A Long-Term Follow-Up Study to Evaluate the Durability of Virologic Response and/or Viral Resistance Patterns of Subjects With Chronic Hepatitis C Who Have Been Previously Treated With MK-5172 in a Prior Clinical Trial
Conditions: Hepatitis C
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT01667081 
Document Date: 
13-Apr-2018
A Long-Term Follow-up Study to Evaluate the Durability of 
Virologic Response and/or Viral Resistance Patterns of Subjects 
With Chronic Hepatitis C Who Have Been Previously Treated with 
MK-5172 in a Prior Clinical Trial

Product:  MK-5172
Page 1
Protocol/Amendment No.:  017-04
Confidential
13-Apr-2018
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., NJ, U.S.A. (MSD)
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (hereafter referred to as 
the SPONSOR or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Administrative 
Binder.
TITLE:
A Long-Term Follow-up Study to Evaluate the Durability of Virologic Response and/or 
Viral Resistance Patterns of Subjects With Chronic Hepatitis C Who Have Been 
Previously Treated with MK-5172 in a Prior Clinical Trial
INVESTIGATOR:
PRIMARY:
CLINICAL PHASE: III
US IND NUMBER:
110,261
EudraCT NUMBER: 2012-002232-85
SITE:
INSTITUTIONAL REVIEW BOARD/ETHICS REVIEW COMMITTEE:
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES...............................................................................................7
Primary Reason(s) for This Amendment:............................................................................7
Additional Change(s) for This Amendment: .....................................................................13
1. SUMMARY.................................................................................................................21
1.1
TITLE ....................................................................................................................21
1.2
INDICATION........................................................................................................21
1.3
SUMMARY OF RATIONALE.............................................................................21
1.3.1
Durability of Virologic Response...................................................................22
1.3.2
Persistence of Virologic Resistance ...............................................................22
1.3.3
Safety..............................................................................................................22
1.3.3.1
Progression of Liver Disease (All Adult Subjects).................................22
1.3.3.2
Progression of Chronic Kidney Disease .................................................22
1.3.3.3
Other (Cardiac and Neurologic)..............................................................23
1.4
SUMMARY OF STUDY DESIGN ......................................................................23
1.4.1
Adult Population.............................................................................................23
1.4.2
Pediatric Population........................................................................................23
1.5
STUDY POPULATION........................................................................................23
1.5.1
Adult Population.............................................................................................24
1.5.2
Pediatric Population........................................................................................24
1.6
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN.........................24
1.7
STUDY FLOW CHART.......................................................................................25
1.7.1
Adult Population.............................................................................................25
1.7.2
Pediatric Population........................................................................................27
2. CORE PROTOCOL.....................................................................................................28
2.1
OBJECTIVES AND HYPOTHESES ...................................................................28
2.1.1
Primary ...........................................................................................................28
2.1.1.1
Adult Population .....................................................................................28
2.1.1.2
Pediatric Population................................................................................28
2.1.2
Exploratory (Adult Population Only).............................................................28
2.2
SUBJECT INCLUSION CRITERIA (ADULT AND PEDIATRIC 
POPULATIONS)...................................................................................................29
2.3
SUBJECT EXCLUSION CRITERIA (ADULT AND PEDIATRIC 
POPULATIONS)...................................................................................................29
2.4
STUDY DESIGN AND DURATION...................................................................30
2.4.1
Summary of Study Design..............................................................................30
2.4.1.1
Adult Population .....................................................................................30
2.4.1.2
Pediatric Population................................................................................30
2.4.2
Treatment Plan................................................................................................30
 
 
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2.5
LIST OF 
EFFICACY/PHARMACOKINETIC/IMMUNOGENICITY 
MEASUREMENTS...............................................................................................31
2.6
LIST OF SAFETY MEASUREMENTS...............................................................32
2.6.1
Adult Population.............................................................................................32
2.6.2
Pediatric Population........................................................................................33
2.7
STATISTICAL ANALYSIS PLAN SUMMARY................................................33
2.7.1
Efficacy Analyses...........................................................................................33
2.7.1.1
Adult Population .....................................................................................33
2.7.1.2
Pediatric Population................................................................................34
2.7.2
Safety Analyses ..............................................................................................35
2.7.2.1
Adult Population .....................................................................................35
2.7.2.2
Pediatric Population................................................................................35
2.7.3
Analysis of Resistant Associated Substitutions..............................................35
2.7.3.1
Adult Population .....................................................................................35
2.7.3.2
Pediatric Population................................................................................35
2.7.4
Power and Sample Size ..................................................................................36
2.7.5
Interim Analysis .............................................................................................36
3. PROTOCOL DETAILS...............................................................................................37
3.1
RATIONALE ........................................................................................................37
3.1.1
Rationale for This Study.................................................................................37
3.1.2
Rationale for Future Biomedical Research.....................................................37
3.2
STUDY PROCEDURES.......................................................................................37
3.2.1
Subject Population..........................................................................................37
3.2.2
Concomitant Medication(s)/Treatment(s) ......................................................38
3.2.2.1
Adult Population .....................................................................................38
3.2.2.2
Pediatric Population................................................................................38
3.2.3
Diet/Activity/Other.........................................................................................38
3.2.4
Procedures ......................................................................................................38
3.2.4.1
Screening/Baseline Visit (Visit 1)...........................................................38
3.2.4.2
Informed Consent/Assent (Adult and Pediatric 
Populations) ............................................................................................40
3.2.4.2.1
General Informed Consent/Assent ..................................................40
3.2.4.2.1.1
Consent/Assent and Collection of Specimens 
for Future Biomedical Research..............................................41
3.2.4.3
Assignment of Baseline (Screening) Number (Adult and 
Pediatric Populations) .............................................................................41
3.2.4.4
Randomization/Allocation (Adult and Pediatric 
Populations) ............................................................................................41
3.2.4.5
Years Post Entry Into Study, Years 1 through 3 (Visits 2 
through 7): Adult and Pediatric Populations...........................................41
3.2.4.6
Years 4 and 5 Post Entry (Visit 8 through 11): Adult 
Population ...............................................................................................41
3.2.4.7
Treatment/Evaluation/Follow-Up ...........................................................42
 
 
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3.2.4.8
Discontinuation/Withdrawal from Study (Adult and 
Pediatric Populations) .............................................................................42
3.2.4.8.1
Discontinuation/Withdrawal Criteria ..............................................42
3.2.4.9
Withdrawal From Future Biomedical Research (Adult 
and Pediatric Populations) ......................................................................42
3.3
DURABILITY, VIRAL RESISTANCE, AND SAFETY
MEASUREMENTS...............................................................................................43
3.3.1
Clinical and Laboratory Measurements for Durability, Viral 
Resistance, and Safety....................................................................................43
3.3.1.1
Adult Population .....................................................................................43
3.3.1.2
Pediatric Population................................................................................46
3.4
SAFETY MEASUREMENTS ..............................................................................47
3.4.1
Clinical and Laboratory Measurements for Safety.........................................47
3.4.1.1
Adult Population .....................................................................................47
3.4.1.2
Pediatric Population................................................................................47
3.4.2
Recording Adverse Experiences (Adult and Pediatric 
Populations)....................................................................................................47
3.4.3
Immediate Reporting of Adverse Events to the SPONSOR ..........................48
3.4.3.1
Serious Adverse Events (Adult and Pediatric Populations)....................48
3.4.3.2
Events of Clinical Interest.......................................................................49
3.4.3.2.1
Adult Population..............................................................................49
3.4.3.2.2
Pediatric Population ........................................................................49
3.4.4
Evaluating Adverse Events (Adult and Pediatric Populations)......................49
3.4.5
SPONSOR Responsibility for Reporting Adverse Events 
(Adult and Pediatric Populations) ..................................................................52
3.5
STATISTICAL ANALYSIS PLAN (SAP)...........................................................52
3.5.1
Responsibility for Analyses/In-House Blinding.............................................52
3.5.2
Estimation.......................................................................................................52
3.5.3
Analysis Endpoints.........................................................................................52
3.5.3.1
Efficacy and RAS Endpoints ..................................................................52
3.5.3.1.1
Adult Population..............................................................................52
3.5.3.1.2
Pediatric Population ........................................................................53
3.5.3.2
Safety Endpoints .....................................................................................53
3.5.3.2.1
Adult Population..............................................................................53
3.5.3.2.2
Pediatric Population ........................................................................53
3.5.4
Analysis Populations ......................................................................................53
3.5.4.1
Efficacy Analysis and RAS Populations.................................................53
3.5.4.1.1
Adult Population..............................................................................53
3.5.4.1.2
Pediatric Population ........................................................................53
3.5.4.2
Safety Analysis Populations....................................................................53
3.5.4.2.1
Adult Population..............................................................................53
3.5.4.2.2
Pediatric Population ........................................................................54
3.5.5
Statistical Methods .........................................................................................54
3.5.5.1
Statistical Methods for Efficacy Analyses..............................................54
3.5.5.1.1
Adult Population..............................................................................54
3.5.5.1.2
Pediatric Population ........................................................................55
 
 
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3.5.5.2
Statistical Methods for Safety Analyses .................................................55
3.5.5.2.1
Adult Population..............................................................................55
3.5.5.2.2
Pediatric Population ........................................................................56
3.5.5.3
Analysis of Resistance Associated Substitutions....................................56
3.5.5.3.1
Adult Population..............................................................................56
3.5.5.3.2
Pediatric Population ........................................................................56
3.5.5.4
Summaries of Baseline Characteristics, Demographics, 
and Other Analyses .................................................................................56
3.5.6
Multiplicity.....................................................................................................57
3.5.7
Sample Size and Power Calculations .............................................................57
3.5.8
Subgroup Analyses and Effects of Baseline Factors......................................57
3.5.9
Interim Analyses.............................................................................................57
3.5.10 Compliance (Medical Adherence)..................................................................57
3.6
LABELING, PACKAGING, STORAGE, DISPENSING, AND 
RETURN OF CLINICAL SUPPLIES...................................................................57
3.7
DATA MANAGEMENT ......................................................................................57
3.8
BIOLOGICAL SPECIMENS................................................................................57
4. ADMINISTRATIVE AND REGULATORY DETAILS............................................58
4.1
CONFIDENTIALITY ...........................................................................................58
4.1.1
Confidentiality of Data...................................................................................58
4.1.2
Confidentiality of Subject Records ................................................................58
4.1.3
Confidentiality of Investigator Information ...................................................58
4.2
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT.............................59
4.3
COMPLIANCE WITH FINANCIAL DISCLOSURE 
REQUIREMENTS ................................................................................................61
4.4
QUALITY CONTROL AND QUALITY ASSURANCE ....................................61
4.5
COMPLIANCE WITH INFORMATION PROGRAM ON 
CLINICAL TRIALS FOR SERIOUS OR LIFE THREATENING 
CONDITIONS.......................................................................................................62
4.6
PUBLICATIONS ..................................................................................................62
5. LIST OF REFERENCES.............................................................................................64
6. APPENDICES .............................................................................................................65
6.1
COLLECTION AND MANAGEMENT OF SPECIMENS FOR 
FUTURE BIOMEDICAL RESEARCH................................................................65
6.1.1
Scope of Future Biomedical Research ...........................................................65
6.1.2
Definitions......................................................................................................65
6.1.3
Summary of Procedures for Future Biomedical Research .............................65
6.1.4
Confidential Subject Information for Future Biomedical 
Research .........................................................................................................67
6.1.5
Biorepository Specimen Usage ......................................................................68
6.1.6
Withdrawal From Future Biomedical Research.............................................68
6.1.7
Retention of Specimens..................................................................................69
6.1.8
Data Security ..................................................................................................69
 
 
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6.1.9
Reporting of FBR Data to Subjects................................................................69
6.1.10 Gender, Ethnicity, and Minorities ..................................................................70
6.1.11 Risks Versus Benefits of Future Biomedical Research..................................70
6.1.12 Self-Reported Ethnicity..................................................................................70
6.1.13 Questions........................................................................................................70
6.2
BLOOD VOLUMES COLLECTED.....................................................................71
6.2.1
Adult Blood Volumes.....................................................................................72
6.2.2
Pediatric Blood Volumes................................................................................73
6.3
LIST OF ABBREVIATIONS ...............................................................................74
7. ATTACHMENTS........................................................................................................77
7.1
MERCK CODE OF CONDUCT FOR CLINICAL TRIALS ...............................77
7.2
PHARMACOGENOMICS INFORMATIONAL BROCHURE 
FOR IRBS/IECS & INVESTIGATIONAL SITE STAFF....................................80
8. SIGNATURES.............................................................................................................89
8.1
SPONSOR’S REPRESENTATIVE ......................................................................89
8.2
INVESTIGATOR..................................................................................................89
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
All
All
The protocol has been updated to include 
enrollment of pediatric subjects from protocol 
MK-5172 PN079. Where applicable, sections, 
enrollment criteria, and/or procedures for the 
pediatric population have been added. In addition, 
enrollment criteria and/or procedures specific to 
the adult population have been clarified.
Subjects enrolled in the pediatric 
protocol MK-5172 PN079 who 
experience virologic failure associated 
with one or more treatment-emergent 
resistant associated substitutions (RASs)
can enroll in this study. Clarification 
between the adult and pediatric 
populations has been added to ease 
review of the protocol by investigators.
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
2.1.1.1
Adult 
Population 
(subsection 
of 
Primary 
Objectives 
and Hypotheses)
Primary Objective #1:

Original wording: To evaluate the durability 
of SVR in subjects who remained HCV RNA 
< LLoQ (either TND or TDu) throughout the 
follow-up period of the treatment protocol and 
did not start any new HCV therapy between 
the end of the previous protocol and entry in 
this study.
o
All subjects (except subjects from PN 
052) with HCV RNA < LLoQ will be 
discontinued from PN 017 after the 
next scheduled visit.  PN 052 subjects 
will remain for a duration of 5 years as 
introduced in AM02. Data collected up 
to a subject’s last visit will be assessed 
for durability. After AM03 approval, 
no additional subjects achieving SVR 
will enroll in PN 017.

Amendment 04 wording: To evaluate the 
durability of response in subjects who 
achieved SVR24 in the prior treatment study 
and at the time of entry into PN017 were HCV 
ribonucleic acid (RNA) <lower limit of 
quantification (LLoQ) (either target not 
detected 
[TND] 
or 
target 
detected, 
unquantifiable [TD(u)]).
The previous wording (“throughout the 
follow-up period…”) was too rigid and 
excluded subjects who had a transient 
HCV RNA increase.
Sub-bullet text was deleted because it is 
found in other sections of the protocol.
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
2.1.1.1
Adult Population 
(subsection of 
Primary Objectives 
and Hypotheses)
Primary Objective #2: 

Original wording:  To evaluate the presence 
of antiviral resistance, NS3/4A, NS5A and/or 
NS5B, (as appropriate) and determine if there 
is a reversion to a wild-type pattern within the 
3 years (all protocols except PN 052) or 5 
years timeframe for PN 052 of this long-term 
follow-up study.
o
Subjects enrolling in PN 017 with 
quantifiable HCV RNA after having 
failed therapy will be followed for 3 
years (all studies except PN 052) or 5 
years (PN 052)

Amendment 04 wording:  To evaluate the 
presence 
of 
treatment-emergent 
antiviral 
resistance to NS3/4A, NS5A and/or NS5B 
regions, (as applicable) and determine if there 
is a reversion to wild-type pattern within the 3-
year time frame of this long-term follow-up 
study (or 5-year time frame for subjects from 
PN052) in subjects with virologic failure in the 
prior treatment study and with HCV RNA 
≥1000 IU/mL in Protocol 017.
The new wording of this objective 
reflects the current interest in the focus 
on treatment-emergent RASs and the 
persistence of these RASs. Additionally, 
wording was added to align with 
Merck’s standard methodology for 
resistance testing (ie, resistance can only 
be assessed in subjects when HCV RNA 
levels are >1000 IU/mL).
Sub-bullet text was deleted because it is 
found in other sections of the protocol.
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
2.2
Subject Inclusion 
Criteria
Inclusion #3:

Original wording:  Subject must be ≥ 18 
years of age and willing to give written 
informed consent.

