Clinical trial NCT03036852
Conditions: Chronic Hepatitis C
Sponsor: Gilead Sciences
Start date: 2017-03-22; Completion date: 2018-11-07
Enrollment: 59 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objectives of this study are to evaluate safety, efficacy, and tolerability of treatment with sofosbuvir/velpatasvir (SOF/VEL) for 12 weeks in adults on dialysis for end stage renal disease (ESRD) with chronic hepatitis C virus (HCV) infection of any genotype.

Detailed description:

Arms: arm 1: SOF/VEL for 12 weeks
Interventions: intervention 1: SOF/VEL
Intervention descriptions: intervention 1: 400/100 mg fixed-dose combination (FDC) tablet(s) administered orally once daily

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2, Multicenter, Open-Label Study to Evaluate the 
Efficacy and Safety of Sofosbuvir/Velpatasvir for 12 Weeks in 
Subjects with Chronic HCV Infection Who are on Dialysis for 
End Stage Renal Disease
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
118605
EudraCT Number:
2016-003625-42
Clinical Trials.gov Identifier:
NCT03036852
Indication:
Hepatitis C Virus Infection
Protocol ID:
GS-US-342-4062
Gilead Study Director:
Name:
Telephone:
Fax:
Email address:
Gilead Medical Monitor:
Name:
Telephone:
Fax:
Email address:
Protocol Version/Date:
Original
23 September 2016
Amendment 1.0:
29 November 2016
Amendment 2.0:
30 January 2017
Amendment 3.0:
02 March 2017
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................11
1.
INTRODUCTION ..............................................................................................................................................15
1.1.
Background ............................................................................................................................................15
1.2.
Sofosbuvir/Velpatasvir Fixed-Dose Combination .................................................................................16
1.2.1.
General Information .............................................................................................................16
1.2.2.
Additional Clinical Information; Study GS-US-334-0154...................................................16
1.2.3.
Additional Non-Clinical Toxicology Information................................................................21
1.3.
Rationale for This Study ........................................................................................................................21
1.4.
Rationale for Dose Selection of SOF/VEL ............................................................................................22
1.5.
Risk/Benefit Assessment for the Study..................................................................................................23
1.6.
Compliance ............................................................................................................................................24
2.
OBJECTIVES.....................................................................................................................................................25
3.
STUDY DESIGN................................................................................................................................................26
3.1.
Study Design..........................................................................................................................................26
3.2.
Visit Schedule ........................................................................................................................................26
3.3.
Duration of Treatment............................................................................................................................26
3.4.
Stopping Rules and Discontinuation Criteria.........................................................................................26
3.4.1.
Toxicity-Based Stopping Criteria.........................................................................................27
3.4.2.
Virologic Response Base Stopping Criteria .........................................................................27
3.5.
HIV Virologic Rebound Criteria............................................................................................................28
3.6.
Pharmacokinetic (PK) Substudies..........................................................................................................30
3.6.1.
.........................................................................................................30
3.6.2.
..................................................................................................30
3.7.
Biomarker Testing..................................................................................................................................30
3.7.1.
Samples for Optional Future Research.................................................................................30
3.7.2.
.....................................................31
4.
SUBJECT POPULATION..................................................................................................................................32
4.1.
Inclusion Criteria....................................................................................................................................32
4.2.
Exclusion Criteria...................................................................................................................................33
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................36
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................36
5.2.
Description and Handling of SOF/VEL FDC ........................................................................................36
5.2.1.
Formulation..........................................................................................................................36
5.2.2.
Packaging and Labeling .......................................................................................................36
5.2.3.
Storage and Handling...........................................................................................................36
5.3.
Dosage and Administration of SOF/VEL FDC......................................................................................37
5.4.
Prior and Concomitant Medications.......................................................................................................37
5.5.
Accountability for SOF/VEL .................................................................................................................38
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................39
6.
STUDY PROCEDURES ....................................................................................................................................40
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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................40
6.1.1.
Pretreatment Assessments ....................................................................................................40
6.2.
Day 1 Assessments.................................................................................................................................42
6.3.
Treatment Assessments..........................................................................................................................43
6.3.1.
Week 2 (± 3 days) ................................................................................................................43
6.3.2.
Week 4 (± 3 days) ................................................................................................................44
6.3.3.
Week 6 (± 3 days) ................................................................................................................44
6.3.4.
Week 8 (± 3 days) ................................................................................................................45
6.3.5.
Week 12 (± 3 days) or Early Termination (ET) ...................................................................46
6.4.
Post-treatment Assessments ...................................................................................................................47
6.4.1.
Posttreatment Week 4 Visit (± 5 days).................................................................................47
6.4.2.
Posttreatment Week 12 (± 5 days)........................................................................................47
6.4.3.
Posttreatment Week 24 Visit (±5 Days): Only for Subjects who Achieved 
SVR12..................................................................................................................................48
6.5.
Early Termination (ET)..........................................................................................................................48
6.6.
Unscheduled Visit ..................................................................................................................................48
6.7.
End of Study...........................................................................................................................................49
6.8.
Post Study Care......................................................................................................................................49
6.9.
Procedures and Specifications................................................................................................................49
6.9.1.
Clinical Laboratory Analytes ...............................................................................................49
6.9.2.
Medical History....................................................................................................................50
6.9.3.
Complete Physical Examination...........................................................................................50
6.9.4.
Height & Weight Measurement............................................................................................50
6.9.5.
Vital Signs............................................................................................................................50
6.9.6.
Body Mass Index (BMI).......................................................................................................50
6.9.7.
12-Lead ECG........................................................................................................................51
6.9.8.
Health Related Quality of Life (HRQoL).............................................................................51
6.9.9.
Viral Sequencing/Phenotyping (Archive) ............................................................................51
6.9.10.
Sparse PK Sample ................................................................................................................51
6.9.11.
.........................................................................................................51
6.9.12.
..................................................................................................52
6.9.13.
..................................................................................................52
6.9.14.
Archive sample.....................................................................................................................52
6.9.15.
Pregnancy Testing................................................................................................................53
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................54
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................54
7.1.1.
Adverse Events.....................................................................................................................54
7.1.2.
Serious Adverse Events........................................................................................................54
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................55
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................55
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................55
7.2.2.
Assessment of Severity ........................................................................................................56
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................56
7.3.1.
Requirements for collection prior to study drug initiation: ..................................................56
7.3.2.
Adverse Events.....................................................................................................................56
7.3.3.
Serious Adverse Events........................................................................................................56
7.3.4.
Electronic Serious Adverse Event (eSAE) Reporting Process .............................................57
7.4.
Gilead Reporting Requirements.............................................................................................................57
7.5.
Toxicity Management ............................................................................................................................58
7.5.1.
Subject Stopping Rules ........................................................................................................58
7.6.
Special Situations Reports......................................................................................................................58
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7.6.1.
Definitions of Special Situations..........................................................................................58
7.6.2.
Instructions for Reporting Special Situations.......................................................................59
8.
STATISTICAL CONSIDERATIONS................................................................................................................61
8.1.
Analysis Objectives and Endpoints........................................................................................................61
8.1.1.
Analysis Objectives..............................................................................................................61
8.1.2.
Primary Endpoint .................................................................................................................61
8.1.3.
Secondary Endpoint .............................................................................................................62
8.1.4.
Other Endpoints of Interest ..................................................................................................62
8.2.
Analysis Conventions.............................................................................................................................62
8.2.1.
Analysis Sets ........................................................................................................................62
8.3.
Data Handling Conventions ...................................................................................................................63
8.4.
Demographic Data and Baseline Characteristics ...................................................................................65
8.5.
Efficacy Analysis ...................................................................................................................................65
8.5.1.
Primary Analysis..................................................................................................................65
8.5.2.
Secondary Analyses .............................................................................................................65
8.6.
Safety Analysis.......................................................................................................................................65
8.6.1.
Extent of Exposure...............................................................................................................65
8.6.2.
Adverse Events.....................................................................................................................66
8.6.3.
Laboratory Evaluations ........................................................................................................66
8.7.
Other Safety Evaluations........................................................................................................................67
8.8.
Pharmacokinetic Analysis......................................................................................................................67
8.9.
Sample Size............................................................................................................................................67
8.10.
Data Monitoring Committee ..................................................................................................................67
9.
RESPONSIBILITIES..........................................................................................................................................68
9.1.
Investigator Responsibilities ..................................................................................................................68
9.1.1.
Good Clinical Practice..........................................................................................................68
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................68
9.1.3.
Informed Consent.................................................................................................................68
9.1.4.
Confidentiality......................................................................................................................69
9.1.5.
Study Files and Retention of Records ..................................................................................69
9.1.6.
Case Report Forms...............................................................................................................70
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................71
9.1.8.
Inspections............................................................................................................................71
9.1.9.
Protocol Compliance............................................................................................................72
9.2.
Sponsor Responsibilities ........................................................................................................................72
9.2.1.
Protocol Modifications.........................................................................................................72
9.2.2.
Study Report and Publications .............................................................................................72
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................72
9.3.1.
Payment Reporting...............................................................................................................72
9.3.2.
Access to Information for Monitoring..................................................................................73
9.3.3.
Access to Information for Auditing or Inspections ..............................................................73
9.3.4.
Study Discontinuation..........................................................................................................73
10.
REFERENCES ...................................................................................................................................................74
11.
APPENDICES ....................................................................................................................................................76
Appendix 1.
Investigator Signature Page....................................................................................................77
Appendix 2.
Study Procedures Table..........................................................................................................78
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............80


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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................102
Appendix 5.
Opportunistic Infections .......................................................................................................105
LIST OF IN-TEXT TABLES
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................38
LIST OF IN-TEXT FIGURES
Figure 3-1.
HIV Virologic Rebound Schema............................................................................................29


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy 
and Safety of Sofosbuvir/Velpatasvir for 12 Weeks in Subjects with 
Chronic HCV Infection Who are on Dialysis for End Stage Renal 
Disease
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
118605
2016-003625-42
NCT03036852
Study Centers Planned:
Approximately 40 sites in North America, Europe, Asia Pacific and 
Middle East.
Objectives:
The primary objectives of this study are:

To evaluate the antiviral efficacy of treatment with 
sofosbuvir/velpatasvir (SOF/VEL) for 12 weeks as measured by 
the proportion of subjects with sustained viral response 12 weeks 
after cessation of treatment (SVR12) 

To evaluate the safety and tolerability of the treatment regimen
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 
24 weeks after cessation of the study treatment regimen (SVR4 
and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the kinetics of circulating HCV RNA during 
treatment and after cessation of treatment

To evaluate the emergence of viral resistance to SOF and VEL 
during treatment and after cessation of treatment

To evaluate the steady-state pharmacokinetics of SOF and its 
metabolites and VEL in subjects who are on dialysis for End 
Stage Renal Disease (ESRD)


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The exploratory objectives of this study are:
 
 
Study Design:
Approximately 100 subjects will be treated with SOF/VEL for 
12 weeks
Substudies
 
 
 
 
 
 
 
 
 
 
 
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Number of Subjects 
Planned:
Approximately 100 subjects
Target Population:
Adults with chronic hepatitis C virus (HCV) infection who are on 
dialysis for ESRD
Duration of Treatment:
Subjects will be treated for 12 weeks
Diagnosis and Main 
Eligibility Criteria:
Chronic HCV infected, male and non-pregnant/non-lactating female 
subjects aged 18 years or older who are on dialysis for ESRD, 
including subjects with HIV co-infection if they are suppressed on a
stable, protocol-approved antiretroviral (ARV) regimen for 
≥8 weeks prior to Screening.
Study Procedures/
Frequency:
All subjects will complete the following study visits: Screening, 
Baseline/Day 1, on-treatment visits at the end of Weeks 2, 4, 6, 8, 
and 12, and posttreatment visits at Week 4 and 12 after completion 
of treatment. Subjects who achieve SVR12 will also complete the 
posttreatment Week 24 visit. 
Screening assessments will be completed within 28 days of the 
Baseline/Day 1 visit. The screening window can be extended up to 
42 days in extenuating circumstances, with the approval of the 
medical monitor.
Screening assessments will include physical examination, medical 
history, height, weight, vital signs, 12-lead electrocardiogram 
(ECG), adverse events (AEs) related to screening procedures, 
concomitant medications, safety laboratory tests (including 
hematology, chemistry, and coagulation), HCV RNA, serology 
(HIV, HCV, HBV), hemoglobin A1c (HbA1c), assessment of the 
presence or absence of cirrhosis, screening for hepatocellular 
carcinoma (HCC) for subjects with cirrhosis, serum β-hCG (females 
of child bearing potential only), HCV genotyping, IL28B 
genotyping, and serum drug screen. HIV/HCV co-infected subjects 
will have additional testing for CD4 T-cell count and HIV-1 RNA
assessments.
On-treatment assessments include adverse events (AEs), 
concomitant medications, study medication pill count, physical 
examination, weight, vital signs, safety laboratory tests, HCV RNA, 
HBV DNA (for HBcAb+ subjects only), sparse PK sampling and 
serum β-hCG (females of child bearing potential only). HIV/HCV 
co-infected subjects will have additional assessments, including CD4 
T-cell count and HIV-1 RNA assessments.


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Single 12-lead ECGs will be collected at Screening, Day 1 (prior to 
study drug administration), and at the on-treatment Week 12 visit or 
Early Termination (ET) visit (if applicable). At the time of 
collection, ECGs will be reviewed by qualified study staff (as 
determined by the investigator) for clinically significant
abnormalities. Week 12 or ET results will be compared to the 
subject’s Day 1 ECG as part of routine safety monitoring.
Post-treatment assessments include AEs, concomitant medications, 
vital signs, physical examination, safety laboratory tests, HCV RNA, 
HBV DNA (for HBcAb+ subjects only), and serum β-hCG (females 
of child bearing potential only). HIV/HCV co-infected subjects will 
have additional assessments, including CD4 T-cell count and HIV-1 
RNA assessments.
HRQoL surveys (SF-36, CLDQ-HCV, FACIT-F, and WPAI) will be 
conducted at Day 1, on-treatment Week 12 or ET (if applicable), and 
posttreatment Week 12.
Samples for HCV or HIV viral sequencing / phenotyping will be 
collected at Baseline/Day 1 and every visit thereafter. 
 
 
 
 
Test Product, Dose, and 
Mode of 
Administration:
SOF/VEL fixed dose combination (FDC) is manufactured as a
400/100mg tablet for oral administration. Subjects will take 1 tablet 
daily with or without food. Doses should be taken at approximately 
the same time each day,
 
Reference Therapy, 
Dose, and Mode of 
Administration:
None.
Criteria for Evaluation:
Safety:
AEs and laboratory tests will be collected throughout the study.
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV 
RNA performed using COBAS® AmpliPrep®/COBAS® TaqMan®
HCV Quantitative Test, v2.0.
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Pharmacokinetics:
The PK of SOF (and metabolites) and VEL may be assessed.
Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all enrolled 
and treated subjects. 
In the primary efficacy analysis, the point estimate and the 2-sided 
95% exact confidence interval of SVR12 rate will be provided.
With a sample size of 100 subjects, a 2-sided 95% exact confidence 
interval will extend at the most 20% in length.
Secondary efficacy endpoints include SVR4, SVR24, and the 
proportion of subjects with virologic failure. Steady-state PK plasma 
parameters will be listed by subject and summarized using 
descriptive statistics for each analyte (SOF [and its metabolites] and
VEL, as appropriate).
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
° C
degrees Celsius
° F
degrees Fahrenheit
Ab
antibody
ABW
Actual body weight
AE(s)
adverse event(s)
ALT
alanine aminotransferase (also SGPT)
ANC
Absolute Neutrophil Count
ARV
antiretroviral
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase (also SGOT)
AV
atrioventricular
BMD
Bone Mineral Density
BMI
Body Mass Index
BW
body weight
CD4+
cluster of differentiation 4+
CFR
Code of Federal Regulations
CHF
congestive heart failure
CI
confidence interval
CLCr
creatinine clearance rate
CLDQ-HCV
Chronic Liver Disease Questionnaire
CM
concomitant medication
cm2
square centimeter
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
CRO
contract (or clinical) research organization
CSR
Clinical study report
CT
Computerized Tomography
DAA
direct-acting antiviral
dL
deciliter
DNA
deoxyribonucleic acid 
DSPH
Gilead Drug Safety and Public Health
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eg
example given
ER
Emergency room
ESRD
End Stage Renal Disease
ET
Early Termination


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EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FACIT-F
Fatigue Index
FAS
full analysis set
FCF
yellow # 6 / sunset yellow FCF aluminum lake
FD&C 
Federal Food, Drug and Cosmetic
FDA
(United States) Food and Drug Administration
FDC
Fixed-dose combination
FEV1
forced expiratory volume in 1 second
FSH
Follicle stimulating hormone
g
grams
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GI
giga
GS-7977
formerly PSI-7977
GSI
Gilead Sciences, Inc.
GT
genotype
h
hour
H2
Histamine
Hb
Hemoglobin 
HbA1c
Hemoglobin A1c 
HBsAg
Hepatitis B surface antigen
HBcAb
Hepatitis B core antibody
HBcAb+
Hepatitis B core antibody-positive
HBsAb
Hepatitis B surface antibody
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDPE
High density polyethylene 
HIV
Human immunodeficiency virus
HLGT
High-Level Group Term
HLT
High-Level Term
HMG-CoA
3-hydroxy-3-methyl-glutaryl coenzyme A
HPF
high power field
HRQoL
Health Related Quality of Life
IB
Investigator Brochure
ICF
Informed consent form 
ICH
International Conference on Harmonization
IEC
independent ethics committee
IFN
Interferon


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IL28B
Interleukin-28B gene
IMB
Intermenstrual Bleeding
IMP
Investigational Medical Product
IND
Investigational New Drug (Application)
INR
International Normalized Ratio of prothrombin time
IRB
institutional review board
IU
International Units
IUD
intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IWRS
interactive web response system
kg
Kilogram
kPa
kilopascal
L
liter
LAM
Lactational amenorrhea method
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification
LLT
Lower-Level Term
m2
square meter
MCV
mean corpuscular volume or mean cell volume
MedDRA
Medical Dictionary for Regulatory Activities
mEq
milliequivalents
mg
milligram
MGB
minor groove binder
mL
Milliliter
mm3
cubic millimeter
mmHg
millimeters mercury
mmol
millimole
n
number
NS (3/4A/5A/5B)
Non-structural Protein
PCR
Polymerase Chain Reaction
Peg-IFN
pegylated interferon
P-gp
P-glycoprotein
PK
Pharmacokinetic
PMDA
Pharmaceuticals and Medical Devices Agency
PPIs
Proton-pump inhibitor
PR
P and R waves (in electrocardiography)
PT
preferred term or prothrombin time
Q1
Quartile 1
Q3
Quartile 3


