Clinical trial NCT03074331
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences
Start date: 2017-03-23; Completion date: 2018-02-07
Enrollment: 130 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objectives of this study are to evaluate the efficacy, safety, and tolerability of treatment with sofosbuvir/velpatasvir (SOF/VEL) fixed-dose combination (FDC) for 12 weeks in adults with chronic hepatitis C virus (HCV) infection.

Detailed description:

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

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Open-label Study to Investigate the Efficacy and Safety of 
Sofosbuvir/Velpatasvir Fixed Dose Combination for 12 weeks in 
Subjects with Chronic Hepatitis C Virus (HCV) infection
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Clinical Trials.gov 
Identifier:
Not Available
Indication:
Hepatitis C Virus Infection 
Protocol ID:
GS-US-342-1521
Gilead Medical 
Monitor and Study 
Director:
Name:
Telephone:
Fax:
Email:
Protocol Version/Date:
Original:
12 February 2016
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The information contained in this document, particularly unpublished data, is the property or 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
PPD
PPD
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS......................................................................8
1.
INTRODUCTION ..............................................................................................................................................11
1.1.
Background ............................................................................................................................................11
1.2.
Sofosbuvir/Velpatasvir Fixed Dose Combination..................................................................................12
1.2.1.
General Information .............................................................................................................12
1.2.2.
Summary of Additional Clinical Experience: Clinical Pharmacology 
Studies..................................................................................................................................12
1.2.3.
Summary of Additional Clinical Experience: Phase 3 Studies.............................................16
1.3.
Rationale for Dose Selection..................................................................................................................31
1.4.
Rationale for This Study ........................................................................................................................32
1.5.
Risk/Benefit Assessment for the Study..................................................................................................33
1.6.
Compliance ............................................................................................................................................34
2.
OBJECTIVES.....................................................................................................................................................35
3.
STUDY DESIGN................................................................................................................................................36
3.1.
Treatment Plan and Regimen .................................................................................................................36
3.2.
Visit Schedule ........................................................................................................................................36
3.3.
HCV Virologic Response-Based Treatment Stopping Criteria..............................................................36
3.4.
Treatment Discontinuation Criteria........................................................................................................36
3.5
Discontinuations.....................................................................................................................................37
3.6.
Archive Samples ....................................................................................................................................37
4.
SUBJECT POPULATION..................................................................................................................................39
4.1.
Number of Subjects and Subject Selection ............................................................................................39
4.2.
Inclusion Criteria....................................................................................................................................39
4.3.
Exclusion Criteria...................................................................................................................................41
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................42
5.1.
Enrollment and Study Drug supply........................................................................................................42
5.2.
Description and Handling of SOF/VEL FDC ........................................................................................42
5.2.1.
Formulation..........................................................................................................................42
5.2.2.
Packaging and Labeling .......................................................................................................42
5.2.3.
Storage and Handling...........................................................................................................42
5.2.4.
Dosage and Administration of SOF/VEL FDC....................................................................43
5.3.
Prior and Concomitant Medications.......................................................................................................43
5.4.
Accountability for SOF/VEL FDC.........................................................................................................44
5.4.1.
Investigational Medicinal Product Return or Disposal.........................................................45
6.
STUDY PROCEDURES ....................................................................................................................................46
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................46
6.2.
Pretreatment Assessments......................................................................................................................46
6.2.1.
Screening Visit .....................................................................................................................46
6.2.2.
Day 1 Assessments...............................................................................................................47
6.3.
Dispensing visits Week 4 and 8 (± 3 days) ............................................................................................48
6.4.
Week 12 (± 3 days) or Early Termination (ET) .....................................................................................48


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6.5.
Unscheduled Visit ..................................................................................................................................49
6.6.
Post-Treatment Assessments (5 days).................................................................................................49
6.6.1.
Post-treatment Week 4 (± 5 days) ........................................................................................49
6.6.2.
Post-treatment Week 12 (± 5 days) ......................................................................................49
6.7.
End of Study...........................................................................................................................................49
6.8.
Procedures and Specifications................................................................................................................50
6.8.1.
Clinical Laboratory Analytes ...............................................................................................50
6.8.2.
Medical History....................................................................................................................50
6.8.3.
Symptom directed Physical Examination.............................................................................50
6.8.4.
Creatinine Clearance ............................................................................................................51
6.8.5.
Pregnancy Testing................................................................................................................51
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................52
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................52
7.1.1.
Adverse Events.....................................................................................................................52
7.1.2.
Serious Adverse Events........................................................................................................52
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................53
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................53
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................53
7.2.2.
Assessment of Severity ........................................................................................................54
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................54
7.4.
Gilead Reporting Requirements.............................................................................................................56
7.5.
Special Situations Reports......................................................................................................................56
7.5.1.
Definitions of Special Situations..........................................................................................56
7.5.2.
Instructions for Reporting Special Situations.......................................................................57
8.
STATISTICAL CONSIDERATIONS................................................................................................................59
8.1.
Analysis Objectives and Endpoints........................................................................................................59
8.1.1.
Analysis Objectives..............................................................................................................59
8.1.2.
Primary Endpoint .................................................................................................................59
8.1.3.
Secondary Endpoint .............................................................................................................59
8.1.4.
Safety Endpoint....................................................................................................................59
8.1.5.
Other Endpoints of Interest ..................................................................................................59
8.2.
Analysis Conventions.............................................................................................................................59
8.2.1.
Analysis Sets ........................................................................................................................60
8.3.
Data Handling Conventions ...................................................................................................................60
8.4.
Demographic Data and Baseline Characteristics ...................................................................................61
8.5.
Efficacy Analysis ...................................................................................................................................61
8.5.1.
Primary Analysis..................................................................................................................61
8.5.2.
Secondary Analyses .............................................................................................................61
8.6.
Safety Analysis.......................................................................................................................................62
8.6.1.
Extent of Exposure...............................................................................................................62
8.6.2.
Adverse Events.....................................................................................................................62
8.6.3.
Laboratory Evaluations ........................................................................................................63
8.6.4.
Other Safety Evaluations......................................................................................................63
8.7.
Sample Size............................................................................................................................................63
9.
RESPONSIBILITIES..........................................................................................................................................64
9.1.
Investigator Responsibilities ..................................................................................................................64
9.1.1.
Good Clinical Practice..........................................................................................................64
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................64


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9.1.3.
Informed Consent.................................................................................................................64
9.1.4.
Confidentiality......................................................................................................................65
9.1.5.
Study Files and Retention of Records ..................................................................................65
9.1.6.
Case Report Forms...............................................................................................................66
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................67
9.1.8.
Inspections............................................................................................................................67
9.1.9.
Protocol Compliance............................................................................................................67
9.2.
Sponsor Responsibilities ........................................................................................................................67
9.2.1.
Protocol Modifications.........................................................................................................67
9.2.2.
Study Report and Publications .............................................................................................68
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................68
9.3.1.
Payment Reporting...............................................................................................................68
9.3.2.
Access to Information for Monitoring..................................................................................68
9.3.3.
Access to Information for Auditing or Inspections ..............................................................69
9.3.4.
Study Discontinuation..........................................................................................................69
10.
REFERENCES ...................................................................................................................................................70
11.
APPENDICES ....................................................................................................................................................72
Appendix 1.
Investigator Signature Page....................................................................................................73
Appendix 2.
Study Procedures Table..........................................................................................................74
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............75
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................98
LIST OF IN-TEXT TABLES
Table 1-1.
NGMN, NG, EE, and VEL Plasma PK Parameters Following Administration of 
NGM/EE alone or with VEL..................................................................................................13
Table 1-2.
Summary of LH, FSH, and Progesterone Concentrations Following Administration 
of NGM/EE alone or with VEL..............................................................................................14
Table 1-3.
Summary of Changes in SOF/VEL PK following administration with 
Representative H2RAs and PPIs ............................................................................................15
Table 1-4.
GS-US-342-1138: SVR12 Overall and by HCV Genotypes ..................................................17
Table 5-1.
List of Disallowed /Use with Caution Medications................................................................44


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 3, Open-label Study to Investigate the Efficacy and Safety of 
Sofosbuvir/Velpatasvir Fixed Dose Combination for 12 weeks in 
Subjects with Chronic Hepatitis C Virus (HCV) infection
Clinical Trials.gov 
Identifier:
Not Available
Study Centers 
Planned:
Approximately 20 centers in India
Objectives:
The primary objectives of this study are as follows:

To evaluate the efficacy of treatment with sofosbuvir 
(SOF)/velpatasvir (VEL,GS-5816) fixed dose combination (FDC) 
for 12 weeks in subjects with chronic HCV infection 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
FDC for 12 weeks
Study Design:
Phase 3, multi-center, open-label study in adult male and female 
subjects with chronic hepatitis C virus (HCV) infection.
Approximately 125 subjects with chronic HCV infection will be 
enrolled.
All subjects will receive SOF/VEL once daily for 12 weeks.
Number of Subjects 
Planned:
Approximately 125 subjects
Target Population:
Adults with chronic HCV infection
Duration of 
Treatment:
Subjects will receive SOF/VEL FDC once daily for 12 weeks


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Diagnosis and Main 
Eligibility Criteria:
Chronic hepatitis C virus (HCV) infected adults. Up to approximately 
20% of subjects may have compensated cirrhosis at baseline and up 
to approximately 20% of subjects may be treatment–experienced.
Refer to Sections 4.2 and 4.3 of the protocol for detailed Inclusion 
and Exclusion Criteria
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the 
Baseline/Day 1 visit. The screening window can be extended to 
42 days in extenuating circumstances.
All subjects will complete the following study visits: Screening, 
Baseline/Day 1, Week 12 (end of treatment), and post treatment at 
Weeks 4 and 12. In addition, subjects will return at weeks 4 and 8 for 
the study medication dispensing visit.
Screening assessments will include medical history, 
symptom-directed physical/vital signs (if indicated), concomitant 
medications (CMs), safety laboratory tests (ie, hematology, 
chemistry, and coagulation), HCV RNA, HCV genotype, HCV and 
HBV serology and HIV testing, assessment of the presence or 
absence of cirrhosis, and a urine pregnancy test (females of child 
bearing potential only).
Baseline/Day 1 assessments include medical history, 
symptom-directed physical examination/vital signs (if indicated), 
adverse events (AEs) and CMs, safety laboratory tests, HCV RNA, 
and a urine pregnancy test (females of child bearing potential only). A 
plasma archive sample will be collected. Study medication will be 
dispensed.
At Weeks 4 and 8, subjects will return to the clinic for study drug 
dispensation. 
At the Week 12 end of treatment visit or early termination (ET) visit, 
assessments include symptom-directed physical examination/vital 
signs (if indicated), AEs, CMs, study medication pill count, safety 
laboratory tests, HCV RNA and urine pregnancy testing. A plasma 
archive sample will be collected.
At post-treatment Week 4, AEs and CMs will be recorded. A 
symptom-directed physical examination/vital signs will be performed 
(if indicated). Safety laboratory and urine pregnancy testing will be 
performed.
At post-treatment Week 12, HCV RNA will be tested. A plasma 
archive sample will also be collected.


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Test Product, Dose, 
and Mode of 
Administration:
SOF/VEL FDC is manufactured as a 400 mg/100 mg FDC tablet for 
oral administration. Subjects will take 1 tablet daily with or without 
food for 12 weeks.
Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for 
Evaluation:
Safety:
Adverse events (AEs) and laboratory tests will be collected 
throughout the study. 
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed.
Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all enrolled 
and treated subjects. In the primary efficacy analysis, the SVR12 rate 
will be compared to a performance goal of 85% using a two-sided 
exact one-sample binomial test at the 0.05 significance level.
The secondary efficacy endpoint is the proportion of subjects with 
virologic failure.
All continuous endpoints (except for safety endpoints) will be 
summarized using an 8-number summary (n, mean, standard 
deviation, and median, Q1, Q3, minimum, maximum). All categorical 
endpoints will be summarized by the number and percentage of 
subjects who meet the endpoint definition.
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnormalities for categorical values or
8-number summary (n, mean, standard deviation, median, Q1, Q3, 
minimum, maximum) for continuous data.
A sample size of 125 subjects will provide 95% power to detect an 
improvement in SVR12 rate from 85% to 95% using a two-sided 
exact one-sample binomial test at a significance level of 0.05.
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
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APRI
AST: platelet ratio index
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase  (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval (tau)
BW
body weight
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
DAA
direct acting antiviral
DCV
daclatasvir (HCV NS5A Inhibitor)
DSPH
Drug Safety and Public Health
ECG
electrocardiogram
eCRF
electronic case report form(s)
ET
Early Termination
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination
FSH
follicle stimulating hormone
g
grams
GCP
Good Clinical Practice 
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
genotype (viral)
H2RA
histamine-2 receptor antagonist.
Hb
hemoglobin
HbA1c
hemoglobin A1c
HBV
hepatitis B virus


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HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IFN
interferon
IL28B
interleukin-28B gene
IND
Investigational New Drug (Application)
INR
international normalized ratio of prothrombin time
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
kg
kilogram
L
liter
LDL
low-density lipoprotein
LDV
ledipasvir
LH
luteinizing hormone
LLN
lower limit of the normal range
LLOQ
lower limit of quantification
LLT
lower-level term 
MedDRA
Medical Dictionary for Regulatory Activities
mIU
milli international units
mL
milliliter
mmHg
millimeters mercury
ng•h/mL
nanograms times hours per milliliter
NGM
norgestimate 
NGM/EE
norgestimate/ethinyl estradiol
NGMN
norelgestromin
NS 
(3/4A/5A/5B)
Non-structural Protein
OC
oral contraceptive
PCR
Polymerase Chain Reaction
Peg-IFN
pegylated interferon
pg
picogram
pg•h/mL
picograms times hours per milliliter
P-gp
P-glycoprotein 