Amendment 04 wording: Subject is male or 
female 3 years of age or older on day of 
signing informed consent/assent.
Inclusion #4:

Original wording:  Subjects who have 
consented for the trial may also provide 
consent for Future Biomedical Research.  
However, the subject may participate in the 
main trial without participating in Future 
Biomedical Research.

Amendment 04 wording: Subject or subject’s 
legally acceptable representative provides 
written informed consent (or written informed 
assent where applicable).  Subjects who have 
consented for the study may also provide 
consent/assent for Future Biomedical Research 
(FBR).  However, the subject may participate 
in PN017 without consenting/assenting for 
FBR.
Revised inclusion criterion #3 and #4 
and added inclusion criterion #6 to allow 
for enrollment of subjects to this study 
from the pediatric protocol MK-5172 
PN079.
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
Inclusion #6:
Amendment 04 added: Pediatric subject must 
have received at least 1 dose of a GZR-containing 
regimen and experienced virologic failure with 1 
or more associated treatment-emergent RASs at 
FW12 in PN079.
2.3
Exclusion Criteria
Exclusion #1:

Original wording:  In the opinion of the 
investigator, if a subject is mentally or legally 
incapacitated at entry, the subject may be 
excluded.

Amendment 04 wording:
Adult subjects: In the opinion of the 
investigator, subject is mentally or legally 
incapacitated at entry into PN017.
Pediatric subjects: The subject has significant 
emotional problems or a clinically significant 
psychiatric disorder that may interfere with 
participant 
treatment, 
assessment, 
or 
compliance with the protocol.
The criterion was updated to be specific 
to adults and pediatric subjects.
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
2.7.1.1
Adult Population 
(subsection of 
Efficacy Analyses)
Aligned the description of the primary objective, 
to state “the primary efficacy objectives of this 
study are to evaluate the durability of response in 
subjects who achieved SVR in the prior treatment 
study...”
This change was made to streamline the 
presentation of information and align 
with changes made to Section 2.1.1.1.
6.2.1 and 
6.2.2
Adult Blood 
Volumes and 
Pediatric Blood 
Volumes
Tables added in each subsection.
Blood volumes defined per visit for adult 
and pediatric subjects.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
All sections
All sections
1. Changed MK-5172 to grazoprevir 
(GZR), MK-8742 to elbasvir (EBR), MK-
8408 to ruzasvir (RZR), and MK-3682 to 
uprifosbuvir (UPR).
2. Changed the word “trial” to “study.”
3. 
Changed 
adverse 
experiences 
to 
adverse events.
4. Changed “patients” to “subjects”.
5. 
The 
term 
“resistance 
associated 
variant” 
(RAV) 
was 
replaced 
with 
“resistance 
associated 
substitution” 
(RAS).
6. 
Other 
editorial 
and 
document 
formatting revisions.
1. Updated to include approved generic 
names.
2. Updated the protocol to use “study” 
consistently throughout the document.
3. Updated the protocol to be in alignment 
with standard nomenclature.
4. The term “subjects” is used throughout 
for consistency.
5. “Resistance associated substitution” has 
recently been adopted as the preferred 
nomenclature [1]. It should be noted that 
in earlier documents, including the original 
study protocol, the term RAV was used to 
describe RAS.
6. Minor, and therefore have not been 
summarized.
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
1
Summary
All subsections within the Summary were 
revised to provide updated information 
and streamline the text.
Revised to align with standard for Merck-
authored HCV protocols.
1.7.1
Study Flow Chart, Adult 
Population
Deleted description of medical history 
procedures; condensed Child-Pugh score 
compilation to one line; added Visits 8 
and 10 to review of ECIs and AEs; and 
clarified visit window duration.
These changes were made to correct 
inconsistencies, provide concise display, 
and to improve clarity of the protocol.  
2.3
Subject Exclusion 
Criteria
Exclusion #3:

Original wording: For Amendment 
03: Subjects who fail therapy due to 
re-infection are excluded.

Amendment 04 wording: Starting 
with AM 03: Subjects who failed 
therapy due to re-infection, defined as:

an HCV RNA sample with a 
different genotype than the 
baseline genotype in the prior 
treatment study, or

an 
HCV 
RNA 
sample 
determined to be reinfection by 
phylogenetic 
analysis 
with 
comparison to the baseline 
sequence in the prior treatment 
study.
The definition of subjects who failed 
therapy was added to exclusion criterion 
#3 to improve clarity of the protocol.
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
2.4.1.1
Adult Population 
(subsection of Summary 
of Study Design)
Item #2:

Original wording: Subjects in PN 
017 who entered with quantifiable  
HCV RNA will continue for 3 years of 
follow-up (except PN 052 subjects) or 
5 years of follow-up (PN 052).

Amendment 04 wording: Subjects in 
PN017 with virologic failure at FW24 
in the prior treatment study will 
continue for 3 years of follow-up 
(other than PN052 subjects) or 5 years 
of follow-up (PN052 subjects).
Item #2 was revised because virologic 
failure criteria is based on failing in the
prior treatment study.
2.7
Statistical Analysis Plan 
Summary
Removed 
details 
from 
introductory 
statement and added reference to Section 
3.5.
These changes were made to streamline 
the presentation of information.
3.2.1
Subject Population
Removed descriptive wording found in 
other sections of protocol.
These changes were made to streamline 
the presentation of information.
3.2.2.1
Adult Population 
(subsection of 
Concomitant 
Medication(s)/
Treatment(s)
Stated clearly that starting with AM 03, 
subjects are not permitted to take any 
therapies used for the treatment of HCV 
concurrently with this protocol.
These changes align with the changes 
made during AM 03 and were made to 
streamline the presentation of information.
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
3.2.4
Procedures
Clarified visit window as must be 
performed within +/- 3 months
This change was made because all study 
visits are to occur every 6 months, 
therefore the statement, “or +/- 6 months 
of the scheduled visit if a year apart”, is 
not applicable.
3.2.4.1
Screening/Baseline Visit 
(Visit 1)
For adult subjects, made the following 
revision: ..”the following medical history 
terms, which occurred after the prior 
treatment study and before study entry,
will be collected:”
These changes were made to improve 
clarity of the protocol and align collection 
of medical history (MH) events and events 
of clinical interest (ECI), as these MH and 
ECI events will be included for analysis.
3.2.4.8.1
Discontinuation/Withdra
wal Criteria
Adjusted introductory paragraph.
These changes were made to streamline 
the presentation of information.
3.3.1.1
Adult Population 
(subsection of Clinical 
and Laboratory 
Measurements for 
Durability, Viral 
Resistance, and Safety)
Reordered details to follow the same order 
as 
the 
study 
flow 
chart. 
Updated 
formatting
These changes were made to streamline 
the presentation of information.
3.4.3.1
Serious Adverse Events
Changed title from Serious Adverse 
Experiences to Serious Adverse Events; 
Moved 
note 
regarding 
drug-related 
serious adverse event reporting. 
These changes were made to provide a 
consistent term throughout document and 
highlight reporting requirements so that 
they are easily identified and understood 
by site(s).
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
3.4.3.2 and 
3.4.3.2.1
Events 
of 
Clinical 
Interest
and subsection 
for Adult Population
1. The title of Section 3.4.3.2 was changed 
from “Selected Adverse Experiences (if 
applicable)”
to 
“Events 
of 
Clinical 
Interest”.
2. Details were added for ECIs of 
hepatocellular carcinoma:
Original wording:

Hepatocellular carcinoma
Amendment 04 wording:

Hepatocellular 
carcinoma; 
Any 
hepatocellular carcinoma that occurred 
and was not previously reported in the 
prior treatment study should be 
reported as an ECI.
3. Details were added to define criteria for
decreased eGFR for PN052 subjects:
Original wording:

eGFR (will be analyzed for change 
from baseline)
Amendment 04 wording:

Decreased eGFR calculated by the 
Modification of Diet in Renal Disease
equation (PN052 subjects will be 
analyzed for change from baseline in 
PN052);
1. Changed to provide a consistent term of 
ECI throughout the document.
2. HCC:  Additional wording was added to 
clarify the need for reporting events that 
occurred between the last visit of the prior 
treatment study and the first visit of 
PN017 as ECIs.
Decreased eGFR:  Additional wording was 
added to clarify when to report this as an 
ECI for CKD subjects. The new wording 
addresses the natural fluctuation in eGFR 
in CKD subjects.
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
o
For this study a decrease in eGFR 
is defined for subjects not on 
dialysis as:

CKD4 (15 to 30 ml/min/1.73 
m2) in PN052 and is now 
CKD5 
(<15 
ml/min/1.73 
m2),

CKD5 without dialysis in PN 
052 and is now CKD5 with 
dialysis, OR

CKD4 in PN 052 and 
initiates dialysis
4. Clarified that kidney transplant, 
decreased eGFR, new onset diabetes, and 
post transplantation glomerulonephritis 
are ECIs recorded only for subjects who 
participated in PN052 as their prior 
treatment study.
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
3.5
Statistical Analysis Plan
Deleted wording for notable changes for 
AM 03:
Wording removed:  
With AM 03, the notable changes and/or 
additions to the SAP include:
1.  The analysis population to characterize 
durability of response was refined.  
Specifically, the requirement that subjects 
needed to be TND at the end of treatment 
in the previous protocol in order to be 
included in the analysis population was 
removed.  The analysis population for the 
time to relapse analysis will be all subjects 
who were < LLoQ during the follow-up 
period of the previous trial (never 
confirmed to be >LLoQ) and entered PN 
017 with HCV RNA <LLoQ and did not 
start any new HCV therapy between the 
end of the previous protocol and entry in 
this study.  
2.  Descriptive statistics will be provided 
for the rate that patients with CKD 
(Protocol 052) require liver transplants 
(See Section 3.5.5.2).
The wording in #1 no longer aligns with
the new objective language, therefore it 
was removed.
The wording in #2 and #3 was included 
elsewhere in Section 3.5.
 
 
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
3.  For the analysis of viral resistance, 
subgroup analyses will be performed by 
class of regimen (e.g. NS3/4A inhibitors, 
NS5A inhibitors and NS5B inhibitors) as 
well as by specific components. (See 
Section 3.5.5.3)
6.3
List of Abbreviations
Abbreviation list added.
List added as a reference for abbreviations 
used in the protocol.
 
 
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1. SUMMARY
1.1
TITLE
A Long-Term Follow-up Study to Evaluate the Durability of Virologic Response and/or 
Viral Resistance Patterns of Subjects With Chronic Hepatitis C Who Have Been 
Previously Treated with MK-5172 in a Prior Clinical Trial
1.2
INDICATION
Grazoprevir (GZR) is being developed for treatment of chronic hepatitis C virus (HCV) 
infection.   
1.3
SUMMARY OF RATIONALE
The HCV clinical development program has evaluated GZR in combination with 
pegylated-interferon, ribavirin, and other direct-acting antiviral (DAA) therapies, 
including elbasvir (EBR), ruzasvir (RZR), and uprifosbuvir (UPR) as various 
investigational HCV treatment regimens. Refer to the respective Investigator Brochures 
(IBs) for background information and study results for the various GZR-containing 
regimens.
Across the program, over 4,500 HCV-infected subjects will have received at least 1 dose 
of GZR in more than 20 Phase 2 and Phase 3 Merck-sponsored clinical studies (hereafter 
referred to as prior treatment study). The totality of Phase 2 and Phase 3 data was used to 
identify a highly effective combination of DAAs for the treatment of chronic HCV. 
During the course of development, different regimens, treatment durations, and 
genotypes (GTs) were assessed. Ultimately, these data were used to support the approval 
of the combination regimen EBR/GZR for 12 to 16 weeks in GT1 and GT4.
This study (Protocol 017; PN017) will assess: 1) durability of virologic response, 
2) monitor persistence of virologic resistance, and 3) safety, including progression of 
liver disease, and for subjects with chronic kidney disease (CKD) from PN052, 
progression of kidney disease.
Enrollment in PN017 includes an adult population (aged ≥18 years) and a pediatric 
population (aged 3 to 18 years), based on subject age at the time of screening in the 
prior treatment study. While many studies are grouped together for objectives and 
analyses, two studies (PN052 and PN079) enrolled special populations that will be 
assessed apart from other populations. Subjects from PN052 all have advanced CKD 
(Stages 4 or 5); these subjects are followed for 5 years to understand the natural history of 
CKD and liver disease progression following HCV therapy. Subjects from PN079 are 
pediatric subjects who will be followed only if the subject experiences virologic failure 
with 1 or more treatment emergent RASs.
A list of abbreviations used within this protocol is in Appendix 6.3.
 