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QA
Quality assurance
QTc
corrected QT
RAV
Resistance-associated variants
RBC
Red blood cell count
RBV
ribavirin
RNA
ribonucleic acid
SADR
Serious adverse drug reaction
SAE
serious adverse event
Scr
serum creatinine (mg/dL)
SD
Standard deviation
sec
seconds
SF-36
36-Item Short Form Health Survey
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SNP
Single nucleotide polymorphism
SOC
System Organ Class
SOF
sofosbuvir, formerly GS-7977
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
SVR12
Sustained Virologic Response 12 weeks after cessation of treatment
SVR24
Sustained Virologic Response 24 weeks after cessation of treatment
SVR4
Sustained Virologic Response 4 weeks after cessation of treatment
TEN
toxic epidermal necrolysis
TND
Target not detected
ULN
Upper limit of normal
US
United States
VEL
Velpatasvir
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment
β-hCG
β-human chorionic gonadotropin
μg
microgram
μL
microliter
μmol
micromole


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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus infection is a global health challenge with the estimated number of persons 
infected ranging from 80 to 150 million worldwide {Gower 2014, World Health Organization 
(WHO) 2014}. Hepatitis C virus has significant genetic (RNA sequence) variability and is 
classified on this basis into at least 6 genotypes. There is significant geographical variation in the 
distribution of HCV genotypes. In North America and Europe, genotype 1 HCV infection 
predominates. In Asia, genotype 1 and 3 HCV infection are the most prevalent. 
Genotype 4, 5 and 6 are highly prevalent in northern Africa, southern Africa, and southeast Asia, 
respectively.
The disease burden of HCV infection is due to progression of chronic liver disease, which can 
lead to cirrhosis, liver failure, hepatocellular carcinoma, and death. Globally, 27% of all subjects
with cirrhosis and 25% of those who develop hepatocellular carcinoma are attributable to HCV 
infection {Perz 2006}. In addition to having a higher incidence of hepatocellular carcinoma, 
subjects with chronic HCV infection have a higher incidence and mortality of many types of 
nonliver cancers including pancreatic, rectal, kidney, non-Hodgkin’s lymphoma and lung 
cancers, compared with the general population {Allison 2015}. Curing HCV infection is 
associated with numerous health benefits including more than 70% reduction in the risk of 
hepatocellular carcinoma and a 90% reduction in the risk of liver-related mortality and liver 
transplantation {Morgan 2013, Poynard 2002, van der Meer 2012, Veldt 2007}. 
Recently, there has been a transformation in the treatment of HCV infection with the 
development of DAAs targeting viral proteins essential to viral replication. DAA-based 
treatment regimens are generally well tolerated and result in high sustained virologic response 
(SVR) at 12 weeks following completion of all treatment (SVR12) rates across most patient 
populations {AbbVie Inc 2016, Bristol-Myers Squibb 2016, Gilead Sciences Inc 2015a, Gilead 
Sciences Inc 2015b, Gilead Sciences Inc 2016, Merck & Co Inc 2016}. Sofosbuvir-based 
regimens (Sovaldi® and Harvoni®) are the most widely prescribed treatments for HCV infection 
due to the efficacy, tolerability, and simplicity of the dosing regimens. In addition, 
sofosbuvir-based regimens offer the advantages of having relatively few drug-drug interactions, 
strong concordance between clinical trial and “real world” data, and absence of a requirement for 
baseline NS5A polymorphism testing. The recent approvals in the US and EU of Epclusa®, a 
fixed dose combination of sofosbuvir and velpatasvir is an important advance in HCV drug 
development as Epclusa® is highly efficacious across all HCV genotypes whereas previously 
approved regimens were HCV genotype specific {Arias 2016, Gilead Sciences Inc 2015a, Gilead 
Sciences Inc 2015b, Ioannou 2016}.
Despite the progress made in the development of effective treatments for HCV infection, many 
challenges remain. These include the evaluation of DAA-based regimens in patient populations 
not evaluated in registration clinical studies, including subjects with advanced hepatic disease, or 
advanced renal disease and in pediatric populations. In addition, the treatment of populations 
with high HCV prevalence such as the incarcerated, or injection drug users will require the 


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development of treatment models tailored to these specific populations. Finally, as the highest 
prevalence of HCV infection occurs in low and middle income countries, the development of 
treatment algorithms that can be implemented in resource limited settings will be necessary to 
decrease the global prevalence and burden of HCV infection.
1.2.
Sofosbuvir/Velpatasvir Fixed-Dose Combination 
Sofosbuvir (SOF) is a nucleotide analog HCV NS5B polymerase inhibitor. Velpatasvir (VEL) is 
a pangenotypic HCV NS5A inhibitor. SOF/VEL (Epclusa®) is a co-formulation of SOF 400 mg 
and VEL 100 mg that is approved in the US, EU and other regions for the treatment of HCV 
infection in adults.
1.2.1.
General Information
Please refer to the Investigator’s Brochure (IB) for additional information on SOF/VEL, and the 
individual components, including:

In-Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.2.2.
Additional Clinical Information; Study GS-US-334-0154
1.2.2.1.
Study Design
Study GS-US-334-0154 is an ongoing Phase 2b, open-label study of SOF-based regimens in 
subjects with severe renal impairment. In Part A, subjects with genotype 1 or 3 HCV infection 
and severe renal impairment were randomized to SOF 200 mg + RBV 200 mg for 24 weeks 
(Cohort 1) or SOF 400 mg + RBV 200 mg (Cohort 2) for 24 Weeks. Based on data from 
Cohort 1 and 2, Cohort 3 was opened for enrollment and subjects with genotype 1 or 4 HCV 
infection and severe renal impairment are treated with LDV/SOF (90/400 mg) for 12 weeks.
Final data is available for Cohort 1 and Cohort 2 and is presented below. Enrollment in Cohort 3 
is ongoing and preliminary data is summarized in Section 1.2.2.8.
1.2.2.2.
Disposition (Cohort 1 and 2)
A total of 20 subjects enrolled and received at least 1 dose of study drug; 10 subjects in
Cohort 1 [SOF 200 mg + RBV 200 mg] and 10 subjects in Cohort 2 
[SOF 400 mg + RBV 200 mg]). The majority of subjects (80.0%) completed study treatment 
(8 subjects in each cohort). Of the 20 enrolled and treated subjects, 4 subjects (20.0%, 2 subjects 
in each cohort) prematurely discontinued study treatment. The reasons for premature 
discontinuation of study treatment were AEs (2 subjects from Cohort 2), noncompliance with 
study drug (1 subject from Cohort 1), and withdrew consent (1 subject in Cohort 1).


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1.2.2.3.
Demographics and Baseline Characteristics (Cohort 1 and 2)
Demographics and baseline characteristics were similar in both treatment groups. The majority 
of subjects were male (70.0%), 45.0% of subjects were black and 35.0% of subjects were white, 
the majority of subjects were non-Hispanic/Latino (85.0%), and the mean age was 60 years 
(range: 45−75). The mean (SD) baseline body mass index (BMI) for subjects was 27.3 (3.71) 
kg/m2, and 70.0% of subjects had BMI < 30 kg/m2.
The majority of subjects had genotype 1a HCV infection (65.0%, 13 subjects), 
20.0% (4 subjects) had genotype 1b, and 15.0% (3 subjects) had genotype 3a. In Cohort 1, the 
majority of subjects had non-CC (CT or TT) IL28B alleles (80.0%); while 50.0% of subjects in 
Cohort 2 had non-CC (CT or TT) IL28B alleles. Overall, the majority of subjects had HCV RNA 
≥6 log10 IU/mL (65.0%, 13 subjects), with a mean (SD) HCV RNA value of 
6.4 (0.47) log10 IU/mL. A total of 4 subjects (20.0%, all in Cohort 2) had cirrhosis at screening. 
In Cohort 1, no subjects reported a known history of cirrhosis; however, 20.0% (2 subjects) had 
FibroTest scores corresponding to stage of F3-F4 (severe fibrosis). In Cohort 1, the median 
(range) estimated glomerular filtration rate using the Cockcroft-Gault equation was 
20.0 (14.4−35.8) mL/min, and in Cohort 2 it was 25.4 (17.5−39.1) mL/min. The majority of 
subjects in Cohort 1 (70.0%) were treatment-naive; the 3 subjects who were treatment 
experienced had failed prior treatment with a direct-acting antiviral + pegylated interferon 
(Peg-IFN) + RBV regimen (2 subjects) or interferon + RBV (1 subject). The majority of subjects 
in Cohort 2 (70.0%) were treatment-experienced; the majority of these subjects (71.4%, 
5 of 7 subjects) had failed prior treatment with Peg IFN+RBV.
1.2.2.4.
Efficacy (Cohort 1 and 2)
The SVR12 rates were as follows:

Cohort 1 (SOF 200 mg + RBV 200 mg): 40.0% (95% CI: 12.2% to 73.8%) of subjects
(4 of 10) achieved SVR12

Cohort 2 (SOF 400 mg + RBV 200 mg): 60.0% (95% CI: 26.2% to 87.8%) of subjects
(6 of 10) achieved SVR12
In Cohort 1, 6 of 10 subjects (60.0%) did not achieve SVR12: 5 subjects (50.0%) relapsed and 
1 subject withdrew consent. In Cohort 2, 4 subjects (40.0%) did not achieve SVR12; all 
4 subjects relapsed. Two of these subjects prematurely discontinued study treatment on Day 64 
and Day 117, respectively, both due to an AE. No subjects in either cohort had on-treatment 
virologic failure (ie, breakthrough, rebound, or nonresponse). The concordance observed 
between SVR12 and SVR24 was 100% in both cohorts. HCV RNA levels (log10 IU/mL) declined 
rapidly with similar decreases in HCV RNA observed in both treatment cohorts. After 1 week of 
treatment, the mean (SD) change from baseline in HCV RNA levels was –4.41 (0.826) log10 
IU/mL in Cohort 1 and –4.68 (0.635) log10 IU/mL in Cohort 2. The decreases were maintained 
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No nonstructural protein 5B (NS5B) nucleoside inhibitor (NI) resistance-associated variants
(RAVs) were detected in any of the subjects at baseline. The NS5B NI RAV E237G was 
detected in 3 subjects at the time of relapse (2 with genotype 1a [1 subject from each cohort] and 
1 with genotype 1b [Cohort 1]). E237G showed a small reduction in susceptibility to SOF 
(1.3-fold change) in a genotype 1a replicon assay, which was within assay variation, and was as 
susceptible as wild-type in the genotype 1b replicon assay (1.0-fold change).
1.2.2.5.
Pharmacokinetics/Pharmacodynamics (Cohort 1 and 2)
SOF AUCtau and Cmax were modestly higher in subjects receiving the 400-mg dose compared 
with the 200-mg dose and AUCtau was generally similar at Week 2 and Week 12 for both doses. 
Compared to historical reference data (SOF US NDA Phase 2/3 HCV-infected subjects without 
renal impairment [creatinine clearance CLcr, ≥ 60 mL/min] administered 
SOF 400 mg + RBV ± Peg-IFN), dose-adjusted SOF AUCtau and Cmax were ~137% and 
~221% higher, respectively, for the 200-mg SOF dose. SOF AUCtau and Cmax were ~36% and 
~100% higher than historical reference data, respectively, for the SOF 400-mg dose. Changes in 
the PK of GS-566500 were generally similar to those observed with SOF, consistent with 
historical data. Higher SOF AUC and Cmax (~503% and ~331%, respectively) were observed 
following the SOF 400-mg dose. No difference in GS-331007 exposure was observed between 
Week 2 and Week 12, suggesting subjects reached steady-state by Week 2. Overall, changes in 
SOF and GS-331007 PK were consistent with results of Phase 1 Study P7977-0915, which 
evaluated SOF PK in HCV-negative subjects with renal impairment.
Consistent with a long t1/2, RBV exposures in both cohorts were higher at Week 12 compared
with Week 2. The RBV AUCtau and Ctau values at Week 12 for both cohorts were similar to those
reported for the administration of RBV 1200 mg/day in subjects with normal renal function.
1.2.2.6.
Safety (Cohort 1 and 2)
Most subjects (Cohort 1: 60.0%, Cohort 2: 80.0%) received study drug for the protocol-specified 
duration of 24 weeks. In Cohort 1, the proportion of subjects with ≥ 90% adherence to SOF 
(80.0%) was higher than to RBV (40.0%). The lower adherence rate to RBV in Cohort 1 was 
primarily due to intentional RBV dose reductions or interruptions instituted by site investigators 
for the management of AEs. In Cohort 2, the proportion of subjects with ≥ 90% adherence to 
SOF (80.0%) was similar to RBV (70.0%).
Most subjects experienced at least 1 AE (Cohort 1: 100.0%, Cohort 2: 90.0%). In Cohort 1, the 
most commonly reported AEs (ie, those occurring in ≥ 2 subjects) were headache (40.0%); 
anemia (30.0%); and hemolytic anemia, hypoesthesia, insomnia, irritability, muscle spasms, 
pruritic rash, and rash (20.0%, each). In Cohort 2, the most commonly reported AEs were anemia 
(40.0%) and dizziness (20.0%). Most AEs were of Grade 1 or Grade 2 severity. Grade 3 AEs 
were reported in 2 subjects (20.0%) in Cohort 1 and 3 subjects (30.0%) in Cohort 2. Anemia was 
the only Grade 3 AE reported in > 1 subject (1 subject in Cohort 1 and 2 subjects in Cohort 2). 
No Grade 4 AEs, deaths, or pregnancies were reported during the study. A total of 4 subjects
(20.0%, 2 subjects in each cohort) had at least 1 treatment-emergent serious adverse event
(SAE), with no SAEs reported for more than 1 subject. All SAEs were considered by the 


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investigators to be not related to study drug. A total of 4 subjects (20.0%, 2 subjects in each
cohort) had AEs leading to premature discontinuation of any study drug. The 2 subjects in
Cohort 1 had AEs leading to premature discontinuation of RBV only (anemia in 1 subject and
fatigue, irritability, and generalized rash in 1 subject; all of these AEs were considered to be
related to study drug). Of the 2 subjects in Cohort 2 experiencing AEs that led to premature
discontinuation of SOF and RBV, 1 subject had a Grade 2 AE of fatigue that was considered to
be related to study drug and 1 subject had a Grade 3 AE of renal failure and an SAE of 
pneumonia that were considered to be not related to study drug.
All subjects had at least 1 laboratory abnormality reported. There were 60.0% of subjects in
Cohort 1 and 70.0% of subjects in Cohort 2 who had a Grade 3 or 4 laboratory abnormality.
Across both cohorts, the observed Grade 3 or 4 hematology abnormalities were decreased
hemoglobin and lymphocytes. Decreased hemoglobin and decreases in lymphocyte count are
known effects of RBV therapy. Across both cohorts, the Grade 3 or 4 chemistry laboratory
abnormalities were increased creatinine, decreased serum bicarbonate, increased serum glucose,
and increased blood urea nitrogen. All 5 subjects with Grade 3 or 4 increases in creatinine
(2 subjects in Cohort 1, 3 subjects in Cohort 2) had Grade 2 or 3 elevations of creatinine at
baseline and throughout study treatment. The 2 subjects with Grade 3 decreases in serum
bicarbonate (1 subject in each cohort) had graded decreases in serum bicarbonate at baseline. All
3 subjects with Grade 3 increased serum glucose had a medical history of diabetes. The 1 subject
in Cohort 2 who had a Grade 3 increase in blood urea nitrogen had graded elevations in blood
urea nitrogen at baseline and throughout study treatment.
Overall, there were 3 subjects (15.0%) with an AE under the Renal and Urinary Disorders
system organ class (SOC): 1 subject in Cohort 1 and 2 subjects in Cohort 2. Of these, 1 subject
(Subject 
 in Cohort 2 discontinued study treatment due to a Grade 3 AE of renal
failure and an SAE of pneumonia. The other AEs in the Renal and Urinary Disorders SOC were
Grade 1 or 2 (chronic kidney disease and nocturia) that did not lead to modification or
interruption of study treatment. One subject (Subject 
 in Cohort 2 started dialysis
during the study due to worsening of subject’s chronic kidney failure from Stage 4 to Stage 5,
which was considered by the investigator to be unrelated to study treatment.
No subjects had clinically significant ECG abnormalities during treatment with SOF+RBV. 
No meaningful change in systolic function measured by ejection fraction was observed in either
treatment cohort. In addition, no subject had a decrease in ejection fraction below 50%. 
The median (Q1, Q3) change in ejection fraction from baseline to Week 24 for Cohort 1 was 
0.09% (−0.97, 2.70), and in Cohort 2 was −0.73% (−4.28, 1.08). As compared to baseline
echocardiograms, there were overall no significant changes in fractional shortening, left
ventricular end diastolic volume (LVEDV), or left ventricular internal dimension in diastole
(LVIDD) at Week 12 or Week 24.
No notable changes from baseline in vital signs (systolic blood pressure, diastolic blood pressure,
or pulse rate) were observed during the study.
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1.2.2.7.
Conclusions (Cohort 1 and 2)
The conclusions for Cohorts 1 and 2 were as follows:

For subjects with severe renal impairment, the overall SVR12 rates following treatment with
SOF (200 mg or 400 mg) in combination with RBV for 24 weeks were as follows:
In Cohort 1 (SOF 200 mg + RBV 200 mg), the SVR12 rate was 40.0%.
In Cohort 2 (SOF 400 mg + RBV 200 mg), the SVR12 rate was 60.0%.

No subjects in either treatment cohort had on-treatment virologic failure (ie, breakthrough,
rebound, or nonresponse).

Virologic relapse was associated with the emergence of the NS5B NI RAV E237G in 3 of
9 subjects (33.3%).

