccines.
o
Drugs known to be hepatotoxic (ie, drugs with a warning of hepatotoxicity in 
the package insert) should be avoided. Investigators are encouraged to review 
each medication for potential hepatotoxicity using the website 
www.livertox.nih.gov.

To minimize the risk of adverse drug interactions, every effort should be made to 
limit the number of concomitant drugs to those that are truly essential.

Non-study HCV medications/therapies, including IFN, are prohibited through FW24.  
Any use should be reported throughout the study duration.
Prohibited Medication
Specific restrictions for concomitant therapy are listed in Table 6.  The medications/therapies 
are not permitted during the dosing period and for 14 days thereafter.
 
 
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Table 6
List of Prohibited Medications
Known hepatotoxic drugs
Etifoxine, isoniazid, nitrofurantoin, phenytoin, oral ketoconazole
Herbal supplements
Including, but not limited to: St. John’s wort 
Strong and moderate 
CYP3A/P-gp inducers, 
including but not limited to
Anti-infectives: nafcillin, rifampin
Anticonvulsants: carbamazepine, phenytoin, phenobarbital
Endothelin antagonists: bosentan
Wakefulness-promoting agents: modafinil
Herbal products: St. John’s wort
HIV medications: efavirenz, etravirine
OATP inhibitors
Immunosuppressants: cyclosporine
Anti-infectives: rifampin
HIV medications: atazanavir, darunavir, lopinavir, saquinavir, 
tipranavir
HCV medications
All non-study HCV medications/therapies
HIV medications, including 
but not limited to
All boosted and unboosted HIV protease inhibitors including, but not 
limited to: atazanavir, darunavir, lopinavir, saquinavir, tipranavir
Cobicistat-containing regimens: 
elvitegravir/cobicistat/emtricitabine/tenofovir (disoproxil fumarate or 
alafenamide)
efavirenz
etravirine
HMG-CoA reductase 
inhibitors (statins)
All statins are prohibited during the dosing period of the study
Investigational agents
All investigational agents (aside from study-related therapies)
Systemic corticosteroids
Systemic corticosteroid use for more than 2 weeks (except 
pulmonary/nasal administration)
AE=adverse event; CYP3A/P-gp=cytochrome P4503A/P-glycoprotein; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; HMG-CoA=3-hydroxy-3-methylglutaryl-coenzyme A; OATP=organic anion-
transporting polypeptide.
In addition to the medications listed in Table 6, participants in the Mini Age Cohorts are 
prohibited from taking the following medications:

Strong CYP3A inhibitors: Including but not limited to, clarithromycin, telithromycin, 
itraconazole, ketoconazole, nefazodone

Methadone
 
 
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Allowed Medications
Table 7
List of Allowed Medications
Commonly Used for the Pediatric Population
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
Acid blockers: H2 blockers and proton pump inhibitors
Asthma
histamine blockers, inhaled/nasal corticosteroids, montelukast
Less Commonly Used for the Pediatric Population
Anti-coagulants
Warfarin, heparin, low molecular weight heparin, aspirin, 
fondaparinux, desirudin, acenocoumarol
Antihypertensives
Angiotensin-converting enzyme inhibitors or angiotensin receptor 
blockers: enalapril, captopril, lisinopril, ramipril, valsartan, losartan, 
telmisartan
Beta blockers: atenolol, metoprolol, propranolol (for other beta 
blockers, please consult with the Sponsor)
Calcium-channel blockers: amlodipine, diltiazem, verapamil (for other 
calcium-channel blockers, please consult with the Sponsor)
Hydralazine, clonidine, minoxidil, isosorbide nitrates
Anemia
Erythropoietin
Diuretics
Hydrochlorothiazide, furosemide, spironolactone, triamterene
Opiate substitution therapy
Buprenorphine/naloxone, methadone
Note: Participants in the Mini Age Cohorts are prohibited from taking 
methadone
Immunosuppressants
Prednisone, daily doses 10 mg or a short course lasting 2 weeks for 
higher doses.
Given that the lists above are not comprehensive, the investigator should use his/her medical 
judgment when a participant presents with a medication not on the list and consult with the 
Sponsor.
Concomitant medications and therapies discontinued 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.
Rescue Medications & Supportive Care
7.7.1
No rescue or supportive medications are specified to be used in this trial.
Treatment After the End of the Study 
7.8
There is no study-specified treatment following the end of the study.
 
 
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Clinical Supplies Disclosure
7.9
This trial is open-label; therefore, the participant/legally acceptable representative, the trial 
site personnel, the Sponsor and/or designee are not blinded. Study treatment (name, strength 
or potency) is included in the label text; random code/disclosure envelopes or lists are not
provided.
8. Discontinuation/Withdrawal Criteria 
Discontinuation of Study Treatment 
8.1
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 2 - SoA and 
Section 9.11.4 – Discontinued Participants Continuing to be Monitored in the Study.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.9 – Withdrawal/Discontinuation.
A participant must be discontinued from study treatment but continue to be monitored in the
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment.
o
Participant meets any HCV virologic failure criteria (see Section 5.4.2.1.1).
o
The participant has a confirmed positive serum pregnancy test.
o
A physician feels it is in the best interest of the participant to discontinue.
o
ALT or AST increases to >500 IU/L and is confirmed with repeat test immediately.
o
ALT or AST increases to 3× baseline and/or nadir, is >100 IU/L, and there is a 
simultaneous increase in total bilirubin >2× ULN and/or INR is increased from the 
baseline value and is >1.5 (unless the participant is on anticoagulation).
o
Alkaline phosphatase increases to >3× ULN, there is a simultaneous increase in total 
bilirubin >2× ULN, and other causes of elevated alkaline phosphatase are excluded.
 
 
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o
Alkaline phosphatase increases to >5× ULN and other causes of elevated alkaline 
phosphatase are excluded.
o
The participant has a life-threatening clinical or laboratory AE or an event that results in 
or prolongs an existing inpatient hospitalization that is assessed to be a study drug-related 
laboratory or clinical AE.
A participant may be discontinued from treatment but continue to be monitored in the study 
for any of the following reasons:
o
SAE assessed by the physician investigator as possibly or probably related to study 
medication. Investigator may continue the participant in the trial, if it is deemed to be in 
the best interest of the participant to stay on the study treatment.
o
Failure to comply with the dosing, evaluations, or other requirements of the trial.
For participants who are discontinued from study treatment but continue to be monitored in 
the trial, all visits and procedures, as outlined in the SoA, should be completed.
Participants may be allowed to begin study treatment again if deemed medically appropriate, 
upon consultation with the Sponsor.
Withdrawal from the Study
8.2
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study including the procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant, as well as 
specific details regarding withdrawal from Future Biomedical Research are outlined in 
Section 9.1.9 – Withdrawal/Discontinuation.
Lost to Follow Up
8.3
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant/legally acceptable representative, the following procedures are to be 
performed:
o
The site must attempt to contact the participant/legally acceptable representative and 
reschedule the missed visit.  If the participant/legally acceptable representative is 
contacted, the participant/legally acceptable representative should be counseled on the 
importance of maintaining the protocol-specified visit schedule.
o
The investigator or designee must make every effort to regain contact with the 
participant/legally acceptable representative at each missed visit (eg, phone calls 
and/or a certified letter to the participant’s/legally acceptable representative’s last 
known mailing address or locally equivalent methods). These contact attempts should 
be documented in the participant’s medical record.
 
 
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o
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant.  The amount of missing data for the participant will be 
managed via the pre-specified data handling and analysis guidelines.
9. Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. 

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

The Investigator is responsible for assuring that procedures are conducted by 
appropriately qualified or trained staff.  Delegation of trial site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.

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, and assent if 
applicable, be obtained from the participant or the participant’s legally acceptable 
representative.  In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
The amount of blood collected from each participant over the duration of the study is
approximately 126 mL for participants in Age Cohort 1 and 119 mL for participants in Age 
Cohorts 2 and 3.  Details regarding specific laboratory assessments/procedures to be 
performed in this study, including approximate blood volumes drawn by visit and by sample 
type per participant, can be found in Appendix 2.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
 
 
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Administrative and General Procedures
9.1
Informed Consent/Assent
9.1.1
The investigator or qualified designee must obtain documented consent, and assent if 
applicable, from each potential participant or each participant’s legally acceptable 
representative prior to participating in a clinical trial or Future Biomedical Research. If there 
are changes to the participant’s status during the trial (eg, health or age of majority 
requirements), the investigator or qualified designee must ensure the appropriate 
consent/assent is in place. 
General Informed Consent
9.1.1.1
Consent/assent must be documented by the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature on a consent/assent form 
along with the dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent/assent form should be given to the participant/legally 
acceptable representative before participation in the trial.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form and any written information provided to the participant/legally 
acceptable representative must receive the IRB/IEC’s approval/favorable opinion in advance 
of use.  The participant or his/her legally acceptable representative should be informed in a 
timely manner if new information becomes available that may be relevant to the 
participant’s/legally acceptable representative’s willingness to continue participation in the 
trial.  The communication of this information will be provided and documented via a revised 
consent/assent form or addendum to the original consent/assent form that captures the 
participant’s dated signature or by the participant’s legally acceptable representative’s dated 
signature.
Specifics about a trial and the trial population will be added to the consent/assent form 
template at the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements. The assent, as applicable will adhere to IRB/ERC requirements, 
applicable laws and regulations and Sponsor requirements.
Consent/Assent and Collection of Specimens for Future Biomedical Research
9.1.1.2
The investigator or qualified designee will explain the Future Biomedical Research 
consent/assent to the participant or the participant’s legally acceptable representative, answer 
all of his/her questions, and obtain written informed consent/assent before performing any 
procedure related to the Future Biomedical Research sub-trial. A copy of the informed 
consent/assent will be given to the participant or the participant’s legally acceptable 
representative.
 