 
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1.3.1
Durability of Virologic Response
At the time of PN017 initiation, FDA guidance for industry specified that HCV-infected 
patients treated with a DAA and achieving sustained viral response (SVR) be followed 
for at least 3 years to ensure durability of response. As the field of HCV therapies 
advanced, data accrued demonstrated that SVR observed at 12 and 24 weeks after DAA 
treatment was durable for years [2][3]. These findings resulted in modifications to the 
regulatory guidance to no longer assess durability of response beyond 24 weeks of 
follow-up [4]. Subjects who achieved SVR in a prior treatment study and were enrolled 
into PN017 were subsequently discontinued at their next visit due to amendment (AM) 
03. All subjects up to discontinuation or study completion will be included in data 
analyses of durability of response. 
1.3.2
Persistence of Virologic Resistance
Following treatment with an appropriate DAA regimen, the majority of HCV-infected 
subjects (>95%) achieve SVR. For subjects who do not achieve SVR, treatment failure is 
often accompanied by the presence or emergence of genetic mutations (resistance-
associated substitutions [RAS]) that generate functional viral proteins with reduced DAA 
susceptibility compared to wild-type virus [5]. The presence or development of RAS may 
have an important impact on efficacy outcomes and retreatment options, and hence, is a
concern for DAA treatment of HCV-infected adult and pediatric populations.
Thus, adult and pediatric subjects enrolled in PN017 will be followed for up to 3 years
(or up to 5 years for PN052 subjects) to assess persistence of virologic resistance.
1.3.3
Safety
The natural history of liver disease after treatment with novel all-oral regimens, as well as 
the natural history of kidney disease of HCV-infected subjects with the co-morbidity of 
CKD, remains to be defined. As such, progression of liver disease and chronic kidney 
disease, as well as the incidence of certain cardiac and neurologic events, will be 
assessed.
1.3.3.1
Progression of Liver Disease (All Adult Subjects)
Progression of liver disease is assessed in all adult subjects in PN017. Specific liver 
related safety events are reported as events of clinical interest (ECIs) in all adult subjects; 
these 
events 
include: 
hepatocellular 
carcinoma, 
variceal 
bleeding, 
ascites, 
encephalopathy, liver transplant, spontaneous bacterial peritonitis, and hepatorenal 
syndrome.
1.3.3.2
Progression of Chronic Kidney Disease
CKD affects approximately 10% of the United States population [6] and is associated 
with multiple co-morbidities (eg. diabetes, hypertension, and cardiovascular disease). 
Thus, enrolling adult HCV-infected subjects with CKD (Stage 4 or 5, including subjects 
on dialysis) from the prior treatment study PN052 into PN017 offers an important 
opportunity to collect long-term data for this subpopulation. For HCV-infected adult 
 
 
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subjects with the co-morbidity of CKD, protocol-specified kidney related ECIs are 
collected, including change from baseline in estimated glomerular filtration rate (eGFR), 
new onset diabetes, cryoglobulinemia, kidney graft rejection, post-transplantation 
glomerulonephritis, and kidney transplant.
1.3.3.3
Other (Cardiac and Neurologic)
Cardiovascular disease and neurologic disorders limited to transient ischemic attack or 
stroke will be collected as ECIs for all adult subjects. These are adverse events associated 
with both liver and kidney disease; as such, cardiovascular disease (angina and 
myocardial infarction), transient ischemic attack, and stroke will be evaluated in all adult 
subjects.
1.4
SUMMARY OF STUDY DESIGN
PN017 is a multicenter, long-term follow-up study for HCV-infected adult and pediatric 
subjects previously treated with at least 1 dose of GZR in a prior treatment study. The 
subject’s age at the time of screening in the prior treatment study will be used for PN017 
criteria, procedures, and analyses. 
1.4.1
Adult Population
Eligible adult subjects enrolled in PN017 will be followed for up to 7 study visits across 3 
years (or up to 11 study visits across 5 years for subjects from prior treatment study 
PN052) after the prior treatment study. Additional visit(s) may be conducted for viral 
confirmation as determined by the investigator.
Evaluation of the adult population enrolled in PN017 will include: 1) the durability of 
response in subjects who had achieved SVR24, 2) the development and persistence of 
virologic resistance, and/or 3) the progression of liver disease and co-morbid conditions 
in all subjects and the progression of kidney disease in subjects with CKD. Assessments 
evaluated for each adult subject will depend on the subject’s prior treatment study and 
whether enrolled into this study prior to or after AM 03.
1.4.2
Pediatric Population
Eligible pediatric subjects enrolled in PN017 will be followed for up to 7 study visits 
across 3 years after prior treatment study PN079 to evaluate the persistence of virologic 
resistance. Additional visit(s) may be conducted for viral confirmation as determined by 
the investigator.
1.5
STUDY POPULATION
The subject’s age at the time of screening for the prior treatment study will be used for 
PN017 criteria, procedures, and analyses.
 
 
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1.5.1
Adult Population
Prior to AM 03, all HCV-infected adult subjects previously treated with GZR in a prior 
treatment study were eligible for enrollment into PN017.

AM 03 limited study eligibility to HCV-infected subjects who had either: 1) failed 
a GZR-containing therapy in a prior treatment study or 2) had CKD and received 
at least 1 dose of GZR in prior treatment study PN052. Starting with AM 03, the 
following adult subjects were discontinued from PN017 based on the new 
eligibility criteria: Subjects who had achieved SVR in a prior treatment study 
(other than PN052).

Subjects who had failed GZR-containing therapy in a prior treatment study and 
received retreatment with a different HCV therapy (either prior to or during active 
participation in PN017).
1.5.2
Pediatric Population
Enrollment is limited to  subjects who experienced virologic failure associated with 1 or 
more treatment-emergent RASs present at 12 weeks after receiving GZR treatment in 
prior treatment study PN079.
1.6
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN
No treatments will be administered.
 
 
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1.7
STUDY FLOW CHART
There are 2 flow charts for this study, 1 for adult subjects and 1 for pediatric subjects. The subject’s age at the time of entering the 
prior treatment study will be used for PN017 procedures.
1.7.1
Adult Population
Visit No.
18
2
3
4
5
6
7
813
913
1013
1113
12
Year 1
Year 2
Year 3
Year 4
Year 5
STUDY PROCEDURES1
Screen/
Baseline4
Mo. 
6
Mo. 
12
Mo. 
18
Mo. 
24
Mo. 
30
Mo. 
3611
Mo. 
42
Mo. 
48
Mo. 
54
Mo. 
6011
(Unscheduled) Viral 
Confirmation Visit10
Informed Consent
X
Informed Consent for FBR 2
X
Provide Subject Identification Card
X
Medical History 12
X
Inclusion/Exclusion Criteria
X
CLINICAL EVALUATIONS
Directed Physical Examination (PE)
X
X
X
X
X
X
X
Child-Pugh score computation
X
X
X
X
X
X
X
Blood pressure (systolic and diastolic) and
heart rate
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
Height
X
Review procedure related AEs, ECIs, and 
drug-related SAEs3
X
X
X
X
X
X
X
X
X
X
X
X
LABORATORY SAFETY EVALUATIONS
Chemistry, hematology,  and coagulation 
panel
X
X
X
X
X
X
X
X
MELD score (with and without dialysis)
X
X
X
X
X
X
X
Fibrosure® (Fibrotest®)
X
X
X
X
X
X
X
eGFR (if prior treatment study was PN052)
X
X
X
X
X
X
X
HCV EVALUATIONS
HCV RNA Level5
X
X
X
X
X
X
X
X
X
X
X
X
Viral Resistance and Biomarker6
X
X
X
X
X
X
X
X
X
X
X
X
Blood  (DNA) for FBR7
X
Blood (Plasma) for FBR7
X
HCV Genotype9
X
X
 
 
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Visit No.
18
2
3
4
5
6
7
813
913
1013
1113
12
Year 1
Year 2
Year 3
Year 4
Year 5
STUDY PROCEDURES1
Screen/
Baseline4
Mo. 
6
Mo. 
12
Mo. 
18
Mo. 
24
Mo. 
30
Mo. 
3611
Mo. 
42
Mo. 
48
Mo. 
54
Mo. 
6011
(Unscheduled) Viral 
Confirmation Visit10
AE=adverse event; DNA=deoxyribonucleic acid; ECI- event of clinical interest; eGFR=estimated glomerular filtration rate; FBR=future biomedical research; HCV=hepatitis C 
virus; MELD=Model for End Stage Liver Disease; Mo.=month; RNA=ribonucleic acid; SAE=serious adverse event
1
Visits should be scheduled as close to the indicated study period as possible.  Visit windows are +/- 3 months. All visits should be recorded on the actual date that they occur 
and any missed or late visits must be documented accordingly.
2     Participation in FBR is voluntary and is not required in order to participate in the study.
3
Protocol specified ECIs, AEs related to protocol-specified procedures (blood draw), and drug related new Serious Adverse Events, which occur following enrollment in the 
present study (after Informed Consent Form is signed) will be reported.
4
If a subject is directly entered into this long-term follow-up protocol on the same day as the last study day of the prior treatment study, since these visits have different 
laboratory requirements, the lab kit for each of the two visits must be used.  Samples are collected for each study separately at the same visit. (See section 3.2.4.1)
5
Subjects who achieved SVR in previous study and who are tested in this study and found to have HCV RNA ≥1000 IU/mL, will have their Viral Resistance sample tested. 
6
HCV sequence analysis will be performed, as appropriate, and will depend on the HCV-RNA level results.  
7
Informed consent for future biomedical research samples must be obtained before the DNA and plasma samples are collected.
8
The screening visit should occur within 3 months of the last visit of the previous protocol.
9
Subjects who had HCV RNA < LLoQ at the end of follow-up in the original treatment protocol and who are tested and have HCV-RNA ≥LLoQ during this study will have 
their HCV Genotype obtained.  If a subject has HCV RNA ≥LLoQ at Visit 1, an HCV Genotype must be performed at that visit.
10 If the unscheduled visit is being performed for follow-up of an AE/SAE (as defined in this protocol), a directed physical exam and safety labs should also be performed at this 
visit.
11 For subjects in the 3 year follow-up who discontinue early, a Visit 7 (Month 36) Visit should be completed as the early discontinuation visit. For subjects in the 5 year follow-
up (eg. PN052) who discontinue early, a Visit 11 (Month 60) visit should be completed as the early discontinuation visit.
12 Refer to Section 3.2.4.1 for required medical history.
13  Visits 8, 9, 10, and 11 will only be performed if subjects were in PN052 as their parent study.
 
 
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1.7.2
Pediatric Population 
Visit No.
15
2
3
4
5
6
7
Unscheduled Visit6
Year 1
Year 2
Year 3
STUDY PROCEDURES1
Screen/Baseline4
Mo. 6
Mo. 12
Mo. 18
Mo. 24
Mo. 30
Mo. 367
Informed Consent/Assent
X
Informed Consent/Assent for FBR2
X
Provide Subject Identification Card
X
Inclusion/Exclusion Criteria
X
Medical History 
X
CLINICAL EVALUATIONS
Directed Physical Examination 
X
X
X
X
X
Weight
X
X
X
X
X
Height
X
X
X
X
X
Date of menarche (females only)
X
X
X
X
X
X
X
Procedure Related AEs and drug-related 
SAEs3
X
X
X
X
X
X
X
X
HCV EVALUATIONS
HCV RNA Level and sequence analysis8
X
X
X
X
X
X
X
X
Viral Resistance and Biomarker8
X
X
X
X
X
X
X
X
AE=adverse event; DNA=deoxyribonucleic acid; FBR=future biomedical research; HCV=hepatitis C virus; Mo.=month; RNA=ribonucleic acid; SAE=serious adverse event
1  Visits should be scheduled as close to the indicated study period as possible. Visit windows are +/- 3 months. All visits should be recorded on the actual date that they occur and 
any missed or late visits must be documented accordingly.
2
Participation in FBR is voluntary and is not required in order to participate in the study.
3
AEs related to protocol-specified procedures (blood draw) and drug related new Serious Adverse Events, which occur following enrollment in the present study (after Informed 
Consent Form is signed) will be reported.
4
If a subject is directly entered into this long-term follow-up protocol on the same day as the last study day of the prior treatment study, only the lab kit from prior treatment 
study needs to be used.
5
The screening visit should occur within 3 months of the last visit of the previous protocol.
6
If the unscheduled visit is being performed for follow-up of an AE/SAE (as defined in this protocol), only a directed physical exam is needed at this visit.  If for follow-up of 
viral resistance, only HCV evaluations are needed.
7    For subjects who discontinue early, a Visit 7 (Month 36) should be completed as the early discontinuation visit.
8    Leftover main study plasma from HCV RNA and resistance will be stored for FBR if the subject/legally acceptable representative consents to FBR.
 
 
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2. CORE PROTOCOL
2.1
OBJECTIVES AND HYPOTHESES
2.1.1
Primary
2.1.1.1
Adult Population
In HCV-infected subjects who received at least 1 dose of GZR in a previous study:
1. Objective:  To evaluate the durability of response in subjects who achieved SVR24 in 
the prior treatment study and at the time of entry into PN017 were HCV ribonucleic 
acid (RNA) lower limit of quantification (LLoQ) (either target not detected [TND]
or target detected, unquantifiable [TD(u)]).  
2. Objective:  To evaluate the presence of treatment-emergent antiviral resistance to
NS3/4A, NS5A and/or NS5B regions, (as applicable) and determine if there is a 
reversion to wild-type pattern within the 3-year time frame of this long-term follow-
up study (or 5-year time frame for subjects from PN052) in subjects with virologic 
failure in the prior treatment study and with HCV RNA ≥1000 IU/mL in Protocol 
017.
3. Objective:  To evaluate the long-term safety.
2.1.1.2
Pediatric Population
In HCV-infected subjects who received at least 1 dose of GZR in a previous study:
1.
Objective: To evaluate the persistence of treatment-emergent antiviral resistance to 
NS3 and NS5A regions within the 3-year time frame of this long-term follow-up study.
2.1.2
Exploratory (Adult Population Only)
1. Objective: To assess liver function using the Model for End-Stage Liver 
Disease (MELD) and/or Child-Pugh scores in all adult subjects.
2. Objective: To assess CKD status by assessing change in estimated glomerular 
filtration rate (eGFR) in subjects from PN052.
3. Objective: To assess complication of CKD by recording new onset diabetes, 
cryoglobulinemia, cardiovascular disease, and/or neurologic disorders (such as 
stroke) in subjects from PN052. 
4. Objective: To assess health outcomes by recording the occurrence of variceal 
bleeding, ascites, spontaneous bacterial peritonitis, encephalopathy, hepatorenal 
syndrome, hepatocellular carcinoma, liver or kidney transplantation, and graft 
rejection in subjects who have undergone liver or kidney transplantation.
 
 
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2.2
SUBJECT INCLUSION CRITERIA (ADULT AND PEDIATRIC
POPULATIONS)
Inclusion criteria apply to both adult and pediatric populations unless otherwise noted.
1. Subjects previously participated in a HCV treatment study and received GZR in the 
treatment regimen.
2. Subject must enroll in PN017 (Visit 1) within 3 months of the last study visit (e.g.
follow-up week [FW] 24) of the prior treatment study in which they received a GZR
containing regimen.  
3. Subject is male or female 3 years of age or older on day of signing informed 
consent/assent.
4. Subject or subject’s legally acceptable representative provides written informed 
consent (or written informed assent where applicable).  Subjects who have consented 
for the study may also provide consent/assent for Future Biomedical Research (FBR).  
However, the subject may participate in PN017 without consenting/assenting for
FBR.
5. Starting with AM 03: Adult subject must have received at least 1 dose of a GZR-
containing regimen in the prior treatment study and identified as having failed therapy
in that study.
6. Pediatric subject must have received at least 1 dose of a GZR-containing regimen and 
experienced virologic failure with 1 or more associated treatment-emergent RASs at 
FW12 in PN079.
2.3
SUBJECT EXCLUSION CRITERIA (ADULT AND PEDIATRIC
POPULATIONS)
Exclusion criteria apply to both the adult and pediatric populations.
1. Adult subjects: In the opinion of the investigator, subject is mentally or legally 
incapacitated at entry into PN017.
Pediatric subjects: The subject has significant emotional problems or a clinically 
significant psychiatric disorder that may interfere with participant treatment, 
assessment, or compliance with the protocol.
2. Subject has received HCV therapy after completion of the prior treatment study and
before entry into PN017.
3. Starting with AM 03: subjects who failed therapy due to re-infection, defined as:

an HCV RNA sample with a different genotype than the baseline genotype in the 
prior treatment study, or
 
 
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
an HCV RNA sample determined to be reinfection by phylogenetic analysis with 
comparison to the baseline sequence in the prior treatment study.
4. Starting with AM 03: subjects who failed therapy in the prior treatment study and 
received retreatment with HCV therapy.
2.4
STUDY DESIGN AND DURATION
2.4.1
Summary of Study Design
This is a multicenter long-term follow-up study for subjects previously treated with at 
least one dose of GZR in a Merck-sponsored clinical study.
2.4.1.1
Adult Population
Prior to AM 03, all HCV-infected adult subjects previously treated with GZR in a Merck-
sponsored clinical study (parent study) were eligible for enrollment into PN017.
Starting with AM 03, several significant changes have been made to the study design and 
duration: 
1.
New enrollment will be limited to those who failed therapy in the prior treatment 
study.
2.
Subjects in PN017 with virologic failure at FW24 in the prior treatment study will 
continue for 3 years of follow-up (other than PN052 subjects) or 5 years of follow-
up (PN052 subjects).
3.
Subjects (other than PN052 subjects) in PN017 who entered with HCV RNA <LLoQ 
were discontinued after the next scheduled visit.
4.
Subjects who receive a new HCV therapy regimen during PN017 will be 
discontinued.
5.
The enrollment window is 3 months after the last visit in the prior treatment study.
There are a total of 7 study visits (11 study visits for PN052 subjects) and, as needed, a 
viral confirmation visit.
2.4.1.2
Pediatric Population
The anticipated duration is 3 years for pediatric subjects. Subject enrollment is limited to 
subjects from PN079 who experienced virologic failure associated with 1 or more 
treatment-emergent RASs present at FW12. There are a total of 7 study visits and, as 
needed, a viral confirmation visit. Pediatric subjects who receive a new HCV therapy 
regimen during PN017 will be discontinued.
2.4.2
Treatment Plan
Not applicable.
 