SOF and GS-331007 exposures in HCV-infected subjects with severe renal impairment in
this study were higher than exposures observed in the reference US Phase 2/3 population of
HCV-infected subjects without renal impairment.
SOF AUCtau and Cmax were 36% and 100% higher, respectively, for the SOF 400-mg 
dose.
GS-331007 AUCtau and Cmax were 503% and 331% higher, respectively, for the SOF 
400-mg dose.
The effect of severe renal impairment on SOF and GS-331007 exposures in HCV
infected subjects administered the SOF 400-mg dose with RBV 200 mg was generally 
comparable with the results from a dedicated renal impairment study in HCV-negative 
subjects (Study P7977-0915).

Sofosbuvir was safe and well tolerated. The AE and laboratory safety profile observed was
consistent with that reported for SOF+RBV in subjects without renal impairment. There were
no new safety signals or toxicities observed in this study of subjects with severe renal
impairment.
1.2.2.8.
Preliminary Data from Cohort 3
As of August 2016, 10 subjects have been enrolled and treated in Cohort 3. Preliminary data
suggest LDV/SOF has been well tolerated. No subjects have discontinued treatment due to AEs. 
There have been 4 SAEs reported; hypoglycemia and syncope in one subject 
(Subject
 and acute renal failure (Subject 
 in one subject, and acute 
kidney injury in one subject (Subject 
 The syncope experienced by
Subject
 was assessed as secondary to hypoglycemia. No SAE was assessed as 
related to study drugs. An analysis of echocardiogram data for 8 subjects demonstrates stable 
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parameters from screening through the end of treatment, and does not suggest an impact of 
LDV/SOF treatment on cardiac function. Eight subjects who have reached posttreatment 
Week 12 to date have achieved SVR12 (100%, 8/8).
1.2.3.
Additional Non-Clinical Toxicology Information
In dogs, repeated administration of GS-9851 (the diastereomeric mixture of SOF and 
GS-491241) or SOF at exposures similar to those expected in ESRD patients may decrease 
erythropoiesis and lower the numbers of circulating red cells (reflected by the decrease in red 
blood cells, hemoglobin concentration, and/or hematocrit). In the 4- and 13-week studies in dogs, 
there were slightly lower average circulating red cell indices, and minimally decreased 
erythropoiesis (observed by bone marrow cytology) at 500 and ≥ 100 mg/kg/day, respectively. 
However, in the 39-week dog study, while minimally decreased erythropoiesis was observed in a 
few dogs, there were no SOF-related effects on circulating red cell indices at 500 mg/kg/day. 
In mice and rats, SOF did not affect hematology parameters at any dose level; specifically, there 
were no effects in mice dosed up to 1000 mg/kg/day for up to 13 weeks or in rats dosed up to 
500 mg/kg/day for up to 26 weeks. There were also no bone marrow cytology findings in rats 
dosed up to 26 weeks. In vitro, the diastereomic mixture GS-9851 also showed low cytotoxicity 
to erythroid cell lines.
1.3.
Rationale for This Study
The GS-US-342-4062 study is a Phase 2, open label multicenter study evaluating the efficacy 
and safety of treatment of SOF/VEL for 12 weeks in subjects on dialysis for ESRD. 
Approximately 100 subjects will be enrolled.
Sofosbuvir/VEL (Epclusa®) is approved in the US, EU and other regions for the treatment of 
HCV infection based on the results of the Phase 3 ASTRAL clinical studies. However, subjects 
with creatinine clearance (CLcr) < 60 ml/min were not eligible for enrollment in the ASTRAL 
1-3 studies and subjects with CLcr < 50 ml/min were not eligible for enrollment in the 
ASTRAL-4 study. There is therefore no dosing recommendation provided for HCV infected 
subjects with severe renal impairment in the prescribing information in the US, EU and other 
regions.
There remains a medical need for highly effective treatment for HCV-infected subjects with 
ESRD on dialysis. Chronic HCV infection has a significant negative impact on morbidity and 
mortality in subjects on dialysis {Fabrizi 2007}. The Kidney Disease International Working 
Group (KDIGO) recommend that HCV infection be treated prior to kidney transplant as there is 
evidence that this leads to improved graft and patient outcomes {Kidney Disease: Improving 
Global Outcomes 2008}.
Although, some regions do have approved HCV treatment options for HCV infected subjects
with severe renal impairment, including Viekira Pak® and Zepatier™{AbbVie Inc 2016, Merck 
& Co Inc 2016}, both regimens have limitations. The use of Viekira Pak® is limited as, in many 
populations, the addition of RBV is required for optimal efficacy and RBV-induced toxicities are 
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(ombitasvir, paritaprevir, ritonavir and dasabuvir) have drug-drug interaction potential which 
adds increasing complexity to the management of subjects with severe renal impairment who 
frequently have multiple comorbid conditions and concomitant medications. The use of Zepatier 
is limited by the requirement for baseline resistance testing for subjects with genotype 1a 
infection and RBV is required for some populations. Furthermore, both regimens carry the risk 
of alanine aminotransferase (ALT) elevations and/or hepatotoxicity and neither regimen is 
pangenotypic.
Sofosbuvir-based regimens are currently the most widely prescribed treatments for HCV 
infection. Despite the lack of dosing recommendations for subjects with severe renal impairment 
in the prescribing information for SOF-based regimens, it is apparent from the number of 
publications of small cohort studies describing treatment of subjects with severe renal 
impairment with SOF-based regimens that such treatment is not uncommon {Bhamidimarri 
2015, Desnoyer 2016, Hundemer 2015, Navarro-Millan 2013, Nazario 2016}. The simplicity of 
SOF-based dosing regimens, relative lack of drug-drug interactions, and absence of a 
requirement for baseline NS5A polymorphism testing or RBV use make SOF-based regimens a 
viable option for physicians, even when considering the lack of dosing recommendations in this 
population. 
The unmet medical need of the population and the ongoing off-label use of SOF-based regimens 
provide a strong rationale for the conduct of this study as the data obtained will address the gaps 
in knowledge regarding the use of SOF-based regimens in subjects with HCV infection and 
severe renal impairment or ESRD.
1.4.
Rationale for Dose Selection of SOF/VEL
Subjects in this study will be administered SOF/VEL, a co formulation of SOF 400 mg and VEL 
100 mg that is approved in the US, EU and other regions as Epclusa® for the treatment of HCV 
infection in adults.
In the Phase 3 ASTRAL 1-3 studies, treatment of HCV infected subjects infected without 
cirrhosis or with compensated cirrhosis for 12 weeks with SOF/VEL was well tolerated and 
resulted in high SVR12 rates. There is no information available on the administration of 
SOF/VEL to subjects with severe renal impairment or those on dialysis as such subjects were not 
enrolled in the Phase 3 ASTRAL studies. The results of a Phase 1 single dose study of VEL in 
subjects with severe renal impairment indicates that there were no relevant differences in VEL 
exposure were observed between subjects with normal renal function and subjects with severe 
renal impairment. In a phase 1 study of the PK of SOF in subjects with renal impairment, the 
SOF and GS-331007 AUC were 171% and 451% higher in subjects with severe renal 
impairment compared to subjects with normal renal function. In subjects with ESRD, SOF and 
GS-331007 AUC was 28-60% and 1280-2070% higher, respectively, compared to subjects with 
normal renal function.
Available data from the GS-US-334-0154 study indicates that administration of SOF 400 mg 
with RBV 200 mg for 24 weeks in subjects with severe renal impairment was well tolerated with 
no specific safety signal associated with the elevated exposures of SOF or the predominant 


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metabolite GS-331007. The exposure of SOF and GS-331007 in the GS-US-334-0154 study are 
consistent with the results of the Phase 1 study of SOF in subjects with severe renal impairment 
or EDRD. Preliminary data from Cohort 3 of the GS-US-334-0154 study suggests that the 
administration of LDV/SOF (90/400 mg) for 12 weeks is well tolerated and is more efficacious 
than administration of SOF 200 mg or 400 mg with RBV 200 mg for 24 weeks. Therefore it is 
anticipated that SOF/VEL will be similarly efficacious and well tolerated as LDV/SOF in 
subjects with severe renal impairment or on dialysis. 
Based on these data, the approved dose of SOF/VEL will be evaluated in this study. Refer to the 
SOF/VEL Investigator’s Brochure for additional information.
1.5.
Risk/Benefit Assessment for the Study
This study will provide data of the safety and efficacy of SOF/VEL in subjects on dialysis for 
ESRD. It is anticipated that these data will support dosing recommendations for SOF/VEL in 
subjects with severe renal impairment and subjects with ESRD on dialysis.
The potential benefits of SOF/VEL over the currently available treatment options are:

SOF/VEL has pangenotypic antiviral activity and therefore may provide a treatment option 
for subjects with genotype 1-6 infection. The currently available treatment options for 
subjects with severe renal impairment and on dialysis for ESRD are restricted to the 
treatment of genotype 1 and 4 HCV infection.

SOF/VEL will provide a highly effective and well tolerated RBV-free treatment option for 
subjects. As RBV-associated toxicities can be exacerbated in subjects with severe renal 
impairment, the availability of a RBV-free treatment option will enable a greater proportion 
of subjects with severe renal impairment to be treated. 

The components of SOF/VEL have limited drug-drug interaction potential with medications 
commonly prescribed to subjects with severe renal impairment or ESRD on dialysis. This 
should reduce the complexity of patient management compared with the use of other antiviral 
treatments.
The risks associated with the evaluations of SOF/VEL in subjects with ESRD on dialysis are 
associated with concerns about the high exposure of the predominant SOF metabolite, 
GS-331007, in subjects with renal impairment and the lack of data on the safety and efficacy of 
SOF/VEL in subjects with renal impairment. In non-clinical studies, GS-331007 exposure 
similar to that projected for patients with ESRD administered SOF/VEL resulted in decreased 
red cells counts (See Section 1.2.3).


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These risks are mitigated by the following:

The Phase 3 SOF/VEL clinical development program included 4 Phase 3 studies of 
HCV-infected subjects in which 1302 subjects with HCV infection were treated with 
SOF/VEL. No clinical safety issued have been associated with SOF/VEL in the Phase 3 
program.

During the conduct of the study, hematologic assessments will be performed routinely and 
results will be reviewed by the investigator and sponsor.

During the conduct of the study, a Data Monitoring Committee (DMC) will evaluate safety 
data in the study after the first n=12 subjects have completed 12 weeks of treatment, or early 
termination, and then every 3 months until the last subject enrolled completes treatment with 
study drugs. Furthermore, the Sponsor and the Investigators will perform ongoing safety 
reviews throughout the study.
Given the medical need for well tolerated, highly effective, pangenotypic, RBV-free treatment 
options for HCV infected subjects with ESRD on dialysis, the benefit/risk assessment of this 
study favors the conduct of the study.
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objectives of this study are:

To evaluate the antiviral efficacy of treatment with sofosbuvir/velpatasvir (SOF/VEL) for 
12 weeks as measured by the proportion of subjects with sustained viral response 12 weeks 
after cessation of treatment (SVR12)

To evaluate the safety and tolerability of the treatment regimen 
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
the study treatment regimen (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of
treatment

To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment

To evaluate the steady-state pharmacokinetics of SOF and its metabolites and VEL in 
subjects who are on dialysis for ESRD
The exploratory objectives of this study are:
 
 
 
CCI


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3.
STUDY DESIGN
3.1.
Study Design
This is a multicenter, open label Phase 2 study that will evaluate the safety, tolerability and 
antiviral efficacy of SOF/VEL in subjects on dialysis for ESRD with genotype 1-6 HCV 
infection.
3.2.
Visit Schedule
Screening assessments will be completed within 28 days of the Day 1 visit. The screening 
window can be extended to 42 days for extenuating circumstances with Sponsor approval.
All subjects will complete the following study visits: Screening, Day 1, on-treatment visits at the 
end of Weeks 2, 4, 6, 8, and 12, and posttreatment visits at Weeks 4 and 12, after completion of 
treatment. Subjects who achieve SVR12 will also complete the posttreatment Week 24 visit.
3.3.
Duration of Treatment
Approximately 100 subjects will be enrolled and treated with SOF/VEL once daily for 12 weeks.
The total time to complete all study visits is approximately 40 weeks (42 weeks for those 
requiring extension of the Screening period):

28 days (4 weeks) screening period (or 42 days for extenuating circumstances)

12 week study treatment period

24 week posttreatment period
3.4.
Stopping Rules and Discontinuation Criteria
If a subject discontinues study dosing (for example, as a result of an adverse event [AE]), every
attempt should be made to keep the subject in the study and continue to perform the required
study-related follow-up procedures (Section 6.4). If this is not possible or acceptable to the
subject or investigator, the subject may be withdrawn from the study.
There is no option for SOF/VEL dose reduction due to toxicity. If SOF/VEL is withheld due to 
toxicity, the subject must discontinue treatment and complete an Early Termination (ET) visit.
For subjects who have completed an ET visit, the posttreatment Week 4 and 12 visits will be
scheduled after last dose of any of the study drug. Subjects who achieve SVR12 (HCV RNA
< LLOQ at posttreatment Week 12) will complete the posttreatment Week 24 visit.
When medically feasible, the medical monitor must be consulted prior to subject discontinuation.


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Study drug(s) must be discontinued in the following instances:

Unacceptable toxicity (as defined in Section 3.4.1) or toxicity that, in the judgment of the 
investigator, compromises the ability to continue study-specific procedures or is considered 
to not be in the subject’s best interest

Virologic failure (as defined in Section 3.4.2)

Pregnancy of female subject (refer to Appendix 4)

Significant protocol violation that impacts subject safety

Subject request to discontinue for any reason; it is important to determine whether the
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason

Subject noncompliance

Discontinuation of the study at the request of Gilead, regulatory agency or an Institutional
Review Board (IRB)/Independent Ethics Committee (IEC)
3.4.1.
Toxicity-Based Stopping Criteria

Subjects who meet any of the following laboratory or adverse event criteria must stop 
treatment with SOF/VEL

Elevation of ALT and/or AST above the upper limit of normal and > 5x Day 1 or nadir, 
confirmed by immediate repeat testing

Abnormal elevation of ALT > 3 x Day 1 and total bilirubin > 2 x ULN, confirmed by 
immediate repeat testing

Elevation of ALT > 15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event assessed as related to SOF/VEL
3.4.2.
Virologic Response Base Stopping Criteria
The following on-treatment virologic response-based treatment stopping criteria will be utilized:

Confirmed HCV RNA ≥ LLOQ after 2 consecutive HCV RNA < LLOQ

Confirmed > 1 log10 increase from on-treatment nadir

HCV RNA ≥LLOQ at Week 8


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Confirmation should be performed as soon as possible and must occur no later than 2 weeks after
an initial observation indicating virologic failure during the on-treatment phase. All subjects who 
terminate treatment early will complete the ET visit and posttreatment Week 4 and 12 visits.
3.5.
HIV Virologic Rebound Criteria
Subjects who have at least two consecutive post-baseline visit plasma HIV-1 RNA levels
≥400 copies/mL (at least two weeks apart) will be considered to have HIV virologic rebound.
Following an initial HIV-1 RNA result of ≥400 copies/mL, subjects will continue to take their 
current ARV regimen and be asked to return to the clinic after 2 weeks for a scheduled or 
unscheduled blood draw for confirmation of HIV virologic rebound. If HIV virologic rebound is 
confirmed at the scheduled or unscheduled visit, the blood samples from this visit will be used 
for HIV-1 genotype/phenotype testing. If no resistance to the subject’s current ARV regimen is 
detected, the subject may continue on the current ARV regimen.
HCV study drug should be continued unless safety events warrant the discontinuation of the 
study drug, as outlined in Section 3.4 of the protocol.
Please refer to Figure 3-1 for the management of subjects who meet the criteria for HIV virologic 
rebound.


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Figure 3-1.
HIV Virologic Rebound Schema
a
HCV study drug should be continued unless safety events warrant the discontinuation of these study drugs, as outlined in
Section 3.4 of the protocol
b
If virologic rebound is not confirmed, the subject should remain on their current ARV regimen.
c
If virologic rebound is confirmed, the HIV-1 genotype and phenotype (reverse transcriptase and protease) should be 
analyzed. Based on the results of the genotype and phenotype assays, the subject may remain on their ARV regimen or a 
new ARV regimen may be configured at the discretion of the Investigator. If the genotype and/or phenotype assay fails to 
provide results, a new ARV regimen may be configured at the discretion of the Investigator in consultation with the Medical
Monitor
HIV-1 RNA ≥ 400 copies/mL
Continue current ARV regimen and return for 
scheduled/unscheduled (at least 2 weeks apart) HIV-1 
RNA and potential genotype/phenotype samplinga
HIV-1 genotype/phenotype
Unconfirmed 
virologic rebound: 
remain on current 
regimenb
Confirmed virologic reboundc
If no resistance to the subject’s current 
ARV regimen is detected, may 
continue on current ARV regimen
Study Period
(On-Treatment)
If resistance to the subject’s 
current ARV regimen is detected, 
discontinue and construct a new 
ARV regimen


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3.6.
Pharmacokinetic (PK) Substudies
 
 
 
 
 
 
 
 
 
 
 
3.7.
Biomarker Testing
3.7.1.
Samples for Optional Future Research
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
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CCI


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4.
SUBJECT POPULATION
Approximately 100 subjects will be enrolled in this study. In order to manage the total study 
enrollment, Gilead Sciences, Inc., at its discretion, may suspend screening and/or enrollment at 
any site or study-wide at any time.
4.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Willing and able to provide written informed consent
2) Male or female age ≥ 18 years
3) Chronic HCV infection (≥ 6 months) as documented by prior medical history or liver biopsy
4) HCV RNA ≥ LLOQ at screening
5) End stage renal disease (ESRD) requiring peritoneal dialysis (PD) or hemodialysis (HD) 
6) The most recent HCV treatment must have been completed at least 8 weeks prior to 
screening
7) Subjects must have a determination of treatment experience (treatment naïve vs. treatment 
experienced). Treatment naïve is defined as having never been exposed to an approved or 
experimental HCV-specific direct acting antiviral agents or prior treatment of HCV with 
interferon or ribavirin. All other subjects will be considered treatment experienced.
8) Subjects must have appropriate testing for determination of cirrhosis status.
a) Presence of cirrhosis is defined as any one of the following:
i)
Fibroscan with a result of > 12.5 kPa 
ii) Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥ 5)
iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score ≥0.75 at 
screening
b) Absence of cirrhosis is defined as any one of the following:
i)
Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Baseline/Day 1
ii) Liver biopsy performed within 2 years of Screening showing absence of cirrhosis
iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score <0.75 at 
screening