 
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Parental Consent to Use and Disclose Personal Data
9.1.1.3
Appropriate written consent must be obtained prior to collecting and disclosing the height(s) 
of the biological mother and father of the subject.  It is the responsibility of the 
investigator/IRB/IEC to ensure the appropriate consent is obtained according to local law and 
IRB/IEC guidelines. The consent form must be approved by the IRB/IEC.  The consent may 
be obtained anytime during the study.  If biological parents are unable to be reached or the 
biological parents do not provide consent to use and disclose his/her personal data, the 
participant may continue in the study.
Inclusion/Exclusion Criteria
9.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study.
Participant Identification Card
9.1.3
All participants or their legally acceptable representative will be given a Participant 
Identification Card identifying them as participants in a research study. 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 participant or their 
legally acceptable representative with a Participant Identification Card immediately after the 
participant or their legally acceptable representative provides written informed 
consent/assent. At the time of treatment allocation/randomization, site personnel will add the 
treatment/randomization number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
9.1.4
A medical history (including any drug allergies, eg, sulfa allergies) will be obtained by the 
investigator or qualified designee.
Prior and Concomitant Medications Review
9.1.5
Prior Medications
9.1.5.1
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 30 days before starting the trial.
Concomitant Medications
9.1.5.2
The investigator or qualified designee will record medication, if any, taken by the participant 
through 2 weeks after the study treatment period.  Non-study HCV medications/therapies are 
prohibited through FW24; any use should be reported throughout the study duration.
The investigator or qualified designee will discuss with the participant specific restrictions 
for concomitant medications per Section 7.7 – Concomitant Therapy.
 
 
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Assignment of Screening Number
9.1.6
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to treatment allocation.  Each 
participant will be assigned only one screening number.  Screening numbers must not be re-
used for different participants.
Any participant 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 9.11.1.  
Assignment of Treatment/Randomization Number
9.1.7
All eligible participants will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
9.1.8
Participants in Mini Age Cohort 1 must be able to demonstrate the ability to swallow the 
adult FDC placebo tablet in order to be eligible for the trial.  Prior to allocation, 
administration of the placebo to EBR/GZR FDC tablet will be witnessed by the investigator 
and/or study staff to participants who have met all other eligibility criteria for allocation into 
Mini Age Cohort 1.  If it is determined by PK analysis that Expanded Age Cohort 1 will also 
receive the adult FDC dose, administration of the placebo FDC tablet will be witnessed by 
the investigator and/or study staff to participants in Expanded Age Cohort 1.  Participants in 
this Age Cohort that cannot swallow the placebo FDC tablet are not eligible to be allocated 
into the trial.
Following completion of the Day 1 procedures per SoA (Section 2) and confirmation of 
eligibility, the site pharmacist or study coordinator will contact the IVRS/IWRS for treatment 
allocation.
NOTE: Sites should not call IVRS/IWRS for treatment assignment until the participant has 
met all criteria for the study and are ready to receive the first dose of study medication on 
Day 1.
Administration of the following doses will be witnessed by the investigator and/or study staff 
during the site visit:

First dose of study medication at Day 1 for all participants. 

TW4

TW8
 
 
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All other dosing will be performed by the participant/legally responsible representative
(ie, unsupervised at his/her home) and recorded on the participant’s SMD.
Timing of Dose Administration
9.1.8.1
Participants will be instructed to take study medication at approximately the same time each 
day.  EBR/GZR (FDC) can be taken without regard to food; however, intake of EBR/GZR 
pediatric formulation must be mixed in a soft food dosing vehicle (applesauce, pudding, or 
yogurt).
If a participant vomits a dose within 30 minutes of ingestion, the full dose can be repeated 
one time.  If a participant vomits and it has been longer than 30 minutes from the time of 
ingestion, the dose should not be repeated.  Take the next dose at the usual time.
Withdrawal/Discontinuation
9.1.9
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of withdrawal.  Any adverse 
events which are present at the time of withdrawal should be followed in accordance with the 
safety requirements outlined in Section 9.3 - Adverse Events.
Withdrawal From Future Biomedical Research
9.1.9.1
A Participant’s consent for Future Biomedical Research may be withdrawn by the participant 
or the participant’s legally acceptable representative (as appropriate) and their specimens and 
all derivatives destroyed.  A participant’s consent may be withdrawn at any time by 
contacting the principal investigator for the main study. If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com).  Subsequently, the participant's consent for 
Future Biomedical Research will be withdrawn.  A letter will be sent from the Sponsor to the 
investigator confirming the withdrawal. It is the responsibility of the investigator to inform 
the participant of completion of withdrawal.  Any analyses in progress at the time of request 
for withdrawal or already performed prior to the request being received by the Sponsor will 
continue to be used as part of the overall research trial data and results.  No new analyses 
would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (eg, 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 
participant’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Participant Blinding/Unblinding
9.1.10
This is an open label trial; there is no blinding for this trial.
 
 
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Domiciling
9.1.11
Participants will report to the clinical research unit on the morning of intensive PK sampling 
visits. Participants are recommended to remain in the unit until 24 hours post-dose. 
Calibration of Equipment
9.1.12
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.
Efficacy Assessments 
9.2
HCV RNA Measurements
9.2.1
Specimens must be obtained from all participants for the following HCV efficacy 
measurements:

HCV GT on baseline sample (for trial entry) using the Food and Drug Administration 
(FDA) approved Abbott HCV Real Time Genotype II assay which detects HCV GT 
1a, 1b, 2, 3, 4, 5, and 6 through the use of GT-specific fluorescent-labeled 
oligonucleotide probes in a real-time reverse transcription polymerase chain reaction 
(RT-PCR) assay.  The RT-PCR reaction uses 3 sets of HCV specific amplification 
primers targeting the 5’ untranslated region (for all GTs) and NS5B regions from 
GT1a and 1b.  The assay has accuracy of >96% for GT1, 1a, 1b, 2, 3 and 5, 89% for 
GT5 and 83% for GT6 with 100% specificity in HCV serologically negative plasma 
samples.  Phylogenetic analyses will be performed using sequences for NS3, NS5A, 
and NS5B regions to ensure accurate assignment of sample GT/subtype.

HCV RNA plasma levels at various time points per the SoA (Section 2).  HCV RNA 
in plasma will be measured using a COBAS® AmpliPrep/COBAS® Taqman® HCV 
Test, v2.0® assay with a LLOQ of 15 IU/mL.  Results from the sample collected at 
the screening visit are used to determine eligibility.  Samples collected at other time 
points, after Day 1, are used for efficacy analyses and to identify participants who 
meet virologic failure criteria. Leftover plasma may be used for viral resistance 
testing if needed.
Viral Resistance Measurements
9.2.2
Specimens will be obtained from participants for HCV viral resistance measurements:

Blood will be drawn from all subjects at screening to assess viral resistance.

Viral resistance testing will be performed for all participants to determine pre-existing 
RASs to EBR and GZR.  Next-generation sequencing will be performed with a 15% 
sensitivity threshold.  Additional resistance testing on these samples may be 
performed.  
 
 
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o
The results of this test will be used for screening criteria in GT1a-infected 
participants. See Section 6.1 for specific criteria for GT1a-infected 
participants.

Blood samples for resistance testing are also collected at follow-up visits and at the 
virologic failure confirmation visit (should this occur) for genotypic and 
investigational assays to assess emergence of resistance to the components of 
EBR/GZR following treatment initiation.

Leftover plasma may be used for FBR only if the participant/legally acceptable 
representative signed for FBR consent.
Adverse Events, Serious Adverse Events and Other Reportable Safety Events 
9.3
The definitions of an adverse event (AE) or serious adverse event (SAE), as well as the 
method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting AE, SAE and other reportable safety event reports can be 
found in Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
9.3.1
Safety Event Information 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant 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, or a procedure. 
From the time of treatment allocation/randomization through 14 days following cessation of 
treatment, all AEs, SAEs and other reportable safety events must be reported by the 
investigator. 
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 8.
 
 
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Table 8
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- subject is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data 
entry 
guidelines
Serious Adverse 
Event (SAE)
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- subject is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest 
Report if:
- due to 
intervention
- causes 
exclusion
Report
- Potential DILI
- Require 
regulatory 
reporting
OR
- Overdose of 
Sponsor’s 
product that is 
not associated 
with clinical 
symptoms or 
abnormal 
laboratory results
Not required
Within 24 
hours of 
learning of 
event
 
 
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Method of Detecting AE, SAE and Other Reportable Safety Events
9.3.2
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and non-leading verbal questioning of the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant’s legally acceptable representative) 
is the preferred method to inquire about AE occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
9.3.3
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events 
including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all non-serious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Appendix 4.
Regulatory Reporting Requirements for SAE
9.3.4

Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
9.3.5
or SAEs
There are no protocol-specific exceptions to the AE experience reporting presented in 
Section 9.3.
Pregnancy and Exposure During Breastfeeding
9.3.6
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
 
 
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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.
Events of Clinical Interest (ECI)
9.3.7
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this trial include: 
1. an overdose of Sponsor's product, as defined in Section 9.4 – Treatment of Overdose, 
that is not associated with clinical symptoms or abnormal laboratory results.
2. first instance of ALT or AST >500 IU/L after initiation of study therapy through 14 
days following treatment.*
3. first instance of ALT or AST >3x nadir AND >100 IU/L after initiation of study 
therapy through 14 days following treatment.*
*Note:  The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require and additional evaluation for an underlying etiology. The trial site guidance 
for assessment and the follow up of these criteria can be found in the Investigator Trial 
File Binders (or equivalent).
Reporting requirements for ECIs are presented in Table 8.  Any ECI involving overdose or 
ALT/AST criteria are to be reported to the Sponsor within 24 hours.
Treatment of Overdose
9.4
In this trial, an overdose is any dose higher than the prescribed dose of EBR/GZR.