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PK
pharmacokinetics
PPI
proton pump inhibitor
PT
preferred term or prothrombin time 
RBC
red blood cell count
RBV
ribavirin
RNA
ribonucleic acid
Scr
serum creatinine (mg/dL)
SADR
serious adverse drug reaction
SAE
serious adverse event
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SOC
System Organ Class
SOF
Sovaldi® or sofosbuvir, formerly GS-7977
SOF/VEL
SOF/VEL fixed dose combination
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
sustained virologic response
ULN
upper limit of the normal range
US
United States
VEL
velpatasvir, formerly GS-5816
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) infection is a global health challenge with estimates ranging up to 
150 million individuals infected worldwide {World Health Organization (WHO) 2014}. In the 
United States (US), approximately 2.7 million people have chronic HCV infection {Denniston et 
al 2014} and HCV infection causes over 15,000 deaths each year {Ly et al 2012}, although 
under-reporting of HCV infection on death certificates may contribute to as much as a 5-fold 
underestimation of the actual number of deaths {Mahajan et al 2014}. Successful treatment of 
chronic HCV infection reduces the need for liver transplant, the incidence of hepatocellular 
carcinoma (HCC) and overall mortality {Backus et al 2011}. Thus, the public health benefit of 
safe and effective HCV treatment regimens is high.
The development of sofosbuvir (Sovaldi®, SOF), a nucleotide analog HCV NS5B polymerase 
inhibitor, represents a major advance in the treatment of HCV as SOF-based regimens are shorter 
in duration, better tolerated, and result in higher SVR rates than prior therapies. SOF is currently 
approved in the US for the treatment of genotype (GT) 1, 2, 3 and 4 HCV infection and in the 
European Union for GT1-6 with different regimens and durations dependent on the HCV 
genotype {Gilead Sciences Inc 2013}. In India, SOF was approved on the 13 January 2015, for 
GT1-6 with different regimens and durations dependent on the HCV genotype. The next wave of 
therapies for the treatment of HCV includes combinations of direct acting antivirals (DAAs) 
including SOF that will obviate the need for administration of Peg-IFN and RBV. The first of 
these treatments, a fixed dose combination (FDC) of SOF and the HCV nonstructural protein 5A 
(NS5A) inhibitor ledipasvir (LDV), has been approved in the US and Europe. The Phase 3 
studies GS-US-337-0102 (ION 1), GS-US-337-0109 (ION 2), and GS-US-337-0108 (ION 3) 
demonstrated that treatment with LDV/SOF with or without RBV for 8, 12 or 24 weeks resulted 
in high SVR12 rates in subjects with GT1 HCV infection {Afdhal et al 2014b}, {Afdhal et al 
2014a}, {Kowdley et al 2014}.
Most current HCV drug development effort focuses on GT1 HCV infection as this is the most 
prevalent HCV genotype in developed countries {Gower et al 2014}. However, over half of all 
HCV infections are non-GT1: estimates from 2 recent meta-analyses indicate GT3 HCV is the 
next most common accounting for 22-30% of infections, while GT2 and GT4 each account for 
approximately 8 to 13%, GT6 for approximately 2 to 5%, and GT5 for approximately 1% of 
HCV infections worldwide. The availability of a well-tolerated, all oral, short duration therapy 
that is effective across all HCV genotypes would be a major advance for the treatment of HCV 
infection globally, particularly in regions where HCV genotyping is not part of routine medical 
care for HCV infection.
Although some individualization of care will be necessary, particularly for patients with 
advanced disease, the development of a pangenotypic regimen of short-duration that may not 
require HCV genotyping, response guided therapy, or intensive safety monitoring due to use of 
Peg-IFN or RBV will enable more patients to be treated.


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1.2.
Sofosbuvir/Velpatasvir Fixed Dose Combination
Sofosbuvir (SOF)/ velpatasvir (VEL, GS-5816) fixed-dose combination (SOF/VEL FDC) 
combines two HCV specific DAAs into a single tablet for the treatment of chronic HCV 
infection.
SOF is a nucleotide analog HCV NS5B polymerase inhibitor currently approved in the US and 
other regions for the treatment of HCV infection as a component of an antiviral treatment 
regimen. VEL (formerly known as GS-5816) is a HCV NS5A inhibitor that has demonstrated 
activity against HCV genotypes 1, 2, 3 and 4 HCV in a 3-day monotherapy study. Phase 2 
studies of SOF +VEL administered as single agents have demonstrated that the combination of 
SOF 400 mg and VEL 100 mg administered for 12 weeks is well tolerated and results in high 
SVR rates across a broad range of HCV genotypes. The SOF/VEL FDC (400 mg/100 mg), is a 
co-formulation of SOF 400 mg and VEL 100 mg FDC has demonstrated similar exposure of 
each component compared to co-administration of the single agents. Of the 1,035 patients treated 
with SOF/VEL for 12 weeks in the phase 3 ASTRAL-1, ASTRAL-2 and ASTRAL-3 studies, 
1,015 (98 percent) achieved the primary efficacy endpoint of SVR12. Detailed results of each of 
the phase 3 ASTRAL studies are summarized in Section 1.2.3.
The development of SOF/VEL may have a major impact of the global prevalence and burden of 
HCV as it may represent a simple, well tolerated, highly efficacious pangenotypic treatment for 
all HCV infected patients.
1.2.1.
General Information
Please refer to the SOF/GS-5816 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.
Summary of Additional Clinical Experience: Clinical Pharmacology Studies
1.2.2.1.
Study GS-US-281-1058
GS-US-281-1058 is an open-label, Phase 1, multiple-dose drug-drug interaction study in healthy 
female subjects of childbearing age evaluating the effect of VEL on the pharmacokinetics of a 
representative hormonal contraceptive medication, norgestimate/ethinyl estradiol (NGM/EE, 
OC). Following screening, eligible subjects were enrolled in a lead-in period (Part A) of 28 days 
during which they completed dosing with the hormonal contraceptive (OC) prior to baseline 
assessments and initiation of Cycle 1 (Part B). Subjects with a documented history of taking 
NGM/EE for at least 1 menstrual cycle could be enrolled directly into Cycle 1. The PK, safety, 
and tolerability of OC and OC + VEL were assessed in Part B of the study, which consisted of 


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2 cycles: subjects received OC alone during Cycle 1, and OC plus VEL 100 mg once daily 
during days 8-14 of Cycle 2. Fifteen subjects were enrolled, and 13 completed the study. 
Two subjects were discontinued from the study prior to initiation of Cycle 2 (OC+VEL) for 
laboratory abnormalities. 
Table 1-1 presents the steady-state PK parameters and statistical comparisons of NGM 
metabolites norelgestromin (NGMN) and norgestrel (NG) and EE following administration alone 
or in combination with VEL. Steady-state VEL PK parameters were also assessed. Norgestimate 
was not quantifiable for all subjects at most time points. Similar systemic exposure of NGMN
and NG were achieved following NGM/EE administration with VEL relative to administration of 
NGM/EE alone. A modest increase in EE Cmax was observed when administered with VEL with 
no change in overall exposure (AUC) or Ctau. The magnitude of increase in EE Cmax when 
administered with VEL is similar to that observed with the concomitant administration of other 
drugs such as voriconazole and etravirine, which did not warrant dose adjustment {Andrews et al 
2008}, {Janssen Pharmaceuticals Inc. 2013}. VEL exposures were consistent with historical data 
(Studies GS-US-281-0115, GS-US-342-0104).
Table 1-1.
NGMN, NG, EE, and VEL Plasma PK Parameters Following 
Administration of NGM/EE alone or with VEL
PK Parameter
Mean (%CV)
GLSM Ratio 
(90% CI) NGM/EE + VEL vs. 
NGM/EE
NGM/EE Alone 
(N = 15)
NGM/EE + VEL 
(N = 13)
Norelgestromin
AUCtau (pg•h/mL)
17,700 (16.7)
15,700 (11.2)
0.90 (0.82, 0.98)
Cmax (pg/mL)
1650 (16.8)
1600 (13.7)
0.97 (0.88, 1.07)
Ctau (pg/mL)
454 (18.5)
416 (14.3)
0.92 (0.83, 1.03)
Norgestrel
AUCtau (pg•h/mL)
47,000 (34.4)
43,000 (32.4)
0.91 (0.73, 1.15)
Cmax (pg/mL)
2410 (30.6)
2330 (31.5)
0.96 (0.78, 1.19)
Ctau (pg/mL)
1760 (34.4)
1640 (35.7)
0.92 (0.73, 1.18)
Ethinyl Estradiol
AUCtau (pg•h/mL)
666 (30.7)
686 (27.3)a
1.04 (0.87, 1.24)
Cmax (pg/mL)
57.5 (27.3)
80.0 (28.4)a
1.39 (1.17, 1.66)
Ctau (pg/mL)
14.8 (39.3)
12.4 (43.9)a
0.83 (0.65, 1.06)
Velpatasvir
AUCtau (ng•h/mL)
--
4680 (35.1)
--
Cmax (ng/mL)
--
626 (22.0)
--
Ctau (ng/mL)
--
68.3 (47.6)
--
Note: preliminary data presented to 3 significant figures.
a
N = 12


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Preliminary luteinizing hormone (LH), follicle stimulating hormone (FSH), and progesterone 
concentrations were similar in both treatment cycles, as presented in Table 1-2. Luteinizing 
hormone and progesterone median values were lower than those expected for ovulatory or luteal 
phases, respectively {Quest Diagnostics 2013b}, {Quest Diagnostics 2013a}, {Barditch-Crovo et 
al 1999}. Follicle stimulating hormone was lower or within the expected range for the ovulatory 
phase {Quest Diagnostics 2013a}. These results are consistent with a possible decrease in serum 
LH and FSH by hormonal contraceptives and absence of ovulation, as assessed by very low 
progesterone values on cycle Day 21.
Table 1-2.
Summary of LH, FSH, and Progesterone Concentrations Following 
Administration of NGM/EE alone or with VEL 
PD Analyte
Median (Q1, Q3)
OC Alone (N = 15)
OC + VEL (N = 13)
LH (mIU/mL)
8.0 (2.7, 12.9)
9.3 (5.4, 14.4)
FSH (mIU/mL)
3.6 (2.0, 6.0)
2.6 (2.2, 5.1)
Progesterone (ng/mL)
0.24 (0.15, 0.40)
0.27 (0.18, 0.80)
Based on these results, no loss in contraceptive efficacy is expected upon administration of 
combined oral contraceptives containing norgestimate/ethinyl estradiol with VEL. 
Study GS-US-334-0146 previously demonstrated that the use of SOF with contraceptives 
(e.g., norgestimate/ethinyl estradiol) is permitted. Accordingly, the use of hormonal 
contraceptives with VEL as a single agent or as part of SOF/VEL FDC is permitted. 
1.2.2.2.
Drug-Drug Interaction Studies with SOF/VEL and Gastric Acid Suppressants
GS-US-342-1346 and GS-US-342-1709 were open-label, Phase 1, single-dose drug-drug 
interaction studies in healthy volunteers evaluating the effect of gastric acid suppressants 
(H2RAs and PPIs) on the PK of SOF/VEL. These studies were conducted because SOF/VEL has 
demonstrated pH-dependent solubility in vitro. A summary of results from these studies is 
presented in the table below.
Study GS-US-342-1346 demonstrated that simultaneous or staggered (12 hour) administration of 
SOF/VEL, administered under fasting conditions, with famotidine 40 mg resulted in no change 
to the AUC of SOF or VEL, suggesting that SOF/VEL can be administered simultaneously or 
staggered with H2RAs at doses comparable to famotidine 40 mg. Study GS-US-342-1346 also 
demonstrated that simultaneous or staggered (12 hour) administration of SOF/VEL, administered 
under fasting conditions, with omeprazole 20 mg resulted in a reduction in VEL AUC of 37% 
and 56%, respectively. The AUC of SOF also decreased 29% to 44%, respectively, though these 
effects are secondary to the impact of PPIs on VEL, as SOF does not demonstrated pH-
dependent solubility. Based on these data, the use of SOF/VEL under fasting conditions with 
PPIs is not recommended. 
Study GS-US-342-1709 evaluated the effect of omeprazole 20 mg or 40 mg on the PK of 
SOF/VEL when SOF/VEL is administered with food. Administration of SOF/VEL with food and 