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9) Liver imaging within 6 months of Baseline/Day 1 is required in cirrhotic subjects only to 
exclude HCC
10) Subjects with HIV-1 coinfection may be eligible, provided they satisfy these additional 
inclusion criteria:
i)
Completed at least 3 months of any prior HIV ARV therapy and maintained HIV 
RNA<50 copies/mL (or <LLOQ if the local laboratory assay’s LLOQ is 
50 ≥copies/mL) and CD4 T-cell count > 100 cells/mm3 prior to Screening. Subjects 
with an isolated or unconfirmed HIV RNA >50 copies/mL (or >LLOQ if the local 
laboratory assay’s LLOQ is 50≥ copies/mL) are not excluded
ii) On a stable ARV regimen for ≥ 8 weeks prior to Screening and is expected to 
continue the current ARV regimen through the end of study (See exclusion criteria 
17). 
11) A negative serum pregnancy test is required for female subjects (unless permanently sterile 
or greater than two years post-menopausal).
12) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 4.
13) Lactating females must agree to discontinue nursing before the study drug is administered.
14) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments.
4.2.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Current or prior history of any of  the following:
a) Clinically-significant illness (other than HCV, HIV, and kidney disease or co-morbidities 
associated with ESRD except as noted below) any other major medical disorder that may 
interfere with subject treatment, assessment or compliance with the protocol; subjects 
currently under evaluation for a potentially clinically significant illness (other than HCV 
or ESRD) are also excluded.
b) Current or prior history of significant cardiac disease including or resulting in: 

Hospital admission for significant cardiovascular disease (myocardial infarction, 
unstable angina, heart failure, hypertensive emergency) or has had a cardiovascular 
procedure (e.g CABG or PTCA), within 6 months of Screening

Cardiomyopathy with ejection fraction <50%


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c) Gastrointestinal disorder or postoperative condition that could interfere with the 
absorption of the study drug.
d) Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy.
e) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).
f)
Solid organ transplantation other than failed kidney transplants (current use of ≤5 mg/day 
of prednisone, or equivalent dose of corticosteroid, allowed).
g) Significant pulmonary disease
h) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of 
their psychiatric illness within the last 2 years.
i)
Malignancy within the 5 years prior to screening, with the exception of specific cancers 
that have been cured by surgical resection (basal cell skin cancer, etc). Subjects under 
evaluation for possible malignancy are not eligible
2) Screening ECG with clinically significant abnormalities  
3) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alfa-1 antitrypsin deficiency, cholangitis).
4) Opportunistic infection (Appendix 5) within 6 months prior to Screening
5) Infection (other than HIV or HCV) requiring parenteral therapy within 30 days prior to 
baseline.
6) Life threatening SAE during the screening period
7) Subjects have the following laboratory parameters at screening:
a) ALT > 10 X the upper limit of normal (ULN)
b) AST > 10 X ULN
c) Direct bilirubin > 1.5 X ULN. For subjects receiving ritonavir boosted atazanavir 
regimen, a direct bilirubin > 1.5 x ULN will be allowed if < 25% of the total bilirubin
d) Platelets < 25,000/μL
e) HbA1c > 9%
f)
Hemoglobin < 9 g/dL


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g) Albumin < 2.8 g/dL
h) INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR
i)
Hepatitis B surface antigen positive
8) Prior exposure to any HCV NS5A inhibitor.
9)
Male with pregnant female partner.
10) Females who may wish to become pregnant and/or plan to undergo egg harvesting during the 
course of the study and up to 30 days of the last dose of study drug
11) Males who may wish to donate sperm during the course of the study until at least 30 days 
after the last dose of study drug
12) Clinically-relevant alcohol or drug abuse within 12 months of screening. A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator.
13) Use of any prohibited concomitant medications as described in Section 5.4.
14) Subjects with HIV-1 coinfection cannot be receiving an ARV regimen containing efavirenz 
(EFV) 
15) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone 
equivalent > 10 mg/day).
16) Known hypersensitivity to the VEL, SOF, the metabolites, or formulation excipient.
17) For subjects with HIV-1 coinfection only:

HIV-1 RNA >50 copies/mL

CD4 T-cell count <100 cells/mm3

HIV-2 positive test


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
This is an open-label, single arm study. An Interactive Web Response System (IWRS) will be 
employed to manage subject enrollment and the study drug dispensing as well as re-supply of
study drug.
5.2.
Description and Handling of SOF/VEL FDC
5.2.1.
Formulation
The SOF/VEL FDC (SOF/VEL 400/100 mg) tablets are pink, diamond-shaped, film-coated 
tablets, containing 400 mg of SOF and 100 mg of VEL. The tablets are debossed with “GSI” on 
one side and “7916” on the other side. In addition to the active ingredients, the SOF/VEL FDC
tablets contain copovidone, microcrystalline cellulose, croscarmellose sodium, magnesium 
stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide red.
5.2.2.
Packaging and Labeling
SOF/VEL FDC (SOF/VEL 400/100 mg) tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 tablets and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant, polypropylene screw cap with an 
induction-sealed, aluminum-faced liner.
SOF/VEL FDC bottles to be distributed to centers in North America, Europe, Asia Pacific and 
Middle East shall be labeled to meet all applicable requirements of the United States Food and 
Drug Administration (FDA), the EU Guideline to Good Manufacturing Practice - Annex 13 
(Investigational Medicinal Products) and/or other local regulations as applicable.
5.2.3.
Storage and Handling
SOF/VEL FDC tablets should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25C (77 F); excursions are permitted 
between 15C and 30C (59F to 86F).
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF/VEL FDC tablets.


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Sufficient quantities of SOF/VEL FDC tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Clinical Supply Management Team (or its 
designee).
5.3.
Dosage and Administration of SOF/VEL FDC
SOF/VEL FDC tablet is to be administered once daily with or without food. Each subject must 
be given instructions to maintain approximately the same daily dosing interval between study 
drugs doses, 
 
For a missed dose of SOF/VEL FDC tablet, subjects should be instructed to take the missed dose 
of study drug as soon as possible during the same day. Subjects should be cautioned never to 
double the next dose with a missed dose of study drug under any circumstances.
Study drugs should not be cut or split.  SOF/VEL FDC tablets will be provided by 
Gilead Sciences for all subjects.
5.4.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 30 days 
after the last dose of study drug, need to be recorded in the source documents and electronic case 
report form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment:

Granulocyte colony stimulating factors (GCSF) and thrombopoietin (TPO) mimetics

Investigational agents or devices for any indication

Chronic use of systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (e.g., infliximab).
Concomitant use of certain medications or herbal/natural supplements (such as moderate to 
potent inducers of drug transporters or metabolizing enzymes, e.g., P-gp, CYP2B6, CYP2C8, or 
CYP3A) with the study drug may result in pharmacokinetic interactions resulting in increases or 
decreases in exposure of the study drug or these medications.
Table 5-1 below contains medications that are prohibited from 21 days prior to Day 1 through 
the end of treatment and those medications that may be used with caution. The use of 
amiodarone is prohibited from 60 days prior to Day 1 through the end of treatment.
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Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton- Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsb
Phenytoin, Carbamazepine, Phenobarbital, 
Oxcarbazepine
Antimycobacterialsb
Rifampicin, Rifabutin, Rifapentine
Cardiac Medicationsc 
Amiodaroned
Digoxine
Herbal/Natural 
Supplementsb
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsf
Rosuvastatin (≤10 mg/day), Atorvastatin
Other
Bosentanb, Modafinil b, Sulfasalazinec, , 
Methotrexatec
a
Co-administration with proton pump inhibitors (PPIs) is not recommended. If it is considered necessary to co-administer, 
then SOF/VEL should be administered with food and taken 4 hours before PPI at max doses comparable to omeprazole 
20 mg. H2-receptor antagonists must not exceed a dose of 40 mg famotidine or equivalent and can be taken simultaneously 
with SOF/VEL and/or staggered by 12 hours. Antacids that directly neutralize stomach acid may not be taken within 4 hours 
(before or after) of SOF/VEL administration.
b
May result in a decrease in the concentration of study drugs.
c
May result in an increase in the concentration of study drugs and/or concomitant medications
d
May result in symptomatic bradycardia. Mechanism is not currently known. The use of amiodarone is prohibited from 
60 days prior to Day 1 through the end of treatment
e
Monitor for signs and symptoms of digoxin toxicity.
f
Use with SOF/VEL may result in an increase in the concentration of HMG-CoA Reductase Inhibitor, rosuvastatin. Monitor 
for signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis. 
Medications for disease conditions excluded from the protocol (e.g., active cancer) are not listed 
under this Concomitant Medication section and are disallowed in the study.
Should subjects have a need to initiate treatment with any excluded concomitant medication, the 
Medical Monitor must be consulted prior to initiation of the new medication. In instances where 
an excluded medication is initiated prior to discussion with the Sponsor, the Investigator must 
notify Gilead as soon as he/she is aware of the use of the excluded medication.
5.5.
Accountability for SOF/VEL
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgement of receipt of each shipment 
of study drug (quantity and condition). All used and unused study drug dispensed to subjects 
must be returned to the site.
SOF/VEL accountability records will be provided to each study site to:

Record the date received and quantity of study drug kits


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
Record the date, subject number, subject initials, the study drug kit number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
Please refer to Section 9.1.7 for information pertaining to study drug return and disposal.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
6.1.1.
Pretreatment Assessments
6.1.1.1.
Screening Visit
Subjects will be screened within 28 days of the Day 1 visit before enrollment to determine 
eligibility for participation in the study. The screening window can be extended up to 42 days for 
subjects requiring additional HCV genotyping (if initial testing is inconclusive), or for 
extenuating circumstances with sponsor approval. 
The following will be performed and documented at screening:

Obtain written informed consent
 

Determine inclusion and exclusion eligibility (Reference Sections 4.1 and 4.2)

Obtain medical history, including
Hepatitis C history
■
Regimen(s)
■
Dates of previous treatment(s)
■
Response to previous treatment (e.g., nonresponder, relapse, discontinuation 
including reason)
Renal dialysis history
■
Type: hemodialysis or peritoneal dialysis
■
Date of initiation
■
Stop date (if applicable)
CCI


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Renal transplant history (if applicable)
■
Date of transplant
■
Date of transplant failure
■
Current immunosuppression

Determine cirrhosis status as defined in Section 4.1.
■
Record liver biopsy or Fibroscan results (if applicable)
■
If the presence of cirrhosis is determined, then appropriate diagnostic imaging should 
be performed or confirmed to have been performed within 6 months of screening to
exclude the presence of hepatocellular carcinoma (HCC)

Obtain details of concomitant medications

Perform 12-lead ECG

Complete physical examination including, vital signs (resting blood pressure, pulse, 
respiratory rate and temperature), body weight, and height

Pregnancy prevention counselling

Obtain blood samples for tests as listed in Section 6.9.1:
Hematology
Chemistry
Coagulation tests
HCV RNA
Determination of HCV viral genotype and subtype
HCV antibody, HIV 1/2 antibody, HBV surface antigen (HBsAg), HBV core antibody 
(HBcAb), and HBV surface antibody (HBsAb)
HbA1c
IL28B genotyping
Serum β-hCG pregnancy test for females of childbearing potential only
HIV-1 RNA and CD4 cell count will only be collected and analyzed for HIV co-infected 
subjects
Fibrotest®
Serum drug screen

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form.


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Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 28 days after screening for enrollment into the study. The screening window can be 
extended up to 42 days for extenuating circumstances with Sponsor approval.
Retests of Screening labs are permitted only if the initial exclusionary value was either due to a
sample processing error or due to extenuating circumstances such as intercurrent illness.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (CRF/eCRF). 
All other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history CRF/eCRF. 
See Section 7 Adverse Events and Toxicity Management for additional details.
6.2.
Day 1 Assessments
The following procedures/assessments are to be completed at Baseline/Day 1 of Dosing:

Confirm Eligibility (See Sections 4.1 and 4.2)

Complete physical examination, including vital signs and body weight

Assessment of AEs and concomitant medications

Perform 12-lead ECG (prior to study drug administration)

Pregnancy prevention counselling

Subject completes Health Related Quality of Life Questionnaire: SF-36, CLDQ-HCV, 
FACIT-F, and WPAI

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing/phenotyping
Serum β-hCG pregnancy test for females of childbearing potential only


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HIV-1 RNA and CD4 cell count will only be collected and analyzed for HIV co-infected 
subjects
HBV DNA (Only in subjects who are HBcAb+ at Screening)
 

Study drug administration
Dispense study drugs as directed by the IWRS
Instruct the subject on the packaging, storage, and administration of the study drugs
Observe the subject taking the first dose of study drug and record the time of first dose 
and whether it was taken with or without food
6.3.
Treatment Assessments
6.3.1.
Week 2 (± 3 days)
The following procedures/assessments are to be completed at the end of Week 2:

Obtain vital signs 

Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing/phenotyping
Sparse PK sample

Assess adherence with study drug dosing regimen including pill count
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6.3.2.
Week 4 (± 3 days)
The following procedures/assessments are to be completed at the end of Week 4:

Obtain vital signs 

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counselling

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing/phenotyping
Sparse PK sample
HIV-1 RNA and CD4 cell count will only be collected and analyzed for HIV co-infected 
subjects
HBV DNA (Only in subjects who are HBcAb+ at Screening)
Serum β-hCG pregnancy test for females of childbearing potential only

Assess adherence with study drug dosing regimen including pill count

Dispense study drug as directed by the IWRS
6.3.3.
Week 6 (± 3 days)
The following procedures/assessments are to be completed at the end of Week 6:

Obtain vital signs 

Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology
Chemistry


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HCV RNA
Viral sequencing/phenotyping
Sparse PK sample

Assess adherence with study drug dosing regimen including pill count
6.3.4.
Week 8 (± 3 days)
The following procedures/assessments are to be completed at the end of Week 8:

Obtain vital signs 

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counselling

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing/phenotyping
Sparse PK sample
HIV-1 RNA and CD4 cell count will only be collected and analyzed for HIV co-infected 
subjects
HBV DNA (Only in subjects who are HBcAb+ at Screening)
Serum β-hCG pregnancy test for females of childbearing potential only

Assess adherence with study drug dosing regimen including pill count

Dispense study drug as directed by the IWRS
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6.3.5.
Week 12 (± 3 days) or Early Termination (ET)
The following procedures/assessments are to be completed at the end of Week 12/ET:

Perform complete physical examination, including vital signs and body weight

Assessment of AEs and concomitant medications

Perform 12-lead ECG

Pregnancy prevention counseling

Subject completes Health Related Quality of Life Questionnaire: SF-36, CLDQ-HCV,
FACIT-F, and WPAI

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing/phenotyping
HIV-1 RNA and CD4 cell count will only be collected and analyzed for HIV co-infected 
subjects
HBV DNA (Only in subjects who are HBcAb+ at Screening)
Sparse PK sample
Serum β-hCG pregnancy test for females of childbearing potential only

Assess adherence with study drug dosing regimen including pill count

Subjects should return all bottles of study drug 
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6.4.
Post-treatment Assessments
6.4.1.
Posttreatment Week 4 Visit (± 5 days)
The following procedures/assessments are to be completed at Posttreatment Week 4:

Perform complete physical examination, including vital signs

Assessment of AEs and concomitant medications

Pregnancy prevention counselling

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing/phenotyping
HIV-1 RNA and CD4 cell count will only be collected and analyzed for HIV co-infected 
subjects
HBV DNA (Only in subjects who are HBcAb+ at Screening)
Serum β-hCG pregnancy test for females of childbearing potential only
6.4.2.
Posttreatment Week 12 (± 5 days)
The following procedures/assessments are to be completed at Posttreatment Week 12 and 24:

Perform complete physical examination, including vital signs

Assessment of SAEs 

Subject completes Health Related Quality of Life Questionnaire: SF-36, CLDQ-HCV, 
FACIT-F, and WPAI 

Obtain blood samples for:
Hematology
Chemistry
HCV RNA


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HBV DNA (Only in subjects who are HBcAb+ at Screening)
Viral sequencing/phenotyping
6.4.3.
Posttreatment Week 24 Visit (±5 Days): Only for Subjects who Achieved 
SVR12
The following procedures/assessments are to be completed at Posttreatment Week 24:

Perform complete physical examination

Vital signs

Assessment of SAEs

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
HBV DNA (Only in subjects who are HBcAb+ at Screening)
Viral sequencing/phenotyping
6.5.
Early Termination (ET)
For subjects who have completed an ET visit, the posttreatment Week 4, 12, and 24 follow-up 
visits will be scheduled after last dose of any of the study drug. Subjects who achieve SVR12 
(HCV RNA < LLOQ at posttreatment Week 12) will complete the posttreatment Week 24 visit.
When medically feasible, the medical monitor must be consulted prior to subject discontinuation.
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 3.4, Criteria for Discontinuation of Study Treatment). If 
this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.
6.6.
Unscheduled Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. 
The assessments are at the investigator’s discretion as clinically indicated, but the investigator 
should, at a minimum, collect AE and concomitant medication information. At all unscheduled 
visits initiated for the purpose of confirming HCV or HIV virologic failure and a sample for 
HCV or HIV viral sequencing/phenotyping must be collected.


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6.7.
End of Study
The end of study will occur at the posttreatment Week 24 visit.
Discontinuation from study drug dosing and discontinuation from the overall study, including the
Posttreatment period, will be collected as two separate events.
6.8.
Post Study Care
No poststudy ongoing care will be provided.
6.9.
Procedures and Specifications
6.9.1.
Clinical Laboratory Analytes
Hematology:
Hematocrit, hemoglobin (Hb), platelet count, red blood cell count (RBC),
white blood cell count (WBC) with differential (absolute and percentage) 
including lymphocytes, monocytes, neutrophils, eosinophils, basophils, 
reticulocyte count and mean corpuscular volume (MCV).
Coagulation:
INR, Prothrombin time (PT), Activated partial thromboplastin time
(APTT)
Chemistry:
Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase 
(AST/SGOT), albumin, alkaline phosphatase, creatinine, total bilirubin, 
direct bilirubin, glucose, potassium, and sodium.
Fibrotest® will be done at screening only.
Virological Tests:
Serologies for HCV and HBV (HBsAg, HBsAb, and HBcAb). HBV DNA 
(Only in subjects who are HBcAb+ at Screening). Serology testing for 
HIV (including reflex testing as necessary), HCV RNA will be measured 
using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for 
Use with the High Pure System. HCV genotype and subtype will be 
determined using the Siemens VERSANT® HCV Genotype, INNO-LiPA 
2.0 Assay. HIV-1 RNA will be measured using the AmpliPrep/COBAS®
TaqMan® HIV-1 Test, v2.0. If HIV-1 virologic rebound is confirmed, 
HIV-1 genotype/phenotype will be determined using the PhenoSense™
Integrase HIV, GeneSeq™Integrase HIV, PhenoSense™HIV, GenoSure 
MG, GeneSeq™HIV, and PhenoSense GT™.
Gilead reserves the right to use alternate assays for HCV RNA, HIV RNA, 
HCV genotype, and HIV-1 genotype/phenotype should the above assays 
become unavailable or the results are indefinitive.
IL28B genotype will be determined by polymerase chain reaction (PCR) 
amplification of the SNP, rs12979860, with sequence specific forward and 
reverse primers and allele specific fluorescently labeled TaqMan® MGB 
probes. Gilead reserves the rights to use alternate assays for IL28B 
determination should the above assay become unavailable.