FDC:  1 tablet once daily

Pediatric Formulation:  Dosage communicated (TBD as informed by PK Modeling)
No specific treatment is recommended for an overdose.  Decisions regarding dose 
interruptions or modifications will be made by the investigator in consultation with the 
Sponsor Clinical Director based on the clinical evaluation of the participant.
Safety 
9.5
Details regarding specific safety procedures/assessments to be performed in this trial are 
provided below. 
Clinically significant findings from any safety assessments conducted prior to starting study 
therapy (eg, physical examinations, vital signs, and ECGs at screening) should be captured in 
the Medical History electronic case report form (eCRF). For safety assessments performed 
during study treatment or follow-up, any clinically significant changes compared with the 
assessments prior to study treatment must be captured as AEs.  Participants may be asked to 
return for unscheduled visits in order to perform additional safety monitoring.
 
 
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Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
9.5.1
All physical examinations must be conducted as per institutional standard by the principal 
investigator or subinvestigator (physician, physician assistant, or nurse practitioner) as 
follows:

A complete physical examination at screening and Day 1 to include 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.

A focused physical examination at any other visit when clinically indicated.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Height and weight will be measured and recorded per the SoA and used by the Sponsor to 
calculate body mass index.
Height of Biological Parent(s)
9.5.1.1
The height of the biological parents will be collected between screening and Day 1.  If 
biological parents are unable to be reached during that period the participant may continue in 
the trial.  Later attempts during the trial will be made to collect these data. Biological 
parental consent must be signed prior to obtaining, using, and disclosing their personal data.
Every effort should be made to measure the height of both biological parents at the study site.  
If this is not feasible for some parents, a self-reported height will be acceptable.  The 
participant may participate in the study without these data and/or consent to obtain, use, and 
disclose parental personal data.
Vital Signs
9.5.2

Vital signs will be measured in a semi-recumbent position after 10 minutes rest and 
will include oral temperature, systolic and diastolic blood pressure, and heart rate.

NOTE: Oral temperatures should be taken, but if oral is not possible, tympanic, 
rectal, or axillary temperatures may be taken. 
Electrocardiograms
9.5.3

Special care must be taken for proper lead placement and participants should be 
shaved as necessary. Participants should be resting in a semi-recumbent position for 
at least 10 minutes prior to having ECG readings obtained.
 
 
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Date of Menarche
9.5.4
The date of menarche must be recorded for females who have previously experienced 
menarche.  Once a date of menarche has been confirmed, the participant is considered to be a 
WOCBP.  For prepubescent females, site staff should continue to review and record, as 
appropriate, at each visit during the treatment period.
Contraception Confirmation
9.5.5
Throughout the screening and treatment periods, precaution must be taken to avoid 
pregnancy in WOCBP. Confirmation must be obtained and documented by site personnel 
that WOCBP are using acceptable methods of contraception (see Appendix 5). This 
assessment must be documented in the participant's study chart at each specified visit.
Clinical Safety Laboratory Assessments
9.5.6
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 

The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).

For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study treatment, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator. 
Fibroscan®
9.5.6.1
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. [Castera, L., et al 2008], in a 
population of participants with chronic HCV infection, a cut-off of 12.5 kPa was selected for 
 
 
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cirrhotics. At this cut-off, the sensitivity and specificity of the test for cirrhosis were 87% 
and 91%, respectively, and the negative predictive value was 95%. Since this analysis was 
assessed specifically in participants with chronic HCV infection, the cut-off value >12.5 kPa 
used by Castera was selected to include cirrhotics in the current study.
Pregnancy Testing
9.5.6.2
For WOCBP (see Appendix 5), a urine pregnancy test must be performed at the site on 
Day 1, with negative results prior to initiating study treatment. 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 participant must be excluded from the study per Section 6.1 –
Inclusion Criteria.
Ongoing pregnancy testing will be conducted per the SoA.  If the participant has a confirmed 
positive serum pregnancy test, study treatment must be discontinued per Section 8.1 –
Discontinuation/Withdrawal Criteria and the pregnancy reported per Section 9.3.6 –
Pregnancy and Exposure During Breastfeeding.
HIV Evaluation
9.5.6.3
HIV serology samples will be collected and processed for all participants at screening.
Hepatitis B Virus Evaluation
9.5.6.4
Samples will be collected from each participant to assess HBsAg and anti-HBc, at screening.
Pharmacokinetics
9.6
The decision as to which plasma samples collected will be assayed for evaluation of PK will 
be collaboratively determined by the department of Quantitative Pharmacology and 
Pharmacometrics and the appropriate department within Clinical Research. If indicated, 
these samples may also be assayed and/or pooled for assay in an exploratory manner for 
metabolites and/or additional PD markers.
PK samples will be collected in all pediatric participants. The proposed PK sampling scheme 
across all age groups is provided below in Table 9.
Blood Collection for Plasma EBR/GZR
9.6.1
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual. 
Pharmacokinetic samples will be collected according to the PK sampling schemes shown in 
Table 9.  To avoid multiple venipunctures in pediatric participants, sites are encouraged to
use a peripheral venous access port to collect multiple blood samples for intensive PK 
sampling.  More details on this procedure for blood collection are provided in the Laboratory 
Manual. 
On all PK visits where a predose sample will be collected, the visit should occur prior to the 
participant’s regular time for taking their study medication and the participant should 
withhold their dose until after the visit. For predose PK visits (ie, Day 1, Week 4, Week 8), 
if it is not feasible to schedule the visit prior to the participant’s regular time for taking their 
 
 
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study medication, the participant should withhold their dose until reporting to the clinic. The 
predose PK sample will be obtained and the dose will be administered at the clinic. The date 
and time of each PK sample as well as the date and time of the last dose of EBR/GZR prior 
to the PK sample will be recorded.
All PK samples will be used to evaluate PK exposures, and potentially also the PK-efficacy 
and PK-AE relationships of EBR and GZR. The date and time of each PK sample as well as 
the date and time of the last dose of EBR/GZR prior to the PK sample will be recorded.
The PK sampling schemes selected for Day 1 and TW4 facilitates the ability to estimate all 
PK parameters specified in the objectives. Day 1 intensive PK will be collected in Mini Age 
Cohort 1 to obtain an early estimate of AUC to confirm that the appropriate dose is selected 
for Mini Age Cohort 2. The PK sampling at TW8 facilitates an assessment of PK exposure 
when ALT and/or AST elevations are anticipated to be maximal, if there are elevations.
The total blood volume required for PK analyses of both GZR and EBR (combined) is 1 mL 
per sample.  The recommendations on safe blood sample volume limits for pediatric clinical 
research is provided in literature [Jack, R. 2001]. The total blood volume at each visit, 
accounting for PK and other sample collections is below the maximum blood limit 
requirements per blood draw on each visit. Also, the total blood volume collected within any 
30-day period is below the maximum blood limit requirements.
Recording and Entering Meal/Soft Food Vehicle Information

Participants will be provided an SMD which contains instructions for recording meal 
data that includes what they eat/drink and the time of the meal. Participants or an 
observer (legally acceptable representative/caregiver) should record ALL meal data 
from 48 hours BEFORE the PK visit through the day of the PK visit.

Participants receiving EBR/GZR pediatric formulation should record the soft food 
that EBR and GZR granules were mixed into as well as the pediatric formulation food 
consumption timeframe (ie, the time from mixing of medication into the soft food 
vehicle to complete consumption of all granules that were mixed into the soft food).  
Participants or an observer should record this information in the SMD for all doses.

The site will be responsible for entering the appropriate data from the SMD, as well 
as the qualitative fat content of the meal, in the eCRF according to the eCRF Entry 
Guidelines.  Meal data should be entered by the site as follows:
o
For visits on Day 1 (there will be no meal data entry for pre-dose sample on 
Day 1), Week 4, and Week 8:
•
Enter all meal data within 2 hours before, and up to 1 hour after the 
EBR/GZR dose administered on the day prior to the predose PK visit.
•
Enter all meal data within 2 hours before, and up to 1 hour after the 
EBR/GZR dose administered at the study site.
 
 
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o
For participants who may take multiple meals during the time window, a 
separate meal entry is recorded on the eCRF for each meal within the 
window.
•
The soft food vehicle as well as the pediatric formulation food 
consumption timeframe recorded in the SMD for each dose of pediatric 
formulation should be entered in the eCRF.
Table 9
Pharmacokinetic Sampling Timepoints for All Age Cohorts
Study Day/Week
Time Relative to Last Dose of EBR/GZR1, 2
Day 1 
Mini Age Cohort 1: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, 24 hr
postdose
All other Cohorts: Predose, 2 hr, 4 hr postdose
Week 4
All Cohorts: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, 24 hr
postdose
Week 8
All Cohorts: Predose and 2 hr postdose
HCV Viral Failure 
Confirmation Visit 
(if applicable)
All Cohorts: Anytime
Early Discontinuation 
Visit (if applicable)
All Cohorts: Anytime
1 mL of blood will be collected at each specified time point for plasma PK assessments of 
EBR/GZR (1 mL whole blood is enough for both analytes)
1 The date and time of the last EBR/GZR dose prior to each PK sample collected must be recorded 
in INFORM
2 The time of each PK sample collection relative to last dose of EBR/GZR must be recorded in 
INFORM 
Note:  At the time of PK sample collection, reference the participant’s Study Medication and Meal 
Diary to obtain the date and time of the last dose of EBR/GZR, prior to the PK sample collection. 
The participant (or their caregiver, surrogate, or legally acceptable representative) should be asked 
to confirm the date and time are correct.
Pharmacodynamics
9.7
Pharmacodynamic parameters will not be evaluated in this study.
Future Biomedical Research Sample Collection 
9.8
The following specimens are to be obtained as part of Future Biomedical Research:
Leftover main study plasma from HCV RNA stored for future research.
Leftover main study plasma from viral resistance stored for future research.
 