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omeprazole did not alter the overall exposure (AUC) of SOF or its metabolites, regardless of 
timing or dose of omeprazole. Administration of SOF/VEL with food and omeprazole resulted in 
a decrease in VEL exposure. The smallest decrease in VEL exposure (AUC: 26%, Cmax: 33%) 
was observed following administration of SOF/VEL with food 4 hours before omeprazole 
20 mg. A slightly greater decrease in VEL exposure (AUC: 38%, Cmax: 48%) was observed when 
SOF/VEL was administered with food 2 hours after omeprazole 20 mg. The largest decline in 
VEL exposure (AUC: 53%, Cmax: 56%) was observed following SOF/VEL administration with 
food 4 hours before the higher dose of omeprazole 40 mg.
Collectively, these studies indicate that PPIs can impact the PK of SOF/VEL. Administration of 
SOF/VEL with food reduces the effect of omeprazole on SOF/VEL PK. The overall exposure of 
SOF and its metabolites were not affected by omeprazole 20 mg when SOF/VEL was 
administered with food, and the reduction in VEL exposure was less when administered with 
food (26% to 38%) compared to fasted administration (37% to 56%). Staggering timing of 
omeprazole 20 mg and SOF/VEL administration also modestly impacted VEL exposure; VEL 
AUC was least impacted when administered 4 hours before omeprazole 20 mg (equivalent to 
20 hours after the previous omeprazole dose). 
Study GS-US-342-1709 also demonstrates that the nature of VEL exposure decrease was not 
uniform across the study population. The largest decreases were observed in subjects with the
highest exposure at the reference condition of dosing, with SOF/VEL fasted without an acid 
reducing agent, and those with low exposure at the reference condition were generally unaffected 
by administration with a PPI. These data suggests that gastric pH is a contributor to the natural 
variability of VEL, and the range of exposure for HCV-infected subjects on PPIs is expected to 
be within that observed in Phase 3 ASTRAL studies. Accordingly, PPI doses comparable with 
omeprazole 20 mg can be administered with SOF/VEL when SOF/VEL is administered with 
food.
Table 1-3.
Summary of Changes in SOF/VEL PK following administration with 
Representative H2RAs and PPIs 
Study
Dosing 
Scheme
SOF PK Parameters
GS-331007 PK Parameters
VEL PK Parameters
AUClast
AUCinf
Cmax
AUClast
AUCinf
Cmax
AUClast
AUCinf
Cmax
GS-US-
342-1346 
(N=60)
SOF/VEL 
(fasted) with 
simultaneous 
FAM 40 mg
↔
↔
↔
↔
↔
↔
↔
↔
↔
SOF/VEL 
(fasted) with 
12 hours 
after FAM 
40 mg
↔
↔
↓23%
↔
↔
↔
↔
↔
↔
SOF/VEL 
(fasted) with 
simultaneous 
OME 20 mg
↓29%
↓29%
↓34%
↔
↔
↔
↓37%
↓36%
↓37%
SOF/VEL 
(fasted) 12 
hours after 
OME 20 mg 
↓44%
↓44%
↓45%
↔
↔
↔
↓56%
↓55%
↓57%


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Study
Dosing 
Scheme
SOF PK Parameters
GS-331007 PK Parameters
VEL PK Parameters
AUClast
AUCinf
Cmax
AUClast
AUCinf
Cmax
AUClast
AUCinf
Cmax
GS-US-
342-1709
(N=40)
SOF/VEL 
(fed) 2 hours 
After OME
20 mg
↔
↔
↓16%
↔
↔
↔
↓38%
↓38%
↓48%
SOF/VEL 
(fed)  4 hours 
Before OME
20 mg
↔
↔
↓21%
↔
↔
↔
↓26%
↓26%
↓33%
SOF/VEL 
(fed) 4 hours 
Before OME
40 mg
↔
↔
↓30%
↔
↔
↔
↓53%
↓53%
↓56%
FAM = famotidine; OME = omeprazole
The 90% CIs of the %GLSM ratios were within (↔), or extended below (↓) the predetermined PK alteration boundary of 70%.
1.2.3.
Summary of Additional Clinical Experience: Phase 3 Studies
Four Phase 3 studies evaluated the efficacy and safety of SOF/VEL in subjects with 
genotype 1-6 HCV infection. Three studies enrolled subjects without cirrhosis or with 
compensated cirrhosis, GS-US-342-1138 (ASTRAL-1), GS-US-342-1139 (ASTRAL-2) and 
GS-US-342-1140 (ASTRAL-3); and one study enrolled subjects with decompensated cirrhosis 
GS-US-342-1137 (ASTRAL-4). Summaries of the results from the individual Phase 3 studies are 
presented below.
1.2.3.1.
Study GS-US-342-1138 (ASTRAL-1)
Design
This Phase 3, randomized, double-blind, placebo-controlled, multicenter, international study 
evaluated the antiviral efficacy, safety, and tolerability of 12 weeks of SOF/VEL treatment 
compared with 12 weeks of SOF/VEL placebo treatment in subjects with chronic genotype 1, 2, 
4, 5, or 6 hepatitis C virus (HCV) infection.
Subjects with genotype 1, 2, 4, or 6 HCV infection were randomized in a 5:1 ratio to treatment 
with SOF/VEL for 12 weeks (SOF/VEL 12 Week group) or SOF/VEL placebo for 12 weeks 
(Placebo 12 Week group). Subjects with genotype 5 HCV infection were enrolled to the 
SOF/VEL 12 Week group. Randomization was stratified by HCV genotype (1, 2, 4, 6, and 
indeterminate) and the presence or absence of cirrhosis at screening.
Disposition
A total of 740 subjects were enrolled and treated; 624 subjects in the SOF/VEL 12 Week group 
and 116 subjects in the Placebo 12 Week group.
The majority of subjects (99.3%) completed study treatment. Five subjects (0.7%) prematurely 
discontinued study treatment; 2 subjects in the SOF/VEL group and 3 subjects in the placebo 
group. The reasons for premature discontinuation of study drug for subjects in the SOF/VEL 


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12 Week group were an AE (1 subject) and lost to follow-up (1 subject) and for subjects in the 
Placebo 12 Week group were AEs (2 subjects) and investigator discretion (1 subject).
Demographics and Baseline Characteristics
Demographics and baseline disease characteristics were generally balanced between the 
SOF/VEL 12 Week and Placebo 12 Week groups.
In the SOF/VEL 12 Week group, the majority of subjects were male (59.9%), and 21.6% of 
subjects had a body mass index (BMI) 30 kg/m2, 19.4% had cirrhosis and most subjects 
(73.9%) had baseline HCV RNA ≥800,000 IU/mL. Of the 624 subjects who received SOF/VEL, 
328 subjects (52.6%) had genotype 1 HCV infection (210 subjects [33.7%] with HCV 
genotype 1a and 118 subjects [18.9%] with HCV genotype 1b), 104 subjects (16.7%) had 
genotype 2 HCV infection, 116 subjects (18.6%) had genotype 4 HCV infection, 35 subjects 
(5.6%) had genotype 5 HCV infection, and 41 subjects (6.6%) had genotype 6 HCV infection.
Efficacy Results 
The SOF/VEL 12 Week group met the primary endpoint of an SVR12 rate that was statistically 
superior relative to the pre-specified performance goal of 85% (p < 0.001). The SVR12 rate was 
as follows:

SOF/VEL 12 Week group: 99.0% (95% CI: 97.9% to 99.6%) of subjects (618 of 624) 
achieved SVR12.
Table 1-4 presents the SVR12 results for the SOV/VEL 12 Week group overall and by HCV 
genotype. A total of 6 of 624 subjects (1.0%) who received SOF/VEL did not achieved SVR12. 
Two subjects had relapse determined at post-treatment week 4; one treatment-naive subject with 
genotype 1a HCV infection without cirrhosis and one treatment experienced subject with 
genotype 1b infection and cirrhosis. Four additional subjects (3 with genotype 1 and 1 with 
genotype 5) did not achieve SVR12 (1 subject withdrew consent, 2 subjects had not returned for 
the post-treatment Week 12 visit, and 1 subject died prior to the post-treatment Week 4 visit).
Table 1-4.
GS-US-342-1138: SVR12 Overall and by HCV Genotypes 
SOF/VEL
12 Weeks 
Total
(All 
Genotypes)
(N = 624)
GT-1a
(N = 210)
GT-1b
(N = 118)
GT-1
Total
(N = 328)
GT-2
(N = 104)
GT-4
(N = 116)
GT-5
(N = 35)
GT-6
(N = 41)
SVR12
618/624 
(99.0%)
206/210 
(98.1%)
117/118 
(99.2%)
323/328 
(98.5%)
104/104 
(100.0%)
116/116 
(100.0%)
34/35 
(97.1%)
41/41 
(100.0%)
GT = genotype


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The SVR4 results for subjects with genotype 1, 2, 4, 5, or 6 HCV infection were the same as the 
SVR12 results with the exception of 1 subject with genotype 1a HCV infection who achieved 
SVR4 but had not returned for his post-treatment Week 12 visit at the time of the analysis.
HCV RNA declined rapidly with similar decreases in HCV RNA observed across all HCV 
genotypes in the SOF/VEL 12 Week group. Consistent with the rapid and sustained decline in 
HCV RNA, > 88.5% of subjects in the SOF/VEL 12 Week group had HCV RNA LLOQ at 
Week 4. Time to virologic suppression was not associated with treatment outcome overall or in 
any genotype.
Virologic Resistance
Deep sequence analyses indicated that subjects in the SOF/VEL 12 Week group had a diverse 
population of HCV with more than 30 subtypes across genotypes 1, 2, 4, 5, 6, and 7. 
Approximately 42% and 9% of subjects in the SOF/VEL 12 Week group had baseline NS5A 
resistance-associated variants (RAVs) and NS5B RAVs, respectively. Baseline NS5A or NS5B 
RAVs had no impact on SVR12, with high SVR12 across all subtypes/genotypes regardless of 
the presence of NS5A RAVs or NS5B RAVs. Two subjects had virologic failure and both had 
baseline NS5A RAVs. At virologic failure time points, both subjects developed additional NS5A 
RAVs (Y93N and Y93H) that conferred a high (> 700) fold shift in EC50 to VEL. No NS5B 
RAVs were detected at baseline or post-treatment in either subject with virologic failure.
Safety Results
Treatment with SOF/VEL was well tolerated. Subjects in the SOF/VEL 12 Week treatment 
group had similar type, incidence, and severity of AEs as subjects in the Placebo 12 Week group.
Grade 3 (severe) and Grade 4 (life-threatening) AEs were rare, 19 of 624 (2.9%) in the SOF/VEL 
12 Week group and 1 of 116 (0.9%) in the Placebo 12 Week group. Two subjects (0.3%) in the 
SOF/VEL 12 Week group had Grade 4 AEs. One subject had a Grade 4 AE of malignant lung 
neoplasm and 1 subject had a Grade 4 AE of sudden death. Both events were assessed by the 
investigators as unrelated to study drugs.
SAEs were rare and occurred in 15 subjects (2.4%) in the SOF/VEL 12 Week group. All SAEs 
were assessed by the investigators as unrelated to study drugs. No placebo treated subjects had 
SAEs. No trends in SAE type or onset time were observed, and no SAE was reported in 
> 1 subject. No SAEs led to treatment discontinuation. One subject death was reported in the 
study. This subject completed 12 weeks of treatment with SOF/VEL and died in his sleep on 
post-treatment Day 8. The death was assessed as not related to study drug by the investigator. 
One subject (0.2%) in the SOF/VEL 12 Week group discontinued study treatment due to a 
Grade 3 AE of anxiety and 2 subjects (1.7%) in the Placebo 12 Week group discontinued study 
treatment due to meeting the prespecified stopping criteria of elevated ALT and/or AST levels 
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Most laboratory abnormalities were Grade 1 or 2 in severity. Subjects in the SOF/VEL 12 Week 
group had Grade 3 or 4 chemistry abnormalities of elevated AST (Grade 3; 1 subject [0.2%]), 
elevated creatine kinase (Grade 3; 2 subjects [0.3%], Grade 4; 2 subjects [0.3%]), hyperglycemia 
(Grade 3, 15 subjects [2.4%]), and elevated lipase (Grade 3; 14 subjects [2.2%], Grade 4, 
2 subjects [0.3%]). Among subjects in the SOF/VEL 12 Week, all Grade 3 or 4 creatinine kinase 
elevations were transient, all Grade 3 or 4 lipase elevations were asymptomatic and generally 
transient, and Grade 3 or 4 hyperglycemia occurred in subjects with a medical history of 
diabetes. The most frequently observed Grade 3 or 4 laboratory abnormalities observed in 
placebo treated subjects were elevated ALT (Grade 3; 6 subjects [5.2%] and Grade 4; 2 subjects 
[1.7%]) consistent with ongoing HCV infection.
No notable changes from baseline in vital signs (systolic blood pressure, diastolic blood pressure, 
or pulse) were observed during the study. No trends in ECG findings suggestive of cardiotoxicity 
were observed.
Conclusions 
The conclusions from this analysis were as follows:

The study met its primary efficacy endpoint demonstrating that the SVR12 rate of 99.0% 
(95% CI: 97.9% to 99.6%) in genotype 1, 2, 4, 5, and 6 HCV-infected subjects treated for 
12 weeks with SOF/VEL was statistically superior to the pre-specified SVR12 performance 
goal of 85% (p<0.001).

High SVR12 rates were achieved across all HCV genotypes and subgroups
Among subjects with cirrhosis, the SVR rate was 99.2%
Among subjects with prior treatment failure, the SVR rate was 99.5%
Among subjects with baseline NS5A RAVs, the SVR12 rate was 99.2%

Treatment with SOF/VEL for 12 weeks was generally well tolerated with a safety profile 
similar to that of placebo treatment. There was a low incidence of SAEs, discontinuations 
due to AEs and no clinically relevant laboratory abnormalities.
1.2.3.2.
Study GS-US-342-1139 (ASTRAL-2)
Study Design
This Phase 3, randomized, open-label, multicenter study evaluated the antiviral efficacy, safety, 
and tolerability of 12 weeks of SOF/VEL treatment compared with 12 weeks of SOF+RBV 
treatment in subjects with chronic genotype 2 HCV infection. The study was conducted in the 
United States (US).