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Pregnancy Tests:
Serum β-hCG
Additional Tests:
Serum drug screen (for amphetamines, cocaine, methadone, opiates), 
HbA1c, CD4 T-lymphocyte (absolute count and %)
6.9.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether
condition(s) is currently ongoing, and medication history will be collected on all subjects during
screening. Obtain HCV treatment history, renal dialysis, and kidney transplant as per Section 4.
6.9.3.
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue;
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails;
musculoskeletal; neurological.
6.9.4.
Height & Weight Measurement
Height will be collected at Screening. Weight measurement will be collected at Screening, 
Day 1, and Week 12 or ET visits.
6.9.5.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature and will be conducted pre-dose as outlined in Appendix Table 1. Blood 
pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.9.6.
Body Mass Index (BMI)
BMI is calculated by the following equation:
BMI=
weight (pounds)
or
Weight in kilograms
(height in inches)2
(height in meters)2


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6.9.7.
12-Lead ECG
Subjects will be required to rest in a supine position for ≥5 minutes prior to making a recording.
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities. End of treatment or ET results will be compared to the 
subject’s Day 1 ECG as part of routine safety monitoring.
6.9.8.
Health Related Quality of Life (HRQoL)
Health Related Quality of Life surveys (HRQoL) included in this study are the SF-36, Chronic 
Liver Disease Questionnaire (CLDQ-HCV), Fatigue Index (FACIT-F), and Work Productivity 
and Activity Impairment Questionnaire: Hepatitis C, v2.0 (WPAI: Hepatitis C), which will be 
completed by subjects at Day 1, Week 12, ET (if applicable), and posttreatment Week 12 visit.
The HRQoL will only be administered to subjects if available at Day 1. The subject should read 
the questionnaire by himself/herself and record the answers by himself/herself.
6.9.9.
Viral Sequencing/Phenotyping (Archive)
Plasma samples will be collected at Day 1 and each subsequent visit for HCV or HIV viral 
sequence and phenotying analysis. At any unscheduled visit initiated for the purpose of
confirming HCV virologic breakthrough, HCV viral sequencing/phenotype plasma sample must 
also be collected. Unused samples may be archived.
Details regarding the collection, processing, and shipping of samples will be included in the lab
manual.
6.9.10.
Sparse PK Sample
Sparse PK blood samples will be collected for all subjects at each on-treatment visit and archived
for PK analysis of SOF (and metabolites) and VEL.
The exact time of the dose taken prior to collection of the PK sample, the exact time the PK
sample is drawn, the exact time of completion of last dialysis, and the type of dialysis (peritoneal 
or hemodialysis) will be recorded in the source documents and eCRFs.
Details regarding the collection, processing, and shipping of samples will be included in the lab
manual.
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6.9.14.
Archive sample
 
 
 
 
 
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6.9.15.
Pregnancy Testing
All females of childbearing potential will have serum pregnancy testing every 4 weeks during the 
dosing period and 30 days after last dose of SOF/VEL, or last visit of the study, whichever 
comes last.
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (ie, decreased hemoglobin).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No:
Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes:
There is reasonable possibility that the event may have been caused by the investigational 
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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting.
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (e.g. venipuncture).
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated 
with laboratory abnormalities, the event should be graded on the basis of the clinical severity in
the context of the underlying conditions; this may or may not be in agreement with the grading 
of the laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
7.3.1.
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs, and all adverse events related 
to protocol-mandated procedures.
7.3.2.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study IMP and report to the CRF/eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
7.3.3.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period, 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the
eCRF completion guideline. 
7.3.4.
Electronic Serious Adverse Event (eSAE) Reporting Process
Site personnel must record all SAE data in the eCRF database and transmit the SAE information 
to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. Detailed 
instructions can be found in the eCRF completion guidelines.
If it is not possible to record and submit the SAE information electronically, because the eCRF 
database cannot be accessed or is not available (including at study start), record the SAE on the 
paper serious adverse event report form and submit by e-mail or fax within 24 hours of the 
investigator’s knowledge of the event to:
Gilead DSPH 
Fax:
E-mail:
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the eCRF 
Database according to instructions in the eCRF completion guidelines.
If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.
Additional information may be requested to ensure the timely completion of accurate safety 
reports.
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
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worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Toxicity Management 
7.5.1.
Subject Stopping Rules
See Section 3.4 for individual subject stopping rules.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, occupational exposure with an AE,  
pregnancy reports regardless of an associated AE and an AE in an infant following exposure 
from breastfeeding.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).


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Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH 
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows:
Email:
Fax:
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH,
Email:
Fax:
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
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7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a non-
Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.6 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are:

To evaluate the antiviral efficacy of treatment with sofosbuvir/velpatasvir (SOF/ VEL) for 
12 weeks as measured by the proportion of subjects with sustained viral response 12 weeks 
after cessation of treatment (SVR12)

To evaluate the safety and tolerability of the treatment regimen 
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
the study treatment regimen (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 

To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment

To evaluate the steady-state pharmacokinetics of SOF and its metabolites and VEL in 
subjects who are on dialysis for ESRD
The exploratory objectives of this study are:
 
 
8.1.2.
Primary Endpoint
The primary end point is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of treatment) in 
the Full Analysis Set (FAS) population.
The primary safety endpoint is any AE that led to permanent discontinuation of study drug.
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8.1.3.
Secondary Endpoint
Secondary endpoints include the following:

The proportion of subjects with HCV RNA < LLOQ at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24)

The proportion of subjects with HCV RNA < LLOQ on treatment

HCV RNA change from Baseline/Day 1

The proportion of subjects with virologic failure

The proportion of subjects who develop viral resistance to SOF and VEL during treatment 
and after cessation of treatment

The steady-state pharmacokinetics of SOF and its metabolite and VEL
8.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include effect of treatment with SOF/VEL on HRQoL 
endpoints.
8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SAS® software (SAS Institute, Cary, North Carolina, USA).
The study drugs in this study are SOF/VEL. Last dose of study drug will be used in the definition 
of treatment emergent AEs and laboratory abnormalities as well as the efficacy endpoints of 
SVR at various posttreatment time points.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis will be the FAS, which includes all enrolled 
subjects who took at least 1 dose of study drug.
8.2.1.2.
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set, which includes all 
subjects who took at least 1 dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose date 
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8.2.1.3.
Pharmacokinetics
The Pharmacokinetic (PK) Analysis Set includes all subjects who took at least 1 dose of the 
study drug and have at least 1 nonmissing postdose concentration value for the corresponding
analyte in plasma. The analytes of interest may include SOF (and its metabolites GS-566500 and 
GS-331007) and VEL. 
 
 
 
 
 
 
8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, values for missing data will not be imputed.
For the analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have 
the missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed 
up to the time of the last dose.
If a data point is missing and is preceded and followed in time by values that are “< LLOQ target 
not detected (TND)”, then the missing data point will be set to “< LLOQ TND”. If a data point is 
missing and preceded and followed by values that are “< LLOQ detected”, or preceded by 
“< LLOQ detected” and followed by “< LLOQ TND”, or preceded by “< LLOQ TND” and 
followed by “< LLOQ detected”, then the missing value will be set to “< LLOQ detected”. In 
these situations the data point will be termed a bracketed success; otherwise, the data point will 
be termed a bracketed failure (i.e., ≥LLOQ detected). If a data point is missing and is not 
bracketed, the missing data point will also be termed a failure (i.e., ≥LLOQ detected) except for 
SVR24, which will be imputed according to the SVR12 status. Success for SVR12 who have no 
further HCV RNA measurements collected will be counted as a success for SVR24 due to the 
high correlation between these 2 endpoints. 
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Where appropriate, safety data for subjects who did not complete the study will be included in 
summary statistics. For example,

If a subject took at least 1 dose of study drug, the subject will be included in a summary of 
AEs according to the treatment received; otherwise, if the subject is not dosed, then they will 
be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of the summary statistics for that time point. If the 
subject is missing a predose value, then the subject will be excluded from the calculation of 
the summary statistics for the predose value and the change from predose values.
Values for missing safety laboratory data will not be imputed; however, a missing 
Baseline/Day 1 result will be replaced with a screening result, if available. If no pretreatment 
laboratory value is available, the Baseline/Day 1 value will be assumed to be normal (i.e., no 
grade [Grade 0]) for the summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing Baseline/Day 1 result 
will be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for the 
calculation of summary statistics for the actual HCV RNA values and the change from baseline 
values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to 
the logarithmic (base 10) scale (log10 IU/mL).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, self-identified race/ethnicity, and age.
Baseline data will include a summary of body mass index, HCV RNA level (log10 IU/mL), 
genotype HCV infection, IL28B genotype, and additional endpoint as necessary
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary endpoint is SVR12 in the Full Analysis Set (FAS) population.
In the primary efficacy analysis, the point estimate and the 2-sided 95% exact confidence 
interval of SVR12 rate will be provided for the overall FAS population and by treatment group.
8.5.2.
Secondary Analyses
The proportion of subjects with HCV RNA below the LLOQ over time (including SVR
endpoints) will be presented in tabular and graphical form.
Descriptive summaries and listings will be provided for additional efficacy evaluations of the 
proportion of subjects who experience virologic failure, HCV RNA actual values and change 
from baseline.
 
Details on efficacy analyses will be described in the statistical analysis plan.
8.6.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests (including HIV-1 RNA and
CD4 T-cell count for HCV/HIV co-infection subjects), physical examinations, vital signs 
measurements at various time points during the study, and by the documentation of AEs.
All safety data collected on or after the first dose of study drug administration up to 30 days after 
the last dose of study drug will be summarized.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the eCRF. Exposure data will be summarized.
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8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event that begins on or after the date of first dose of 
study drug up to the date of last dose of study drug plus 30 days, or any AE leading to premature 
discontinuation of the study drug.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
and PT) will be provided by treatment group:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs

All treatment-related SAEs

All AEs leading to premature discontinuation of the study drug

All AEs leading to temporary interruption of the study drug
All AEs collected during the study will be presented in the data listings.
8.6.3.
Laboratory Evaluations
Graded laboratory abnormalities will be defined using the laboratory toxicity grading defined in 
Appendix 3. The incidence of treatment-emergent laboratory abnormalities, defined as values 
that increase by at least one toxicity grade from Baseline/Day 1 at any time postbaseline up to 
the date of last dose of study drug plus 30 days will be summarized.
Values for missing safety laboratory data will not be imputed; however, a missing 
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laboratory value is available, the Baseline/Day 1 value will be assumed to be normal (i.e., no 
grade [Grade 0]) for the summary of graded laboratory abnormalities.
All laboratory abnormalities will be included in the listings of laboratory data.
8.7.
Other Safety Evaluations
Individual data for 12-lead ECG, vital signs measurements will be listed by subject and 
summarized by treatment group by incidence of events/abnormalities or descriptive statistical 
summaries (n, mean, SD, median, Q1, Q3, minimum, and maximum), as appropriate.
8.8.
Pharmacokinetic Analysis
In the PK analysis set, plasma concentrations of the study drug over time will be listed. Details 
of the analysis will be provided in the pharmacokinetic reporting and analysis plan.
 
 
8.9.
Sample Size
With a sample size of 100 subjects, a 2-sided 95% exact confidence interval will extend at the
most 20% in length.
8.10.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform an interim review of safety data once the first 12 subjects have completed 
12 weeks of treatment, or early termination. After the initial meeting, safety reviews will be 
conducted at approximately 3 month intervals during the trial until the last enrolled subject 
completes study treatment. These safety reviews will alternate between the following:

A review by the DMC chair of all SAEs and deaths 

A review of safety data by the DMC meeting as specified in the DMC charter
The DMC will provide recommendation to Gilead on whether the nature, frequency, and severity 
of adverse effects associated with study treatment warrant the early termination of the study in 
the best interests of the participants, whether the study should continue as planned, or the study 
should continue with modifications. The DMC may also provide recommendations as needed 
regarding study design, conduct, and the need for additional meetings or an alternative meeting 
schedule. The DMC’s specific activities will be defined by a mutually agreed charter, which will 
define the DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject.: These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. 


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The investigator must use the most current IRB/IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB/IEC local
requirements.
 
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB/IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions for further details.
NOTE: The investigator must keep a screening log showing codes, names, and addresses for all 
subjects screened and for all subjects enrolled in the trial. Subject data will be processed in 
accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);
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
Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled;

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. 
The investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF casebook will be completed by an authorized study staff 
member whose training for this function is completed in EDC. The eCRF casebook will only 


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capture the data required per the protocol schedule of events and procedures. The 
Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data 
related to eligibility have been received. Subsequent to data entry, a study monitor will perform 
source data verification within the EDC system. System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or internal 
Gilead staff, who routinely review the data for completeness, correctness, and consistency. The 
site coordinator is responsible for responding to the queries in a timely manner, within the 
system, either by confirming the data as correct or updating the original entry, and providing the 
reason for the update (e.g. data entry error). Original entries as well as any changes to data fields 
will be stored in the audit trail of the system. Prior to any interim time points or database lock (as 
instructed by Gilead), the investigator will use his/her log in credentials to confirm that the forms 
have been reviewed, and that the entries accurately reflect the information in the source 
documents. At the conclusion of the trial, Gilead will provide the site with a read-only archive 
copy of the data entered by that site. This archive must be stored in accordance with the records 
retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Where possible, IMP should be destroyed at the site. If the site does not have acceptable
procedures in place for drug destruction, arrangements will be made between the site and Gilead 
Sciences (or Gilead Sciences’ representative) for return of used and unused IMP supplies.
The study monitor will provide instructions for return.
The study monitor will evaluate each study center’s study drug disposal procedures and provide
appropriate instruction for destruction of unused IMP supplies. If the site has an appropriate 
standard operating procedure (SOP) for drug destruction as determined by Gilead, the site may 
destroy used (empty or partially empty) and unused IMP supplies in accordance with that site’s 
approved SOP. A copy of the site’s approved SOP will be obtained for central files.
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
Refer to the Pharmacy Binder for study drug disposal/return instructions.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/IEC, or to regulatory authority or health authority 
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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IECs in
accordance with local requirements and receive documented IRB/IECs approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 


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expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
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Desnoyer A, Pospai D, Le MP, Gervais A, Heurgue-Berlot A, Laradi A, et al. Pharmacokinetics, 
safety and efficacy of a full dose sofosbuvir-based regimen given daily in 
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Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA. Revised November 2015a:
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Gilead Sciences Inc. EPCLUSA® (sofosbuvir and velpatasvir) tablets, for oral use. US 
Prescribing Information. Foster City, CA. Revised June.  2016:
Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype 
distribution of the hepatitis C virus infection. J Hepatol 2014.
Hundemer GL, Sise ME, Wisocky J, Ufere N, Friedman LS, Corey KE, et al. Use of sofosbuvir-
based direct-acting antiviral therapy for hepatitis C viral infection in patients with 
severe renal insufficiency. Infectious diseases 2015;47 (12):924-9.


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Ioannou GN, Beste LA, Chang MF, Green PK, Lowey E, Tsui JI, et al. Effectiveness of 
Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and 
Dasabuvir Regimens for Treatment of Patients With Hepatitis C in the Veterans 
Affairs National Healthcare System [Accepted Manuscript]. Gastroenterology 
2016;151:457-71.
Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guidelines for the 
prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney 
disease. Kidney international. Supplement 2008 (109):S1-99.
Merck & Co Inc. ZEPATIER™ (elbasvir and grazoprevir) tablets, for oral use. US Prescribing 
Information. Whitehouse Station, NJ. Revised January.  2016:
Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of Hepatitis C 
Virus Infection and the Development of Hepatocellular Carcinoma. Ann Intern 
Med 2013;158 (5 (Part I)).
Navarro-Millan I, Sattui SE, Curtis JR. Systematic review of tumor necrosis factor inhibitor 
discontinuation studies in rheumatoid arthritis. Clin Ther 2013;35 (11):1850-61 
e1.
Nazario HE, Ndungu M, Modi AA. Sofosbuvir and simeprevir in hepatitis C genotype 1-patients 
with end-stage renal disease on haemodialysis or GFR <30 ml/min. Liver Int 
2016;36 (6):798-801.
Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus 
and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J 
Hepatol 2006;45 (4):529-38.
Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et al. Impact of 
pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic 
hepatitis C. Gastroenterology 2002;122 (5):1303-13.
van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association 
between sustained virological response and all-cause mortality among patients 
with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012;308 
(24):2584-93.
Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Zeuzem S, et al. Sustained 
virologic response and clinical outcomes in patients with chronic hepatitis C and 
advanced fibrosis. Ann Intern Med 2007;147 (10):677-84.
World Health Organization (WHO). Hepatitis C Fact Sheet No. 164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/#. Accessed 20 June 2014:1-
7.