 
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Biomarkers
9.9
Biomarkers will be evaluated as part of the Future Biomedical Research sub-study.
Palatability and Acceptance Assessment
9.10
The PAA (see Appendix 7) is to be completed for all participants at the time of EBR/GZR 
administration at TW4 and TW8 of the study. The PAA should be implemented with the 
following recommendations: 

Ages 3-4 years:  Completion by an observer (legally acceptable 
representative/caregiver/healthcare provider).

Ages 5-13 years:  Combined completion where the participant completes the faces 
question, and the observer completes the remaining questions.

Ages 14-18 years:  Completion directly by the participant, preferred when possible.
Observer assessments should be based on what the legally acceptable 
representative/caregiver/healthcare provider has observed directly during and after 
medication administration, including the participant’s facial expressions, behavior, and what 
the participant says. Only individuals who have actually observed the participant taking the 
medication should complete the assessment.
Visit Requirements
9.11
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
9.11.1
Within 45 days prior to treatment allocation, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 6 – Study Population. 
The investigator will discuss with each potential participant the nature of the study, its 
requirements, and its restrictions. Verification should be obtained to confirm the 
participant’s cirrhosis status; the participant’s fibrosis score must be reported to support 
secondary data analysis.
Screening procedures may be repeated after consultation with the Sponsor.
Rescreening
Participants who have previously completed the screening visit (Visit 1) and were deemed
eligible for allocation into this study, but failed to be allocated within the 45-day window, 
may be rescreened to re-evaluate study eligibility. To reconfirm the participant's eligibility, 
all pre-study evaluations should be repeated, after approval from the Sponsor, except for the 
following:

HCV GT determination

HCV Viral Resistance/RAS 
 
 
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
Hepatitis B virus screening

HIV serology

Liver biopsy/FibroScan®

Liver imaging

12-lead ECG
If any of the laboratory or ECG exclusion criteria are met, the site may have the abnormal 
value retested one time.
Treatment Period
9.11.2
Drug Dispense
Sites should dispense open-label containers of EBR/GZR FDC tablets (2 open-label 
containers at Day 1 and 1 container at each subsequent dispensing visit) or EBR and GZR 
pediatric formulation packets at each dispensing visit per the SoA.
An unscheduled visit must occur to get additional medication if the participant will run out of 
study medication prior to the next scheduled visit. 
Dosing
Administration of study medication will be witnessed by the investigator and/or study staff at 
the first treatment visit and recorded on the participant’s SMD.  Participants should complete 
study therapy as defined by the treatment regimen and per Section 7 – Treatments. If dosing 
is missed or interrupted, the assigned study therapy regimen should still be completed as per 
Section 7.6 – Treatment Compliance. Additional instructions related to drug administration 
on PK visit days is provided in Section 9.6.1 – Blood Collection for Plasma EBR/GZR.
Study Medication and Meal Diary
The investigator/study coordinator will give the participant/legally acceptable representative
an SMD to be completed during the treatment period of the study.  The investigator/study
coordinator will be responsible for entering the participant’s identification (allocation 
number), visit number, and the dates before giving the SMD to the participant/legally 
acceptable representative.  The participant/legally acceptable representative will be instructed 
to record dates/times and the number of tablets/packets of study medication dosed in the 
SMD for the entire treatment period as well as soft food information (participants on 
EBR/GZR pediatric formulation only) and meal data as described in Section 9.6.1 – Blood 
Collection for Plasma EBR/GZR.  Only the participant/legally acceptable representative
should enter information into the SMD.  The participant/legally acceptable representative is 
to return the completed SMD at each scheduled visit.  At all visits during the treatment 
period, site personnel must verify the accuracy of the dosing SMD by comparing entries with 
amounts of unused study medication.  If a discrepancy is noted, investigator/study
coordinator must discuss the discrepancy with the participant/legally acceptable 
representative, and the explanation must be documented.  Only the participant/legally 
acceptable representative shall make any changes to the entries on the SMD.  The 
 
 
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investigator/study coordinator will be responsible for transferring the appropriate information 
from the SMD onto the appropriate case report form (CRF).
Contraception Confirmation
Throughout the treatment period precaution must be taken to avoid pregnancy in WOCBP.  
Confirmation must be obtained and documented by site personnel that WOCBP are using 
acceptable methods of contraception (see Appendix 5). This assessment must be 
documented in the participant's study chart at each specified visit.
Follow-Up Period
9.11.3
At the completion of study therapy, participants will be seen for follow-up visits at 4, 12, and 
24 weeks after the last dose of study medication.  Follow-up visits at 8, 16, and 20 weeks 
after the last dose of study medication will be completed by telephone contact, at which time, 
site personnel will confirm the participant is doing well and provide a reminder for the FW24 
visit.
Discontinued Participants Continuing to be Monitored in the Study
9.11.4
Discontinuation during Treatment Period
Participants who discontinue therapy prior to the last scheduled treatment visit should 
complete an Early Discontinuation visit and then continue into follow-up visits.
During the Early Discontinuation visit, every effort should be made to:

Perform all procedures and evaluations per the SoA

Retrieve all study medication(s) from the participant

Schedule follow-up contact(s) (telephone or site visit) as appropriate

Collect the following information, at a minimum:
o
Reason the participant discontinued
o
Date of the last dose of study medication
o
Date of the last assessment and/or contact.
o
All AEs.
Discontinuation for Virologic Failure
Participants who discontinue because they have met criteria for virologic failure 
(Section 5.4.2.1.1 – HCV RNA Measurements and Endpoint Definitions) while on study 
therapy should complete an Early Discontinuation visit as outlined in the SoA (Section 2), 
and will be seen for follow-up visits at 4, 12, and 24 weeks following confirmation of 
virologic failure.
 
 
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Participants who meet the virologic failure criterion for relapse (HCV RNA ≥LLOQ 
following the end of all study therapy, after becoming TND at the end of treatment) will be 
seen for the remainder of their follow-up visits (eg, 4, 12, and 24 weeks) as outlined in the 
SoA (Section 2).
Participants who have met virologic failure criteria and are identified as having a treatment-
emergent RAS, will be offered follow-up in a 3-year long-term follow-up protocol, 
MK-5172-017, to determine the persistence of RASs and to determine time course of 
reversion to wild-type.
Discontinuation during Follow-up Period(s)
Participants who discontinue during the follow-up period (eg, FW4 through FW24) for 
reasons other than virologic failure should complete an Early Discontinuation Visit as 
outlined in the SoA (Section 2).  
At a minimum, the following information should be collected:

The reason the participant discontinued.

The date of the last assessment and/or contact. A follow-up contact (telephone or 
visit) will be arranged as appropriate.

SAEs (per reporting requirements outlined in Section 9.3 – Adverse Events, Serious 
Adverse Events and Other Reportable Safety.
10. Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the trial.  Changes to 
analyses made after the protocol has been finalized will be documented in a supplemental 
Statistical Analysis Plan (sSAP) and referenced in the CSR for the trial.  Post hoc exploratory 
analyses will be clearly identified in the CSR.
 
 
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Statistical Analysis Plan Summary
10.1
Key elements of the Statistical Analysis Plan (SAP) are summarized below; the 
comprehensive plan is provided in Sections 10.2 to 10.12.
Study Design Overview
A Phase IIb Study to Assess the Pharmacokinetics, Safety, and 
Efficacy of the Combination Regimen of Elbasvir (EBR)/Grazoprevir 
(GZR) in Pediatric Participants Aged 3 to Less Than 18 Years with 
Chronic Hepatitis C Infection
Treatment Assignment
This will be an open-label, non-randomized trial.
Participants infected with HCV GT1a without baseline NS5A RASs at 
position 28, 30, 31, and/or 93; GT1b/1-other; or GT4 with HCV RNA 
800,000 IU/mL; TN or PR TE (GT1 only); cirrhotic or NC, will be 
treated with EBR/GZR for 12 weeks within Age Cohorts (12 to 18 
years, 7 to 12 years, and 3 to 7 years). 
Approximately 22 participants in the oldest cohort (12 to 18 years) 
will be enrolled.  Approximately 34 participants will be enrolled in the 
two younger cohorts, with 12 to 22 participants in each.  The total 
number of participants enrolled in the three cohorts will be ~56.
Analysis Populations
PK:  Per-Protocol (PP)
Safety: All Participants as Treated (APaT)
Efficacy: Full Analysis Set (FAS) and modified FAS (mFAS)
Primary Endpoints
AUC0-24, Cmax, Ctrough, and CL/F of EBR and GZR.
Secondary Endpoints
1.
Number of participants experiencing AEs and discontinuing study 
drug due to AEs.
2.
SVR12 (Sustained Virologic Response 12 weeks after the end of 
all study therapy), defined as HCV RNA <LLOQ (either TD[u] or 
TND) 12 weeks after the end of all study therapy.
Statistical Methods for Key 
Pharmacokinetic and Efficacy 
Analyses
Geometric means and 95% confidence intervals (CIs) will be 
provided for AUC0-24, Cmax, and CL/F of EBR and GZR by age 
cohort and dose level.
The proportion of participants achieving SVR12 will be estimated 
using a 95% CI (via the Clopper-Pearson method). The missing data 
approach will be Missing=Failure (M=F). 
Statistical Methods for Key 
Safety Analyses
Safety and tolerability will be assessed by clinical review of all 
relevant parameters including AEs and laboratory tests. Descriptive 
statistics will be provided for these safety parameters.
Interim Analyses
Periodic safety analyses will be conducted for the accruing data and 
will be reviewed by an eDMC at regular intervals as outlined in the 
eDMC charter.  This will supplement routine in house medical 
monitoring.
Multiplicity
No multiplicity adjustment is planned in this Phase IIb study.
Sample Size and Power
With 22 participants in a particular age cohort, it is ~80% likely that 
the lower and upper bounds of the 95% CI for EBR and 
GZR AUC0-24 will lie within 44% of the observed GM.
 