 
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2.5
LIST OF EFFICACY/PHARMACOKINETIC/IMMUNOGENICITY 
MEASUREMENTS
The following measurements are applicable for the adult and pediatric populations.
HCV Genotype
Samples will be genotyped using the Food and Drug Administration (FDA) approved 
Abbott HCV Real Time Genotype II assay which detects HCV GT1a, 1b, 2, 3, 4, 5, and 6
through the use of genotype-specific fluorescent-labeled oligonucleotide probes in a real-
time reverse transcriptase-polymerase chain reaction (RT-PCR) assay. The RT-PCR 
reaction uses 3 sets of HCV specific amplification primers targeting the conserved 
5’untranslated region (for all genotypes) and NS5B regions from GT1a and 1b. The assay 
has accuracy of >96% for GT1, 1a, 1b, 2, 3 and 4, 89% for GT5 and 83% for GT6 with 
100% specificity in HCV serologically negative plasma samples. Phylogenetic analyses 
will be performed using sequences for NS3/4A, NS5A and NS5B to ensure accurate 
assignment of sample genotype/subtype.
HCV RNA
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. HCV RNA definitions are 
presented in Table 1.
Table 1
HCV RNA Definitions
Abbreviation
Definition
HCV RNA Level
TND
Target not detected
HCV RNA not detected
TD(u)
Target detected, unquantifiable
HCV RNA < LLoQ
TD(q)
Target detected, quantifiable
HCV RNA ≥ LLoQ
HCV=hepatitis C virus; LLoQ=lower limit of quantification; RNA=ribonucleic acid
For subjects enrolled prior to AM 03, durability of virologic response will be assessed in 
all subjects who are HCV RNA <LLoQ (either TND orTD[u]) on Day 1 of entry into this 
protocol and excluding any subject who is TND/TD(u) due to having received an anti-
viral treatment after having failed previous therapy in the parent study.
Failure of therapy due to relapse more than 24 weeks after the end of therapy (termed late 
relapse) in this group of subjects will be measured as an HCV RNA that is confirmed to 
be >LLoQ and is not due to a new infection or re-infection. Confirmation is defined as an 
HCV RNA that is target detected, quantifiable (TD[q]) from a separate blood draw 
repeated in approximately 4 weeks.
 
 
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Subjects who entered this protocol with HCV RNA TND or TD(u) and without 
confirmation of having failed therapy in the prior treatment study will be categorized as 
maintaining SVR. These subjects will be assessed for late relapse at every visit in this 
protocol, including the entry visit.  See Table 2 below for actions and interpretations 
based on HCV RNA results of scheduled and viral confirmation visits.
Table 2
Actions and interpretations based on HCV RNA results of scheduled and Viral 
Confirmation visits
Scheduled Visit 
Result
Action
Result of Viral 
Confirmation
Interpretation
TND
None
N/A
SVR
TD(u)
None
N/A
SVR
TD(q)
Not previously 
determined to be a 
relapse, e.g. first 
time HCV RNA ≥ 
LLoQ
Viral 
Confirmation 
Visit
TND/TD(u)
SVR
≥TDq
Relapse
HCV=hepatitis C virus; LLoQ=lower limit of quantification; RNA=ribonucleic acid; SVR=sustained 
virologic 
response; 
TND=target
not 
detected;
TD(q)=target 
detected, 
quantifiable; 
TD(u)=target detected, unquantifiable
Any relapse subject with HCV RNA ≥1000 IU/mL will have a sequence analysis performed on all 
samples where HCV RNA ≥1000 IU/mL.
Viral Resistance Measurements
A viral resistance sample will be collected for every subject at every visit.  For subjects 
with HCV RNA ≥LLoQ (TD[q]) sequence analysis will be performed if HCV RNA 
≥1000 IU/mL.
2.6
LIST OF SAFETY MEASUREMENTS
2.6.1
Adult Population
The long-term safety will be assessed by twice yearly study visits.  Once yearly, there 
will be a directed physical exam and standard laboratory safety tests.  Twice yearly, there 
will be a collection of ECIs (as specified in Section 3.4.3.2), any adverse events (AEs)
related to protocol-specified procedures (blood draw), and drug-related serious adverse 
events (SAEs) as specified in the study flow chart in Section 1.7.1. For details on ECIs 
collected, see Section 3.4.3.2. 
 
 
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Hematologic/Chemistry Measurements
The following laboratory tests will be performed yearly:

Hematology- hemoglobin (Hgb), hematocrit (HCT), red blood cell (RBC) count, 
white blood cell (WBC) count, lymphocytes, neutrophils, and platelet count;

Chemistry- alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
creatinine, alkaline phosphatase, total bilirubin (direct and indirect), urea nitrogen, 
total protein, albumin, and glucose;

Coagulation panel-
including prothrombin time (PT), activated partial 
thromboplastic time (aPTT), and international normalized ratio (INR) of the 
prothrombin time; and

Computed MELD score- Sponsor will calculate based on available data for study 
visit for all adult subjects (at the time of entry in the prior treatment study).
2.6.2
Pediatric Population
The long-term safety will be assessed by twice yearly study visits.  Once yearly, there 
will be a directed physical exam.  Twice yearly, there will be a collection of any AEs 
related to protocol-specified procedures (blood draw) and drug related SAEs as specified 
in the study flow chart in Section 1.7.2. There are no ECIs or laboratory safety tests 
collected for the pediatric population.
2.7
STATISTICAL ANALYSIS PLAN SUMMARY
Key elements of the statistical analysis plan (SAP) are summarized below; the 
comprehensive plan is provided in Section 3.5.  The adult population and pediatric 
population will be summarized separately.
2.7.1
Efficacy Analyses
2.7.1.1
Adult Population
The primary endpoints, primary analysis population, and statistical methods that will be 
employed for the efficacy analyses in the adult population are presented in Table 3. 
There will be no formal efficacy hypothesis testing conducted in this study.
The primary efficacy objectives of this study are to evaluate the durability of response in 
subjects who achieved SVR in the prior treatment study, as follows, and the evaluation 
of antiviral resistance to GZR, as described in 2.7.3.  
Durability of SVR will primarily be evaluated based upon the time to viral relapse, which 
is defined as the time from last dose of study therapy taken in the prior treatment study
until the date where HCV RNA is ≥LLoQ (see Section 2.5).  The analysis population for 
the time to relapse analysis will be all subjects who achieved SVR during the follow-up 
 
 
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period of the prior treatment study and did not start any new HCV therapy between the 
end of the prior treatment study and entry in this study.  
The distribution of time to viral relapse will be summarized using Kaplan-Meier 
estimates.  In addition, the percentage of subjects who remain HCV RNA <LLoQ during 
the course of this study will be summarized.
Subjects who receive other treatments for HCV concurrently with this protocol or prior to 
PN017 and after completion of therapy in the prior treatment study will be discontinued 
from PN017, and their data excluded from analysis from the time of initiation of new 
therapy. 
Table 3
Summary of Analysis Strategy for Key Efficacy Endpoints
(Adult Population)
Endpoint/Variable
Statistical Method
Analysis Population
Missing Data
Approach
Primary:
Durability of SVR 
(Time to viral relapse)
Kaplan-Meier plot and 
summary statistics  
All adult subjects entered who 
achieved SVR in the prior treatment 
study and who did not start new HCV 
treatment between end of the prior 
treatment study and study entry in 
PN017.
Data as 
Observeda
Antiviral resistance 
Descriptive statistics
RAS Analysis Population is defined as 
allocated adult subjects who met 
Virologic Failure criteria in the prior 
treatment study or up to entry into 
PN017 and who entered PN017 with 
TD(q) HCV RNA, excluding subjects 
who were reinfected or who meet any 
of the following criteria: Failure to 
receive at least 1 dose of GZR in the 
prior treatment study or subject had 
another protocol violation.
Data as 
Observed
GZR=grazoprevir; HCV=hepatitis C virus; LLoQ=lower limit of quantification; PN=protocol number; 
RAS=resistance associated substitution(s); RNA=ribonucleic acid; SVR=sustained virologic response
aSubjects who discontinue without relapsing will be censored at the time of discontinuation. 
2.7.1.2
Pediatric Population
There will be no efficacy assessment of durability of long-term SVR in this population as 
enrollment in this study will be limited to pediatric subjects who were virologic failures 
and had treatment emergent RAS present at FW12 in the prior treatment study.
 
 
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2.7.2
Safety Analyses
2.7.2.1
Adult Population
The safety analyses will be based on data from all adult subjects entering the study.  
Long-term safety, drug-related SAEs, ECIs, any AEs related to protocol-specified 
procedures (blood draw), and laboratory data will be summarized for all adult subjects 
using descriptive statistics.  Follow-up data collected after a subject started HCV 
treatment will be summarized separately.
2.7.2.2
Pediatric Population
The safety analyses will be based on data from all pediatric subjects entering the study.  
Long-term safety, any AEs related to protocol-specified procedures (blood draw), and 
drug-related SAEs will be summarized for all pediatric subjects using descriptive 
statistics.
2.7.3
Analysis of Resistant Associated Substitutions
2.7.3.1
Adult Population
The evaluation of antiviral resistance to GZR will be obtained on subject samples with 
HCV RNA ≥1000 IU/mL at study entry or during the course of this study; the presence of 
RASs and the persistence of RASs over time will be summarized using descriptive 
statistics, with subgroup analyses by class of regimen (e.g. NS3/4A inhibitors, NS5A 
inhibitors and NS5B inhibitors) as well as by specific components (Table 3). Only 
subjects who experienced virologic failure (other than reinfection) will be included in 
these analyses.
2.7.3.2
Pediatric Population
The primary endpoints, primary analysis population, and statistical methods that will be 
employed for the RAS analyses in the pediatric population are presented in Table 4. 
Table 4
Summary of Analysis Strategy for Resistant Associated Substitutions
(Pediatric Population)
Endpoint/Variable
Statistical Method
Analysis Population
Missing Data 
Approach
Primary:
Antiviral resistance 
Descriptive statistics
RAS Analysis Population is defined as 
allocated pediatric subjects who met 
Virologic Failure criteria in the prior 
treatment study with treatment emergent 
RAS present at follow-up Week 12, 
excluding subjects who were reinfected or 
who meet any of the following criteria: 
Failure to receive at least one dose of GZR
in the prior treatment study or subject had 
another protocol violation.
Data as 
Observed
GZR=grazoprevir; HCV=hepatitis C virus; LLoQ=lower limit of quantification; PN=protocol number; 
RAS=resistance associated substitution(s); RNA=ribonucleic acid; SVR=sustained virologic response
 
 
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2.7.4
Power and Sample Size
The sample size of this study is not pre-set.  
2.7.5
Interim Analysis
Annual reporting of data available may be performed, as necessary.
 
 
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3. PROTOCOL DETAILS
3.1
RATIONALE
3.1.1
Rationale for This Study
For the rationale for this study refer to Section 1.3.
3.1.2
Rationale for Future Biomedical Research
Conduct of FBR applies to both adult and pediatric subjects who provided consent/assent 
for FBR.
Merck will conduct FBR on blood (deoxyribonucleic acid [DNA]) and blood (plasma)
specimens collected during this clinical study.  This research may include genetic 
analyses (DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, 
plasma) and/or the measurement of other analytes. Samples may also be used for future 
assay development.
Such research is for biomarker testing to address emergent questions not described 
elsewhere in the protocol (as part of the main study) and will only be conducted on 
specimens from appropriately consented subjects. The objective of collecting specimens 
for FBR is to explore and identify biomarkers that inform the scientific understanding of 
diseases and/or their therapeutic treatments.  For instance, exploratory pharmacogenetics 
(PGt) studies may be performed if significant Pharmacokinetic (PK)/Pharmacodynamic 
(PD) relationships are observed or AEs are identified.  Genomic markers of disease may 
also be investigated. Such retrospective pharmacogenetic studies will be conducted with 
appropriate biostatistical design and analysis and compared to PK/PD results or clinical 
outcomes.  Any significant PGt relationships to outcome would require validation in 
future clinical studies.  The overarching goal is to use such information to develop safer, 
more effective drugs, and/or to ensure that subjects receive the correct dose of the correct 
drug at the correct time.  The details of the FBR sub-study are presented in Appendix 6.1.  
Additional informational material for institutional review boards/ethics committees 
(institutional review boards [IRB]/ ethical review committees [ERC]) and investigational 
site staff is provided in Section 7.
3.2
STUDY PROCEDURES
There are a total of 7 study visits (11 study visits for PN052 subjects) and, as needed, a 
viral confirmation visit.   
3.2.1
Subject Population 
Only adult and pediatric subjects who received at least 1 dose of GZR in a previous 
Merck-sponsored clinical study are eligible for enrollment in PN017. For full details on 
adult and pediatric subjects eligible for enrollment in this study, refer to Sections 2.4.1.1 
and 2.4.1.2, respectively.
 