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Subjects with genotype 2 HCV infection were randomized (1:1) to treatment with SOF/VEL for 
12 weeks (SOF/VEL 12 Week group) or SOF+RBV for 12 weeks (SOF+RBV 12 Week group). 
Randomization was stratified by the presence or absence of cirrhosis at screening and prior 
treatment experience (treatment naive vs. treatment experienced).
Disposition
A total of 266 subjects were randomized and treated; 132 in the SOF/VEL 12 Week group and 
134 in the SOF+RBV 12 Week group. The majority of subjects (99.2%) completed study 
treatment. Two subjects (0.8%), 1 in each treatment group, prematurely discontinued study 
treatment. One subject in the SOF/VEL 12 Week group discontinued study treatment on Day 1 
(after receiving 1 dose of study drug) due to AEs of disturbance in attention, headache, and 
anxiety. One subject in the SOF+RBV 12 Week group completed the Week 10 study visit, but 
did not return for any subsequent study visits and was assumed to be lost to follow-up; the last 
confirmed dosing date was Day 71.
Demographics and Baseline Characteristics
Overall, demographics and baseline disease characteristics were balanced across both treatment 
groups. The majority of subjects were male (59.4%), and 32.7% of subjects had a BMI 
30 kg/m2. A total of 38 subjects (14.3%) had cirrhosis at screening. Overall, the majority of 
subjects had HCV RNA 800,000 IU/mL (79.7%). Overall, 14.7% (39 subjects) were treatment 
experienced.
Efficacy Results
The SOF/VEL 12 Week group met the primary endpoint of an SVR12 rate that was non-inferior 
to the SVR12 rate in the SOF+RBV 12 Week group. The SVR12 rates were as follows:

SOF/VEL 12 Week group: 99.3% (95% CI: 95.9% to 100%) of subjects (133 of 134) 
achieved SVR12

SOF+RBV 12 Week group: 93.9% (95% CI: 88.4% to 97.3%) of subjects (124 of 132) 
achieved SVR12
The strata-adjusted difference (95% CI) in the proportions was 5.2% (0.2% to 10.3%). Since the 
lower bound of the 2-sided 95% CI for the difference between groups was greater than the pre-
specified non-inferiority margin of −10%, the efficacy of SOF/VEL for 12 weeks was 
demonstrated to be statistically non-inferior to SOF+RBV for 12 weeks. There was sufficient 
evidence to demonstrate the statistical superiority of treatment with SOF/VEL for 12 weeks over 
SOF+RBV for 12 weeks for SVR12 (p = 0.018; CMH test stratified by cirrhosis status and prior 
treatment experience).
In the SOF/VEL 12 Week group, 1 of 134 subjects (0.7%) did not achieve SVR12: the subject 
discontinued study treatment on Day 1 (after receiving 1 dose) due to AEs of difficulty 
concentrating, headache, and anxiety. The subject never achieved HCV RNA LLOQ. In the 


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SOF+RBV 12 Week group, 8 of 132 subjects (6.1%) did not achieve SVR12. Of these, 
6 subjects relapsed and 2 were lost to follow-up. Four relapses occurred by the post-treatment 
Week 4 visit and 2 relapses occurred between the post-treatment Week 4 and 12 visits. The low 
number of virologic failures in the study precluded meaningful subgroup analysis of SVR.
The SVR4 results were similar to the SVR12 results with the exception of 3 subjects in 
SOF+RBV 12 Week group: 1 subject was lost to follow-up after post-treatment Week 4 and 
2 subjects relapsed between the post-treatment Week 4 and Week 12 visits.
HCV RNA levels (log10 IU/mL) declined rapidly with similar decreases in HCV RNA observed 
in both treatment groups. After 1 week of treatment, the mean change from baseline in HCV 
RNA levels was 4.51 log10 IU/mL in both treatment groups. The decreases in HCV RNA were 
maintained from Weeks 2 through 12. Consistent with the rapid and sustained decline in 
HCV RNA, 90.2% of subjects in both treatment groups had HCV RNA LLOQ at Week 4.
There was a lack of correlation of time to suppression with virologic outcome in the SOF/VEL 
12 week group as all subjects who completed treatment achieved SVR regardless of the time to 
suppression.
Virologic Resistance
Deep sequencing analyses indicated that genotype 2a and 2b were the predominant HCV 
subtypes in subjects who were randomized and treated in this study. Approximately 60% and 
10% of subjects in the SOF/VEL 12 Week group had pretreatment NS5A and NS5B RAVs, 
respectively. The most prevalent NS5A RAV observed was L31M in 51% of subjects. Despite 
the presence of pretreatment NS5A and NS5B RAVs, no subjects in the SOF/VEL 12 Week 
group experienced virologic failure in this study. Two of the 6 subjects who relapsed in the 
SOF+RBV 12 Week group had low levels of the NS5B NI RAV L159F detectable at failure.
Safety Results
Overall, treatment with SOF/VEL or SOF+RBV for 12 weeks was generally safe and well 
tolerated. A smaller percentage of subjects in the SOF/VEL 12 Week group experienced any AE 
(68.7%, 92 of 134) compared with the SOF+RBV 12 Week group (76.5%, 101 of 132), 
including treatment-related AEs (SOF/VEL, 33.6%; SOF+RBV, 56.8%) and AEs leading to 
modification or interruption of any study drug (SOF/VEL, 0; SOF+RBV, 9.8%).
The most common AEs (ie, AEs reported in > 10% of subjects in either group) were reported by 
a smaller percentage of subjects in the SOF/VEL 12 Week group compared with the SOF+RBV 
12 Week group, including fatigue (14.9% vs. 35.6%), headache (17.9% vs. 22.0%), nausea 
(10.4% vs. 14.4%), and insomnia (4.5% vs. 13.6%). 
Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. Grade 3 (severe) AEs were 
rare (SOF/VEL, 2.2%; SOF+RBV, 2.3%). No Grade 4 (life-threatening) AEs were reported. 
Anxiety was the only Grade 3 AE reported in > 1 subject in the SOF/VEL 12 Week group (n = 2, 
1.5%).


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Serious adverse events (SAEs) were also rare (1.5%, 4 of 266 subjects [2 in each treatment 
group]). No SAE was reported in 1 subject. All SAEs were considered by the investigators to 
be not related to study drug. Two non-treatment-emergent deaths were reported during the study 
(metastatic lung cancer and cardiac arrest after treatment completion). No pregnancies were 
reported during the study. Only 1 subject permanently discontinued any study drug (SOF/VEL) 
due to AEs. After receiving 1 dose of SOF/VEL, the subject, who had a medical history of 
depression, insomnia and post-traumatic stress disorder, discontinued study treatment due to 
Grade 3 AEs of difficulty concentrating, headache, and anxiety that were assessed as related to 
study drugs by the investigator.
Most subjects had at least 1 laboratory abnormality reported, with the majority being Grade 1 
(104 of 266 subjects, 39.1%) or Grade 2 (70 of 266 subjects, 26.3%) in severity. A smaller 
percentage of subjects had Grade 3 laboratory abnormalities in the SOF/VEL 12 Week group 
(7.5%, 10 subjects) compared with the SOF+RBV 12 Week group (13.6%, 18 subjects). This 
difference was accounted for primarily by the expected decreases in hemoglobin observed with 
RBV therapy. No subjects in the SOF/VEL 12 Week group had a Grade 3 or 4 hematology 
laboratory abnormality. The only Grade 3 hematology laboratories abnormality in the SOF+RBV 
12 Week group were decreased hemoglobin (5.3%, 7 subjects) and increased lymphocytes 
(0.8%, 1 subject). The most common Grade 3 or 4 chemistry laboratory abnormalities in both 
treatment groups were increased serum glucose (hyperglycemia) and increased lipase. Grade 3 
increases in lipase were reported for 7 subjects (5.3%) in the SOF/VEL 12 Week group and 
2 subjects (1.5%) in the SOF+RBV 12 Week group. Grade 4 increases in lipase were reported for 
1 subject (0.8%) in each treatment group. All of the Grade 3 lipase elevations were transient and 
asymptomatic, with no cases of clinical pancreatitis. In the SOF/VEL 12 Week group, 1 subject 
each experienced a Grade 3 or 4 increase in creatine kinase following workout sessions. Grade 3 
hyperbilirubinemia was only observed in the SOF+RBV 12 Week group and was consistent with 
RBV-associated hemolysis. Grade 4 chemistry laboratory abnormalities were reported for lipase 
and creatine kinase.
No notable changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse) or 
ECGs were reported during the study.
Conclusions 
The conclusions from this analysis were as follows:

The study met its predefined primary efficacy endpoint, demonstrating that the SVR12 rate 
of 99.3% with SOF/VEL for 12 weeks was non-inferior to the SVR12 rates of 93.9% with 
SOF+RBV for 12 weeks.

Treatment with SOF/VEL for 12 weeks led to a statistically superior SVR12 rate compared 
with SOF+RBV for 12 weeks (p = 0.018). 


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
No subjects treated with SOF/VEL experienced virologic failure, including subjects with 
cirrhosis (14%), prior treatment failure (14%), and baseline NS5A RAVs (60%).

SOF/VEL was generally well tolerated and, compared with SOF+RBV, lacked toxicities 
associated with RBV. No treatment-emergent deaths, Grade 4 AEs, treatment-related SAEs, 
or clinically relevant laboratory abnormalities were observed.
1.2.3.3.
Study GS-US-342-1140 (ASTRAL-3)
Study Design
This Phase 3, randomized, open-label, multicenter study evaluated the antiviral efficacy, safety, 
and tolerability of 12 weeks of SOF/VEL treatment compared with 24 weeks of SOF+RBV 
treatment in subjects with chronic genotype 3 HCV infection.
Subjects with genotype 3 HCV infection were randomized (1:1) to treatment with SOF/VEL for 
12 weeks (SOF/VEL 12 Week group) or SOF+RBV for 24 weeks (SOF+RBV 24 Week group). 
Randomization was stratified by the presence or absence of cirrhosis at screening and prior 
treatment experience (treatment naive vs. treatment-experienced).
Disposition
A total of 552 subjects were randomized and treated (277 subjects in the SOF/VEL 12 Week 
group and 275 subjects in the SOF+RBV24 Week group). A total of 21 subjects (7.6%) in the 
SOF+RBV 24 Week group discontinued treatment compared with 2 subjects (0.7%) in the 
SOF/VEL 12 Week group. The most common reason for discontinuation of treatment for 
subjects in the SOF+RBV 24 Week group was AEs (9 subjects, 3.3%).
Demographics and Baseline Characteristics
The majority of subjects were male (62.3%), and 20.3% of subjects had a BMI ≥30 kg/m2. 
Overall, the majority of subjects had HCV RNA ≥800,000 IU/mL (69.7%). A total of 
163 subjects (29.5%) had cirrhosis at screening. Overall, 25.7% (142 subjects) were treatment 
experienced.
Efficacy Results
The study met the primary efficacy endpoint. The SVR12 rate for the SOF/VEL 12 Week group 
was statistically non-inferior to the SVR12 rate for the SOF+RBV 24 Week group. The SVR12 
rates were as follows:

SOF/VEL 12 Week group: 95.3% (95% CI: 92.1% to 97.5%) of subjects (264 of 277) 
achieved SVR12.