 
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Responsibility for Analyses/In-House Blinding
10.2
The statistical analysis of the data obtained from this trial will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. The statistical analyses of the PK data will
be conducted in collaboration with the Quantitative Pharmacology and Pharmacometrics and 
Clinical Research departments of the Sponsor. 
This trial is being conducted as a non-randomized, open-label study. The Clinical 
Biostatistics department will generate the allocation schedule for study treatment assignment.
Allocation numbers will be assigned via an IVRS/IWRS. Planned interim analyses for 
ongoing safety monitoring are described in Section 10.7.  Study enrollment is likely to be 
ongoing at the time of any interim analyses.  The results of interim analyses will not be 
shared with the investigators prior to the completion of the trial.  The eDMC will serve as the 
primary reviewer of the results of these analyses and will make recommendations for 
discontinuation of the trial or protocol modifications to an executive committee of the 
Sponsor.  
An internal statistician not otherwise connected with the trial will conduct analyses and 
present results to the eDMC.  This statistician will not be involved in any discussions 
regarding modifications to the protocol, statistical methods, identification of protocol 
deviations, or data validation efforts after the interim analyses.  Additional logistical details 
will be provided in the eDMC Charter.  Key aspects of the interim analyses are described in 
Section 10.7.
Hypotheses/Estimation
10.3
There are no hypotheses to be tested in this trial.  Objectives of the trial are stated in 
Section 4.0.
Analysis Endpoints
10.4
Pharmacokinetic, safety, and efficacy endpoints that will be evaluated are listed below.
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
10.4.1
Pharmacokinetic Endpoints
10.4.1.1
An initial description of PK endpoints is provided in Section 5.4.2.4.  AUC0-24, Cmax, Ctrough, 
and CL/F of EBR and GZR obtained by non-compartmental analysis (NCA) using intensive 
PK samples at Week 4 are the primary PK endpoints.  The meal and soft food vehicle 
information may be considered in the PK analyses.
Efficacy Endpoints
10.4.1.2
An initial description of efficacy measures is provided in Section 5.4.2.1.  The key efficacy 
endpoint is SVR12, (HCV RNA <LLOQ, either TD[u] or TND, 12 weeks after the end of all 
study therapy).
An additional efficacy endpoint is SVR24 (HCV RNA <LLOQ, either TD[u] or TND, 
24 weeks after the end of all study therapy).
 
 
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Safety Endpoints
10.4.2
An initial description of safety measures is provided in Section 5.4.2.3 and ECIs are defined 
in Section 9.3.7. For this protocol, the proportion of participants who experience AEs of 
elevated laboratory values reported as ECIs (as described in Section 9.3.7) during the study 
therapy period will be estimated.
The proportions of participants with AEs of the following types at any time during the study 
therapy period will also be summarized:  1) with at least 1 AE; 2) with at least 1 drug-related 
AE; 3) with at least one SAE; 4) with at least 1 serious and drug-related AE; and 5) who 
discontinue due to an AE.
Analysis Populations
10.5
PK Analysis Population
10.5.1
The PP Population will serve as the primary population for the analyses of PK data in this 
study.  The PP population consists of the subset of participants who comply with the protocol 
sufficiently to ensure that their PK data will be likely to exhibit the effects of treatment, 
according to the underlying scientific model. Compliance covers such considerations as 
exposure to treatment (participants’ dosing compliance should be such that their PK is 
expected to be at steady state at the time of Week 4 assessment), availability of 
measurements, and absence of major protocol deviations that may affect achievement of 
steady state at the time of Week 4 assessment.  Major protocol deviations will be identified to 
the extent possible prior to final database lock.  Any participants or data values excluded 
from analysis will be identified, along with their reason for exclusion, in the CSR.  At the end 
of the trial, all participants who are compliant with the trial procedures as aforementioned 
and have available data at the Week 4 PK visit will be included in the PP population.
Efficacy Analysis Populations
10.5.2
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study.  The FAS population consists of all allocated participants who receive at least one 
dose of study treatment. 
The mFAS will be used for supportive analysis of the efficacy endpoints of SVR12 and 
SVR24.  The mFAS population is a subset of the FAS population, with participants excluded 
for study discontinuation for reasons unrelated to the treatment regimen.  Examples include
loss to follow-up, discontinuation from the study due to non-drug-related AEs, informed 
consent withdrawal, and other non-virologic failures.  
The final determination on the exclusion of participants from an analysis population will be 
made prior to the final database lock and will be documented in a separate memo. Details on 
the approach to handling missing data are provided in Section 10.6, Statistical Methods.
Safety Analysis Populations
10.5.3
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all allocated participants who received at least one dose of study 
 
 
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treatment. The safety analyses will include all participants who receive any dose of active 
treatment, but participants who receive different doses will be reported separately.
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 10.6, Statistical Methods.
Statistical Methods
10.6
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory objectives will be described in the sSAP.
Statistical Methods for Pharmacokinetic Analyses
10.6.1
Each NCA PK parameter of interest (AUC0-24, Cmax, Ctrough, and CL/F) of EBR and GZR at 
Week 4 will be summarized separately by Age Cohort and treatment as appropriate, with 
GMs and 95% CIs based on natural log-transformed analysis and t distribution.
Individual values will also be listed for each PK parameter at Week 4 by Age Cohort and 
dose level as appropriate, and the following (non-model-based) descriptive statistics will be 
provided: N (number of participants with non-missing data), arithmetic mean, standard 
deviation, arithmetic percent coefficient of variation (CV) (calculated as 100 × standard 
deviation/arithmetic mean), median, minimum, maximum, GM, and geometric percent CV 
(calculated as 100 × sqrt (exp(s2) - 1), where s2 is the observed variance on the natural log-
scale).  Descriptive statistics will also be provided for concentrations/PK parameters obtained 
at other time points, as appropriate.
Modeling and Simulation for Dose Selection
10.6.2
The starting dose for Mini Age Cohort 2 may be refined, if needed, based on the descriptive 
PK data for Day 1 from Mini Age Cohort 1.  All PK data from Mini Age Cohort 1 and Mini 
Age Cohort 2 will be incorporated with previous adult data into the adult population PK and 
PBPK models, which will be continuously updated as pediatric PK data become available 
from each Age Cohort.  Modeling and simulation will be used to select doses for Mini Age 
Cohort 3 and Expanded Age Cohort 1.  All PK from these cohorts will in turn be used to 
update the models, and select the dose for Expanded Age Cohort 2/3.  Dose selection by 
weight bands will be used.  Weight bands will be determined based on PK analyses. At each 
step, the goal of model-based simulations will be to derive a dosing regimen expected to 
provide similar exposures in pediatric patients as in adults.  A separate Modeling and 
Simulation Analysis Plan with further details on the methodology may be prepared.
Statistical Methods for Efficacy Analyses
10.6.3
Efficacy results will be presented by Age Cohorts (12 to <18 years, 7 to <12 years, 3 to <7 
years).  Results of participants in the Expanded Age Cohorts will be reported separately from 
those in the Mini Age Cohorts, unless the same dose was given to both Mini and Expanded 
 
 
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Cohorts within the age group. If all participants in an Age Cohort received the same dose, 
then results of participants in both Mini and Expanded Age Cohorts will be reported together.
Missing Values
A missing data point for a given study visit may be due to any one of the following reasons: 
a visit occurred but data were not collected or were unusable; a visit did not occur; or a 
participant discontinued from the study before reaching the visit. Participants who 
prematurely discontinued the assigned treatment are encouraged to remain in the study for 
the follow-up, if possible.
The HCV RNA outcome is categorized as TND, TD(u), and TD(q). There are 3 types of 
missing data handled by different approaches.
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 will be imputed to the worst 
outcome of the two. For example, if a missing data point is preceded by TD(q) and 
followed by TD(u) or TND, then the missing value would be imputed as TD(q); if a 
missing data point is preceded by TD(u) and followed by TND, then the missing 
value would be imputed as TD(u); when a missing value is flanked by two TND, then 
the missing value would be imputed as TND.
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: Missing values due to 
premature study discontinuations with reasons related to treatment either for safety or 
efficacy. 

Type 3 -- Non-intermittent missing unrelated to the study drug:  Missing data due to 
premature study discontinuations with reasons unrelated to treatment such as loss to 
follow-up, protocol violation, withdrawal of consent/assent, administrative reasons, 
etc.
The following two 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 section below and in Table 10.

Missing = Failure (M=F) approach: Participants with non-intermittent missing results 
(ie, Type 2 or Type 3 missing) will be imputed as having failed, regardless of the 
reason for study discontinuation.