 
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3.2.2
Concomitant Medication(s)/Treatment(s)
3.2.2.1
Adult Population
In the original protocol, subjects were permitted to participate in other treatment studies 
for HCV concurrently with this protocol.  
Starting with AM 03, subjects are not permitted to receive any therapies used for the 
treatment of HCV concurrently with this protocol. 
3.2.2.2
Pediatric Population
Pediatric subjects enrolled in this study are required to discontinue from the study if they 
receive any HCV therapy.
3.2.3
Diet/Activity/Other
There are no dietary or activity restrictions for this study.
3.2.4
Procedures
Unless otherwise noted, the procedures described below apply to both adult and pediatric 
subjects.
Procedures visits should be scheduled as close to the indicated study weeks as possible 
but must be performed within +/- 3 months.  Refer to the Study Flow Charts in Section 
1.7 for a complete listing of study procedures required at each study visit.
3.2.4.1
Screening/Baseline Visit (Visit 1)
Within 3 months of the last visit (e.g. FW24) of their prior treatment study, potential 
subjects will be evaluated to determine if they fulfill the Inclusion/Exclusion entry 
requirements as described in Sections 2.2 and 2.3, respectively.  The investigator will 
discuss with each potential subject the nature of the study, its requirements, and its 
restrictions.  Informed consent/assent, as described below, must be obtained prior to 
initiation of any screening/baseline procedures or evaluations.
All procedures must be completed and subject eligibility confirmed by the investigator 
prior to the subject receiving an allocation number by the study site.  
Electronic transfer of data from the prior treatment study will occur for the following 
data:

Dosage and length of therapy (start date/end date) of GZR from the prior 
treatment study

All HCV RNA

Date declared relapse in prior treatment study (if applicable)

HCV Genotype
 
 
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
All sequence analysis 

All laboratory results:
o
Hemoglobin
o
Hematocrit
o
Red Blood Cell Count
o
Total White Blood Cell count
o
Lymphocytes
o
Neutrophils
o
Platelet Count
o
ALT
o
AST
o
Creatinine
o
eGFR (if prior treatment study was PN052)
o
Alkaline phosphatase
o
Total Bilirubin (direct and indirect)
o
Urea nitrogen
o
Total Protein
o
Albumin
o
Glucose
o
Coagulation panel: PT, INR and aPTT
In addition, the following information will be collected at the screening/baseline visit and 
must be manually entered into the data collection system:

Protocol number and subject allocation number from the prior treatment study.

Name, dosages and length of therapy (start date/end date) of all other HCV 
therapies including other research protocols or standard of care.

For adult subjects, the following medical history terms, which occurred after the 
prior treatment study and before study entry, will be collected:
o
Spontaneous bacterial peritonitis;
o
Variceal bleeding;
o
Ascites;  
o
Encephalopathy;
o
Hepatorenal syndrome;
o
Hepatocellular carcinoma (collected as an ECI);
o
Change in chronic kidney disease as assessed by eGFR (collected as an ECI);
o
Liver transplant;
o
Kidney transplant (PN052 subjects; collected as an ECI);
o
New onset diabetes, cryoglobulinemia, cardiovascular disease limited to new 
onset angina, myocardial infarction, or neurologic disorders limited to
transient ischemic attack (TIA) or stroke; 
 
 
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o
Graft rejection in subjects
who have undergone liver
or kidney 
transplantation; and
o
Post transplantation glomerulonephritis.
In some cases, the subject may have a combined visit (the initial visit for PN017 occurs
on the same day as the last study day of the prior treatment study).  For adult subjects, the 
lab kit from each study for its designated visit must be used so that samples are collected 
for each study separately at the same visit. For pediatric subjects, only one lab kit is 
required as there are no additional tests for PN017.
All subjects will be given a card, at the time of screening, identifying them as subjects in 
a research study.  The card will contain contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.
3.2.4.2
Informed Consent/Assent (Adult and Pediatric Populations)
The investigator or qualified designee must obtain documented consent, and assent if 
applicable, from each potential subject or each subjects’ legally acceptable representative 
prior to participating in a clinical trial or FBR. If there are changes to the subjects’ status 
during the study (eg, health or age of majority requirements), the investigator or qualified 
designee must ensure the appropriate consent/assent is in place.
3.2.4.2.1
General Informed Consent/Assent
Consent/assent must be documented by the subject’s dated signature or by the subjects’
legally acceptable representative’s dated signature on a consent/assent form along with 
the dated signature of the person conducting the consent/assent discussion. 
A copy of the signed and dated consent/assent form should be given to the subject/legally 
acceptable representative before participation in the study.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form and any written information provided to the subject/legally 
acceptable representative must receive the IRB/IEC’s approval/favorable opinion in 
advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant 
to the subject’s/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 subject’s dated signature or by the subject’s
legally acceptable 
representative’s dated signature.
Specifics about a study and the study population will be added to the consent/assent form 
template at the protocol level.  
The informed consent/assent will adhere to IRB/IEC requirements, applicable laws and 
regulations and Sponsor requirements. 
 
 
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3.2.4.2.1.1
Consent/Assent and Collection of Specimens for Future Biomedical 
Research
The investigator or qualified designee will explain the FBR consent/assent to the subject
or the subject’s legally acceptable representative, answer all of his/her questions, and 
obtain written informed consent/assent before performing any procedure related to the 
FBR sub-trial.  A copy of the informed consent/assent will be given to the subject or the 
subject’s legally acceptable representative.
The following specimens are to be obtained as part of FBR for adult subjects:

Blood (DNA) for genomics use; and

Blood (Plasma) for FBR
For pediatric subjects, leftover plasma may be used for FBR only if the subject/legally 
acceptable representative signed for FBR consent/assent.
3.2.4.3
Assignment of Baseline (Screening) Number (Adult and Pediatric 
Populations)
For identification purposes during the pre-study (screening) period, each subject will be 
assigned a unique baseline (screening) number from the group of numbers provided by 
the SPONSOR.  Once a baseline number has been assigned to a subject, the baseline 
number should not be reassigned for any reason.  If a subject needs to be rescreened for 
any reason, the same baseline number will be used.
3.2.4.4
Randomization/Allocation (Adult and Pediatric Populations)
Subjects will not be randomized in this study.  Subjects will be assigned an allocation 
number by interactive voice/web response system (IXRS).
A single subject cannot be assigned more than 1 allocation number.
3.2.4.5
Years Post Entry Into Study, Years 1 through 3 (Visits 2 through 7): Adult 
and Pediatric Populations
All procedures for Visits 2 through 7 should be performed for adult and pediatric subjects 
entering the study as indicated on the Study Flow Charts in Section 1.7.1 and Section 
1.7.2, respectively.  After initiation of AM 03, not all subjects will complete all visits 
through Visit 7.  
3.2.4.6
Years 4 and 5 Post Entry (Visit 8 through 11): Adult Population
Subjects from PN052 will have a year 4 and year 5 visit.  
With initiation of AM 03, follow-up beyond year 3 will no longer be necessary for 
subjects enrolling from PN059.  
 
 
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3.2.4.7
Treatment/Evaluation/Follow-Up
Not applicable.  This is a long-term follow-up study and no treatments will be 
administered. 
3.2.4.8
Discontinuation/Withdrawal from Study (Adult and Pediatric Populations)
Subjects may withdraw at any time or be dropped from the study at the discretion of the 
investigator should any untoward effects occur. In addition, a subject may be withdrawn 
by the investigator or the SPONSOR if he/she violates the study plan or for 
administrative and/or other safety reasons. The investigator or study coordinator must 
notify the SPONSOR immediately when a subject has been discontinued/ withdrawn due 
to an adverse experience (telephone or FAX). When a subject discontinues/withdraws 
prior to study completion, all applicable activities scheduled for the final study visit 
should be performed at the time of discontinuation. Any AEs which are present at the 
time of discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 3.
3.2.4.8.1
Discontinuation/Withdrawal Criteria
With the exception of subjects previously enrolled in PN052, if a subject is discontinued 
early from the study the subject should complete their last visit as Visit 7 (Month 36). If a 
subject from PN052 is discontinued early from the study, the subject should complete 
their last visit as Visit 11 (Month 60).
A subject will be discontinued from the study for any of the following reasons:

The Investigator feels that it is in the best interest of the subject to discontinue.

Request 
of 
the 
subject/subject’s 
legally 
acceptable 
representative
(subject/subject’s legally acceptable representative has the right to discontinue 
from the study at any time for any reason).

Following AM 03 all subjects (except PN052) who entered PN017 with HCV 
RNA TND or TD(u) were discontinued. For these subjects, participation was
discontinued at the next scheduled visit for each subject.

Following AM 03, all subjects who initiated HCV treatment after enrollment in 
PN017 were discontinued.
3.2.4.9
Withdrawal From Future Biomedical Research (Adult and Pediatric 
Populations)
Subjects may withdraw their consent/assent for FBR and have their specimens and all 
derivatives destroyed.  Subjects/subject’s legally acceptable representative may withdraw 
consent/assent at any time by writing to the principal investigator for the main study. If 
medical records for the main study are still available, the Investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com), and 
a form will be provided by the Sponsor to obtain appropriate information to complete 
 
 
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specimen withdrawal. Subsequently, the subject's specimens will be removed from the 
biorepository and be destroyed. A letter will be sent from the Sponsor to the investigator 
confirming the destruction. It is the responsibility of the Investigator to inform the subject 
of completion of destruction. Any analyses in progress at the time of request for 
destruction or already performed prior to the request being received by the Sponsor will 
continue to be used as part of the overall research study data and results. No new 
analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (e.g., if 
the investigator is no longer required by regulatory agencies to retain the main study
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens.  In this situation, the 
request for specimen destruction cannot be processed.  
3.3
DURABILITY, VIRAL RESISTANCE, AND SAFETY MEASUREMENTS
3.3.1
Clinical and Laboratory Measurements for Durability, Viral Resistance, and 
Safety
3.3.1.1
Adult Population
The primary measurement for durability of response in this study is repeat HCV RNA 
measurements at all study visits.  Resistance will be assayed by sequence analysis, and 
safety will be assessed by directed physical exam, standard laboratory safety tests, and 
collection of ECIs, any AEs related to protocol-specified procedures (blood draw), and 
drug related SAE's at each visit as specified in the study flow chart in Section 1.7.1.
Clinical Evaluations

Directed Physical Examination: Yearly as described in the flow chart.
o
The examination must be performed by the Principal Investigator or Sub-
Investigator (physician, physician assistant or nurse practitioner) listed on 
FDA Form 1572 or equivalent document.

Collection of therapies used for the treatment of HCV:  All visits.
NOTE: Following AM 03, all subjects who initiated HCV treatment after 
enrollment in PN017 were discontinued.

Childs-Pugh Score: Computed from safety laboratory data and clinical assessment 
obtained at baseline and every year for adult subjects
o
http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality/

Blood pressure and heart rate

Weight and height
 
 
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
Review procedure related AEs, ECIs, and drug-related SAEs
Unscheduled Visits:  

Unscheduled visits may be performed at any time at the discretion of the 
Investigator.
Laboratory Safety Evaluations
The following will be collected (as defined in Section 2.6.1):

Chemistry (Abbreviated Non-fasting), hematology, and coagulation panel-
collected yearly, with an additional collection at 6 months; 

MELD score (with and without dialysis): Computed from safety laboratory data 
obtained at baseline, and every year for all adult subjects (at the time of entry in 
the prior treatment study).

Fibrosure® (Fibrotest®) - collected at 6 months post study entry and then yearly 
beginning at 12 months in all adult subjects (at the time of entry in the prior 
treatment study); and

eGFR (collected yearly in PN052 subjects only).
HCV Evaluations

HCV RNA quantitation - collected at all visits;
o
If any subject’s HCV-RNA result is increased from prior HCV RNA result 
(e.g. previously TND and now TD[u] or ≥LLoQ), the subject will be asked 
to return to the clinic within 14 days for a Viral Confirmation Visit (Visit 
8). Various scenarios, actions, and interpretations are described in Table 5
below.
o
Plasma samples for HCV-RNA must be obtained and processed as 
instructed by the central laboratory.

HCV Viral Resistance and Biomarker:  Collected at all visits, tested as 
appropriate.
o
HCV population sequence analysis will be conducted, as appropriate to 
evaluate the presence of HCV resistance associated substitutions in
NS3/4A, NS5A, or NS5B as appropriate and based on the regimen they 
received in the prior treatment study.  Sequence analysis will be performed 
on any sample with HCV RNA >1000 IU/mL using the viral resistance 
samples that are collected and stored at every visit.
 
 
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o
Protein, RNA levels, metabolites, bile acids, and other markers of disease 
may be measured from blood samples to compare biomarkers measured 
during the prior treatment study to biomarkers measured at various time 
points during this protocol.  An example of a method that may be used to 
measure protein levels is mass spectrometry.  Plasma samples will be 
digested into peptides by proteases.  These peptides will then be measured 
by mass spectrometry to determine the sequence and/or abundance of tens 
of thousands of peptides.  The pattern of peptides will be compared 
between subjects who respond to drug treatment and subjects who do not 
respond to treatment.  In addition to mass spectrometry, standard 
immunoassays for protein characterization such as enzyme-linked 
immunosorbent assays may be used to characterize levels of specific 
proteins identified by the mass spectrometry analysis.  RNA levels will be 
measured in blood samples by array hybridization and/or by Polymerase 
Chain Reaction.  Metabolites will be measured by mass spectrometry or 
other standard assays to identify and/or quantify thousands of metabolites 
in plasma.  For all of the plasma biomarkers measured, associations 
between relapse or response to drug treatment and biomarker levels will 
be assessed.

FBR Sample:  Screening/Baseline visit for adult subjects who provided consent.

HCV GT:  Collected at Baseline (if HCV RNA >LLoQ) and Viral Confirmation 
Visit.
o
If a subject achieved SVR at the end of follow-up in the prior treatment
study and, is tested and found to have HCV RNA quantifiable during this 
study, that first sample with quantifiable HCV RNA will be tested for 
HCV GT.  This is performed to determine if this is a relapse of the 
primary infection or a re-infection.
o
Plasma samples for HCV GT must be obtained and processed as instructed 
by the central laboratory.
 
 
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Table 5
Actions and Interpretations Based on HCV RNA Results of Scheduled and Viral 
Confirmation Visits
Scheduled Visit 
Result
Action
Result of Viral 
Confirmation
Interpretation
TND
None
N/A
SVR
TD(u)
None
N/A
SVR
TD(q)
Not 
previously 
determined to be a 
relapse, e.g. first 
time HCV RNA 
quantifiable
Viral Confirmation
Visit
TND/TD(u)
SVR
HCV 
RNA 
quantifiable
Relapse
HCV=hepatitis C virus; N/A=not applicable; RNA=ribonucleic acid; SVR=sustained virologic response;
TND=target not detected; TD(q)=target detected, quantifiable; TD(u)=target  detected but unquantifiable
Blood volumes collected at each visit are detailed in Appendix 6.2.1.
3.3.1.2
Pediatric Population
To assess persistence of virologic resistance, HCV RNA measurements will be taken at 
all study visits and resistance will be assayed by sequence analysis. Safety will be 
assessed by directed physical exam and collection of any AEs related to protocol-
specified procedures and drug-related SAEs at each visit as specified in the study flow 
chart in Section 1.7.2.
Clinical Evaluations

Directed Physical Examinations: Yearly as described in the flow chart.
o
The examination must be performed by the Principal Investigator or Sub 
Investigator (physician, physician assistant or nurse practitioner) listed on 
FDA Form 1572 or equivalent document.

Weight and height

Date of menarche (females only)

Review procedure-related AEs and drug-related SAEs
 
 
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Unscheduled Visits:

Unscheduled visits may be performed at any time at the discretion of the 
Investigator.
HCV Evaluations

HCV RNA quantitation – collected at all visits
o
Plasma samples for HCV-RNA must be obtained and processed as 
instructed by the central laboratory.