SOF+RBV 24 Week group: 80.4% (95% CI: 75.2% to 84.9%) of subjects (221 of 275) 
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The strata-adjusted difference (95% CI) in the proportions was 14.8% (9.6% to 20.0%). The 
superiority of treatment with SOF/VEL for 12 weeks over SOF+RBV for 24 weeks for SVR12 
was also demonstrated (p < 0.001; CMH test stratified by cirrhosis status and prior treatment 
experience).
In the SOF/VEL 12 Week group, 13 of 277 subjects (4.7%) did not achieve SVR12. Of these, 
no subjects had on-treatment virologic failure, 11 subjects relapsed, and 2 subjects were lost to 
follow-up. In the SOF+RBV 24 Week group, 54 of 275 subjects (19.6%) did not achieve SVR12. 
Of these, 1 subject had on-treatment virologic failure (nonresponse), 38 subjects relapsed, and 
15 subjects did not achieve SVR12 for reasons other than virologic failure. These 15 subjects 
included 6 subjects who were lost to follow-up or who did not attend a post-treatment Week 12 
visit, 4 subjects who withdrew from the study due to AEs, 2 subjects who withdrew consent from 
the study, 2 subjects who died, and 1 subject who only received 2 days of study drug, did not 
achieve HCV RNA < LLOQ on treatment, and did not meet the protocol definition for virologic 
failure.
Most relapses occurred by the post-treatment Week 4 visit. In the SOF/VEL 12 Week group, 8 of 
11 relapses occurred by post-treatment Week 4, and 3 of 11 relapses occurred between post-
treatment Weeks 4 and 12. 
Across the 2 treatment groups, the SVR12 rates consistently favored the SOF/VEL 12 Week 
group over the SOF+RBV 24 Week group. Within each treatment group, the SVR12 rates for 
most subgroups were generally consistent with those observed in the overall population. In the 
SOF/VEL 12 Week group, the SVR12 rates for subjects with and without cirrhosis were 91.3% 
(73 of 80) and 97.0% (191 of 197), respectively, and the SVR12 rates for treatment-naive and 
treatment-experienced subjects were 97.1% (200 of 206) and 90.1% (64 of 71), respectively. In 
the SOF+RBV 24 Week group, subjects with cirrhosis had considerably lower SVR12 rates 
(66.3%; 55 of 83) than subjects without cirrhosis (87.2%; 163 of 187), and subjects with prior 
treatment experience had considerably lower SVR12 rates (63.4%; 45 of 71) than 
treatment-naive subjects (86.3%; 176 of 204).
HCV RNA levels (log10 IU/mL) declined rapidly, with similar decreases in HCV RNA observed 
in both treatment groups. Consistent with the rapid and sustained decline in HCV RNA, 91.7% 
of subjects in the SOF/VEL 12 Week group and 88.2% of subjects in the SOF+RBV 24 Week 
group had HCV RNA < LLOQ at Week 4. Time to virologic suppression did not impact 
virologic outcomes in the SOV/VEL 12 Week group: SVR12 rates were 96.0% and 95.7% 
among those subjects with HCV RNA < LLOQ and those with HCV RNA ≥LLOQ at Week 4, 
respectively.
Virologic Resistance
Pretreatment NS5A and NS5B NI RAVs were present in 16% and 4% of subjects, respectively, 
in the SOF/VEL 12 Week group. There was a numerically lower SVR12 rate in 
SOF/VEL-treated subjects with baseline NS5A RAVs compared with subjects without NS5A 
RAVs (88% vs. 97%, respectively). All subjects with NS5B NI RAVs in the SOF/VEL 12 Week 
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A total of 10 subjects in the SOF/VEL 12 Week group relapsed, and 1 subject was re-infected. 
All 10 subjects had the NS5A RAV Y93H detected at relapse time points. No SOF/VEL-treated 
subjects had NS5B NI RAVs emerge at relapse. The NS5B NI RAVs (N142T, L159F, or 
V321A) emerged in 7 of 39 subjects in the SOF+RBV 24 Week group who had virologic failure.
Safety Results
Overall, treatment with SOF/VEL for 12 weeks or SOF+RBV for 24 weeks was generally safe 
and well tolerated. A lower percentage of subjects in the SOF/VEL 12 Week group experienced 
any AE (88.4%; 245 of 277) compared with the SOF+RBV 24 Week group (94.5%; 260 of 275). 
Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. Grade 3 (severe) AEs were 
reported for 4.3% (12 subjects) in the SOF/VEL 12 Week group and 7.3% (20 subjects) in the 
SOF+RBV 24 Week group. Grade 4 (life-threatening) AEs were reported for no subjects in the 
SOF/VEL 12 Week group and 1.1% (3 subjects) in the SOF+RBV 24 Week group (death due to 
natural causes in 1 subject, cerebrovascular accident in 1 subject, and multiple gunshot wounds 
in 1 subject).
Of the most common AEs (ie, AEs reported in ≥10% of subjects in either treatment group), a 
lower percentage of subjects in the SOF/VEL 12 Week group compared with the SOF+RBV 
24 Week group experienced fatigue (25.6% vs. 38.2%), insomnia (11.2% vs. 26.9%), nausea 
(16.6% vs. 21.1%), irritability (8.3% vs. 14.5%), cough (5.1% vs. 12.7%), pruritus (2.9% vs.
12.7%), and dyspepsia (3.2% vs. 10.9%).
Serious adverse events were reported for 2.2% (6 subjects) in the SOF/VEL 12 Week group and 
5.5% (15 subjects) in the SOF+RBV 24 Week group. No SAE was reported in > 1 subject, and 
no SOV/VEL-treated subject had a treatment-related SAE. Three subject deaths were reported 
during the study (1 treatment-emergent death due to natural causes, 1 treatment-emergent death 
due to multiple gunshot wounds, and 1 non treatment-emergent death due to an unknown cause); 
all 3 subjects were in the SOF+RBV 24 Week group. A total of 9 subjects (in the SOF+RBV 
24 Week group) prematurely discontinued study drugs due to an AE. The most common AE 
resulting in discontinuation of study drug in the SOF+RBV 24 Week group was insomnia (1.1%, 
3 subjects).
Most subjects had at least 1 laboratory abnormality reported, with the majority being Grade 1 
(36.3%; 200 of 551 subjects) or Grade 2 (29.6%; 163 of 551 subjects) in severity. A lower 
percentage of subjects had Grade 3 laboratory abnormalities in the SOF/VEL 12 Week group 
(5.8%, 16 of 276) compared with the SOF+RBV 24 Week group (14.2%, 39 of 275). This 
difference was accounted for primarily by the expected decreases in hemoglobin observed during 
treatment with RBV. Grade 4 laboratory abnormalities were similarly low in the SOF/VEL 
12 Week group (1.4%, 4 of 276) compared with the SOF+RBV 24 Week group (2.9%, 8 of 275).
The only Grade 3 or 4 hematology laboratory abnormality in the SOF/VEL 12 Week group 
occurring in more than 1 subject was decreased lymphocytes (1.1%, 3 of 276 subjects). 
One subject had normal lymphocytes throughout treatment and a Grade 3 decrease at the 


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post-treatment Week 4 visit. The other 2 subjects had Grade 2 or 3 decreased lymphocytes at 
baseline that transiently decreased by 1 grade during treatment.
The most common Grade 3 or 4 chemistry laboratory abnormalities in both treatment groups 
were increased lipase, increased serum glucose (hyperglycemia), and increased creatine kinase. 
Grade 3 or 4 increases in lipase were reported for 9 subjects (3.3%) in the SOF/VEL 12 Week 
group and 5 subjects (1.8%) in the SOF+RBV 24 Week group. All of the Grade 3 or 4 increases 
in lipase were asymptomatic, with no cases of clinical pancreatitis. Grade 3 increases in serum 
glucose (hyperglycemia) were reported for 4 subjects (1.4%) in the SOF/VEL 12 Week group 
and 5 subjects (1.8%) in the SOF+RBV 24 Week group. All subjects with Grade 3 increased 
serum glucose had either a medical history of diabetes or HbA1c ≥6.0% at screening. Grade 3 
or 4 increases in creatine kinase were reported for 2 subjects (0.7%) in the SOF/VEL 12 Week 
group and 4 subjects (1.5%) in the SOF+RBV 24 Week group. All of the Grade 3 or 4 creatine 
kinase elevations were transient and asymptomatic; the majority were associated with exercise. 
Grade 3 or 4 increases in total bilirubin (hyperbilirubinemia) were observed only in the 
SOF+RBV 24 Week group (Grade 3: 2 subjects, 0.7%; Grade 4: 1 subject, 0.4%). The timing 
and magnitude of the increases in total bilirubin were consistent with RBV-induced hemolysis.
No notable changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse) 
were reported during the study.
Conclusions 
The conclusions from this analysis were as follows:

The study met its predefined primary efficacy endpoint: subjects with genotype 3 HCV 
infection in the SOF/VEL 12 Week group achieved an SVR12 rate of 95.3% that was 
statistically non-inferior to the SVR12 rate of 80.4% achieved by subjects with genotype 3 
HCV infection in the SOF+RBV 24 Week group.
The superiority of treatment with SOF/VEL for 12 weeks over SOF+RBV for 24 weeks 
for SVR12 was also demonstrated (p < 0.001).

Across the 2 treatment groups, the SVR12 rates consistently favored the SOF/VEL 12 Week 
group over the SOF+RBV 24 Week group. 
For subjects with cirrhosis, the SVR12 rates (SOF/VEL 12 Weeks vs. SOF+RBV 
24 Weeks) were 91.3% and 66.3%, respectively.
For treatment-experienced subjects, the SVR12 rates (SOF/VEL 12 Weeks vs.
SOF+RBV 24 Weeks) were 90.1% and 63.4%, respectively.


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
Among the 16% of SOF/VEL-treated subjects with baseline NS5A RAVs, the SVR12 rate 
was numerically lower (88%) compared with subjects without baseline NS5A RAVs (SVR12 
rate of 97%).

SOF/VEL was generally well tolerated and, compared with SOF+RBV, lacked toxicities 
associated with RBV. No treatment-emergent deaths, Grade 4 AEs, treatment-related SAEs, 
discontinuations due to AEs, or clinically relevant laboratory abnormalities were observed in 
SOF/VEL-treated subjects.
1.2.3.4.
Study GS-US-342-1137 (ASTRAL-4)
Study Design
This  Phase 3, randomized, open-label, multicenter study evaluated the antiviral efficacy, safety, 
and tolerability of SOF/VEL±RBV for 12 weeks and SOF/VEL for 24 weeks in subjects with 
chronic HCV infection and Child-Pugh-Turcotte (CPT) class B cirrhosis. The study was 
conducted in the US.
Subjects with genotype 1 to 6 HCV infection with CPT class B cirrhosis were randomized 
(1:1:1) to SOF/VEL for 12 weeks (SOF/VEL 12 Week group), SOF/VEL+RBV for 12 weeks 
(SOF/VEL+RBV 12 Week group), or SOF/VEL for 24 weeks (SOF/VEL 24 Week group). 
Randomization was stratified by HCV genotype (1, 2, 3, 4, 5, 6, and indeterminate).
Disposition
A total of 267 subjects were included in the Safety and Full Analysis Sets (90 subjects in the 
SOF/VEL 12 Week group, 87 subjects in the SOF/VEL+RBV 12 Week group, and 90 subjects in 
the SOF/VEL 24 Week group).
Of the 90 subjects in the SOF/VEL 12 Week group, 89 subjects (98.9%) completed study drug 
and 1 subject (1.1%) discontinued due to an AE.
Of the 87 subjects in the SOF/VEL+RBV 12 Week group, 82 subjects (94.3%) completed study 
drug; 4 subjects (4.6%) discontinued due to AEs and 1 subject (1.1%) discontinued due to 
virologic failure (pharmacokinetic [PK] data for this subject indicated noncompliance with study 
drugs).
Of the 90 subjects in the SOF/VEL 24 Week group, 84 subjects (93.3%) completed study drug; 
4 subjects (4.4%) discontinued due to AEs, 1 subject (1.1%) discontinued due to virologic 
failure, and 1 subject (1.1%) discontinued due to noncompliance with study drug.
Demographics and Baseline Characteristics
Overall, demographics and baseline disease characteristics were balanced across the treatment 
groups. Of the 267 subjects randomized and treated, 207 subjects (77.5%) had genotype 1 HCV 
infection, 12 subjects (4.5%) had genotype 2 HCV infection, 39 subjects (14.6%) had genotype 3 


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HCV infection, 8 subjects (3.0%) had genotype 4 HCV infection, and 1 subject (0.4%) in the 
SOF/VEL 24 Week group had genotype 6 HCV infection. The majority of subjects were male 
(69.7%), and 42.3% of subjects had a BMI 30 kg/m2. Most subjects (55.1%) had prior 
treatment experience and the majority of subjects had HCV RNA ≥800,000 IU/mL (55.8%).
Efficacy Results
The SVR12 rates were as follows:

SOF/VEL 12 Week group: 83.3% (95% CI: 74.0% to 90.4%) of subjects (75 of 90) achieved 
SVR12

SOF/VEL+RBV 12 Week group: 94.3% (95% CI: 87.1% to 98.1%) of subjects (82 of 87) 
achieved SVR12

SOF/VEL 24 Week group: 85.6% (95% CI: 76.6% to 92.1%) of subjects (77 of 90) achieved 
SVR12
All 3 treatment groups met their primary efficacy endpoints with SVR12 rates that were
statistically superior compared with the assumed spontaneous rate of 1%. The p-value 
was < 0.001 for the comparison with the SVR12 for each treatment group. 
Among subjects with genotype 1 HCV infection, the SVR12 rate was higher for those in the 
SOF/VEL+RBV 12 Week group (95.6%, 65 of 68) compared with the SOF/VEL 12 Week group 
(88.2%, 60 of 68) or the SOF/VEL 24 Week group (91.5%, 65 of 71). Similarly, among subjects 
with genotype 3 HCV infection, the SVR12 rate was higher for those in the SOF/VEL+RBV 
12 Week group (84.6%, 11 of 13) compared with the SOF/VEL 12 Week group (50.0%, 7 of 14) 
or the SOF/VEL 24 Week group (50.0%, 6 of 12).
All subjects with genotype 2, 4, or 6 HCV infection achieved SVR12 across all treatment groups 
with the exception of 1 subject with genotype 2 HCV infection in the SOF/VEL 24 Week group 
who died 39 days after completing 28 days of treatment.
Most virologic failures were due to relapse. One subject with genotype 3 HCV infection in the 
SOF/VEL+RBV 12 Week group had on-treatment breakthrough with PK data showing 
undetectable plasma drug levels consistent with non-adherence to study drug and 1 subject with 
genotype 3 HCV infection in the SOF/VEL 24 Week group had on-treatment breakthrough.
There was 1 subject (1.5%) with genotype 1 HCV infection with virologic failure in the 
SOF/VEL+RBV 12 Week group compared with 5 subjects (7.4%) in the SOF/VEL 12 Week 
group and 3 subjects (4.2%) in the SOF/VEL 24 Week group. Among subjects with genotype 3 
HCV infection, the lowest rate of virologic failure was observed in the SOF/VEL+RBV 12 Week 
group with 2 failures (15.4%) compared with 6 (42.9%) in the SOF/VEL 12 Week group and 
5 (41.7%) in the SOF/VEL 24 Week group. 


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There were no virologic failures in subjects with genotype 2, 4, or 6 HCV infection in any of the 
treatment groups.
Treatment with SOF/VEL+RBV for 12 weeks resulted in high SVR12 rates irrespective of 
genotype, prior treatment history, baseline HCV RNA, and presence of pretreatment NS5A or 
NS5B RAVs. Furthermore, there was no impact of demographic factors such as age, sex, BMI, 
or IL28B genotype on treatment outcome in the SOF/VEL+RBV 12 Week group.
Overall, 108 subjects (47.2%) had an improvement in CPT score (range: 1−5 points) while 
99 subjects (43.2%) had no change. A minority of subjects (9.6%, 22 subjects) experienced an 
increase (worsening) in CPT score from baseline to post-treatment Week 12. A higher 
percentage of subjects receiving SOF/VEL for 24 weeks (54.7%) compared with subjects 
receiving SOF/VEL±RBV for 12 weeks (40.7%−46.6%) had improvements in CPT score from 
baseline to post-treatment Week 12; this difference likely reflects the longer time of observation 
with HCV RNA suppression. The improvements in CPT score were largely due to improvements 
in bilirubin and albumin. 
Overall, the majority of subjects who achieved SVR12 also had a decrease (improvement) 
(55.5%, 127 of 229 subjects) in MELD score between baseline and post-treatment Week 12 
(range: 1−11 points). Among subjects who had MELD score < 15 at baseline and achieved 
SVR12, 197 of 203 subjects (97.0%) remained < 15 at post-treatment Week 12. A total of 
16 subjects (61.5%) with baseline MELD score ≥15 who achieved SVR12 improved to < 15. 
Improvements in MELD score were largely due to improvements in total bilirubin.
Virologic Resistance
Pretreatment NS5A RAVs were observed in 26% to 29% of subjects across the treatment groups. 
The presence of pretreatment NS5A RAVs did not impact treatment outcome in the 
SOF/VEL+RBV 12 Week group. Slightly lower SVR rates were observed in subjects with 
genotype 1 HCV infection with NS5A RAVs treated with SOF/VEL for 12 or 24 weeks 
compared to subjects without pretreatment NS5A RAVs. No virologic failures were observed in 
subjects with genotype 2, 4, or 6 HCV infection. The small numbers of subjects with genotype 3 
HCV infection with pretreatment NS5A RAVs precluded meaningful subgroup analysis. The 
presence of pretreatment NS5B RAVs did not impact treatment outcome in any treatment group.
The majority of subjects had NS5A RAVs present at virologic failure with Y93H being the most 
common variant. NS5B NI RAVs were less common and typically observed at low levels. Of the 
9 subjects with genotype 1 HCV infection with virologic failure, 6 had NS5A RAVs at failure 
(5 treatment emergent and 1 maintained from pretreatment). Two genotype 1 HCV-infected 
subjects had L159F and S282T NS5B NI RAVs present at failure; both of these subjects had 
multiple NS5A RAVs at pretreatment that reduce susceptibility to VEL. All 13 subjects with 
genotype 3 HCV infection with virologic failure had Y93H at failure (10 were treatment 
emergent). Three genotype 3 HCV-infected subjects had low levels of NS5B NI RAVs emerge at 
virologic failure.