Treatment-Related Discontinuation = Failure (TRD=F) approach: Participants with 
treatment-related Type 2 missing data will be considered as having failed; whereas 
participants who have Type 3 missing values and have not experienced virologic 
failure during the observed study period will be excluded from the analysis for the 
time points following their study withdrawal. Participants 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.
 
 
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In addition, a missing baseline/Day 1 HCV RNA result will be replaced with a screening 
result, if available.
Proportions of Participants With Virologic Responses
For the efficacy analysis to estimate the proportion of participants achieving SVR12, a 
95% CI will be calculated using the Clopper-Pearson method [Clopper, C. J. and Pearson, E. 
S 1934]. The missing data approach of M=F described above will be utilized for the key
analysis. The same method will be used to analyze all binary endpoints.
Sensitivity analyses will be performed for the primary endpoint using the mFAS population 
and the TRD=F missing data approach.
Table 10 includes a summary of the key efficacy analyses.
Table 10
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time point)
Primary 
vs 
Secondary 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach ‡
Proportion of participants
achieving SVR12
P
95% 
Confidence 
Interval
(Clopper-
Pearson)
FAS
M=F
Proportion of participants
achieving SVR12
S
95% 
Confidence 
Interval 
(Clopper-
Pearson)
mFAS
TRD=F
† P=Primary approach; S=Secondary approach.
‡ Imputation for specific missing values described in Section 10.6.2.
FAS = Full Analysis Set; M=F = Missing = Failure; mFAS = modified Full Analysis Set; TRD=F = Treatment-Related 
Discontinuation = Failure.
Participant Virologic Failure: Non-Response, Rebound, Breakthrough, or Relapse
Summary statistics will be provided to describe the rates of occurrence of virologic 
non-response, rebound, breakthrough, or relapse. Definitions for virologic non-response, 
rebound, breakthrough, or relapse are in Section 5.4.2.1.1.
Statistical Methods for Safety Analyses
10.6.4
Safety results will be presented by Age Cohorts (12 to <18 years, 7 to <12 years, 3 to <7 
years).  Results of participants in the Expanded Cohorts will be reported separately from 
those in the Mini Cohorts, unless the same dose was given to both Mini and Expanded 
Cohorts within the age group.
Safety and tolerability will be assessed by clinical review of all relevant parameters,
including AEs and laboratory parameters.  
The analysis of safety parameters will follow a tiered approach (Table 11).  The tiers differ
with respect to the analyses that will be performed.
 
 
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The first tier includes (1) AEs of elevated laboratory values that are reported as ECIs
described in Section 9.3.7; (2) any AE; (2) a drug-related AE; (4) an SAE; (5) a serious and 
drug-related AE; and (6) an AE leading to discontinuation.  Point estimates and 95% CIs will 
be provided for the proportion of participants with first tier AEs.  The 95% CIs for the safety 
parameters will be estimated using the Clopper-Pearson method [Clopper, C. J. and Pearson, 
E. S 1934].
The second tier includes specific AEs by system organ class, vital signs, and standard 
laboratory safety tests at time points specified in the SoA.  Point estimates will be provided
for the proportion of participants with second tier AEs.
Missing safety laboratory or vital signs will be handled using the Data As Observed 
approach, that is, any missing value will be excluded from the analysis.  The only exception 
is when a Baseline/Day 1 result is missing, this will be replaced with the latest pre-treatment 
result, if available.
The primary safety analysis will summarize the safety data for participants during the 
treatment period plus 14 days of follow-up.
Table 11
Analysis Strategy for Safety Parameters
Safety Endpoint
95% CI 
Descriptive 
Statistics
AEs of elevated laboratory values that are reported as 
ECIs
X
X
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs or SOCs or PDLCs
X
Change from Baseline Results (laboratory vital signs)
X
95% confidence intervals will be calculated using the Clopper-Pearson method.
Note:  AE = adverse event; CI = confidence interval; ECI = event of clinical interest; 
PDLC = pre-defined limits of change; SOC = System Organ Class; X = results will be posted.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
10.6.5
Demographic and Baseline Characteristics
10.6.5.1
Baseline characteristics for all allocated and treated participants will be summarized by the 
use of descriptive statistics. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of participants screened and allocated, and the 
primary reasons for screen failure and discontinuation will be displayed. Demographic 
variables (eg, age, gender, race, and GT subtype) and prior and concomitant therapies will be 
summarized using descriptive statistics for continuous or categorical variables, as 
 
 
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appropriate. Summary statistics for baseline efficacy measures such as HCV RNA will also 
be provided.
Growth
10.6.5.2
Height and weight will be compared to the normative population based on age as well as the 
mid-parental height. Summary statistics and changes from baseline at each time point during 
follow-up will be reported, where baseline is the start of the treatment period.
Viral Resistance Measurements
10.6.5.3
Viral resistance testing will focus on the entire NS3/4A and NS5A regions for all participants
and for those who meet the virologic failure criteria (see Section 5.4.2.1.1).
Palatability and Acceptance Assessment
10.6.5.4
Each participant will rate the palatability and respond to questions on the acceptability of 
treatment with EBR/GZR on TW4 and TW8 of the study.  This will be based on the FHS 
facial expression scale depicting various degrees of pleasure as an assessment of palatability 
(Section 5.4.2.2 and Section 9.10).
Descriptive statistics will be used to summarize the palatability and acceptability responses. 
Missing data will not be imputed, and the analyses will be based on observed data only. 
These analyses will be based on the FAS population.
Interim Analyses
10.7
To supplement the routine safety monitoring outlined in this protocol, the eDMC will 
monitor ongoing safety data and provide recommendations to ensure the safety of study 
participants and the integrity of the trial to the EOC (see Appendix 3 – Committees Structure 
– Executive Oversight Committee).  HCV RNA data may be included as part of the reviews
to allow for an assessment of benefit-risk.  The eDMC will monitor the trial with suggested 
periodic reviews to occur approximately every 6 months.  An internal statistician not 
otherwise connected with the trial will conduct the analyses and present results to the eDMC.
Multiplicity
10.8
There will be no multiplicity adjustments in the analysis of this trial.
Sample Size and Power Calculations
10.9
Sample Size and Power for PK Analyses
10.9.1
The precision of the estimates of EBR and GZR PK obtained from this study can be 
described in terms of the relative length of the 95% CIs expected for the given sample size 
and assumed variability.  The calculations for AUC0-24 below are based on assumed true 
between-subject standard deviations (log-scale) of 0.452 and 0.731 for EBR and GZR, 
respectively, as observed in MK-5172 Protocol 059 (a Phase II/III non-randomized, 
unblinded, open-label study that evaluated the efficacy and safety of EBR/GZR in subjects 
with chronic HCV and advanced cirrhosis and hepatic insufficiency) and take into account 
 
 
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the sampling distribution of the observed sample variance as described in Wang et al [Wang, 
Y., et al 2012].
For the given sample size and assumed between-subject variability, there is ~80% probability 
that the 95% CI for the true GM AUC0-24 will lie within the ranges shown in Table 12, 
expressed relative to the observed GM.  For example, given 22 participants in an Age Cohort, 
it is ~80% likely that the lower and upper bounds of the 95% CI for GZR AUC0-24 will lie 
within 44% of the observed GM.
Table 12
Expected Precision (80% Likely) for Estimates of GZR and EBR AUC0-24
Analyte
N
95% CI within X % of 
Observed GM
GZR
5
204%
12
71%
15
59%
22
44%
EBR
5
99%
12
40%
15
33%
22
25%
Sample Size and Power for Efficacy Analyses
10.9.2
The key efficacy objective will be assessed based on the proportion of participants achieving 
SVR12, defined as HCV RNA <LLOQ 12 weeks after the end of all study therapy. This is an 
estimation study with no hypotheses. The expected response rate is ~95% based on previous 
EBR/GZR clinical trials. Treatment is expected to be similarly active in different Age 
Cohorts in either TN or TE pediatric participants with or without cirrhosis.
Efficacy results will be presented by Age Cohorts.  Results of participants in the Expanded 
Cohorts will be reported separately from those in the Mini Cohorts, unless the same dose was 
given to both Mini and Expanded Cohorts within the age group.  If all participants in an Age 
Cohort receive the same dose, then results of participants in Mini and Expanded Cohorts will 
be reported together.  Table 13 shows the 95% CIs for SVR12 given varying assumptions of 
number of successes for 5, 12, 15, and 22 participants.  Note that the intervals are not 
symmetric around the point estimate.
 
 
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Table 13
Two-Sided 95% Confidence Intervals for SVR12 (FAS Population) 
Observed Number of Successes (%)
Two-Sided 95% Confidence Interval†
N=5
3 (60.0%)
(14.7, 94.7)
4 (80.0%)
(28.4, 99.5)
5 (100.0%)
(47.8, 100.0)
N=12
9 (75.0%)
(42.8, 94.5)
10 (83.3%)
(51.6, 97.9)
11 (91.7%)
(61.5, 99.8)
12 (100.0%)
(73.5, 100.0)
N=15
12 (80.0%)
(51.9, 95.7)
13 (86.7%)
(59.5, 98.3)
14 (93.3%)
(68.1, 99.8)
15 (100.0%)
(78.2, 100.0)
N=22
18 (81.8%)
(59.7, 94.8)
19 (86.4%)
(65.1, 97.1)
20 (90.9%)
(70.8, 98.9)
21 (95.5%)
(77.2, 99.9)
22 (100.0%)
(84.6, 100.0)
FAS = Full Analysis Set
† Based on the two-tailed exact confidence interval for a binomial proportion (Clopper and Pearson) [Clopper, C. J. and Pearson, E. S 
1934]
Sample Size and Power for Safety Analyses
10.9.3
The key 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 10.6.3 of 
this document.  Safety results will be presented by Age Cohorts.  Results of participants in 
the Expanded Cohorts will be reported separately from those in the Mini Cohorts, unless the 
same dose was given to both Mini and Expanded Cohorts within the age group.  If all 
participants in an Age Cohort received the same dose, then results of participants in Mini and 
Expanded Cohorts will be reported together.
The probability of observing at least one of a particular type of AE depends on the number of 
participants treated and the underlying percentage of participants with that AE in the study 
population. For instance, if the underlying incidence of a particular AE is 1% (1 of every 
100 participants receiving the drug), there is a 20% chance of observing at least one AE of 
that type among 22 participants. If no AE of that type is observed among the 22 participants, 
this study will provide 95% confidence that the underlying percentage of participants with 
that particular AE is 15.4%.
The estimate of, and the upper bound of the 95% CI for, the underlying percentage of 
participants with an AE given various hypothetical observed number of participants with the 
AE are provided in Table 14. These calculations are based on the exact binomial method 
proposed by Clopper and Pearson [Clopper, C. J. and Pearson, E. S 1934].
 