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc. 
Amendment 3.0
CONFIDENTIAL
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02 March 2017
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 5.
Opportunistic Infections
Appendix Table 1.
Screening/Baseline/ On-Treatment and Post Treatment Study Visits


PPD
PPD


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 78
02 March 2017
Appendix 2.
Study Procedures Table
Appendix Table 1.
Screening/Baseline/ On-Treatment and Post Treatment Study Visits
Screen
Baseline/Day1a
On-Treatment Week (±3 Days)
Post-Treatment Week (±5 Days)
2
4
6
8
12/ET
4
12
24
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
X
X
Height
X
Weight
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
AEs/SAEb
X
X
X
X
X
X
X
X
Xb
Xb
Concomitant Medications
X
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
X
X
X
Health-Related Quality of Lifec
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
Study Drug Dispensingd
X
X
Hematology, Chemistry 
X
X
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
Viral Sequencing 
/Phenotypingf
X
X
X
X
X
X
X
X
X
Sparse PK
X
X
X
X
X
CCI
CCI


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 79
02 March 2017
Screen
Baseline/Day1a
On-Treatment Week (±3 Days)
Post-Treatment Week (±5 Days)
2
4
6
8
12/ET
4
12
24
Serum β-hCG Pregnancy Testl
X
X
X
X
X
X
Serum Drug Screen
X
HCV & IL28B Genotyping
X
HCV, HIV, HBV Serology
X
HBV DNAk
X
X
X
X
X
X
X
HbA1c
X
Fibrotest®
X
CD4 Cell Count m
X
X
X
X
X
X
HIV-1 RNAm
X
X
X
X
X
X
a
Baseline/Day 1 assessments must be performed prior to dosing
b
Only SAEs will be collected at post-treatment Weeks 12 and 24.
c
Health Related Quality of Life (HRQoL) Surveys (e.g., SF-36, CLDQ-HCV, FACIT-F and WPAI) will be conducted for all subjects where the surveys are available at Day 1, 
Week 12, ET (if applicable) and posttreatment Week 12.
d
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
f.
Plasma samples will be collected for possible viral resistance testing and other virology studies.
 
 
 
k.
Only for subjects who are HBcAb+ at Screening
l.
For females of child bearing potential
m.
For HIV/HCV co-infected subjects only.
CCI
CCI
CCI
CCI
CCI
CCI


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 80
02 March 2017
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count  
(ANC)
Adult and Pediatric, 
≥ 7 Months# 
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 81
02 March 2017
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 
# An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
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02 March 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L            
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L            
2.0 t o <2.5 mmolL
2.0 mEq/L               
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L            
6.5 to 7.0 mmol/L
7.0 mEq/L               
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 83
02 March 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL              
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL             
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL            
1.51 to < 1.74 mmolL
< 6.1 mg/dL                
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 84
02 March 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 85
02 March 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 86
02 March 2017
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 87
02 March 2017
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 88
02 March 2017
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(e.g., malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(e.g., malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(e.g., tamponade) OR Urgent 
intervention indicated


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 89
02 March 2017
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, e.g., Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, e.g., Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(e.g., anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (e.g., 
pulmonary embolism, life-
threatening thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 90
02 March 2017
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 91
02 March 2017
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or  
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 92
02 March 2017
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [e.g., tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (e.g., diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(e.g., sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(e.g., obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(e.g., hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 93
02 March 2017
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (e.g., aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (e.g., 
IV fluids)
Life-threatening consequences 
(e.g., hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(e.g., sepsis, circulatory 
failure, hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(e.g., perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(e.g., hypotensive shock)


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 94
02 March 2017
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (e.g., 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (e.g., 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 95
02 March 2017
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 96
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (e.g., 
status epilepticus), or difficult 
to control (e.g., refractory 
epilepsy)
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (e.g., 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (e.g., 
status epilepticus), or difficult 
to control (e.g., refractory 
epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


SOF/VEL FDC
Protocol GS-US-342-4062
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 97
02 March 2017
MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic self-
care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing 
inability to perform usual 
social & functional activities
Disabling muscle pain causing 
inability to perform basic self-
care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-
care functions


SOF/VEL FDC
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Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
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SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
laryngeal edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic self-
care functions OR 
Hospitalization (other than ER 
visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight from 
baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  Aggressive 
intervention indicated [e.g., 
tube feeding or total parenteral 
nutrition]


SOF/VEL FDC
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INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain (pain 
without touching)
Or Tenderness (pain when 
area is touched) 
Pain/tenderness causing no 
or minimal limitation of use 
of limb
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual 
social & functional activities
Pain/tenderness causing inability 
to perform basic self-care 
function OR Hospitalization 
(other than ER visit) indicated 
for management of 
pain/tenderness
Injection Site Reaction 
(Localized), 15 Years
Erythema OR Induration
of 5 5 cm to 9 9 cm (or 
2581 cm2)
Erythema OR Induration OR 
Edema 9 cm any diameter 
(or 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and 
deeper tissue)
Pediatric 15 Years
Erythema OR Induration 
OR Edema present but 
2.5 cm diameter
Erythema OR Induration 
OR Edema > 2.5 cm 
diameter but < 50% surface 
area of the extremity 
segment (e.g., upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment (e.g., 
upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving dermis and 
deeper tissue)
Pruritis Associated with 
Injection 
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to injection 
site AND Relieved 
spontaneously or with 
48 h treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring 48 h treatment 
Generalized itching causing 
inability to perform usual 
social & functional activities
NA


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ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (e.g., back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(e.g., ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(e.g., thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(e.g., myxedema coma)
Lipoatrophy (e.g., fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated
Urinary Tract 
obstruction (e.g., stone)
NA
Signs or symptoms of urinary
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (e.g., septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following menarche until becoming post-menopausal, unless permanently sterile or with 
medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are ≥54 years of age with 
cessation of previously occurring menses for ≥12 months without an alternative cause.  
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of SOF have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies of SOF 
have demonstrated no adverse effect on fertility or embryo-fetal development
Data from clinical pharmacokinetic interaction studies of VEL have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies of 
GS-5816 have demonstrated no adverse effect on fertility or embryo-fetal development. 
However, the risks of treatment with SOF/VEL during pregnancy in humans have not been 
evaluated. Please refer to the latest version of the investigator’s brochure for additional 
information.
b) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable 
effective contraceptive measure. They must have a negative serum pregnancy test at Screening 
and a negative pregnancy test on the Baseline/Day 1 visit prior to randomization.  A pregnancy 
test will be performed at the Post Treatment Week 4 visit. They must also agree to one of the 
following from Screening until 30 days of the last dose of SOF/VEL.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.


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Or

Consistent and correct use of 1 of the following methods of birth control listed below in 
addition to a male partner who correctly uses a condom from the date of Screening until 
30 days after the last dose of SOF/VEL. 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
Tubal sterilization
Essure micro-insert system 
Vasectomy in the male partner 
Barrier methods 
■
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel or etonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of SOF/VEL.
3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use  
condoms until 30 days after the last dose of SOF/VEL treatment when engaging in intercourse of 
reproductive potential. If their female partner is of childbearing potential (as defined above), 
their female partner must use 1 of the methods of birth control listed above from the date of 
Screening until 30 days after the last dose of SOF/VEL.
Male subjects must agree to refrain from sperm donation until 30 days after the last dose of 
SOF/VEL.


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4) Unacceptable Methods of Contraception
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of the last dose of SOF/VEL. Subjects who 
become pregnant or who suspect that they are pregnant must report the information to the 
investigator and discontinue study drug immediately. Subjects whose partner has become 
pregnant or suspects she is pregnant must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.6.2.1.


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Appendix 5.
Opportunistic Infections
Non-inclusive list of opportunistic infections base on AIDS-Indicator Conditions from CDC 
Classification System for HIV Infection Clinical Category C:

Bacterial pneumonia, recurrent (two or more episodes in 12 months)

Candidiasis of the bronchi, trachea, or lungs

Candidiasis, esophageal

Cervical carcinoma, invasive, confirmed by biopsy

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (>1 month in duration)

Cytomegalovirus disease (other than liver, spleen, or nodes)

Encephalopathy, HIV-related

Herpes simplex: chronic ulcers (>1 month in duration), or bronchitis, pneumonitis, or 
esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (>1-month in duration)

Kaposi sarcoma

Lymphoma, Burkitt, immunoblastic, or primary central nervous system

Mycobacterium avium complex (MAC) or Mycobacterium kansasii, disseminated or 
extrapulmonary

Mycobacterium tuberculosis, pulmonary or extrapulmonary

Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jiroveci (formerly carinii) pneumonia (PCP)

Progressive multifocal leukoencephalopathy (PML)

Salmonella septicemia, recurrent (nontyphoid)

Toxoplasmosis of brain

Wasting syndrome caused by HIV (involuntary weight loss >10% of baseline body weight) 
associated with either chronic diarrhea (two or more loose stools per day for ≥1 month) or 
chronic weakness and documented fever for ≥1 month

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Multicenter, Open-Label Study to Evaluate the
Efficacy and Safety of Sofosbuvir/Velpatasvir for 12 Weeks in
Subjects with Chronic HCV Infection Who are on Dialysis for
End Stage Renal Disease
Name of Test Drug:
Sofosbuvir/Velpatasvir
Study Number:
GS-US-342-4062
Protocol Version/Date:
Amendment 3: 02 March 2017
Analysis Type:
SVR12 and Final Analyses
Analysis Plan Version:
Version 1
Analysis Plan Date:
5 September 2018
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF ABBREVIATIONS........................................................................................................................................4
1
INTRODUCTION ................................................................................................................................................6
1.1
Study Objectives ......................................................................................................................................6
1.2
Study Design............................................................................................................................................7
1.3
Sample Size and Power............................................................................................................................7
2
TYPE OF PLANNED ANALYSIS ......................................................................................................................8
2.1
DMC Analyses.........................................................................................................................................8
2.2
Interim Analyses ......................................................................................................................................8
2.2.1
Posttreatment Week 4 Analysis..............................................................................................8
2.2.2
Posttreatment Week 12 Analysis............................................................................................8
2.3
Final Analysis ..........................................................................................................................................8
3
GENERAL CONSIDERATIONS FOR DATA ANALYSES..............................................................................9
3.1
Analysis Sets............................................................................................................................................9
3.1.1
All Enrolled Analysis Set.......................................................................................................9
3.1.2
Full Analysis Set ....................................................................................................................9
3.1.3
Safety Analysis Set.................................................................................................................9
3.1.4
Pharmacokinetic (PK) Analysis Set .......................................................................................9
3.1.4.1
.................................................................9
3.1.4.2
.......................................................10
3.2
Subject Grouping ...................................................................................................................................10
3.3
Examination of Subject Subsets.............................................................................................................10
3.4
Missing Data and Outliers......................................................................................................................11
3.4.1
Missing Data ........................................................................................................................11
3.4.2
Outliers.................................................................................................................................11
3.5
Data Handling Conventions and Transformations .................................................................................12
3.6
Visit Windows........................................................................................................................................13
3.6.1
Definition of Study Day .......................................................................................................13
3.6.2
Analysis Windows................................................................................................................14
3.6.3
Selection of Data in the Event of Multiple Records in an Analysis 
Window................................................................................................................................15
4
SUBJECT DISPOSITION ..................................................................................................................................16
4.1
Subject Enrollment and Disposition.......................................................................................................16
4.2
Extent of Exposure.................................................................................................................................17
4.2.1
Duration of Exposure to Study Drug....................................................................................17
4.2.2
Adherence to Study Drug.....................................................................................................17
4.3
Protocol Deviations................................................................................................................................18
5
BASELINE DATA .............................................................................................................................................19
5.1
Demographics ........................................................................................................................................19
5.2
Other Baseline Characteristics ...............................................................................................................19
5.3
Medical History......................................................................................................................................20
6
EFFICACY ANALYSES ...................................................................................................................................21
6.1
Primary Efficacy Endpoint.....................................................................................................................21
6.1.1
Definition of the Primary Efficacy Endpoint .......................................................................21
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6.1.2
Primary Analysis of the Primary Efficacy Endpoint ............................................................21
6.1.3
Subgroup Analysis of the Primary Efficacy Endpoint .........................................................21
6.2
Secondary Efficacy Endpoints ...............................................................................................................21
6.2.1
Definition of Secondary Efficacy Endpoints........................................................................21
6.2.2
Analysis Methods for Secondary Efficacy Endpoints..........................................................22
6.3
Exploratory Efficacy Endpoints.............................................................................................................23
6.3.1
Definition of Exploratory Efficacy Endpoints......................................................................23
6.3.2
Analysis Methods for Exploratory Efficacy Endpoints........................................................23
6.4
Changes From Protocol-Specified Efficacy Analyses............................................................................23
7
SAFETY ANALYSES........................................................................................................................................24
7.1
Adverse Events and Deaths....................................................................................................................24
7.1.1
Adverse Event Dictionary ....................................................................................................24
7.1.2
Adverse Event Severity........................................................................................................24
7.1.3
Relationship of Adverse Events to Study Drug....................................................................24
7.1.4
Serious Adverse Events........................................................................................................24
7.1.5
Treatment-Emergent Adverse Events...................................................................................24
7.1.5.1
Definition of Treatment-Emergent .................................................................24
7.1.5.2
Incomplete Dates ............................................................................................25
7.1.6
Summaries of Adverse Events and Deaths...........................................................................25
7.2
Laboratory Evaluations ..........................................................................................................................26
7.2.1
Summaries of Numeric Laboratory Results .........................................................................27
7.2.2
Graded Laboratory Values ...................................................................................................27
7.2.2.1
Treatment-Emergent Laboratory Abnormalities.............................................28
7.2.2.2
Summaries of Laboratory Abnormalities........................................................28
7.3
Body Weight, Height, and Vital Signs...................................................................................................28
7.4
Concomitant Medications ......................................................................................................................29
7.5
Electrocardiogram Results .....................................................................................................................29
7.6
Other Safety Measures ...........................................................................................................................29
7.7
Changes From Protocol-Specified Safety Analyses...............................................................................29
8
PHARMACOKINETIC ANALYSES ................................................................................................................30
9
REFERENCES ...................................................................................................................................................31
10
SOFTWARE.......................................................................................................................................................32
11
SAP REVISION..................................................................................................................................................33
12
APPENDICES ....................................................................................................................................................34
Appendix 1
Schedule of Assessments........................................................................................................35
Appendix 2.
QOL Score Calculation Algorithms .......................................................................................37
LIST OF IN-TEXT-TABLES
Table 1.
Analysis Windows for On-treatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................14
Table 2.
Analysis Windows for Posttreatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................14


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
APRI
AST:platelet ratio index
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase  (also SGOT)
BPM
beats per minute
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CSR
clinical study report
DAA
direct acting antiviral
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form
EOT
end of treatment
ESRD
End Stage Renal Disease
FAS
full analysis set
FDC
fixed-dose combination
FU
follow-up
GT
genotype
HCV
hepatitis C virus
HLGT
high level group term
HLT
high level term
HRQoL
health related quality of life
INR
international normalized ratio of prothrombin time
IWRS
interactive web response system
LLOQ
lower limit of quantitation
LLT
lower level term
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End-Stage Liver Disease
Peg-IFN
pegylated interferon
PK
pharmacokinetics
PT
preferred term
Q1
first quartile
Q3
third quartile
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation


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SOC
system organ class
SOF
sofosbuvir (Sovaldi®)
SVR
sustained virologic response
SVRx
sustained virologic response x weeks after stopping study drug
TE
treatment-emergent
TFLs
tables, figures, and listings
TND
target not detected
ULN
upper limit of normal
VEL
Velpatasvir
VF
virologic failure
WHO
World Health Organization


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1
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-342-4062. This SAP is based on the amended study protocol dated 
02 March 2017 and the electronic case report form (eCRF). The SAP will be finalized prior to
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR.
1.1
Study Objectives
The primary objectives of this study are:

To evaluate the antiviral efficacy of treatment with sofosbuvir/velpatasvir (SOF/VEL) for 
12 weeks as measured by the proportion of subjects with sustained viral response 12 weeks
after cessation of treatment (SVR12)

To evaluate the safety and tolerability of treatment with SOF/VEL 
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
the study treatment regimen (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment

To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment

To evaluate the steady-state pharmacokinetics of SOF and its metabolites and VEL in 
subjects who are on dialysis for End Stage Renal Disease (ESRD)
The exploratory objectives of this study are:
 
 
 
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1.2
Study Design
This is a multicenter, open label Phase 2 study that will evaluate the safety, tolerability and 
antiviral efficacy of SOF/VEL in subjects on dialysis for ESRD with genotype 1-6 HCV 
infection.
Approximately 100 subjects will be enrolled and treated with SOF/VEL once daily for 12 weeks.
The total time to complete all study visits is approximately 40 weeks (42 weeks for those
requiring extension of the Screening period):

28 days (4 weeks) screening period (or 42 days for extenuating circumstances)

12 week treatment period

Up to 24 week posttreatment period
The schedule of assessments is provided as an appendix to the SAP (Appendix 1).
1.3
Sample Size and Power
With a sample size of 100 subjects, a 2-sided 95% exact confidence interval will extend at the
most 20% in length.


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2
TYPE OF PLANNED ANALYSIS
2.1
DMC Analyses
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of 
the study and perform interim reviews of safety data in order to protect subject welfare and 
preserve study integrity. The DMC will recommend to the sponsor whether the nature, 
frequency, and severity of adverse effects associated with study treatment warrant the early 
termination of the study in the best interests of the participants, whether the study should 
continue as planned, or whether the study should continue with modifications.
Reviews will be conducted after the first 12 subjects have completed 12 weeks of treatment, or 
early termination. After the initial meeting, safety reviews will be conducted at approximately 
3 month intervals during the trial until the last enrolled subject completes study treatment. These 
safety reviews will alternate between the following:

A review by the DMC chair of all SAEs and deaths

A review of safety data by the DMC meeting as specified in the DMC charter.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
provided in a mutually agreed upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency. 
2.2
Interim Analyses
2.2.1
Posttreatment Week 4 Analysis
A posttreatment Week 4 analysis will be conducted for administrative purposes after all subjects 
complete the posttreatment Week 4 visit or prematurely discontinue from study. All safety and 
efficacy data through the posttreatment Week 4 visit will be included. The results will be 
restricted to a limited group of individuals within Gilead. There will be no changes to the study 
design, study conduct, or the sample size as a result of this administrative analysis. 
2.2.2
Posttreatment Week 12 Analysis
The analysis for the primary efficacy endpoint SVR12 will be conducted when all subjects have 
completed the posttreatment Week 12 visit or have prematurely discontinued from study. All the 
safety and efficacy data through the Posttreatment Week 12 visit will be cleaned, finalized and 
included for the analysis.
2.3
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved, and the
database has been cleaned and finalized, the final analysis of the data will be performed.