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Safety Results
Overall, treatment with SOF/VEL±RBV for 12 weeks or SOF/VEL for 24 weeks was generally 
safe and well tolerated. Adverse events were consistent with the expected clinical sequelae in the 
setting of decompensated cirrhosis and, in addition, with the known toxicities of RBV in the 
SOF/VEL+RBV 12 Week group.
A smaller percentage of subjects in the SOF/VEL 12 Week and SOF/VEL 24 Week groups 
experienced any AE (81.1% in each group) compared with the SOF/VEL+RBV 12 Week group 
(90.8%). The higher frequency of AEs observed in the SOF/VEL+RBV 12 Week group was 
primarily due to AEs consistent with RBV-associated toxicity. No treatment-related Grade 3 AEs 
were reported in > 1 subject in any group or overall. 
Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. Overall, the most commonly 
reported Grade 3 or 4 AEs were hepatic encephalopathy and sepsis (5 subjects each), which are 
consistent with the natural history of disease progression in a population with decompensated 
liver disease. 
Serious adverse events (SAEs) occurred in 17.6% of subjects in similar proportions across 
treatment groups, and only 1 subject (0.4%) experienced SAEs considered related to SOF/VEL. 
The most commonly reported SAEs were hepatic encephalopathy and sepsis (5 subjects each). 
Nine deaths occurred during the study, 2 of which were treatment emergent, and none of which 
was assessed as related to study drugs. One subject in the SOF/VEL 24 Week group underwent a 
liver transplantation on post-treatment Day 8 after completing 35 days of treatment.
Nine subjects discontinued all study drugs due to an AE (SOF/VEL 12 Week group: 1.1%, 
1 subject; SOF/VEL+RBV 12 Week group: 4.6%, 4 subjects; SOF/VEL 24 Week group: 4.4%, 
4 subjects). No AE leading to discontinuation of study drugs was reported in > 1 subject. A total 
of 31.0% (27 of 87) of subjects had modified or interrupted RBV dosing due to AEs, and 10.3% 
(9 of 87) of subjects permanently discontinued RBV due to AEs while continuing SOF/VEL.
The majority of subjects had at least 1 Grade 3 or 4 laboratory abnormality (42.7% and 12.4%, 
respectively) with the highest rates observed in the SOF/VEL+RBV group (Grade 3: 43.7%; 
Grade 4 18.4%) due to a higher rate of hematologic abnormalities. The most commonly observed 
Grade 3 or 4 hematology laboratory abnormalities were decreased lymphocytes, hemoglobin, 
and platelet counts, all of which are a known effect of RBV therapy or expected in a subject 
population with decompensated liver disease. 
The most commonly observed Grade 3 or 4 chemistry laboratory abnormalities were increased 
glucose and increased total bilirubin. All of the Grade 3 or 4 increased glucose abnormalities 
occurred in subjects with a history of diabetes mellitus or had elevated glucose at baseline or 
continuing through the post-treatment period. The majority of subjects with Grade 3 or 4, 
increased total bilirubin (71.7%, 22 of 31 subjects) were in the SOF/VEL+RBV 12 Week group, 
primarily in a pattern that was consistent with RBV-induced hemolysis. 


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No notable changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse) 
were reported during the study. No trends in electrocardiogram findings suggestive of 
cardio-toxicity were observed.
Conclusions 
The conclusions from this analysis were as follows:

Treatment with SOF/VEL±RBV for 12 or 24 weeks in subjects with decompensated cirrhosis 
resulted in high SVR12 rates:
In the SOF/VEL 12 Week group, the SVR12 rate was 83.3% (75 of 90 subjects).
In the SOF/VEL+RBV 12 Week group, the SVR12 rate was 94.3% (82 of 87 subjects).
In the SOF/VEL 24 Week group, the SVR12 rate was 87.8% (79 of 90 subjects).

The SVR12 rates were highest in subjects treated with SOF/VEL+RBV for 12 weeks with 
few virologic failures:
In subjects with genotype 1 HCV infection, the virologic failure rate was 1.5% (1 of 
68 subjects).
In subjects with genotype 3 HCV infection, the virologic failure rate was 15.4% (2 of 
13 subjects), of which 1 subject had on-treatment breakthrough with PK data showing 
undetectable plasma drug levels consistent with non-adherence to study drug.

Overall, there were no virologic failures in subjects with genotype 2, 4, or 6 HCV infection.

The SVR12 rates between the SOF/VEL 12- and 24-week treatment durations were similar 
across all genotypes.

The presence of pretreatment NS5A and NS5B RAVs did not impact treatment outcome with 
SOF/VEL+RBV for 12 weeks.

Approximately half of subjects who achieved SVR12 experienced an early improvement in 
CPT and MELD scores, primarily related to improvements in synthetic function (albumin) 
and decreases in bilirubin.

SOF/VEL was generally well tolerated in these subjects with decompensated liver disease, as 
evidenced by low rates of study treatment discontinuation and the majority of Grade 3 and 4 
AEs, SAEs, and laboratory abnormalities being consistent with clinical sequelae of advanced 
liver disease and RBV toxicity.
1.3.
Rationale for Dose Selection
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without Peg-IFN
has demonstrated broad genotypic efficacy and favorable safety profile in over


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1700 HCV-infected subjects across multiple patient populations in Phase 2 and 3 trials. This 
dose is the approved marketed dose of sofosbuvir for the treatment of HCV-infection and as 
such, was selected for co-formulation with VEL into a fixed-dose combination tablet.
VEL 100 mg was administered in combination with SOF 400 mg for 12 weeks to 
237 HCV-infected subjects in Phase 2 studies. VEL 100 mg was selected for co-formulation with 
SOF based on the Phase 2 safety, PK and antiviral activity (studies GS-US-342-0102, GS-US-
342-0109, and GS-US-337-0122 [Cohort 4]). The Phase 1 study GS-US-281-0102 established 
the anti-HCV activity of VEL and indicated that the exposures achieved following administration 
of doses > 25 mg provide at least 80% of maximal antiviral response in all HCV genotypes. 
SOF/VEL (400 mg /100 mg) FDC tablet was evaluated in the phase 3 ASTRAL program. The 
favorable safety and efficacy profiles of SOF/VEL (400 mg/100 mg) in the ASTRAL studies 
support evaluation of this combination in India. 
1.4.
Rationale for This Study
This Phase 3 study has been designed as a multicenter, open-label, non-randomized study 
evaluating SOF/VEL for 12 weeks. Approximately 125 subjects will be enrolled. The population 
of the study will be subjects with chronic HCV infection of any genotype, with up to 
approximately 20% having prior treatment failure with an interferon-based regimen and up to 
approximately 20% having evidence of compensated cirrhosis at screening.
The ASTRAL phase 3 studies demonstrated that the simple treatment regimen of SOF/VEL for 
12 weeks is well tolerated and results in SVR12 rates of ≥95% across all HCV genotypes, 
including patients with compensated cirrhosis. These results support that SOF/VEL provides a 
significant advance for the treatment of HCV infection, particularly in countries with diverse 
genotype distribution, high prevalence of HCV genotype 3, extensive rural populations, and 
resource limited settings. 
In India with a population of approximately 1.21 billion (2011 census), the burden of disease due 
to HCV is substantial. The prevalence of HCV is estimated to be between 0.5 and 1.5%  {Puri et 
al 2014}, and that 12 to 24 million people are infected with chronic HCV, with less than 0.1% of 
those infected are being treated {Sievert et al 2011}, {Saravanan et al 2008}, {Datta 2008}, 
{Chowdhury et al 2003},{Puri et al 2012}. HCV genotype diversity is high in India: genotype 3 is 
most common, representing approximately 60% of cases, while approximately 30% of cases are 
genotype 1, genotypes 4 and 6 are found in some geographic areas, and genotype 5 is also 
occasionally found {Gower et al 2014, Puri et al 2014}. A single pangenotypic regimen would 
be of benefit for this diverse HCV population. 
Therapies which are not administered by injection nor associated with IFN-related or 
RBV-related adverse events are likely to improve patient treatment adherence and support high 
rates of viral cure. For example, hemoglobinopathies, including thalassemia, are the most 
common hereditary disorders in India {Mohanty et al 2013} and, as a result of blood 
transfusions, the prevalence of HCV in patients with thalassemia has been reported to range from 
2% to 62% {Puri et al 2014}. The availability of a ribavirin-free treatment for these patients 


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would be of great benefit. It is also likely that agents with favorable safety profiles which do not 
require frequent dose modification nor intensive monitoring of clinical adverse events and 
laboratory abnormalities will facilitate patient management. In India, patients’ ability to return 
for frequent visits to specialized health centres and clinicians for HCV treatment may be limited 
by their distance from such centres as approximately 69% of the population lives in rural areas
(2011 census). 
Data from this study will support the development of a well-tolerated, short duration, RBV-free 
regimen for all genotypes of HCV infection that has the potential to make an impact on the 
global prevalence and burden of HCV infection.
In particular, the availability of a single, pangenotypic regimen is anticipated to be especially 
beneficial in India where genotype diversity is high and genotyping may not be readily available 
or routinely done. Access to treatment for patients with HCV infection would be expanded as a 
result.  
1.5.
Risk/Benefit Assessment for the Study
This study will provide information of the safety and efficacy of SOF/VEL, a potent HCV 
nucleotide inhibitor and a potent HCV NS5A inhibitor. This combination has the potential to be 
a once-daily pangenotypic regimen for the treatment of chronic HCV infection. 
The potential benefits of SOF/VEL for the treatment of chronic HCV are:

A once-daily, single tablet, single duration, pangenotypic therapy for HCV infection could 
simplify treatment algorithms and impact worldwide disease prevalence

A reduction in the AEs currently associated with the use of Peg-IFN and RBV

A short duration of therapy which should lead to better outcomes through improved 
adherence
The safety profile of SOF in clinical studies includes over 1700 chronic HCV-infected subjects 
that have been administered 12 weeks of SOF and RBV+/-Peg-IFN.  No safety issues 
specifically related to SOF in clinical studies have been identified to date. 
The safety profile of SOF/VEL administered for 12 weeks has been established in over 
1000 subjects in Phase 3 studies. No clinical safety issues specifically related to VEL or SOF + 
VEL or SOF/VEL have been identified to date. No clinical safety issues specifically related to 
the NS5A inhibitor class including daclatasvir (DCV) and LDV have been identified to date 
{Afdhal et al 2014b}, {Afdhal et al 2014a}, {Kowdley et al 2014}.
During the conduct of the study, the sponsor will perform ongoing safety review.
In summary, if high rates of SVR can be obtained with a short, IFN-free, RBV-free, 
pangenotypic regimen, the anticipated improvements in safety and tolerability would offer a 


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favourable risk-benefit determination for patients with chronic HCV infection and enhance 
access to treatment.
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 efficacy of treatment with SOF/VEL FDC for 12 weeks in subjects with 
chronic HCV infection 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 FDC for 12 weeks


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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is a multicenter, open-label study that will evaluate the safety, tolerability and antiviral 
efficacy of SOF/VEL FDC for 12 weeks in subjects with chronic HCV infection. Subjects with 
or without cirrhosis will be enrolled. 
Approximately 20% of subjects may be treatment experienced and up to 20% of subjects may 
have compensated cirrhosis at baseline. Approximately 125 subjects with chronic HCV infection 
will be enrolled in the study and all subjects will receive SOF/VEL FDC once daily for 
12 weeks.
3.2.
Visit Schedule
All subjects will complete screening, on-treatment, and post-treatment assessments. 
Screening assessments will be completed within 28 days of the Baseline/Day 1 visit. The 
screening window can be extended to 42 days in extenuating circumstances. 
All subjects will complete the following study visits: Screening, Baseline/Day 1, and Week 12
(end of treatment). In addition, subjects will return at Weeks 4 and 8 for the drug dispensing 
visit. Following the last dose of study drug, all subjects will also complete post-treatment 
Week 4 and 12 visits, including those subjects who terminate the study drug treatment early. 
Viral breakthrough or relapse must be confirmed.  
The assessments performed at each visit are described in Section 6 and shown in Appendix 2
3.3.
HCV Virologic Response-Based Treatment Stopping Criteria
If patient has unscheduled HCV RNA test during treatment period that is positive (Provided 
study drug adherence), treatment may be discontinued at the investigator's discretion if the test 
result is confirmed on repeat testing.
Confirmation should be performed as soon as possible and must occur no later than 2 weeks after 
an initial observation indicating virologic failure. 
3.4.
Treatment Discontinuation Criteria
When medically feasible, the Medical Monitor must be consulted prior to subject 
discontinuation. 
Study drug must be discontinued in the following instances:

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


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
Pregnancy of female subject

Efficacy failure 

Significant protocol violation

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

Discontinuation of the study at the request of Gilead, regulatory agency, or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)
If a subject meets discontinuation criteria during treatment, an ET visit will be required 
(Section 6.4). Early Termination visits should be scheduled as soon as possible following 
discontinuation of treatment. All subjects will complete the post-treatment Week 4 and 12 visits. 
3.5
Discontinuations
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an ET visit (see Section 6.4).  All subjects who terminate treatment early will complete 
the ET visit and post-treatment Week 4 and Week 12 visits.
3.6.
Archive Samples
Patients will provide archive samples at the Baseline/Day 1, Week 12 or ET visit and Post-
treatment Week 12 visit. These samples may be used during the course of this study for 
additional assessments to facilitate evaluation of the study objectives. Consequently, these 
archive samples may be used before study completion to test the amount of HCV in the blood, 
determine HCV viral sequencing/resistance data, pharmacokinetic concentration data, additional 
clinical safety laboratory data, or host or virus parameters that have been associated with efficacy 
in HCV treatment such as IL28B status.  
 