 
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Table 14
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Numbers of Participants with AEs
N
Hypothetical Number of 
Participants with an AE 
(Estimate of Incidence)
95% Upper Confidence 
Bound†
5
0 (0.0%)
52.2%
1 (20.0%)
71.6%
12
0 (0.0%)
26.5%
1 (8.3%)
38.5%
2 (16.7%)
48.4%
15
0 (0.0%)
21.8%
1 (6.7%)
31.9%
2 (13.3%)
40.5%
3 (20.0%)
48.1%
22
0 (0.0%)
15.4%
1 (4.5%)
22.8%
2 (9.1%)
29.2%
3 (13.6%)
34.9%
5 (22.7%)
45.4%
†Based on the two-tailed exact confidence interval for a binomial proportion (Clopper and Pearson) 
[Clopper, C. J. and Pearson, E. S 1934].
Subgroup Analyses
10.10
To assess the consistency of the response across various subgroups, the SVR12 rate and 
associated 95% CIs will be estimated within each category of the following classification 
variables:

Sex (female, male)

GT (1a, 1 non-a, 4)

Age (3 to <7 years, 7 to <12 years, 12 to <18 years)

HCV RNA at baseline, (≤800,000 IU/mL, >800,000 IU/mL; ≤2 million IU/mL, 
>2 million IU/mL)

Stage of fibrosis (Non-cirrhotic, Cirrhotic)

Prior treatment history (TN, TE)

Weight bands
The analyses by weight bands may be performed separately by age cohort and/or separately 
for Mini and Expanded Age Cohorts.
 
 
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Compliance (Medication Adherence)
10.11
In this trial, the SMD will be used to monitor and document a participant’s drug compliance.  
Data reported on the SMD will serve as the primary data for compliance analysis.
A day within the study will be considered an “On-Therapy” day if the participant takes the 
assigned treatment as noted in Section 7.5.1.
For a participant who is followed for the entire study period, the “Number of Days Should be 
on Therapy” is the total number of days from dosing to the last scheduled day for treatment 
administration for that participant.  For a participant who discontinued from the study 
permanently, the “Number of Days Should be on Therapy” is the total number of days from 
dosing to the date of the last dose of study medication.
For each participant, percent compliance will then be calculated using the following formula:
Therapy
on 
be
  
Should
  
Days
of
Number  
Therapy
on 
  
Days
of
Number  
  
Compliance
Percent  

× 100
Summary statistics will be provided for percent compliance for the FAS population.
Extent of Exposure
10.12
The Extent of Exposure to study treatment will be evaluated by summary statistics (N, mean,
and range) for the “Number of Days on Therapy”.
11. References
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MK-5172)/Elbasvir (EBR, MK-8742) in treatment-
naive and treatment-experienced patients with 
Hepatitis C virus genotype 1 infection and chronic 
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Meeting 2015; 2015 Nov 13-17; San Francisco, CA: 
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Calleja JL, Hofer H, et al. Grazoprevir and elbasvir 
plus ribavirin for chronic HCV genotype-1 infection 
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[Hanafiah, K. M., et 
al 2013]
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2011]
Kelly DA, Haber B, Gonzalez-Peralta RP, Murray 
KF, Jonas MM, Molleston JP, et al. Durability of 
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chronic hepatitis C who were treated with interferon 
alfa-2b plus ribavirin. J Viral Hepat 2011:1-8.
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2014]
Lawitz E, Gane E, Pearlman B, Tam E, Ghesquiere 
W, Guyader D, et al. Efficacy and safety of 12 weeks 
versus 18 weeks of treatment with grazoprevir (MK-
5172) and elbasvir (MK-8742) with or without 
ribavirin for hepatitis C virus genotype 1 infection in 
previously untreated patients with cirrhosis and 
patients with previous null response with or without 
cirrhosis (C-WORTHY): a randomised, open-label 
phase 2 trial. Lancet. 2014 Nov 11. [Epub ahead of 
print].
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[M&S Analysis Rpt 
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Modeling & Simulation Analysis Report: 
ELBASVIR SIMCYP PBPK Modeling, 2015.
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[M&S Analysis Rpt 
2015]
Modeling & Simulation Analysis Report: 
Grazoprevir (MK-5172) Simcyp PBPK Model, 2015.
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[Mack, C. L., et al 
2012]
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Narkewicz MR, Roberts EA, et al. NASPGHAN 
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[Martinot-
Peignoux, M., et al 
2010]
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P, Boyer N, Leclere L, et al. Twelve weeks 
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determine the sustained virologic response in patients 
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[McHutchison, J. 
G., et al 2009]
McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, 
Galler GW, McCone J, et al. Peginterferon alfa-2b or 
alfa-2a with ribavirin for treatment of hepatitis C 
infection. N Engl J Med 2009;361(6):580-93.
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[Narkewicz, M. R., 
et al 2007]
Narkewicz MR, Cabrera R, Gonzalez-Peralta RP. 
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2014]
Prasad B, Evers R, Gupta A, Hop CE, Salphati L, 
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and sex. Drug Metab Dispos. 2014 Jan;42(1):78-88.
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al 2015]
Rockstroh JK, Nelson M, Katlama C, Lalezari J, 
Mallolas J, Bloch M, et al. Efficacy and safety of 
grazoprevir (MK-5172) and elbasvir (MK-8742) in 
patients with hepatitis C virus and HIV co-infection 
(C-EDGE CO-INFECTION): a non-randomised, 
open-label trial. Lancet HIV. 2015 Aug;2(8):e319-27. 
Erratum in: Lancet HIV. 2015 Oct;2(10):e416. 
Lancet HIV. 2015 Aug;2(8):e316.
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[Roth, D., et al 
2015]
Roth D, Nelson DR, Bruchfeld A, Liapakis A, Silva 
M, Monsour H Jr, et al. Grazoprevir plus elbasvir in 
treatment-naive and treatment-experienced patients 
with hepatitis C virus genotype 1 infection and stage 
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weeks versus 12 weeks of treatment with grazoprevir 
(MK-5172) and elbasvir (MK-8742) with or without 
ribavirin in patients with hepatitis C virus genotype 1 
mono-infection and HIV/hepatitis C virus co-
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al. Best practice recommendations regarding the 
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Expression Patterns of Organic Anion Transporting 
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1999]
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2012]
Wang Y, Jadhav PR, Lala M, Gobburu JV. 
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[Wirth, S., et al 
2010]
Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti 
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[Zeuzem, S., et al 
2015]
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047F85
 
 
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12. Appendices
Appendix 1: Abbreviations and Trademarks
12.1
Term
Definition
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
ALT
Alanine aminotransferase
Anti-HBc
Hepatitis B core antibody
APaT
All Participants as Treated
AST
Aspartate aminotransferase
AUC
Area under the time-concentration curve
AUC0-24
AUC over 24 hours
CI
Confidence interval
CL/F
Apparent clearance
Cmax
Maximum observed drug concentration
CRF/eCRF
Case report form/electronic case report form
CSR
Clinical Study Report
Ctrough
Plasma concentration immediately predose
CYP3A
Cytochrome P450 3A 
CV
Coefficient of variation
DAA
Direct-acting antiviral
DNA
Deoxyribonucleic acid
EBR
Elbasvir
ECG
Electrocardiogram
ECI
Events of clinical interest
eDMC
External Data Monitoring Committee
EOC
Executive Oversight Committee
ERC
Ethics Review Committee
EU
European Union
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration, US
FDC
Fixed dose combination
FHS
Facial hedonic scale
FW
Follow-up Week
GM
Geometric mean
GT
Genotype
GZR
Grazoprevir
HBsAg
Hepatitis B surface antigen
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HIV-1
Human immunodeficiency virus type 1
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Institutional Ethics Committee
IFN
Interferon
INR
International normalized ratio
IRB
Institutional Review Board
IVRS/IWRS
Interactive voice response system/integrated web response system
LLOQ
Lower limit of quantification
M=F
Missing = Failure
mFAS
Modified Full Analysis Set
NCA
Non-compartmental analysis
OATP
Organic anion-transporting polypeptide
 