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GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard error (SE), median, first 
quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
Data collected in the study will be presented in by-subject listings for all subjects in the Safety 
Analysis Set, unless otherwise specified. All by-subject listings will be presented by subject 
identification (ID) number in ascending order, unless otherwise specified.
3.1
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The number of subjects eligible for each analysis set will be 
provided. Subjects who were excluded from each analysis set will be summarized or provided in 
a by-subject listing by genotype.
3.1.1
All Enrolled Analysis Set
All Enrolled Analysis Set includes all subjects enrolled in the study after screening. Subjects are 
grouped within the All Enrolled Analysis Set by genotype.
3.1.2
Full Analysis Set
The Full Analysis Set (FAS) includes subjects who are enrolled into the study and received at 
least 1 dose of study drug. The study drugs in this study are SOF/VEL. Subjects are grouped 
within the FAS by genotype. 
This is the primary analysis set for efficacy analyses.
3.1.3
Safety Analysis Set
The Safety Analysis Set includes all subjects who received at least 1 dose of study drug. This is 
the primary analysis set for safety analyses.
3.1.4
Pharmacokinetic (PK) Analysis Set
The Pharmacokinetic (PK) Analysis Set includes all subjects who took at least 1 dose of the
study drug and have at least 1 nonmissing postdose concentration value for the corresponding
analyte in plasma. The analytes of interest may include SOF (and its metabolites GS-566500 and
GS-331007) and VEL.
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3.2
Subject Grouping
For analyses based on the All Enrolled Analysis Set, FAS, or demographic and baseline 
characteristics tables, subjects will be grouped according to the HCV genotype . Unless 
otherwise specified, groups by genotype including GT1a, GT1b, GT1 Other, GT1 total, GT2, 
GT3, GT4, and GT6, Indeterminate, and Total.
3.3
Examination of Subject Subsets
Subject subsets within each genotype will also be explored by baseline characteristics for the 
primary efficacy endpoint, SVR12. The baseline characteristics include the following:

age (< 65 years, ≥ 65 years)

sex (male, female)

cirrhosis (presence, absence) 

prior HCV treatment experience (treatment naive, treatment experienced)

prior HCV treatment for treatment experienced subjects [DAA Naive (Peg-IFN + RBV, 
Other)]

HCV genotype

baseline HCV RNA (< 800,000 IU/mL, ≥ 800,000 IU/mL)

baseline body mass index (BMI) (< 30 kg/m2, ≥ 30 kg/m2)

baseline alanine aminotransferase  (ALT) (≤1.5 × upper limit of normal (ULN), 
> 1.5 × ULN)

IL28B (CC, non-CC; with non-CC further broken down to CT, TT)

type of current dialysis (Hemodialysis, Peritoneal Dialysis)

adherence to study regimen (< 80%, ≥ 80%)
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3.4
Missing Data and Outliers
3.4.1
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
For missing last dosing date of study drug, imputation rules are described in Section 3.6.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in 
Section 7.1.5.2, and for prior and concomitant medications in Section 7.4
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have missing data imputed up to the 
time of the last dose (for on-treatment displays). If the study day associated with the last dosing 
date of any study drug is greater than or equal to the lower bound of a visit window, and the 
value at the visit is missing, then the value will be imputed. If the study day associated with the 
last dosing date is less than the lower bound of a visit window then the on-treatment value at that 
visit will remain missing. 
If a HCV RNA data point is missing and is preceded and followed in time by values that are 
“< lower limit of quantification (LLOQ) target not detected (TND),” then the missing data point 
will be set to “< LLOQ TND.” If a data point is missing and preceded and followed by values 
that are “< LLOQ detected,” or preceded by “< LLOQ detected” and followed by 
“< LLOQ TND,” or preceded by “< LLOQ TND” and followed by “< LLOQ detected,” then the 
missing value will be set to “< LLOQ detected.” In these situations the data point will be termed 
a bracketed success; otherwise, the data point will be termed a bracketed failure 
(ie, ≥LLOQ detected). If a data point is missing and is not bracketed, the missing data point will 
also be termed a failure (ie, ≥LLOQ detected) except for SVR24, which will be imputed 
according to SVR12 status. Success for SVR12 who have no further HCV RNA measurements 
collected will be counted as a success for SVR24 due to the high correlation between these 
2 endpoints.
For the analyses of continuous HCV RNA efficacy data, when and only when a missing HCV 
RNA value is imputed as < LLOQ TND or < LLOQ detected according to the imputation rule 
described above, the corresponding continuous value will be imputed to LLOQ − 1 IU/mL. No 
other imputation will be performed for continuous HCV RNA data. 
For health-related quality of life data including SF-36, CLDQ-HCV, FACIT-F, and 
WPAI: Hep C, missing data at on-treatment visits and posttreatment follow-up Week 12 (FU-12) 
visit will not be imputed. For SF-36, if there are multiple responses to an item, the response will 
be set to missing.
3.4.2
Outliers
Outliers will be identified during data management and data analysis process, but no sensitivity 
analyses will be conducted. All data will be included in the data analysis.


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3.5
Data Handling Conventions and Transformations
By-subject listings will be presented for all subjects in the Safety Analysis Set and sorted by 
subject ID number, visit date, and time (if applicable) unless otherwise specified. Data collected 
on log forms, such as AEs, will be presented in chronological order within subject. 
Age (in years) on the date of the first dose of study drug and sex at birth will be used for analyses 
and presentation in listings.
If a subject was not dosed with study drug at all, then the date the informed consent was signed 
will be used instead of the first dose date of study drug. 
Non-pharmacokinetic (PK) data that are continuous in nature but are less than the lower limit of 
quantitation or above the upper limit of quantitation will be imputed as follows:

A value that is one unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “x” (where x is considered the 
limit of quantitation). For example, if the values are reported as < 50 and < 5.0, values of 
49 and 4.9, respectively, will be used for calculation of summary statistics. An exception for 
this rule is any value reported < 1. For the values reported as < 1 or < 0.1, value of 0.9 or 
0.09 will be used for calculation of summary statistics.

A value that is one unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “> x” (where x is considered the 
limit of quantitation). Values with decimal points will follow the same logic as above.

The limit of quantitation will be used for calculation of descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the limit of quantitation).
COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, v2.0 will be used to determine 
HCV RNA results in this study. The lower limit of quantitation (LLOQ) of the assay is 15 IU/mL.
When the calculated HCV RNA value is within the linear range of the assay, then the result will 
be reported as the “<< numeric value>> IU/mL.” This result will be referred to in this document 
as the numeric result or as “≥ LLOQ detected” for categorical result.
When HCV RNA is not detected, the result is reported as “No HCV RNA detected” or “target 
not detected”. This result will be referred to in this document as “< LLOQ target not detected” or 
“< LLOQ TND.”
When the HCV RNA IU/mL is less than LLOQ of the assay, the result is reported as 
“< 15 IU/mL HCV RNA detected”. This result will be referred to in this document as 
“< LLOQ detected.”
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For numerical HCV RNA data, values below LLOQ will be set to the LLOQ −1 IU/mL 
(ie, 14 HCV RNA IU/mL). HCV RNA values returned as “No HCV RNA detected” will also be 
set to 14 IU/mL.
For selected analyses, HCV RNA data (IU/mL) will be transformed to the logarithmic (base 10) 
scale (log10 IU/mL).
Natural logarithm-transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma concentration values that are below the limit of quantitation (BLQ) will 
be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 
at predose time points, and one-half the value of the lower limit of quantitation (LLOQ) at 
postbaseline time points.
The following conventions will be used for the presentation of summary and order statistics:

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
3.6
Visit Windows
3.6.1
Definition of Study Day 
Study day is the day relative to the date of the first dose of study drug. Study Day 1 will be 
defined as the day of first dose of study drug administration.
Study day will be calculated from the date of first dose of study drug administration and derived 
as follows:

For postdose study days: Assessment Date – First Dose Date + 1

For days prior to the first dose: Assessment Date – First Dose Date 
The last dose date will be the end date on study drug administration eCRF for the record where 
the “subject permanently discontinued” flag is ‘Y’. The last dose date will be defined as the 
maximum of the last dose dates of the study drugs. If there are subjects for whom the date of last 


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study drug is unknown due to the reason that the subject was lost to follow-up and not able to be 
contacted, the date of last dose will be estimated using the maximum of nonmissing study drug 
start or stop dates, visit dates, and laboratory collection dates (posttreatment visits and 
unscheduled visits are not included).
3.6.2
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purposes of analysis, 
observations will be assigned to analysis windows.
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of study drug. 
HCV RNA, vital signs, and safety laboratory data collected up to the last dose date + 3 days are 
considered to be on-treatment data and HCV RNA, vital signs, and safety laboratory data 
collected after the last dose date + 3 days are considered posttreatment data. The analysis 
windows for on-treatment HCV RNA, vital signs and safety laboratory data are provided in
Table 1.
Table 1.
Analysis Windows for On-treatment HCV RNA, Vital Signs and 
Safety Laboratory Data
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 2
14
2
21
Week 4
28
22
35
Week 6
42
36
49
Week 8
56
50
70
Week 12
84
71
>=85
HCV RNA, vital sign, and safety laboratory data collected after the last dose date + 3 days will 
be assigned to the posttreatment follow-up (FU) visits. Visit windows will be calculated from the 
last dose date (ie, FU Day = collection date minus the last dose date) as shown in Table 2.
Table 2.
Analysis Windows for Posttreatment HCV RNA, Vital Signs and 
Safety Laboratory Data
Nominal 
FU a Visit
HCV RNA
Vital Signs and Safety Laboratory Data b
Nominal FU 
Day
Lower Limit
Upper Limit
Nominal FU 
Day
Lower Limit
Upper Limit
FU-4
28
21
69
28
4
30
FU-12
84
70
146
NA
NA
NA
FU-24
168
147
210
NA
NA
NA
a.
FU-x visit = posttreatment Week-x follow-up visit.
b.
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3.6.3
Selection of Data in the Event of Multiple Records in an Analysis Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. 
If multiple valid nonmissing numeric observations exist in an analysis window, records will be 
chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, average (arithmetic mean) will be used for the baseline value. 

For postbaseline visits: 
The record closest to the nominal day for that visit will be selected except for HCV RNA 
posttreatment follow-up visits, for which the latest record in the analysis window will be 
selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.
If multiple valid nonmissing categorical observations exist in a window, records will be selected 
as follows:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, the value with the lowest severity will be selected (eg, normal will be selected over 
abnormal). If multiple ECG measurements occur on the same day prior to the first dose of 
any study drug, the value with the lowest severity will be selected regardless of the timing of 
these multiple ECG measurements.

For postbaseline visits, follow the same rules described above for postbaseline numeric 
observations, except that if there are multiple records on the same day, the most conservative 
value will be selected (eg, abnormal will be selected over normal).


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4
SUBJECT DISPOSITION
4.1
Subject Enrollment and Disposition
A summary of subject enrollment will be provided for each country and investigator. The 
summary will present the number and percentage of subjects in the Safety Analysis Set. For each 
column, the denominator for the percentage calculation will be the total number of subjects 
analyzed for that column. 
A summary of subject disposition will be provided by genotype. This summary will present the 
number of subjects screened, the number of subjects not enrolled, the number of subjects 
enrolled, the number of subjects enrolled but never treated, the number of subjects enrolled and 
treated (ie, safety analysis set), in FAS, in PK Analysis Set, 
 
 and the number and percentage of subjects in 
each of the categories listed below. The denominator for the percentage calculation will be the 
total number of subjects in the Safety Analysis Set for each column. 

Continuing study treatment (if applicable)

Completed study treatment

Did not complete study treatment with reasons for premature discontinuation of study 
treatment

Completed study

Did not complete the study with reasons for premature discontinuation of study
Among subjects who completed study treatment and who discontinued study treatment, the 
number and percentage of subjects will be summarized for:

Who had no HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 
Assessment and thereafter)

Who had HCV posttreatment Week 4 assessment but no HCV posttreatment Week 12 and 
thereafter (With HCV FU-4 but No FU-12 and thereafter)
If a subject did not have any HCV RNA assessment ≥ 21 days after the last dose of any study 
drug (ie, lower bound of FU-4 visit for HCV RNA data), the subject is categorized as having 
“No HCV FU-4 and thereafter.” If a subject had the HCV FU-4 assessment but did not have any 
HCV RNA assessment ≥ 70 days after the last dose of any study drug (ie, lower bound of 
FU-12 visit for HCV RNA data), the subject is categorized as having “With HCV FU-4 but No 
FU-12 and thereafter.”
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In addition, the total number of subjects who were enrolled, and the number of subjects in each 
of the disposition categories will be depicted by a flowchart.
The following by-subject listings will be provided by subject ID number in ascending order to 
support the above summary tables:

Disposition for subjects who complete study treatment and study

Disposition for subjects who did not complete study treatment and/or study with reasons for 
premature discontinuation of study treatment and/or study

Lot number and kit ID (if applicable)
4.2
Extent of Exposure
Extent of exposure to study drug will be examined by assessing the total duration of study drug 
exposure and the level of adherence to the study drug regimen specified in the protocol.
4.2.1
Duration of Exposure to Study Drug
Total duration of exposure to study drug will be defined as last dose date minus first dose date 
plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.8 weeks). 
The total duration of exposure to study drug will be summarized using descriptive statistics 
(n, mean, SD, median, Q1, Q3, minimum, and maximum) and using the number 
(ie, cumulative counts) and percentage of subjects exposed through the following time periods: 
Baseline (Day 1), Week 4 (Day 28), Week 8 (Day 56), and Week 12 (Day 84). A 3-day window 
is applied to the last planned on-treatment visit to match with the protocol-specified visit 
window, ie number of subjects exposed through Week 12 will be calculated as the number of 
subjects who were exposed to study drug for at least 81 days. 
4.2.2
Adherence to Study Drug 
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:







returned
Tablets
of
No.
 Dispensed
Tablets
of
No.
ed
Administer
 Doses
of
Number 
Total
The level of adherence to the study drug regimen will be assessed based on the total amount of 
study drug administered relative to the total amount of study drug prescribed at baseline. 


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The level of adherence will be expressed in percentage using the following formula:
100
  
baseline
at 
Prescribed
Drug
Study 
of
Amount 
Total
  
ed
Administer
Drug
Study 
of
Amount 
Total
(%)
Adherence
of
Level








Note: If calculated adherence is greater than 100%, the result will be set to 100%.
In this study, the total amount of SOF/VEL (400/100 mg) prescribed for 12 weeks would require 
84 tablets.
Subjects who prematurely discontinue study drug for lack of efficacy (ie, virologic failure) will 
have the total amount of study drug prescribed calculated up to the first date when virologic 
failure criteria were met. For virologic failure confirmed by 2 consecutive measurements, the 
date of the first measurement will be used. If study drug bottles are dispensed on or after the 
subject first met virologic failure criteria, these bottles will not be included in the calculation of 
adherence. If a bottle is dispensed and the bottle is returned empty, then the number of tablets 
returned will be entered as zero. If a bottle is dispensed but not returned (missing), the number of 
tablets taken from that bottle will be counted as zero. 
Descriptive statistics for the level of adherence (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) with the number and percentage of subjects belonging to adherence categories 
(eg, {< 80%, ≥ 80 to < 90%, ≥ 90%}) will be provided for the Safety Analysis Set. Categorical 
displays also will be provided for the number of subjects who are at least 80% adherent to their 
drug regimen (ie, adherence is ≥80% for the study drugs).
No inferential statistics will be provided for duration of exposure and adherence to study drug.
A separate by-subject listing of study drug administration and drug accountability will be 
provided by subject ID number (in ascending order) and visit (in chronological order).
4.3
Protocol Deviations
A summary of important protocol deviations will be provided by the Clinical Operations group 
for subjects in the Safety Analysis Set.


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5
BASELINE DATA
5.1
Demographics 
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by genotype 
and using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for age
and BMI (kg/m2), and using the numbers and percentages of subjects for age categories 
(< 65 years, ≥65 years), BMI categories (< 30 kg/m2, ≥ 30 kg/m2), sex, race, and ethnicity. Age 
is calculated in years at the date of initial study drug administration. If a subject did not receive 
study drug after enrollment, the subject’s age will be calculated from the date that the subject 
signed the informed consent form. The summary of demographic data will be provided for the 
Safety Analysis Set.
A by-subject demographic listing, which includes first dose date, will be provided by subject ID 
number in ascending order.
5.2
Other Baseline Characteristics
Other baseline characteristics include:

HCV genotype and subtypes

IL28B (CC, Non-CC (including CT, and TT))

baseline HCV RNA as a continuous variable and as categories (< 800,000 IU/mL,
≥800,000 IU/mL)

baseline ALT as a continuous variable and for categories (≤1.5 × ULN, > 1.5 × ULN)

prior HCV treatment experience (treatment naïve, treatment experienced)

cirrhosis (presence, absence, missing)

cirrhosis determination method (fibrotest and APRI, liver biopsy, transient elastography)

renal transplant (yes, no)

prior HCV treatment for treatment experienced subjects [DAA Naive (Peg-IFN + RBV, 
Other)]

prior HCV treatment response (non-responder , relapse/breakthrough, early treatment
discontinuation, and unknown) for treatment experienced subjects

type of current dialysis (Hemodialysis, Peritoneal Dialysis)


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These baseline characteristics will be summarized by genotype using descriptive statistics 
(n, mean, SD, median, Q1, Q3, minimum, and maximum) for continuous variables and using the 
numbers and percentages of subjects for categorical variables. The summary of baseline 
characteristics will be provided for the Safety Analysis Set.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
A separate by-subject data listing for cirrhosis determination will be provided for all subjects at 
screening.
A separate by-subject data listing for prior HCV treatment and response will be provided for all 
treatment experienced subjects. The listing will display the prior HCV regimen(s) and 
treatment(s) including the treatment duration, and the prior HCV treatment response.
5.3
Medical History
Medical history collected at screening will be coded using the current Medical Dictionary for
Regulatory Activities (MedDRA). Medical history will be summarized by system organ class
(SOC) and preferred term (PT). Subjects who report 2 or more medical history items that are 
coded to the same SOC and/or PT will be counted only once by the unique coded term in the 
summary. The summary will be provided for the Safety Analysis Set. No inferential statistics 
will be generated.
A by-subject listing of disease-specific medical history will be provided by subject ID number 
(in ascending order) and medical history of abnormalities (in chronological order).
A by-subject listing of renal transplant will be provided by subject ID number.