 
 
 
 
 
 
 
PPD


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PPD


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 125 chronic HCV subjects will be enrolled in this study with up to approximately 
20% of subjects may have compensated cirrhosis at baseline and approximately 20% may be 
treatment-experienced.
In order to manage the total study enrollment, Gilead Sciences, Inc., at its sole discretion, may 
suspend screening and/or enrollment at any site or study-wide at any time.
4.2.
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) HCV RNA detected at Screening
4) Chronic HCV infection (≥ 6 months) documented by medical history or liver biopsy
5) Classification as treatment naïve or treatment experienced. Approximately 20% may be 
treatment-experienced.
a) Treatment naïve is defined as having never been exposed to approved or experimental 
HCV-specific direct-acting antiviral agents or prior treatment of HCV with interferon or 
ribavirin
b) Treatment experienced is defined as prior treatment failure to a regimen containing 
interferon either with or without RBV that was completed at least 8 weeks prior to Day 1. 
6) Cirrhosis determination (approximately 20% may have cirrhosis)
a) Cirrhosis is defined as any one of the following:
i)
Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥5)
ii) Fibroscan® with a result of >12.5 kPa 
iii) Results of laboratory tests for cirrhosis during screening including
(1) FibroTest® score > 0.75 


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(2) AST:platelet ratio index (APRI) > 2 during Screening
(3) FIB-4 > 5.88 
(4) Result of another  serum laboratory test used to determine cirrhosis that meets the  
standard accepted criterion to define cirrhosis 
iv) Abdominal ultrasound or radiographic imaging demonstrating the features consistent 
with cirrhosis
b)
Absence of cirrhosis is defined as any one of the following:
i)
A liver biopsy performed within 2 years of Day 1 showing absence of cirrhosis
ii) Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Day 1
iii) Results of laboratory tests for cirrhosis during screening including
(1) FibroTest score ≤ 0.48 
(2) APRI ≤ 1
(3) FIB-4  ≤1.21
(4) Result of another  serum laboratory test used to determine cirrhosis that meets the  
standard accepted criterion of no cirrhosis
iv) Abdominal ultrasound or radiographic imaging within ≤ 6 months of Day 1 
demonstrating features consistent with absence of cirrhosis
If any of test results are conflicting or indeterminate, any test that indicates the patient has 
cirrhosis will be considered as definitive. If all results are indeterminate, transient 
elastography or liver biopsy will be required.
7) Females of childbearing potential (as defined in Appendix 4) must have a negative urine
pregnancy test at Screening and on Day 1 prior to enrollment.
8) 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 
(as defined in Appendix 4).
9) Lactating females must agree to discontinue nursing before the study drug is administered
10) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments


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4.3.
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) or any other major medical disorder that 
may interfere with subject treatment, assessment or compliance with the protocol
b) Clinical hepatic decompensation (ie, ascites, encephalopathy or variceal hemorrhage)
c) Liver transplantation
d) HCC (as determined by appropriate imaging at screening for those with cirrhosis) or 
current malignancy for which the patient is receiving treatment or which may interfere 
with subject treatment, assessment or compliance with the protocol.
2) Any of the following laboratory parameters at screening: 
a) ALT > 10 the upper limit of normal  (ULN)
b) AST > 10 ULN
c) Platelets < 30,000/L
d) Creatinine clearance (CLcr) < 30 mL /min as calculated by the Cockcroft-Gault equation 
{Cockcroft et al 1976}
e) Hemoglobin < 8 g/dL
3) Prior exposure to HCV NS5A inhibitor
4) Pregnant female 
5) Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, alfa-1 
antitrypsin deficiency, cholangitis)
6) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
7) Active alcohol or drug abuse that would interfere with study participation. 
8) Use of any prohibited concomitant medications as described in Section 5.3.
9) Known hypersensitivity to VEL, SOF, or formulation excipients


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment and Study Drug supply
An Interactive Web Response System (IWRS) will be employed to manage subject enrollment, 
and study drug dispensing and re-supply. Eligible subjects will be enrolled and assigned to the 
open-label treatment. Every subject will receive SOF/VEL tablet for 12 weeks.
5.2.
Description and Handling of SOF/VEL FDC
5.2.1.
Formulation
The SOF/VEL (400 mg/100 mg) tablets are pink, diamond-shaped, film-coated tablets, debossed 
with “GSI” on one side and “7916” on the other side. In addition to the active ingredients, the 
SOF/VEL 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 (400 mg/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 screw cap with an induction-sealed, 
aluminum-faced liner.
SOF/VEL bottles to be distributed to centers in participating countries shall be labeled to meet 
all applicable requirements of the United States Food and Drug Administration (FDA), EU 
Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products),
and/or other local regulations.
5.2.3.
Storage and Handling
SOF/VEL 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 tablets.
Sufficient quantities of SOF/VEL to complete the entire study will be shipped to the investigator 
or qualified designee from the Gilead Supply Management Team (or its designee).


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5.2.4.
Dosage and Administration of SOF/VEL FDC
SOF/VEL tablet is to be administered once daily for 12 weeks with or without food. Each subject 
must be given instructions to maintain approximately the same daily dosing interval between 
study drug doses.
For missed dose(s) of study medication, subjects should be instructed to take the missed dose of 
study medication 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.
5.3.
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 need to be recorded in the source documents and eCRFs.
The following medications are prohibited from 28 days prior to the Day 1 visit through the end 
of treatment:

Investigational agents or devices for any indication
Concomitant use of certain medications or herbal/natural supplements (such as substrates, 
inhibitors or inducers of drug transporters or metabolizing enzymes, eg, P-gp 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 
Baseline/Day 1 through the end of treatment.


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Table 5-1.
List of Disallowed /Use with Caution Medications
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton-Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsb
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Antimycobacterialsb
Rifabutin, Rifapentine, Rifampin
Cardiac Medicationsc
Amiodaroned
Diltiazem, Verapamil, Dronedarone, 
Quinidine, Ranolazine, Bosentan, 
Olmesartan, Valsartan, Digoxine
Herbal/Natural 
Supplementsb
St. John’s Wort, Echinacea. Milk thistle 
(ie, silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsf
Rosuvastatin (≤10 mg/day)
Other
Modafinil b, Sulfasalazinec, Methotrexatec
a
Proton pump inhibitor (PPI) doses comparable with omeprazole 20 mg can be administered with SOF/VEL when SOF/VEL 
is administered with food.. 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 (i.e. 
Tums, Maalox) 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 Baseline/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 Inhibitors, rosuvastatin. Monitor 
for signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis.
Medications for disease conditions excluded from the protocol (eg, HIV infection, active cancer, 
transplantation) 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.
5.4.
Accountability for SOF/VEL FDC
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug (SOF/VEL FDC). 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.


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SOF/VEL FDC accountability records will be captured in IWRS:

Record the date received and quantity of study drug shipments

Record the date, subject number, subject initials, the study drug bottle number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.
At the Day 1 visit, subjects will be dispensed 2 bottles of SOF/VEL so that they have sufficient 
tablets to cover the 3 day time window around the Week 4 and 8 visit. Subjects must be 
instructed to bring back the study drug in the original container at every post-Day 1 study visit
through the end of treatment. The extra bottle dispensed at Day 1 must be brought to each on-
treatment visit for accountability purposes and will be re-dispensed to the subject except at the 
Week 12 or ET visit. 
5.4.1.
Investigational Medicinal Product Return or Disposal
Please refer to Section 9.1.7 for Investigational Medicinal Product Accountability and Return.


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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. All eligible subjects will
complete Screening, Baseline/Day 1, Week 12 (end of treatment) visit, and post treatment at 
Weeks 4 and 12. In addition, subjects will return at weeks 4 and 8 for study medication
dispensing visit.
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
Eligible subjects will be enrolled on Day 1 and will be assigned to receive SOF/VEL FDC for 
12 weeks. 
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 28 days of the Day 1 visit to determine eligibility for 
participation in the study. The screening window can be extended to 42 days prior to Day 1 for 
extenuating circumstances with sponsor approval.
The following assessments will be performed and documented at screening:

Obtain signed informed consent

Obtain medical history, including information on prior HCV treatment history,
If available, treatment-experienced patients will be classified as:
— Non-Responder: Subject did not achieve undetectable HCV RNA levels while on 
treatment, 
— Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during treatment 
or within 4 weeks of the end of treatment but did not achieve SVR
— Treatment-intolerant

Obtain demographic information

Perform symptom directed physical examination and vital signs if indicated

Obtain details on AEs related to screening procedures (See Section 7.1 for details)

Obtain details of concomitant medications


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
Obtain blood samples for 
— Hematology, chemistry and Coagulation tests
— HCV RNA
— HCV genotype 
— HCV antibody, HIV testing, and HBV surface antigen (HBsAg)
— Obtain urine sample for -hCG pregnancy test for females of childbearing potential 
only

Determine cirrhosis status based on inclusion criteria #6
— If the presence of cirrhosis is determined, appropriate diagnostic imaging (eg, CT or 
ultrasound) should be performed to exclude the presence of HCC
Retests of Screening labs are permitted only if there is reason to believe the retest value will be 
within accepted parameters, for example, if the initial exclusionary value was either due to a 
sample processing error or due to extenuating circumstances such as intercurrent illness.
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.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, all serious adverse events (SAEs), as well as any adverse events related to 
protocol-mandated procedures will be recorded on the adverse events case report form (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 eCRF. See 
Section 7, Adverse Events and Toxicity Management for additional details.
6.2.2.
Day 1 Assessments 
Day 1 tests and procedures must be completed prior to enrollment and dosing/dispensing of 
study drug (see Appendix 1).
At the Day 1 visit, complete the following:

Confirm eligibility

Symptom directed physical examination including vital signs, if required

Assessment of AEs and concomitant medications

Obtain blood samples for:
— Hematology, chemistry and coagulation tests


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— HCV RNA
— archive sample

Obtain urine sample for -hCG pregnancy test for females of childbearing potential only

Dispense the study drug as directed by IWRS

Instruct the subject on the packaging, storage and administration of study drug
6.3.
Dispensing visits Week 4 and 8 (± 3 days)
The following treatment procedures/assessments are to be completed at the end of Weeks 4, and 
8, for all subjects (see Appendix 2)

Dispense study drugs as directed by the IWRS 

Collect returned study drug
6.4.
Week 12 (± 3 days) or Early Termination (ET) 
If a subject discontinues treatment early for any reason they should complete the week 12 Visit 
assessments and the Post-Treatment Week 4 visit assessments (4 weeks following the last dose 
of the study drug) (see Appendix 2).
The following procedures/assessments are to be completed at the Week 12 /ET Visit:

Symptom directed physical examination and vital signs, if indicated

Assessment of AEs and concomitant medications

Obtain blood samples for:
— Hematology, chemistry and coagulation tests
— HCV RNA
— archive sample 

Obtain urine sample for:
— β -hCG pregnancy test for females of childbearing potential only

Review study drug compliance
— Reconcile study drug administration using pill counts


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— Study drug should be returned at this visit
When medically feasible, the Medical Monitor must be consulted prior to subject 
discontinuation. The sponsor (eg, Medical Monitor and Clinical Program Manager)/CRO must 
be informed as soon as possible when a subject discontinues treatment.
6.5.
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, 
6.6.
Post-Treatment Assessments (5 days)
All subjects will complete the Post-treatment Week 4 and 12 visits. The Post-Treatment visits 
must be scheduled relative to the date of last administration of study drug (see Appendix 2.).
6.6.1.
Post-treatment Week 4 (± 5 days)
The following procedures/assessments are to be completed for all subjects, 4 weeks after taking 
the last dose of SOF/VEL FDC:

Symptom directed physical examination and vital signs, if indicated

Assessment of AEs and concomitant medications

Obtain blood samples for:
— Hematology, chemistry and coagulation tests

Obtain urine sample for:
— β -hCG pregnancy test for females of childbearing potential only
6.6.2.
Post-treatment Week 12 (± 5 days)
The following procedures/assessments are to be completed for Post- Treatment Week 12:

Obtain blood samples for:
— HCV RNA
— archive sample 
6.7.
End of Study
Discontinuation from study drug dosing and discontinuation from the overall study, including the 
Post-Treatment period, will be collected as two separate events.