 
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Term
Definition
PAA
Palatability Acceptance Assessment
PBPK
Physiologically based pharmacokinetic
PD
Pharmacodynamics
P-gp
P-glycoprotein
PK
Pharmacokinetics
PP
Per-Protocol
PR
Pegylated-interferon with RBV
QD
Once daily
RAS
Resistance-associated substitution
RBV
Ribavirin
RNA
Ribonucleic acid
RT-PCR
Reverse transcription polymerase chain reaction
SAE
Serious adverse event
SAP
Statistical Analysis Plan
sSAP
Supplemental Statistical Analysis Plan
SMD
Study Medication and Meal Diary
SoA
Schedule of Activities
SVR
Sustained virologic response
SVR12
Sustained virologic response 12 weeks after the end of all study therapy
SVR24
Sustained virologic response 24 weeks after the end of all study therapy
TD(q)
Target detected, quantifiable
TD(u)
Target detected, but unquantifiable
TE
Treatment-experienced
TK
Toxicokinetic
Tmax
Time to maximum concentration
TN
Treatment-naïve
TND
Target not detected
TRD=F
Treatment-Related Discontinuation = Failure
TW
Treatment Week
ULN
Upper limit of normal
US
United States
WOCBP
Woman of childbearing potential
 
 
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Appendix 2: Clinical Laboratory Tests 
12.2

Laboratory tests to be performed in this study are specified in Table 15 and will be 
conducted by the central laboratory. The total amount of blood/tissue to be 
drawn/collected over the course of the study (from pre-study to post-study visits), 
including approximate blood/tissue volumes drawn/collected by visit and by sample 
type per participant can be found in Table 16.
Table 15
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hematocrit 
Albumin
Blood
Coagulation Panel
‒PT
‒INR
Hemoglobin 
ALP
Glucose
Choriogonadotropin beta (urine 
pregnancy test kits to sites)
Platelet count 
ALT
Protein
Serum human chorionic 
gonadotropin (reflex when urine 
pregnancy test is “positive”)
RBC
AST
Specific gravity 
HCV, Genotype
WBC
Bicarbonate
Microscopic exam (if 
abnormal results are 
noted)
HCV, Viral Load RNA 
(quantitative) 
WBC 
Differential 
(result in % and 
Abs)
‒Basophils
‒Eosinophils
‒Lymphocytes
‒Monocytes
‒Neutrophils 
(Total)
Calcium
Bilirubin
FibroScan®
Chloride
Ketones
Creatinine
Leukocyte esterase
Hepatitis B Serology Panel
‒HBsAg (perform at screening in 
all participants
‒Anti-HBc, Total (screening only)
Creatinine clearance 
(eGFR estimated by 
MDRD‒NKDEP)
(screening only)
Nitrite
HIV Serology Panel
‒HIV, Types 1 & 2
‒HIV, Types 1 & 2 Confirmation 
by Inno-Lia HIV score‒
CPK
pH
(
 
 
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Hematology
Chemistry
Urinalysis
Other
GGT
WBC
Amylase
Bacteria
Lipase
Squamous epithelial 
cells
Glucose
RBC
Phosphorus
Potassium
Sodium
Total bilirubin
Direct bilirubin (if 
total bilirubin is 
elevated above the 
ULN)
Total protein
Blood urea nitrogen
ALP=alkaline phosphatase; ALT=alanine aminotransferase; Anti-HBc=hepatitis B core antibody; Anti-HBs=hepatitis B surface 
antibody; AST=aspartate aminotransferase; CPK=creatine phosphokinase; eGRF=estimated glomerular filtration rate; 
GGT=gamma-glutamyl transpeptidase; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; INR=international normalized ratio; MDRD-NKDEP=Modification of Diet in Renal Disease‒National 
Kidney Disease Education Program; PT=prothrombin time; RBC=red blood cell; RNA=ribonucleic acid; ULN=upper limit of 
normal; WBC=white blood cell.
Abbreviated blood chemistry includes only ALT, AST, ALP, total bilirubin, albumin, GGT, and CPK
 
 
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Table 16
Approximate Blood Volumes Collected
Test
Screenin
g
Day 1
TW 2
TW 4
TW 6
TW  8
TW 10
TW 12
FW 4
FW 12
FW  24
Total Volume in 
mL
Coagulation
1.8
1.8
1.8
1.8
1.8
1.8
10.8
HBsAg
Anti-HBc
2
2
Chemistry (complete)
2
2
2
2
2
2
2
14
Chemistry (abbreviated)
2
2
2
2
8
Hematology
2
2
2
2
2
2
2
2
16
EBR/GZR PK
31
10
3
162
HCV Genotype
4
4
HCV RNA Level
4
4
4
4
4
4
4
28
HCV Viral Resistance/
Resistance Associated 
Substitutions (RAS)
4
4
4
4
16
HIV Serology
4
4
Total Volume in mL
23.8
8.83
2
18
2
12.8
2
9.8
12
13.8
13.8
118.84
1 Subjects in Mini Age Cohort 1 only (age 12 to 18 years; N=7) will have 10 mL of blood drawn for PK sampling on Day 1. All other participants will have 3 mL of blood 
drawn for PK sampling on Day 1.
2 Subjects in Mini Age Cohort 1 only (age 12 to 18 years; N=7) will have a total of 23 mL of blood drawn for PK sampling. All other participants will have a total of 16 mL 
of blood drawn for PK sampling.
3 Subjects in Mini Age Cohort 1 only (age 12 to 18 years; N=7) will have a total of 15.8 mL of blood drawn on Day 1. All other participants will have a total of 8.8 mL of 
blood drawn on Day 1.
4 Subjects in Mini Age Cohort 1 only (age 12 to 18 years; N=7) will have a total of 125.8 mL of blood drawn overall. All other participants will have a total of 118.8 mL of 
blood drawn overall.
 
 
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Appendix 3: Study Governance Considerations
12.3
Merck Code of Conduct for Clinical Trials
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 participant 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 (eg, 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 
participant preferences, etc.  
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research participants 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 participants, 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. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that 
changes required urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC 
approval. For each site, the IRB/IEC and Merck will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance.  
Potential participants 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. Participants are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent 
for participation.  Participants 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 participant 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 participant 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 participants 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 participant referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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/IEC 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 (eg, 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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Financial Disclosure
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.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
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/IEC) 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 Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, 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 participant 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
 
 
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worksheet/case report form information, the participant 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 participant data used and 
disclosed in connection with this trial in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
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.
Committees Structure
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
Data Monitoring Committee (DMC) regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (eg, they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 10.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
 
 
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If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are 
participant to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Compliance with Law, Audit and Debarment
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 (eg, 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 this appendix 
under the Merck Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the trial 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
The Investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
 
 
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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.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
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 or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the trial documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
 
 
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Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
 
 
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
12.4
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the sponsor for human use in this study.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test 
result.  An overdose without any associated clinical symptoms or abnormal laboratory 
results is reported using the terminology “accidental or intentional overdose without 
adverse effect.”
●
Any new cancer or progression of existing cancer.
 
 
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Events NOT Meeting the AE Definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has 
not worsened.
●
Refer to section 9.3.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing 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.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
 
 
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e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events reported in the same manner as SAE
Additional Events which require reporting in the same manner as SAE
●
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 new cancer;
●
Is associated with an overdose.
Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
 
 
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Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) reported during the study and assign it to 1 of the 
following categories: 
●
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.  (for pediatric trials, 
awareness of symptoms, but easily tolerated)
●
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities. (for pediatric trials, definitely acting like something is wrong)
●
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe 
(for pediatric trials, extremely distressed or unable to do usual activities).
Assessment of Causality
●
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 product 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 participant 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)?
 
 
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●
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
●
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 participant 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 PARTICIPANT THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study 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.
●
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 
 
 
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another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant 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 participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor 
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information for reporting time 
requirements 
 
 
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●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or by 
telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or 
secure e-mail of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
 
 
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Appendix 5: Contraceptive Guidance and Pregnancy Testing
12.5
Definitions 
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Requirements
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described in consistently and correctly during the protocol-
defined time frame in Section 6.1.
 
 
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Table 17
Contraceptive Methods
Acceptable Contraceptive Methods 
Failure rate of >1% per year when used consistently and correctly.
●
Male or female condom with or without spermicide
●
Cervical cap, diaphragm or sponge with spermicide
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraception b
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b, c
●
Intrauterine hormone-releasing system (IUS) b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least [X days, corresponding to time needed to eliminate study treatment plus 30 days for study 
treatments with genotoxic potential]  after the last dose of study treatment .
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
 
 
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. 
Following initiation of treatment additional pregnancy testing will be performed every 4 
weeks during the treatment period and at 4 weeks, after the last dose of study treatment and 
as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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Appendix 6: Collection and Management of Specimens for Future Biomedical 
12.6
Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 9.8 – Future 
Biomedical Research Sample Collection will be used in various experiments to 
understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants 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 participants on the visit designated in 
 
 
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the SoA.  If delayed, present consent at next possible Participant Visit.  Consent 
forms signed by the participant will be kept at the clinical trial site under secure 
storage for regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for Future Biomedical Research will be 
captured in the electronic Case Report Forms (eCRFs). Any specimens for which 
such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the SoA. In general, if additional blood specimens are being collected for 
Future Biomedical Research, these will usually be obtained at a time when the 
participant is having blood drawn for other trial purposes.
4. Confidential Participant 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 participant' 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 participant 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the trial site.  No personal identifiers will 
appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (eg, 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.
 
 
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6. Withdrawal From Future Biomedical Research 
Participants may withdraw their consent for Future Biomedical Research and ask that 
their biospecimens not be used for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main trial. If 
medical records for the main trial are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for Future Biomedical Research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable.  
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research trial data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main trial are no longer available (eg, 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 participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
 
 
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9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants.  Participants 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 participants 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 participant have been minimized. No 
additional risks to the participant have been identified as no additional specimens are 
being collected for Future Biomedical Research (ie, only leftover samples are being 
retained).
The Sponsor has developed strict security, policies and procedures to address participant 
data privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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Appendix 7: Palatability and Acceptance Assessment Form
12.7
 
 
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