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6
EFFICACY ANALYSES 
6.1
Primary Efficacy Endpoint
6.1.1
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint is SVR12 defined as HCV RNA < LLOQ 12 weeks after
discontinuation of study drug in the FAS. The COBAS® AmpliPrep/COBAS® TaqMan® HCV 
Quantitative Test, v2.0 will be used to measure HCV RNA. The LLOQ for this assay is 
15 IU/mL.
6.1.2
Primary Analysis of the Primary Efficacy Endpoint
The SVR12 rate in each of genotype will be calculated along with 2-sided 95% exact CI based 
on Clopper-Pearson method {Clopper 1934}.
6.1.3
Subgroup Analysis of the Primary Efficacy Endpoint
The point estimates and 95% exact CIs of the SVR12 rates will be displayed by genotype for 
subgroups outlined in Section 3.3.
SVR12 rates will be summarized by categories of early viral response to explore possible early 
on-treatment predictors of SVR12. The relationship between SVR12 and study drug interruption
may also be explored.
A forest plot will graphically present estimates and 95% CIs in SVR12 rates for each of the 
subgroups.
6.2
Secondary Efficacy Endpoints
6.2.1
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include the following:

The percentage of subjects with HCV RNA < LLOQ at 4 and 24 weeks after discontinuation
of treatment (SVR4 and SVR24)

The percentage of subjects with HCV RNA < LLOQ while on treatment by study visit

HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) through end 
of treatment (EOT)

The percentage of subjects with virologic failure as the following:
On-treatment virologic failure
■
HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ, while on 
treatment, confirmed with 2 consecutive values (note, second confirmation value can 
be posttreatment), or last available on-treatment measurement with no subsequent 
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■
> 1 log10IU/mL increase in HCV RNA from nadir while on treatment, confirmed with 
2 consecutive values (note, second confirmation value can be posttreatment), or last 
available on-treatment measurement with no subsequent follow up values 
(ie, rebound)
■
HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (ie, nonresponse)
Relapse
■
HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA 
< LLOQ at end of treatment, confirmed with 2 consecutive values or last available 
posttreatment measurement

The steady-state pharmacokinetics of SOF and its metabolites and VEL in subjects who are 
on dialysis for ESRD.

Characterization of HCV drug resistance substitutions at baseline, during, and after therapy
with SOF/VEL.
6.2.2
Analysis Methods for Secondary Efficacy Endpoints
For analyses of HCV RNA < LLOQ by visit while on treatment and during the posttreatment 
(SVR) follow-up period, subjects will be assigned a value at each visit based on the analysis visit 
windows specified in Section 3.6.2. Missing values will be imputed based on the categorical 
imputation rules described in Section 3.4.1. The 2-sided 95% exact CI based on 
Clopper-Pearson method will be provided for the percentage of subjects with HCV RNA 
< LLOQ at each visit within each genotype. The overall category for “HCV RNA < LLOQ” will 
be split into the following 2 subcategories: “< LLOQ TND” for subjects with target not detected 
and “< LLOQ detected” for subjects with < LLOQ in tabular displays. 
Graphs for the percentage of subjects with HCV RNA < LLOQ over time during treatment will 
be displayed by genotype.
Summary statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 IU/mL), by genotype and by visit through EOT. Imputation rules described in
Section 3.4.1 will be used to assign HCV RNA values for missing values at a visit that are 
bracketed by “< LLOQ TND” and/or “< LLOQ detected”. Otherwise, a missing = excluded 
analysis will be performed. Plots of the mean ± SD and median (Q1, Q3) of absolute values and 
changes from baseline in HCV RNA through EOT will be presented.
For the SVR12 endpoint analysis, a summary table of the number and percentage of subjects 
with SVR12, virologic failure, and Other by genotype will be created. All subjects who achieve 
SVR12 will be categorized as SVR12. Virologic failure will be descriptively summarized as 
“on-treatment virologic failure” and relapse (which will be broken down by study drug 
completed yes/no). Subjects who do not achieve SVR12 and do not meet criteria for virologic 
failure will be categorized as “Other.” The denominator for relapse will be the number of 
subjects who had HCV RNA < LLOQ on their last observed on-treatment HCV RNA 
measurement; otherwise, the denominator will be the number of subjects in the FAS.


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A concordance table between SVR12 and SVR24 will be provided for each genotype. Subjects 
with both observed SVR12 and observed SVR24 data will be included for this analysis.
Drug resistant substitutions will be analyzed and reported based on change from baseline 
sequence and/or change from HCV genotype reference strain as part of the Virology Study 
Report.
6.3
Exploratory Efficacy Endpoints
6.3.1
Definition of Exploratory Efficacy Endpoints
 
6.3.2
Analysis Methods for Exploratory Efficacy Endpoints
 
 
 
 
 
 
 
 
 
 
6.4
Changes From Protocol-Specified Efficacy Analyses
There are no planned changes from protocol-specified efficacy analyses.
CCI
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7
SAFETY ANALYSES
7.1
Adverse Events and Deaths
The primary safety endpoint is any AE that led to permanent discontinuation of study drug.
7.1.1
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA. System organ class (SOC), high-level group term (HLGT), high-level term (HLT), 
preferred term (PT), and lower-level term (LLT) will be provided in the AE dataset.
7.1.2
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria
specified in the protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings, and the most 
severe will be considered (for sorting purpose only) in data presentation.
7.1.3
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE case report form 
(CRF) to the question of “Related to Study Treatment.” Events for which the investigator did not 
record the relationship to study drug will be considered to be related to study drug for summary 
purposes. However, by-subject data listings will show the relationship as missing from that 
captured on the CRF.
7.1.4
Serious Adverse Events
Serious adverse events will be identified and captured as SAEs if AEs met the definitions of SAE 
specified in the study protocol. Serious adverse events captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead Drug Safety and 
Public Health Department before database finalization.
7.1.5
Treatment-Emergent Adverse Events
7.1.5.1
Definition of Treatment-Emergent
Treatment-emergent adverse events (TEAEs) are defined as one or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.


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7.1.5.2
Incomplete Dates
If the onset date of AE is incomplete, then the month and year (or year alone if month is not 
recorded) of onset determine whether an AE is treatment emergent, as long as the AE stop date is 
not prior to the first dose date of study drug. The event is considered treatment emergent if both
of the following 2 criteria are met:

The AE onset and end dates are the same as or after the month and year (or year) of the first 
dose date of study drug

The AE onset date is the same as or before the month and year (or year) of 30th day after the 
date of the last dose of study drug 
An AE with a completely missing onset and stop dates, or with the onset date missing and a 
stop date later than the first dose date of study drug, will be considered to be treatment-emergent.
7.1.6
Summaries of Adverse Events and Deaths
A brief high-level summary of TEAEs will be provided by the number and percentage of 
subjects who had the following: any AE, any AE of Grade 3 or above, any AE of Grade 2 or 
above, any treatment-related AE, any treatment-related AE of Grade 3 or above, any 
treatment-related AE of Grade 2 or above, any SAE, any treatment-related SAE, and any AE that
led to premature discontinuation of SOF/VEL, and any AE that led to interruption of SOF/VEL. 
All deaths (including those that are treatment emergent and those that are not treatment 
emergent) observed during the study will also be summarized and included in this table. 
Adverse event summaries will provide the number and percentage of subjects with TEAEs by 
SOC and PT based on the safety analysis set as follows:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs 

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs

All treatment-related SAEs 

AEs leading to premature discontinuation of SOF/VEL

Adverse Events Leading to Interruption of SOF/VEL


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Multiple events will be counted once only per subject in each summary. Adverse events will be 
summarized and listed in alphabetic order of SOC and then by PT in order of descending 
incidence within each SOC. In summaries by severity grade, the most severe grade will be used 
for those AEs that occurred more than once in an individual subject during the study. 
In addition to the above summary tables, TEAEs will also be summarized by PT only, in order of 
descending incidence for:

All AEs

AEs that occurred in at least 5% of subjects 

AEs of Grade 3 or above

All treatment-related AEs

All SAEs

AEs leading to premature discontinuation of SOF/VEL

AEs leading to interruption of SOF/VEL
All deaths (including those that are treatment emergent and those that are not treatment 
emergent) observed during the study will also be summarized.
In addition to the summaries described above, data listings will be provided for the following:

All AEs

AEs of Grade 3 or above

SAEs

Deaths

AEs leading to premature discontinuation of SOF/VEL

AEs leading to interruption of SOF/VEL

AE with changes other than resolution dates between the SVR12 and SVR24 analyses 
(provided only at the final analysis)
7.2
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
safety analysis set and will include data collected up to last dose of any study drug plus 30 days 
for subjects who have permanently discontinued study drug. The analysis will be based on values 
reported in conventional units. When values are below the limit of quantitation, they will be 


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listed as such, and the closest imputed value will be used for the purpose of calculating summary 
statistics. For example, if “< 0.2” was recorded, a value of 0.1 will be used for the purpose of 
calculating summary statistics; if “< 0.1” was recorded, a value of 0.09 will be used for the 
purpose of calculating summary statistics. 
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, coagulation, and urinalysis separately. 
Values falling outside of the relevant reference range and/or having a severity grade of 1 or 
higher on the Gilead Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities will be flagged in the data listings, as appropriate.
No inferential statistics will be generated.
7.2.1
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
for ALT, aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, white blood 
cell (WBC) counts, neutrophils, lymphocytes, hemoglobin, platelets, reticulocytes, and 
international normalized ratio (INR) as follows:

Baseline values 

Values at each postbaseline visit

Change from baseline at each postbaseline visit
A baseline laboratory value will be defined as the final assessment performed on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
will be displayed to reported number of digits, SD to reported number of digits plus 1.
Median (Q1, Q3) of the observed values for ALT, AST, total bilirubin, alkaline phosphatase, 
hemoglobin, reticulocytes, WBC, neutrophils, lymphocytes, and platelets will be plotted using a 
line plot by visit. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.6.3 (Selection of Data in the Event of Multiple Records in a Window).
7.2.2
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used for assigning toxicity grades to laboratory results for analysis as Grade 0, Grade 1 (mild), 
Grade 2 (moderate), Grade 3 (severe), or Grade 4 (potentially life threatening). Grade 0 includes 
all values that do not meet criteria for an abnormality of at least Grade 1. Some laboratory tests 
have laboratory toxicity criteria for both increased and decreased levels; analyses for each 
direction (ie, increased, decreased) will be presented separately.


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7.2.2.1
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug, or all 
available data in the database snapshot for subjects still on treatment at the time of the interim 
analysis. If the relevant baseline laboratory value is missing, then any abnormality of at least 
Grade 1 will be considered treatment emergent.
7.2.2.2
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by analyte; subjects will be categorized according to the most 
severe postbaseline abnormality grade for a given analyte:

Graded laboratory abnormalities

Grade 3 or above laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dose of study drug for the laboratory 
parameter of interest.
A by-subject listing of treatment-emergent Grade 3 or above laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the analyte of interest, with all applicable 
severity grades or abnormal flags displayed.
7.3
Body Weight, Height, and Vital Signs
Vital signs (systolic and diastolic blood pressure [mmHg], pulse [beats/min]) at each visit, and 
change from baseline at each visit will be summarized for the safety analysis set using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum). The baseline 
value will be defined as the last available value collected on or prior to the date/time of first dose 
of study drug. Change from baseline to a postbaseline visit will be defined as the postbaseline 
value minus the baseline value.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.6.3 (Selection of Data in the Event of Multiple Records in a Window). 
No inferential statistics will be generated.
A by-subject listing of vital signs (systolic and diastolic blood pressure [mmHg], 
pulse [beats/min], respiration [breaths/min], and body temperature [°C]) will be provided by 
subject ID number and visit in chronological order. In the same manner, a by-subject listing of 
body weight, height, and BMI will be provided separately.


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7.4
Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary. The medications will be categorized 
as prior, concomitant, or both using the following definitions:

Prior medications: any medications taken prior to the initial study drug dosing date 

Concomitant medications: any medications initially taken on or after the initial study drug 
dosing date and within the study drug’s treatment period (including study drug’s therapeutic 
reach).

Prior and concomitant medications: any medications taken both prior to and on or after the 
initial study drug dosing date and within the study drug’s treatment period (including study 
drug’s therapeutic reach); or any medications taken prior to the baseline visit date with a stop 
date of “continuing” 
Concomitant medications will be summarized by preferred name using the number and 
percentage of subjects. A subject reporting the same medication more than once will be counted 
only once when calculating the number and percentage of subjects who received that medication. 
The summary of concomitant medications will be ordered by descending frequency of preferred 
names. For drugs with the same frequency, sorting will be done alphabetically. For purposes of 
analysis, any medication with a stop date that is on or prior to the initial study drug dosing date 
or start date that is after the last study drug dosing date will be excluded from a concomitant 
medication summary. If a partial stop date is entered, any medication with the month and year 
(if day is missing) or year (if day and month are missing) prior to the initial study drug dosing
date will be excluded from the concomitant medication summary. If a partial start date is entered, 
then any medication with the month and year (if day is missing) or year (if day and month are 
missing) after the study drug stop date will be excluded from the concomitant medication 
summary. Medications with completely missing dates will be included in the concomitant 
medication summary. Summaries will be based on the Safety Analysis Set. No inferential 
statistics will be generated.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.5
Electrocardiogram Results
A by-subject listing for ECG assessment results will be provided by subject ID number and visit
in chronological order.
7.6
Other Safety Measures
A data listing will be provided for subjects who become pregnant during the study.
7.7
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8
PHARMACOKINETIC ANALYSES
Plasma concentrations of SOF (and its metabolites GS-566500 and GS-331007) and VEL in 
plasma will be determined using validated bioanalytical assays. 
Population PK models for SOF, GS-331007 and VEL, previously developed for the Phase 2/3
SOF/VEL US NDA population analyses, will be applied to the data from all PK samples
collected in this study. Details of the population PK analysis will be provided in a separate
population PK analysis plan. 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
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9
REFERENCES
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Dec. Biometrika 1934;26 (4):pp. 404-13.


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10 SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
WinNonlin® Phoenixsoftware v6.3 (Pharsight Corporation, Mountain View, CA).


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11 SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision


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12 APPENDICES
Appendix 1
Schedule of Assessments
Appendix 2.
QOL Score Calculation Algorithms


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Appendix 1
Schedule of Assessments
Appendix Table 1.
Screening/Baseline/ On-Treatment and Post Treatment Study Visits
Screen
Baseline/Day 1a
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)i
2
4
6
8
12/ET
4
12
24
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
X
X
Height
X
Weight
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
12-Lead ECGc
X
X
X
AEs /SAEb
X
X
X
X
X
X
X
X
Xb
Xb
Concomitant Medications
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling
X
X
X
X
X
X
Health Related Quality of Lifec
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
Study Drug Dispensingd
X
X
Laboratory Assessments
Hematology, Chemistry 
X
X
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
Viral Sequencing/Phenotypingf
X
X
X
X
X
X
X
X
X
Sparse PK
X
X
X
X
X
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Screen
Baseline/Day 1a
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)i
2
4
6
8
12/ET
4
12
24
Serum β-hCG Pregnancy Testl
X
X
X
X
X
X
Serum Drug Screen
X
HCV & IL28B Genotyping
X
HCV, HIV, HBV Serology
X
HBV DNA k
X
X
X
X
X
X
X
HbA1c
X
Fibrotest  ®
X
CD4 Cell Count m
X
X
X
X
X
X
HIV-1 RNA m
X
X
X
X
X
X
a
Baseline/Day 1 assessments must be performed prior to dosing
b
Only SAEs will be collected at post-treatment Weeks 12 and 24.
c
Health Related Quality of Life (HRQoL) Surveys (e.g., SF-36, CLDQ-HCV, FACIT-F and WPAI) will be conducted for all subjects where the surveys are available at Day 1, 
Week 12, ET (if applicable) and posttreatment Week 12.
d
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
f.
Plasma samples will be collected for possible viral resistance testing and other virology studies.
 
 
k.
Only for subjects who are HBcAb+ at Screening
l.
For females of child bearing potential
m.
For HIV/HCV co-infected subjects only.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Appendix 2.
QOL Score Calculation Algorithms
CLDQ – HCV
CLDQ-HCV scores are calculated using subject responses to 29 questions in the questionnaire. If 
Ri is the score for the patient’s response to the item i, for i=1, 2, …., 29 then the 4 domain scores 
are calculated as follows:
Activity/Energy (AE) = Mean of {R1, R3, R4, R5, R7, R18}
Emotion (EM) = Mean of {R6, R8, R9, R11, R16, R23, R24, R27, R28}
Worry (WO) = Mean of {R14, R15, R17, R19, R20, R21, R22, R29}
Systemic (SY) = Mean of {R2, R10, R12, R13, R25, R26}
Here “Mean” is the average of nonmissing items (SAS mean function). Each score is calculated 
only if at least half of corresponding items are not missing. Otherwise, the score will be missing.
Over all CLDQ-HCV score is calculated by taking the mean of 4 domain scores {AE, EM, WO, 
SY}.
FACIT-F
Patient responses to 40 questions in FACIT-F questionnaire are rated in 0-4 score.
If less than 50% of responses in the corresponding domain are missing, the subscales for 
five domains are calculated as follows:
Physical Well-Being (PWB) = 7 × Mean of {GP1-GP7}
Social/Family Well-Being (SWB) = 7 × Mean of {GS1-GS7}
Emotional Well-Being (EWB) = 6 × Mean of {GE1-GE6}
Functional Well-Being (FWB) = 7 × Mean of {GF1-GF7}
Fatigue Subscale (FS) = 13 × Mean of {HI7, HI12, An1-An5, An7, An8 An12, An14-An16}
and
FACIT-F Trial Outcome Index (TOI) = PWB+FWB+FS
If less than 20% of all 40 questions are not missing, 
TACIT-F Total Score = PWB+SWB+EWB+FWB+FS


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WAPI: Hepatitis C
The response to Question 1 of this questionnaire provides the binary endpoint whether had been 
in a paid employment during the week prior to assessment.
If the patient has been in a paid employment (Response to Q1 is “Yes”) at the visit when 
questionnaire was given, then following three scores are derived:
Percent work time missed due to hepatitis C = 100×Q2/(Q2+Q4)
Percent impairment while working due to hepatitis C = 100×Q5/10
Percent overall work impairment due to hepatitis C = 


















10
5
)
4
2
2
1
)
4
2
(
2
100
Q
Q
Q
Q
Q
Q
Q
Question 6 is applicable to all subjects:
Percent activity impairment due to hepatitis C = 100×Q6/10.