HCV Viral Resistance and Biomarker – collected at all visits, tested as 
appropriate.
o
HCV sequence analysis will be conducted, as appropriate, to evaluate the 
presence of HCV RASs in NS3/4A or NS5A as appropriate and based on 
the regimen they received in the prior treatment study.  Sequence analysis 
will be performed on any sample with HCV RNA 1000 IU/mL using the 
viral resistance samples that are collected and stored at every visit.
o
If consent/assent is obtained, protein, RNA levels, DNA, metabolites, bile 
acids, and other markers of disease may be measured from blood samples 
to compare biomarkers measured during the prior treatment study to 
biomarkers measured at various time points during this protocol.
Blood volumes collected at each visit are detailed in Appendix 6.2.2.
3.4
SAFETY MEASUREMENTS
3.4.1
Clinical and Laboratory Measurements for Safety
3.4.1.1
Adult Population
The long-term safety will be assessed by directed physical exam, standard laboratory 
safety tests, and collection of ECIs, AEs related to protocol-specified procedures (blood 
draw), and drug related SAE's at each visit as specified in the Study Flow Chart 1.7.1.  
3.4.1.2
Pediatric Population
The long-term safety will be assessed by directed physical exam and collection of AEs 
related to protocol-specified procedures and drug-related SAEs at each visit as specified 
in the Study Flow Chart 1.7.2.
3.4.2
Recording Adverse Experiences (Adult and Pediatric Populations)
ECIs, as described in Section 3.4.3.2 will be collected in the adult population.  In 
addition, any AEs related to protocol-specified procedures (blood draw) will be collected
in adult and pediatric populations.  All other AEs will not be collected in this long term 
follow-up study.
 
 
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An AE is defined as any unfavorable and unintended change in the structure, function, or 
chemistry of the body temporally associated with the use of the SPONSOR’s product, 
whether or not considered related to the use of the product. Any worsening (i.e., any 
clinically significant adverse change in frequency and/or intensity) of a preexisting 
condition which is temporally associated with the use of the SPONSOR’s product, is also 
an AE.
Changes resulting from normal growth and development which do not vary significantly 
in frequency or severity from expected levels are not to be considered AEs. Examples of 
this may include, but are not limited to, teething, typical crying in infants and children, 
and onset of menses or menopause occurring at a physiologically appropriate time.
AEs may occur in the course of the use of a Merck product in clinical studies or within 
the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse, and from withdrawal.
AEs may also occur in screened subjects during any preallocation baseline period as a 
result of a protocol-specified intervention including washout or discontinuation of usual 
therapy, diet, placebo treatment, or a procedure.
Such events will be recorded at each examination on the AE case report form
(CRF)/Worksheets.
3.4.3
Immediate Reporting of Adverse Events to the SPONSOR
3.4.3.1
Serious Adverse Events (Adult and Pediatric Populations)
The following will be collected during the study:

Drug related SAEs.

All deaths of any cause will be collected. 

Any SAE considered by an investigator who is a qualified physician to be 
possibly, probably, or definitely related to the investigational product that is 
brought to the attention of the investigator at any time outside of the time period 
specified in the previous paragraph also must be reported immediately to one of 
the individuals listed on the sponsor contact information page found in the 
administrative binder.
All subjects with SAEs must be followed for outcome.
Note: Any drug-related SAE, or death due to any cause, which occurs to a subject must 
be reported within 24 hours to one of the individual(s) listed on the contact information 
page.
 
 
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3.4.3.2
Events of Clinical Interest
3.4.3.2.1
Adult Population
ECIs will be recorded on the AE CRFs/Worksheets. ECIs defined for this protocol 
include:

Spontaneous bacterial peritonitis;

Variceal bleeding;

Ascites;  

Encephalopathy;

Hepatorenal syndrome;

Hepatocellular carcinoma; - Any hepatocellular carcinoma that occurred and was 
not previously reported in the prior treatment study should be reported as an ECI;

Liver transplant;

Kidney transplant (PN052 subjects only) – any kidney transplant that occurred 
and was not previously reported in the prior treatment study should be reported as 
an ECI;

Decreased eGFR calculated by the Modification of Diet in Renal Disease
equation (PN052 subjects will be analyzed for change from baseline in PN052);
o
For this study a decrease in eGFR is defined for subjects not on dialysis 
as:

CKD4 (15 to 30 ml/min/1.73 m2) in PN052 and is now CKD5 (<15 
ml/min/1.73 m2), 

CKD5 without dialysis in PN 052 and is now CKD5 with dialysis, 
OR

CKD4 in PN 052 and initiates dialysis  

New onset diabetes (PN052 subjects only);

Cryoglobulinemia (PN052 subjects only);

Cardiovascular disease limited to angina and myocardial infarction;

Neurologic disorders limited to TIA or stroke;

Graft rejection in subject who has undergone liver or kidney transplantation; or

Post transplantation glomerulonephritis (PN052 subjects only).
3.4.3.2.2
Pediatric Population
No ECIs are defined for pediatric subjects and will not be collected.
3.4.4
Evaluating Adverse Events (Adult and Pediatric Populations)
Refer to Table 6 for instructions in evaluating AEs.
 
 
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Table 6
Instructions for Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric studies, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric studies, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric studies, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse experience is any adverse experience occurring at any dose that:
†Results in death; or
†Is life threatening; or places the subject/patient, in the view of the investigator, at immediate risk of death from the experience as it occurred [Note: This does not 
include an adverse experience that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.)   (Note:  Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse experience.); or
†Is a congenital anomaly/birth defect (in offspring of subject/patient taking the product regardless of time to diagnosis); or
Is a cancer; or
Is an overdose (Whether accidental or intentional.)  Any overdose whether or not associated with an adverse experience must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse experience when, 
based upon appropriate medical judgment, the event may jeopardize the subject/patient and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse experience.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse experience cause the test drug to be discontinued?
Relationship to 
test drug 
Did the test drug cause the adverse experience?   The determination of the likelihood that the test drug caused the adverse experience will be provided by an investigator 
who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet, that supports the causality noted on the AE form, ensures that 
a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The criteria below are intended 
as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse experience based upon the available 
information.  
The following components are to be used to assess the relationship between the test drug and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the test drug caused the adverse experience (AE):
Exposure
Is there evidence that the subject/patient was actually exposed to the test drug 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 test drug? 
Is the time of onset of the AE compatible with a drug-induced effect?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE:  (continued)
to test drug
(continued)
Dechallenge
Was the dose of test drug discontinued or 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 test drug; or (3) the study is a single-dose drug study.)
Rechallenge
Was the subject/patient reexposed to the test drug in this study?
      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 study is a single-dose drug study.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE TEST DRUG, OR IF REEXPOSURE TO THE TEST DRUG POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO 
THE SUBJECT/PATIENT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AND 
THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Study 
Drug Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the test drug or drug class pharmacology or 
toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a drug relationship).
Yes, there is a reasonable 
possibility of drug relationship.
There is evidence of exposure to the test drug.  The temporal sequence of the AE onset relative to the administration of the test drug is reasonable.  
The AE is more likely explained by the test drug than by another cause.
Depending on data collection method employed, drug relationship may be further graded as follows:
Definitely 
related 
There is evidence of exposure to the test drug.  The temporal sequence of the AE onset relative to administration of the test drug is reasonable.   The 
AE is more likely explained by the test drug than by another cause.  Dechallenge is positive.  Rechallenge (if feasible) is positive.  The AE shows a 
pattern consistent with previous knowledge of the test drug or test drug class.
Probably 
related 
There is evidence of exposure to the test drug.  The temporal sequence of the AE onset relative to administration of the test drug is reasonable.  The 
AE is more likely explained by the test drug than by another cause.  Dechallenge (if performed) is positive.
Possibly related 
There is evidence of exposure to the test drug.  The temporal sequence of the AE onset relative to administration of the test drug is reasonable.  The 
AE could have been due to another equally likely cause.  Dechallenge (if performed) is positive.
No, there is not a reasonable 
possibility of drug relationship
Subject did not receive the test drug OR temporal sequence of the AE onset relative to administration of the test drug is not reasonable OR there is 
another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
Depending on data collection method employed, drug relationship may be further graded as follows:
Probably not 
related 
There is evidence of exposure to the test drug.  There is another more likely cause of the AE.  Dechallenge (if performed) is negative or ambiguous.  
Rechallenge (if performed) is negative or ambiguous.
Definitely not 
related 
The subject/patient did not receive the test drug.   OR    Temporal sequence of the AE onset relative to administration of the test drug is not 
reasonable.   OR   There is another obvious cause of the AE.
 
 
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3.4.5
SPONSOR Responsibility for Reporting Adverse Events (Adult and 
Pediatric Populations)
All AEs will be reported to regulatory agencies, IRB/IECs, and investigators in 
accordance with all applicable global laws and regulations.
3.5
STATISTICAL ANALYSIS PLAN (SAP)
This section outlines the statistical analysis strategy and procedures for the study.  If, 
after the study has begun, changes are made to primary and/or key secondary objectives, 
or the statistical methods related to those objectives, then the protocol will be amended 
(consistent with International Committee on Harmonisation [ICH] Guideline E-9).  
Changes to exploratory or other non-confirmatory analyses made after the protocol has 
been finalized, along with an explanation as to when and why they occurred, will be 
listed in the clinical study report (CSR) for the study.  Post hoc exploratory analyses will 
be clearly identified in the CSR.  No separate SAP will be issued for this study.
3.5.1
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of 
the Clinical Biostatistics department of the SPONSOR.
This study is being conducted as a long-term follow-up study during which no study 
treatment will be administered.
3.5.2
Estimation
Objectives of the study are stated in Section 2.1.
3.5.3
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
3.5.3.1
Efficacy and RAS Endpoints
3.5.3.1.1
Adult Population
The primary efficacy endpoint in the adult population is the durability of long-term SVR 
which will be evaluated based upon the time to viral relapse.  Viral relapse is defined as 
any subject who has confirmed HCV RNA ≥LLoQ and had achieved SVR in the follow-
up in the prior treatment study (see Section 2.5). Relapse would be indicated so long as 
this was the same genotype of the virus seen in the prior treatment study (e.g. not a new 
infection or re-infection (see Section 2.5).  Time to relapse is defined as the time from 
last dose of study therapy taken in the prior treatment study until the date where HCV 
RNA is ≥LLoQ.  The percentage of subjects who remain HCV RNA <LLoQ during the 
course of this study will also be estimated.
In adult subjects with HCV RNA ≥1000 IU/mL at entry or during the study period, HCV 
sequence analysis will be performed to evaluate the presence of RASs and the persistence 
of RASs over time.
 
 
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3.5.3.1.2
Pediatric Population
There will be no efficacy assessment of durability of long-term SVR in this population as 
enrollment in this study will be limited to pediatric subjects who were virologic failures 
and had emergent RAS present at FW12 in the prior treatment study.
In pediatric subjects, HCV sequence analysis will be performed to evaluate the presence 
of RASs and the persistence of RASs over time.
3.5.3.2
Safety Endpoints
3.5.3.2.1
Adult Population
Safety and signs of disease progression are assessed for all adult subjects by physical 
examination, drug-related SAEs, ECIs, any AEs related to protocol-specified procedures 
(blood draw), and laboratory tests.  
3.5.3.2.2
Pediatric Population
The safety analyses will be based on data from all pediatric subjects entering the study.  
Long-term safety assessments include any AEs related to protocol-specified procedures 
(blood draw) and drug-related SAEs.
3.5.4
Analysis Populations
3.5.4.1
Efficacy Analysis and RAS Populations
3.5.4.1.1
Adult Population
The analysis population for the time to relapse analysis will be all adult subjects who 
achieved SVR and were not a virologic failure in the prior treatment study nor received a 
new HCV therapy after completing treatment with a GZR containing regimen in the prior 
treatment study.
HCV sequence substitutions will be evaluated in adult subjects who sign an informed 
consent for this study and have HCV RNA ≥1000 IU/mL at study entry and/or at any 
visit during the study period.
3.5.4.1.2
Pediatric Population
All pediatric subjects included in the study will be evaluated for RASs.  There will be no 
efficacy assessment of durability of long-term SVR in this population as enrollment in 
this study will be limited to pediatric subjects who were virologic failures and had
emergent RAS present at FW12 in the prior treatment study.  
3.5.4.2
Safety Analysis Populations
3.5.4.2.1
Adult Population
All data from adult subjects who sign an informed consent/assent for this study will be 
included in the safety evaluation.
 
 
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3.5.4.2.2
Pediatric Population
All data from pediatric subjects who sign an informed consent/assent for this study will 
be included in the safety evaluation.
3.5.5
Statistical Methods
No hypothesis testing will be performed in this non-drug long-term follow-up study. 
Efficacy and safety data will be summarized using descriptive statistics. As subjects are 
permitted to participate in other treatment studies for HCV concurrently with this 
protocol, all follow-up data collected after subjects started HCV treatment will be 
summarized separately. 
3.5.5.1
Statistical Methods for Efficacy Analyses
3.5.5.1.1
Adult Population
The efficacy endpoint of time to viral relapse will be summarized using Kaplan-Meier 
methodology at fixed time points (6-month intervals). These time points represent the 
follow-up time since the last dose of study therapy taken in the prior treatment study. 
Subjects who do not relapse during the current study will be censored on the last visit 
date.  Any subject who relapsed between the end of the prior treatment study and entry 
into this study will be considered a relapse at the time of study entry.
Relative days ranges, calculated from the date of last dose of therapy taken in the prior 
treatment study, will be used to define the months of follow-up for the analysis of time to 
viral relapse. These relative day ranges will be continuous and stretch from the date of 
last dose in the prior treatment study to the midpoint between the first 2 time points (i.e. 6 
and 12 months --> midpoint: 9 months), from midpoint to midpoint between each 
successive pair of time points and above the last midpoint for the last time point. As the 
screening visit could occur within 1-year of the last dose of therapy taken in the prior 
treatment study for subjects enrolled prior to AM 03, certain subjects may have a follow-
up time close to 6 years.  Day ranges are therefore defined up to Month 72 and are 
provided in Table 7.  
 
 
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Table 7
Definition of Months of Follow-up for Time to Relapse Analysis
Month
Relative Day Rangea
6
1 to 274
12
275 to 456
18
457 to 638
24
639 to 821
30
822 to 1003
36
1004 to 1186
42
1187 to 1368
48
1369 to 1550
54
1551 to 1733
60
1734 to 1915
66
1916 to 2098
72
≥ 2098
a Day range relative to date of last dose of therapy taken in the prior 
treatment study.
Missing Values
Only observed data will be included in the analyses.  For the time to relapse analysis, 
subjects missing an HCV RNA evaluation at any particular visit will be considered a non-
relapser for that visit.  Subjects who discontinue the study without relapsing will be 
censored at the time of discontinuation.
3.5.5.1.2
Pediatric Population
There will be no efficacy assessment in this population as enrollment in this study will be 
limited to pediatric subjects who were virologic failures and had emergent RAS present 
at FW12 in the prior treatment study.  
3.5.5.2
Statistical Methods for Safety Analyses
3.5.5.2.1
Adult Population
Safety and tolerability in adult subjects will be assessed by clinical review of all relevant 
parameters including drug-related SAEs, ECIs, and laboratory parameters.
The number and proportion of subjects with ECIs will be tabulated.  Continuous 
laboratory parameters will be summarized by 12-month intervals using descriptive 
statistics.  These 12-months intervals are related to the Study Months and are determined 
by a set of continuous relative day ranges, calculated from study entry.  Day ranges for 
safety evaluation are provided in Table 8.
 
 
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Table 8
Definition of Study Months for Safety Evaluation
Month
Relative Day Rangea
Screening/Baseline
-91 to 30
12
-31 to 547
24
548 to 912
36
913 to 1277
48
1278 to 1642
60
≥1643
a Day range relative to study entry, i.e. date of screening/baseline 
visit
Yearly changes from baseline in MELD and Child-Pugh scores will be summarized in all 
adult subjects using descriptive statistics.  Changes in eGFR will be summarized for 
subjects from PN052.  Descriptive statistics will be provided for the rate that subjects 
with CKD (PN052) require liver and/or kidney transplants.
Missing values will be handled using the Data-As-Observed approach.
3.5.5.2.2
Pediatric Population
AEs related to protocol-specified procedures (blood draw), and drug-related SAEs will be 
tabulated for all pediatric subjects using descriptive statistics (number and proportion).
3.5.5.3
Analysis of Resistance Associated Substitutions
3.5.5.3.1
Adult Population
HCV sequence substitutions for adult subjects will be summarized using descriptive 
statistics.  A Kaplan-Meier method may be used to estimate the rate of return of 
individual resistance mutations to wild type, with subgroup analyses by class of regimen 
(e.g. NS3/4A inhibitors, NS5A inhibitors and NS5B inhibitors) as well as by specific 
components. All data collected after a subject started HCV treatment will be summarized 
separately.
3.5.5.3.2
Pediatric Population
The evaluation of antiviral resistance to EBR and GZR in the pediatric population will be 
analyzed separately from the adult population. A Kaplan-Meier method may be used to 
estimate the rate of return of individual resistance mutations to wild type, with subgroup 
analyses for both NS3/4A and NS5A RASs.
3.5.5.4
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized separately 
by adult and pediatric populations. 
 
 
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The number and percentage of subjects enrolled, completed, discontinued and the 
primary reason for discontinuation will be displayed.  Demographic variables (e.g., age, 
gender, race), medical history, concomitant therapies and IL28 genotype will be 
summarized either by descriptive statistics or categorical tables.  The percentage of 
subjects whose HCV RNA was TD(q) at the end of the prior treatment study, at Visit 1 
and at study entry will also be provided.  HCV RNA at study entry is defined as HCV 
RNA of Visit 1 if available, otherwise the RNA assessment at the last visit in the prior 
treatment study provided this last visit is no more than 3 months prior to the first visit of 
PN017.  
All demographic and baseline characteristics will be summarized for the overall 
population and for subjects with detectable (TD(q)) or <LLoQ HCV RNA at study entry.
3.5.6
Multiplicity
No adjustments for multiplicity are planned for this follow-up study.
3.5.7
Sample Size and Power Calculations
The sample size is not determined by any statistical considerations and is not pre-set.
3.5.8
Subgroup Analyses and Effects of Baseline Factors
The time to viral relapse in adult subjects will be summarized for categories of 
classification variables, shown to be associated with response such as genotype.  Time to 
viral relapse and antiviral resistance will be summarized based upon the prior treatment 
study in which GZR was administered.
3.5.9
Interim Analyses
Annual reporting of data available may be performed, as necessary.  Demographic, 
efficacy and safety data available in the database by a specified cut-off date will be 
summarized.
3.5.10 Compliance (Medical Adherence)
Not applicable as there is no study treatment administered.
3.6
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
CLINICAL SUPPLIES
There are no clinical drug supplies for this study.
3.7
DATA MANAGEMENT
Information regarding Data Management procedures for this protocol will be provided by 
the SPONSOR.
3.8
BIOLOGICAL SPECIMENS
Information regarding biological specimens for this protocol will be provided by the 
SPONSOR.
 
 
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4. ADMINISTRATIVE AND REGULATORY DETAILS
4.1
CONFIDENTIALITY
4.1.1
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/ERC), or similar or expert committee; affiliated institution; and 
employees only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study 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.
4.1.2
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the SPONSOR (or SPONSOR 
representative), Institutional Review Board/Independent Ethics Committee (IRB/IEC), or 
Regulatory Agency representatives may consult and/or copy study documents in order to 
verify worksheet/CRF data. By signing the consent/assent form, the subject agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the subject will be identified by unique code only; full 
names/initials will be masked prior to transmission to the SPONSOR.
By signing this protocol, the investigator agrees to treat all subject data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, 
rules and regulations, including all applicable provisions of the Health Insurance 
Portability and Accountability Act and its implementing regulations, as amended from 
time to time.
4.1.3
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all sub investigators and study site 
personnel, may be used and disclosed for study management purposes, as part of a 
regulatory submissions, and as required by law. This information may include:

name, address, telephone number, and email address;

hospital or clinic address and telephone number;

curriculum vitae or other summary of qualifications and credentials; and

other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
SPONSOR, and subsidiaries, affiliates and agents of the SPONSOR, in your country and 
 
 
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other countries, including countries that do not have laws protecting such information. 
Additionally, the investigator’s name and business contact information may be included 
when reporting certain SAEs to regulatory agencies or to other investigators. By signing 
this protocol, the investigator expressly consents to these uses and disclosures.
In order to facilitate contact between investigators, the SPONSOR may share an 
investigator’s name and contact information with other participating investigators upon 
request.
4.2
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of 
Good Clinical Practice (GCP); and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is attached.
The investigator also agrees to allow monitoring, audits, IRB/ IEC review, and regulatory 
agency inspection of study-related documents and procedures and provide for direct 
access to all study-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the SPONSOR.
The Investigator shall prepare and maintain complete and accurate study documentation 
in compliance with GCP standards and applicable federal, state, and local laws, rules and 
regulations; and, for each subject participating in the study, provide all data, and upon 
completion or termination of the clinical study submit any other reports to the SPONSOR 
as required by this protocol or as otherwise required pursuant to any agreement with the 
SPONSOR.
Study documentation will be promptly and fully disclosed to the SPONSOR by the 
investigator upon request and also shall be made available at the investigator’s site upon 
request for inspection, copying, review, and audit at reasonable times by representatives 
of the SPONSOR or any regulatory agencies. The investigator agrees to promptly take 
any reasonable steps that are requested by the SPONSOR as a result of an audit to cure 
deficiencies in the study documentation and worksheets/CRFs.
The investigator must maintain copies of all documentation and records relating to the
conduct of the study in compliance with all applicable legal and regulatory requirements. 
This documentation includes, but is not limited to, the protocol, worksheets/CRFs,
advertising for subject participation, AE reports, subject source data, correspondence 
with regulatory authorities and IRBs/ERCs, consent/assent forms, investigator’s curricula 
vitae, monitor visit logs, laboratory reference ranges, laboratory certification or quality 
 
 
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control procedures and laboratory director curriculum vitae. By signing this protocol, the 
investigator agrees that documentation shall be retained until at least 2 years after the last
approval of a marketing application in an ICH region or until there are no pending or
contemplated marketing applications in an ICH region or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. Because the clinical development and marketing application process is variable, 
it is anticipated that the retention period can be up to 15 years or longer after protocol
database lock. The Sponsor will determine the minimum retention period and notify the 
investigator when documents may be destroyed. The Sponsor will determine the 
minimum retention period and upon request, will provide guidance to the investigator 
when documents no longer need to be retained. The sponsor also recognizes that 
documents may need to be retained for a longer period if required by local regulatory 
requirements. All study documents shall be made available if required by relevant 
regulatory authorities. The investigator must consult with and obtain written approval by 
the Sponsor prior to destroying study and/or subject files.
ICH GCP guidelines (Section 4.3.3) recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the study if the subject has a 
primary physician and if the subject agrees to the primary physician being informed.
According to European legislation, a Sponsor must designate an overall coordinating
investigator for a multi-center study (including multinational). When more than one study
site is open in an European Union country, Merck, as the Sponsor, will designate, per 
country, a national principal coordinator (protocol Coordinating Investigator [CI]), 
responsible for coordinating the work of the principal investigators at the different study
sites in that Member State, according to national regulations. For a single-center study, 
the protocol CI is the principal investigator. In addition, the Sponsor must designate a 
principal or coordinating investigator to review the study report that summarizes the 
study results and confirm that, to the best of his/her knowledge, the report accurately 
describes the conduct and results of the study (CSRCI). The Sponsor may consider one or 
more factors in the selection of the individual to serve as the protocol CI and or CSR CI 
(e.g., availability of the CI during the anticipated review process, thorough understanding 
of clinical study methods, appropriate enrollment of subject cohort, timely achievement 
of study milestones). The protocol CI must be a participating study investigator.
The investigator will promptly inform the SPONSOR of any regulatory agency 
inspection conducted for this study.
Persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on this SPONSOR’s studies. 
The investigator will immediately disclose in writing to the SPONSOR if any person who 
is involved in conducting the study is debarred, or if any proceeding for debarment is 
pending or, to the best of the investigator’s knowledge, threatened.
In the event the SPONSOR prematurely terminates a particular study site, the SPONSOR 
will promptly notify that site’s IRB/IEC.
 
 
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4.3
COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS
Financial Disclosure requirements are outlined in the US FDA Regulations, Financial 
Disclosure by Clinical Investigators (Title 21 Code of Federal Regulations [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/sub 
investigator’s responsibility to comply with any such request.
The investigator/sub investigator(s) agree, if requested by the Sponsor in accordance with 
Title 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 further agrees to provide this information on a 
Financial Disclosure/Certification Form that is provided by the Sponsor. This 
requirement also extends to sub investigators. The investigator also consents 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.
4.4
QUALITY CONTROL AND QUALITY ASSURANCE
By signing this protocol, the SPONSOR agrees to be responsible for implementing and 
maintaining quality control and quality assurance systems with written standard operating 
procedures (SOP) to ensure that studies are conducted and data are generated, 
documented, and reported in compliance with the protocol, accepted standards of GCP, 
and all applicable federal, state, and local laws, rules and regulations relating to the 
conduct of the clinical study.
The investigator or qualified designee is responsible for recording and verifying the 
accuracy of subject data. By signing this protocol, the investigator acknowledges that 
his/her electronic signature is the legally binding equivalent of a written signature. By 
entering his/her electronic signature, the investigator confirms that all recorded data have 
been verified as accurate.
 
 
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4.5
COMPLIANCE WITH INFORMATION PROGRAM ON CLINICAL 
TRIALS FOR SERIOUS OR LIFE THREATENING CONDITIONS
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 study is solely responsible for determining whether the study is subject 
to requirements for submission to http://clinicaltrials.gov, www.clinicaltrialsregister.eu or 
other local registries.  Merck, as SPONSOR of this study, will review this protocol and 
submit the information necessary to fulfill this requirement.  Merck entries are not limited 
to FDAAA or the EMA clinical trial directive mandated trials.  Information posted will 
allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on 
appropriate study locations and site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligation 
under FDAAA, the EMA clinical trials directive or other mandated registries are that of 
the SPONSOR and agrees not to submit any information about this study to those 
registries.
4.6
PUBLICATIONS
This study is intended for publication, even if terminated prematurely. Publication may 
include any or all of the following: posting of a synopsis online, abstract and/or 
presentation at a scientific conference, or publication of a full manuscript.  The 
SPONSOR will work with the authors to submit a manuscript describing study results 
within 12 months after the last data become available, which may take up to several 
months after the last subject visit in some cases such as vaccine studies.  However, 
manuscript submission timelines may be extended on overt-the-counter studies.  For 
studies intended for pediatric-related regulatory filings, the investigator agrees to delay 
publication of the study results until the SPONSOR notifies the investigator that all 
relevant regulatory requirements on the study drug have been fulfilled with regard to 
pediatric-related regulatory filings.   Merck will post a synopsis of study results for 
approved products on www.clinicalstudyresults.org and www.clinicaltrials.gov by 12 
months after the last subject's last visit for the primary outcome, 12 months after the 
decision to discontinue development, or product marketing (dispensed, administered, 
delivered or promoted), whichever is later.  These timelines may be extended for 
products that are not yet marketed, if additional time is needed for analysis, to protect 
intellectual property, or to comply with confidentiality agreements with other parties.  
Authors of the primary results manuscript will be provided the complete results from the 
CSR, subject to the confidentiality agreement. 
 
 
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For multicenter studies, subsequent to the multicenter publication (or after public 
disclosure of the results online at www.clinicaltrials.gov if a multicenter manuscript is 
not planned), an investigator and his/her colleagues may publish their data independently.  
In most cases, publication of individual site data does not add value to complete 
multicenter results, due to statistical concerns.  In rare cases, publication of single site 
data prior to the main paper may be of value.  Limitations of single site observations in a 
multicenter trial should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and 
design, or acquisition of data, or analysis and interpretation of data; 2) drafting the article 
or revising it critically for important intellectual content; and 3) final approval of the 
version to be published. Authors should meet conditions 1, 2, and 3.  Significant 
contributions to study execution may also be taken into account to determine authorship, 
provided that contributions have also been made to all three of the preceding authorship 
criteria. Although publication planning may begin before conducting the study, final 
decisions on authorship and the order of authors’ names will be made based on 
participation and actual contributions to the study and writing, as discussed above. The 
first author is responsible to defend the integrity of the data, method(s) of data analysis, 
and the scientific content of the manuscript.  
The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, 
or 
presentations 
regarding 
this 
study 
45
days 
prior 
to 
submission 
for 
publication/presentation. Any information identified by the SPONSOR as confidential 
must be deleted prior to submission. SPONSOR review can be expedited to meet 
publication timelines.
 
 
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5. LIST OF REFERENCES
[1]
Pawlotsky JM. Hepatitis C Virus Resistance to Direct-Acting Antiviral Drugs 
in Interferon-Free Regimens. Gastroenterology. 2016 Jul;151(1):70-86.
[2]
Martinot-Peignoux M, Stern C, Maylin S, Ripault M-P, Boyer N, Leclere L, 
et al. Twelve weeks posttreatment follow-up is as relevant as 24 weeks to 
determine the sustained virologic response in patients with hepatitis C virus 
receiving pegylated interferon and ribavirin. Hepatology 2010;51(4):1122-6.
[3]
Chen J, Florian J, Carter W, Fleischer RD, Hammerstrom TS, Jadhav PR, et 
al. Earlier sustained virologic response end points for regulatory approval and 
dose selection of hepatitis C therapies. Gastroenterology 2013;144(7):1450-
5e2.
[4]
Food and Drug Administration (CDER). Chronic hepatitis C virus infection: 
developing direct-acting antiviral drugs for treatment - guidance for industry 
[Internet]. Washington, D.C.: U.S. Department of Health and Human 
Services; 
2016. 
Available 
from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInform
ation/Guidances/UCM225333.pdf.
[5]
Sarrazin C. The importance of resistance to direct antiviral drugs in HCV 
infection in clinical practice. J Hepatol. 2016 Feb;64(2):486-504.
[6]
Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic 
kidney disease and decreased kidney function in the adult US Population: 
Third national health and nutrition examination survey. Am J Kidney Dis 
2003;41(1):1-12.
 
 
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6. APPENDICES
6.1
COLLECTION AND MANAGEMENT OF SPECIMENS FOR FUTURE 
BIOMEDICAL RESEARCH 
6.1.1
Scope of Future Biomedical Research
The DNA and plasma specimens collected in the current study will be used to study 
various causes for how subjects may respond to a drug.  The DNA and plasma specimens 
will be stored to provide a resource for future studies conducted by Merck focused on the 
study of biomarkers responsible for how a drug enters and is removed by the body, how a 
drug works, other pathways a drug may interact with, or other aspects of disease.  
Samples may also be used for future assay 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, 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 Merck or designees and research will be 
monitored and reviewed by a committee of our scientists and clinicians.
6.1.2
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 response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
6.1.3
Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
                                                
1
National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2
International Conference on Harmonization: Definitions For Genomic Biomarkers, Pharmacogenomics, 
Pharmacogenetics, Genomic Data and Sample Coding Categories - E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf.
 
 
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All subjects enrolled in the clinical study will be considered for enrollment in the 
Future Biomedical Research sub-study.
b. Informed Consent/Assent
Informed consent/assent for specimens (i.e., DNA, RNA, protein, etc.) will be 
obtained during screening for protocol enrollment from all subjects or legal 
guardians, at a study visit by the investigator or his or her designate.  Informed 
consent/assent for FBR should be presented to the subjects on Visit 1.  If delayed, 
present consent/assent at next possible Subject Visit.  Informed consent/assent forms
must be obtained prior to collection of all FBR specimens.
Subjects are not required to participate in the FBR sub-study in order to participate in 
the main study. 
Consent/assent forms signed by the subject will be kept at the clinical study site under 
secure storage for regulatory reasons.  Information contained on the consent/assent
form alone cannot be traced to any specimens, test results, or medical information 
once the specimens have been rendered de-identified.  Subjects who decline to sign 
the Future Biomedical Research informed consent/assent will not have the specimen 
collected nor will they be discontinued from the main study. 
A template of each study site’s approved informed consent/assent will be stored in the 
Sponsor’s clinical document repository.  Each consent/assent will be assessed for 
appropriate specimen permissions.  
Each informed consent/assent approved by an ethics committee is assigned a unique 
tracking number.  The tracking number on this document will be used to assign 
specimen permissions for each specimen into the Entrusted Keyholder’s Specimen 
Database.
c.
electronic Case Report Forms (eCRFs) Documentation for FBR Specimens
Documentation of both consent/assent and acquisition of Future Biomedical Research 
specimens will be captured in the eCRFs.  Reconciliation of both forms will be 
performed to assure that only appropriately-consented specimens are used for this 
sub-study's research purposes. Any specimens for which such an informed 
consent/assent cannot be verified will be destroyed.
d. FBR Specimen Collections 
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other study purposes.  
Specimens will be collected and sent to the laboratory designated for the study where 
they will be processed (e.g., DNA or RNA extraction, etc.) following the Merck 
approved policies and procedures for specimen handling and preparation.
 
 
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6.1.4
Confidential Subject Information for Future Biomedical Research
In order to optimize the research that can be conducted with FBR specimens, it is critical 
to link subject' clinical information with future test results. In fact little or no research can 
be conducted without connecting the clinical study data to the specimen. The clinical data 
allow specific analyses to be conducted. Knowing subject characteristics like gender, age, 
medical history and treatment outcomes are critical to understanding clinical context of 
analytical results.
To maintain privacy of information collected from specimens obtained for FBR, Merck 
has developed secure policies and procedures.  All specimens will be de-identified as 
described below. 
At the clinical site, unique codes will be placed on the FBR specimens for transfer to the 
storage facility.  This first code is a random number which does not contain any 
personally identifying information embedded within it.  The link (or key) between subject 
identifiers and this first unique code will be held at the study site.  No personal identifiers 
will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the 
study to be associated with the specimen.  This second key will be transferred under 
secure procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  
The second code will be logged into the primary biorepository database at Merck and, in 
this database, this identifier will not have identifying demographic data or identifying 
clinical information (i.e., race, sex, age, diagnosis, lab values) associated with it. The 
specimen will be stored in a designated biorepository site with secure policies and 
procedures for specimen storage and usage.
 
 
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The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
health authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the health authority.
6.1.5
Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the FBR specimens may be performed by Merck, or an additional third 
party (e.g., a university investigator) designated by Merck.  The investigator conducting 
the analysis will be provided with double coded specimens.  Re-association of analysis 
results with corresponding clinical data will only be conducted by the Merck Entrusted 
Keyholder.  Any contracted third party analyses will conform to the specific scope of 
analysis outlined in this sub-study.  FBR specimens remaining with the third party after 
the specific analysis is performed will be returned to the sponsor or destroyed and 
documentation of destruction will be reported to Merck.
6.1.6
Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent/assent for FBR and have their specimens and all 
derivatives destroyed.  Subjects may withdraw consent/assent at any time by writing to 
the principal investigator for the main study.  If medical records for the main study are 
still available, the Investigator will contact MERCK using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by MERCK to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the
subject's specimens will be removed from the biorepository and be destroyed.  A letter 
will be sent from MERCK to the investigator confirming the destruction.  It is the 
responsibility of the Investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the sponsor will continue to be used as part of the overall 
research study data and results.  No new analyses would be generated after the request is 
received.
 
 
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In the event that the medical records for the main study are no longer available (e.g., if 
the investigator is no longer required by regulatory agencies to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction cannot be processed. 
6.1.7
Retention of Specimens
FBR specimens will be stored in the biorepository for potential analysis for up to 20 
years from acquisition.  Specimens may be stored for longer if a regulatory or 
governmental agency 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 site will be shipped to a central laboratory and then shipped to the 
Merck 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 Merck policies and procedures and this 
destruction will be documented in the biorepository database.
6.1.8
Data Security
Separate databases for specimen information and for results from the FBR sub-study will 
be maintained by Merck.  This is done to separate the future exploratory test results 
(which include genetic data) from the clinical study database thereby maintaining a 
separation of subject number and these results.  The separate databases are accessible 
only to the authorized sponsor and the designated study administrator research personnel 
and/or collaborators.  Database user authentication is highly secure, and is accomplished 
using network security policies and practices based in international standards (e.g., 
ISO17799) to protect against unauthorized access.  The Merck Entrusted Keyholder 
maintains control over access to all specimen data.  These data are collected for FBR
purposes only as specified in this sub-study will not be used for any other purpose.
6.1.9
Reporting of FBR Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
study subject.  Some guidelines advocate a proactive return of data in certain instances.  
No information obtained from exploratory laboratory studies will be reported to the 
subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation, and absence of good clinical practices standards in 
exploratory research typically used for diagnostic testing.
 
 
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If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical study is still ongoing, investigators will be contacted with information 
as to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that  counseling should be made available for all who choose to 
participate in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical study, Merck will publish the results without revealing specific 
subject information, inform all sites who participated in the Merck clinical study, and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., Disease societies who have primary interest in the results) in order 
that physicians and subjects may pursue clinical diagnostic testing if they wish to do so.
6.1.10 Gender, Ethnicity, and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
studies for FBR.  When studies with specimens are conducted and subjects identified to 
serve as controls, every effort will be made to group specimens from subjects and 
controls to represent the ethnic and gender population representative of the disease under 
current investigation.
6.1.11 Risks Versus Benefits of Future Biomedical Research 
For FBR, risks to the subject have been minimized.  Risks include those associated with 
venipuncture to obtain the whole blood specimen.  This specimen will be obtained at the 
time of routine blood specimens drawn in the main study. 
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be reassociated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from FBR will be entered into clinical records, nor will it be released to outside 
persons or agencies, in any way that could be tied to an individual subject.
6.1.12 Self-Reported Ethnicity
Subjects who participate in FBR will be asked to provide self-reported ethnicity.  
Subjects who do not wish to provide this data may still participate in FBR.
6.1.13 Questions
Any 
questions 
related 
to 
the 
FBR
should 
be 
e-mailed 
directly 
to 
clinical.specimen.management@merck.com.
 
 
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6.2
BLOOD VOLUMES COLLECTED
 
 
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6.2.1
Adult Blood Volumes 
Test
Screening
Screening
a
Month 6
Month 12
Month 18
Month 24
Month 30
Month 36
Month 
42b
Month 
48b
Month 
54b
Month 
60b
Coagulation
2.7
.
2.7
2.7
.
2.7
.
2.7
.
2.7
.
2.7
Chemistry (complete)
6
.
6
6
.
6
.
6
.
6
.
6
FibroTest
.
.
6
6
.
6
.
6
.
6
.
6
Hematology
2
.
2
2
.
2
.
2
.
2
.
2
HCV Genotype
4
.
.
.
.
.
.
.
.
.
.
HCV RNA Level
10
.
10
10
10
10
10
10
10
10
10
10
HCV Viral Resistance/RAS
6
.
6
6
6
6
6
6
6
6
6
6
Plasma for FBR
.
10
.
.
.
.
.
.
.
.
.
.
DNA for FBR
.
8.5
.
.
.
.
.
.
.
.
.
.
Total Volume in mL
30.7
18.5
32.7
32.7
16
32.7
16
32.7
16
32.7
16
32.7
DNA=deoxyribonucleic acid; FBR=future biomedical research; HCV=hepatitis C virus ; RAS= resistance associated substitution; RNA=ribonucleic acid
a FBR consented subjects only.
b Month 42 through Month 60 visits are for Protocol 052 subjects only.
 
 
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6.2.2
Pediatric Blood Volumes 
Test
Screening
Month 6
Month 12
Month 18
Month 24
Month 30
Month 36
HCV RNA Level
4
4
4
4
4
4
4
HCV Viral Resistance/RAS
4
4
4
4
4
4
4
Total Volume in mL
8
8
8
8
8
8
8
HCV=hepatitis C virus; RAS= resistance associated substitution; RNA=ribonucleic acid
 
 
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6.3
LIST OF ABBREVIATIONS
Abbreviation/Term
Definition
AE
Adverse event
ALT
Alanine aminotransferase 
AM
Amendment
aPTT
Activated partial thromboplastic time 
AST
Aspartate aminotransferase 
CFR
Code of Federal Regulations
CI
Coordinating Investigator
CKD
Chronic kidney disease
CRF
Case report form
CSR
Clinical study report
DAA
Direct-acting antiviral
DNA
Deoxyribonucleic acid
EBR
Elbasvir; MK-8742
ECI
Event of clinical interest; selected adverse experiences
eCRF
Electronic case report forms
eGFR
estimated glomerular filtration rate 
EMA
European Medicines Agency 
ERC
Ethical review committee
FBR
Future Biomedical Research 
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act 
FW
Follow-up week
GCP
Good Clinical Practice
GT
Genotype
GZR
Grazoprevir; MK-5172
HCT
Hematocrit
HCV
Hepatitis C virus 
Hgb
Hemoglobin
IB
Investigators brochure
 
 
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Abbreviation/Term
Definition
ICH
International Committee on Harmonisation
IEC
Independent ethics committee
INR
International normalized ratio 
IRB
Institutional review board
IXRS
Interactive voice/web response system 
LLoQ
Lower limit of quantification
MELD
Model for End-Stage Liver Disease
NS
Nonstructural protein
PD
Pharmacodynamic
PGt
Pharmacogenetics
PK
Pharmacokinetic
PN
Protocol number
PR
Pegylated-interferon + RBV
PT
Prothrombin time 
RAP
Resistance associated polymorphisms 
RAS
Resistance associated substitution
RBC
Red blood cell
RBV
Ribavirin
RNA
Ribonucleic acid
RT-PCR
Reverse transcriptase-polymerase chain reaction
RZR
Ruzasvir; MK-8408
SAE
Serious adverse event
SAP
Statistical analysis plan
SOP
Standard operating procedures
SVR
Sustained virologic response
SVR12
Sustained virologic response 12 weeks after the end of all 
study therapy. The subject has HCV RNA < LLOQ [either 
TD (u) or TND] 12 weeks after the end of all study therapy
SVR24
Sustained virologic response 24 weeks after the end of all 
study therapy. The subject has HCV RNA < LLOQ [either 
TD (u) or TND] 24 weeks after the end of all study therapy
 
 
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Abbreviation/Term
Definition
TD(q)
Target detected, quantifiable
TD(u)
Target detected, unquantifiable
TIA
Transient ischemic attack 
TND
Target not detected
UPR
Uprifosbuvir; MK-3682
US
United States
WBC
White blood cell
 
 
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7. ATTACHMENTS
7.1
MERCK CODE OF CONDUCT FOR CLINICAL TRIALS
 
 
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Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these 
trials in compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding 
concern in the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with 
local and/or national regulations and in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of 
the party (parties) employed for their execution (e.g., contract research organizations, collaborative research 
efforts). This Code is not intended to apply to trials which are observational in nature, or which are retrospective. 
Further, this Code does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific 
purpose of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of 
facilities and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial 
initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus 
source documentation according to standard operating procedures.  Per Merck policies and procedures, if 
fraud, misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When 
necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review committees 
notified and data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase 
or pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication 
of results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical 
issues of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able 
to defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, 
except that changes required urgently to protect subject safety and well-being may be enacted in anticipation of 
IRB/ERC approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  
Potential subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.  Subjects are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed 
consent for participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their 
access to, or receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by 
law, only the investigator, sponsor (or representative) and/or regulatory authorities will have access to 
confidential medical records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized 
by an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives 
to enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may 
be made to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or 
sponsoring institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC 
may wish to alter the wording of the disclosure statement to be consistent with financial practices at that 
institution.  As noted above, publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will 
be consistent with local guidelines and practices including, in the U.S., those established by the American 
Medical Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in 
signing the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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7.2
PHARMACOGENOMICS INFORMATIONAL BROCHURE FOR IRBS/IECS & INVESTIGATIONAL SITE STAFF
 
 
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8. SIGNATURES
8.1
SPONSOR’S REPRESENTATIVE
TYPED NAME
SIGNATURE
DATE
8.2
INVESTIGATOR
I agree to conduct this clinical study in accordance with the design outlined in this 
protocol and to abide by all provisions of this protocol (including other manuals and 
documents referenced from this protocol); deviations from the protocol are acceptable 
only with a mutually agreed upon protocol amendment. I agree to conduct the study in 
accordance with generally accepted standards of Good Clinical Practice. I also agree to 
report all information or data in accordance with the protocol and, in particular, I agree to 
report any SAEs as defined in the SAFETY MEASUREMENTS section of this protocol. 
I also agree to handle all clinical supplies provided by the SPONSOR and collect and 
handle all clinical specimens in accordance with the protocol. I understand that 
information that identifies me will be used and disclosed as described in the protocol, and 
that such information may be transferred to countries that do not have laws protecting 
such information. Since the information in this protocol and the referenced Investigator’s 
brochure is confidential, I understand that its disclosure to any third parties, other than 
those involved in approval, supervision, or conduct of the study is prohibited. I will 
ensure that the necessary precautions are taken to protect such information from loss, 
inadvertent disclosure, or access by third parties.
TYPED NAME
SIGNATURE
DATE
 
 
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