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The end of the study will occur at the post-treatment Week 12 visit.
6.8.
Procedures and Specifications
6.8.1.
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: international normalized ratio (INR), Prothrombin time (PT), Activated partial 
thromboplastin time (APTT).
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatinine, Total and direct Bilirubin (reflex to Direct 
Bilirubin), Glucose, Lipase, Potassium, Sodium, and Direct Bilirubin.
Virological Tests: Serologies for HCV and HBV. Serology and/or antigen testing for HIV 
(including reflex testing) as necessary, HCV RNA may be measured qualitatively or qualitatively 
using a validate assay. Gilead reserves the right to use alternate assays for HCV RNA should the 
above assays becomes unavailable.
Pregnancy Tests: Urine β-hCG 
 
6.8.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history, including prior HCV treatment history
if available will be collected on all subjects during screening.
6.8.3.
Symptom directed Physical Examination
A symptom directed physical examination should be conducted if medically indicated. Vital 
signs should be completed if medically indicated.
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6.8.4.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft et al 1976} using 
actual body weight (BW). The calculation will be performed by the central laboratory.
Male:
CLcr (mL/min) = [140 - age (years)] BW(kg)
72 Scr
Female:
CLcr (mL/min) = [140 - age (years)] BW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
6.8.5.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing at Screening, Day 1, end 
of treatment at week 12 and Post-Treatment week 4.


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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 7.5.1)

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.)

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity


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
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 (eg, 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 (eg, 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 (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Appendix 3.
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 (eg, 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 medicinal product.


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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 (eg, 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, (eg., 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 
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 adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, all AEs, regardless of cause or relationship, pregnancy 
and other special situation reports, until 30 days after last administration of study drug must be 
collected / reported to the 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.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs 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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Any SAEs and deaths that occur after the post-treatment follow-up visit and within 30 days of 
the last dose of study drug, regardless of causality, should also be reported. 
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. 
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there 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 for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead DSPH
Email:
Fax:

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.
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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 
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.
Special Situations Reports
7.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
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).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  


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7.5.2.
Instructions for Reporting Special Situations
7.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and within 30 days of the last dose of SOF/VEL FDC, to the 
Gilead DSPH or the CRO using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to Section 7.3 and the CRF/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 (eg, 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 
7.3. 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 or the CRO 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: 
 and 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 or the CRO
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, fax 
number 
 or email 
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH or the CRO 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. 
PPD
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Special situations involving non-Gilead concomitant medications does 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 9.3 and the CRF/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 CRF/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 efficacy of treatment with  SOF/VEL FDC for 12 weeks in subjects with 
chronic HCV infection as measured by the proportion of subjects with SVR12

To evaluate the safety and tolerability of treatment with SOF/VEL FDC for 12 weeks
8.1.2.
Primary Endpoint
The primary efficacy endpoint is SVR12 (HCV RNA negative 12 weeks after cessation of 
therapy) in the Full Analysis Set (FAS) population. 
8.1.3.
Secondary Endpoint
Secondary efficacy endpoint is the proportion of subjects with virologic failure.
8.1.4.
Safety Endpoint
The primary safety endpoint is any AE leading to permanent discontinuation of the study drug.
8.1.5.
Other Endpoints of Interest
Other endpoints of interest may include:

The proportion of subjects with HCV RNA negative at the end of treatment.
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 drug in this study is SOF/VEL FDC. Last dose of SOF/VEL FDC will be used as the 
last dose of the study drugs and will be used in the definition of treatment-emergent AEs and 
laboratory abnormalities as well as the efficacy endpoints of SVR at various post-treatment time 
points


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8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which include 
all enrolled subjects who took at least one dose of study drug.
8.2.1.2.
Safety
The Safety Analysis Set will include all subjects who took at least one dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of 
study drug through the date of last dose of study drug plus 30 days.
All data collected during treatment will be included in the safety summaries.
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 analysis of post-baseline categorical efficacy endpoints, if a data point is missing and is 
preceded and followed in time by values that are deemed successes, then the missing data point 
will be termed a success; otherwise the data point will be termed a failure.
Any subject with missing data due to premature discontinuation of the study medication will be 
considered a failure at the date of premature discontinuation and all time points subsequent to the 
date of premature discontinuation.  If no HCV RNA values are obtained after the last dose of 
study medication, the subject will be considered a treatment failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject took at least 1 dose of study medication, the subject will be included in a 
summary of adverse events; otherwise, 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 summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose 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 pre-treatment 
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.


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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.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods 
Demographic summaries will include sex, race/ethnicity, and age.
Baseline data will include body mass index, prior treatment experience, cirrhosis status, 
genotype of HCV infection, and additional endpoints as necessary
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy endpoint is SVR12 (HCV RNA negative 12 weeks after discontinuation of 
therapy) in the FAS population. The primary analysis will be performed after all enrolled 
subjects have been followed through post-treatment Week 12 or discontinued from study.
In the primary efficacy analysis, the SVR12 rate will be compared to the pre-specified 
performance goal of 85% by using a two-sided exact one-sample binomial test at the 0.05 
significance level. The null (H0) and alternative (H1) hypotheses used to assess superiority of 
SOF/VEL FDC relative to the performance goal of 85% are:

H0: SVR12 rate = 85%

H1: SVR12 rate ≠ 85%
It is difficult to characterize a single historical control rate for all genotypes included in this 
study given the different standards of care of each genotype (some of which include interferon), 
and the lack of historical data for genotype 4, 5, and 6 participants. Given these difficulties, 
rather than use a historical control rate as the basis for assessing the primary endpoint, a 
pre-specified performance goal is defined as a benchmark against which the efficacy of 
SOF/VEL FDC will be tested. The benchmark sets a high bar of 85%.  The basis for this 
benchmark includes the overall trend toward increasing SVR rates in recent years, the higher 
SVR rates observed with Peg-IFNα + RBV treatment in Asian subjects {Yu et al 2009}
compared with other races, and the general appeal of using a fixed clinically relevant threshold 
as a measure of treatment benefit {Weins et al 2013} of SOF/VEL FDC.
8.5.2.
Secondary Analyses
Descriptive summaries and listings will be provided for additional efficacy evaluations of the 
proportion of subjects who experience virologic failure. 


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The proportion of subjects with HCV RNA negative at end of treatment will be presented in 
tabular form.
 
 
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, 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 CRF. Exposure data will be summarized.
8.6.2.
Adverse Events
Clinical and laboratory AEs 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 with onset date of on or after the study drug 
start date and no later than 30 days after permanent discontinuation of study drug or any adverse 
event leading to premature discontinuation of study.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC 
and preferred term) will be provided:

All AEs,

All study drug-related AEs,

AEs of Grade 2 and above,

AEs of Grade 3 and above,
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
Treatment-related AEs of Grade 2 and above,

Treatment-related AEs of Grade 3 and above,

AEs leading to permanent discontinuation from study drug,

All SAEs (including death), and

All treatment-related SAEs
All AEs collected during the course of the study will be presented in data listings.
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by study visit along with corresponding change from Baseline/Day 1.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading defined in 
Appendix 3 of this protocol. The incidence of treatment-emergent laboratory abnormalities, 
defined as values that increase by at least one toxicity grade from Day 1 at any time post-
baseline 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 Day 1 result 
will be replaced with a screening result, if available. If no pre-treatment 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.
8.6.4.
Other Safety Evaluations
Individual data for vital signs measurements will be listed by subject and summarized overall by 
incidence of events/abnormalities or descriptive statistical summaries (n, mean, SD, median, Q1, 
Q3, minimum, and maximum), as appropriate. 
8.7.
Sample Size
A sample size of 125 subjects will provide 95% power to detect an improvement in SVR12 rate 
from 85% to 95% using a two-sided exact one-sample binomial test at a significance level of 
0.05.


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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.
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 sub-investigator’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. The 
investigator must use the most current IRB- or 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.


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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 and 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. 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 
and 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);

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;


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
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 will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  The Eligibility Criteria eCRF 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. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 
as described in the clinical data management plan), 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. The eCRF capture the data required per the protocol 
schedule of events and procedures. 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 


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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). 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
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP 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 QA, 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.
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 and IEC, or to regulatory authority or health authority 
inspectors.
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 and 
IEC in accordance with local requirements and receive documented IRB and IEC approval 
before modifications can be implemented.


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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 
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.


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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.
REFERENCES
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and 
sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 
2014a;370 (16):1483-93.
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for 
untreated HCV genotype 1 infection. N Engl J Med 2014b;370 (20):1889-98.
Andrews E, Damle BD, Fang A, Foster G, Crownover P, LaBadie R, et al. Pharmacokinetics and 
tolerability of voriconazole and a combination oral contraceptive co-administered 
in healthy female subjects. Br J Clin Pharmacol 2008;65 (4):531-9.
Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic 
response reduces risk of all-cause mortality in patients with hepatitis C. Clin 
Gastroenterol Hepatol 2011;9 (6):509-16 e1.
Barditch-Crovo P, Trapnell CB, Ette E, Zacur HA, Coresh J, Rocco LE, et al. The effects of 
rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a 
combination oral contraceptive. Clin Pharmacol Ther 1999;65 (4):428-38.
Chowdhury A, Santra A, Chaudhuri S, Dhali GK, Chaudhuri S, Maity SG, et al. Hepatitis C 
virus infection in the general population: a community-based study in West 
Bengal, India. Hepatology 2003;37 (4):802-9.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Datta S. An overview of molecular epidemiology of hepatitis B virus (HBV) in India. Virology 
journal 2008;5:156.
Denniston MM, Jiles RB, Drobeniuc J, Klevens RM, Ward JW, McQuillan GM, et al. Chronic 
Hepatitis C Virus Infection in the United States, National Health and Nutrition 
Examination Survey 2003 to 2010. Ann Intern Med 2014;160:293-300.
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information.  
Foster City, CA. December 2013:
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.
Janssen Pharmaceuticals Inc. INTELENCE® (etravirine) tablets for oral use. US Prescribing 
Information. 2008 Titusville NJ. Revised February 2013.


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Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and 
sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 
2014;370 (20):1879-88.
Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of 
mortality from viral hepatitis in the United States between 1999 and 2007. Ann 
Intern Med 2012;156 (4):271-8.
Mahajan R, Xing J, Liu SJ, Ly KN, Moorman AC, Rupp L, et al. Mortality Among Persons in 
Care With Hepatitis C Virus Infection: The Chronic Hepatitis Cohort Study 
(CHeCS), 2006-2010. Clin Infect Dis 2014.
Mohanty D, Colah RB, Gorakshakar AC, Patel RZ, Master DC, Mahanta J, et al. Prevalence of 
beta-thalassemia and other haemoglobinopathies in six cities in India: a 
multicentre study. J Community Genet 2013;4 (1):33-42.
Puri P, Anand AC, Saraswat VA, Acharya SK, Dhiman RK, Aggarwal R, et al. Consensus 
Statement of HCV Task Force of the Indian National Association for Study of the 
Liver (INASL). Part I: Status Report of HCV Infection in India. J Clin Exp 
Hepatol 2014;4 (2):106-16.
Puri P, Saraswat VA. Back from the Future: Treating Hepatitis C Virus with Conventional 
Interferon. Journal of Clinical and Experimental Hepatology 2012;2 (1):3-6.
Quest Diagnostics. FSH and LH Reference Ranges.  2013a:
Quest Diagnostics. Progesterone, LC/MS/MS Reference Ranges.  2013b:
Saravanan S, Velu V, Kumarasamy N, Shankar EM, Nandakumar S, Murugavel KG, et al. The 
prevalence of hepatitis B virus and hepatitis C virus infection among patients with 
chronic liver disease in South India. Int J Infect Dis 2008;12 (5):513-8.
Sievert W, Altraif I, Razavi HA, Abdo A, Ahmed EA, Alomair A, et al. A systematic review of 
hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int 2011;31 
Suppl 2:61-80.
Weins BL, Lystig TC, Berry SM. Recent Statistical Contributions to Medical Device 
Development. Therapeutic Innovation & Regulatory Science 2013:1-8.
World Health Organization (WHO). Hepatitis C Fact sheet N°164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/#. Accessed: 20 March.  
2014.
Yu ML, Chuang WL. Treatment of chronic hepatitis C in Asia: when East meets West. J 
Gastroenterol Hepatol. 2009;24 (3):336-45.


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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


PPD
PPD
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Appendix 1. 
Investigator Signature Page 
GU.EAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Open-label Study to Investigate the Efficacy and Safety ofSofosbuvirNelpatasvir 
Fixed Dose Combination for 12 weeks in Subjects with Chronic Hepatitis C Virus (HCV) 
infection 
GS-US-342-1521, Original, 12 February 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Signature 
Medical Monitor 
f~ 
\(:; 1 wt' 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
1 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page73 
12 February 2016 


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Appendix 2.
Study Procedures Table
Screening2
(Day -28 to Day 0)
Baseline/Day 1
On-treatment Study Week (± 3 days)
Post-treatment 
Study Week (± 5 days)
Week 4
Week 8
End of Treatment 
Week 12 or ET1
Week 4
Week 12
Written Informed Consent
X
Medical History 
X
X
Symptom-Directed Physical and 
Vital Signs if indicated
X
X
X
X
AEs and Concomitant Medications
X3
X
X
X
Review of Study Medication 
Compliance
X
Hematology, Chemistry, 
Coagulation
X
X
X
X
HCV RNA
X
X
X
X
HCV Genotyping
X
HIV testing, HCV and HBV 
Serology
X
Archive Sample
X
X
X
Cirrhosis determination
X
Urine Pregnancy Testing4
X
X
X
X
Study Medication Dispensation
X
X
X
1
ET = Early Termination
2
The screening window can be extended to 42 days prior to Day 1 for extenuating circumstances with sponsor approval
3
Concomitant medications and AE related to Screening Procedures only
4
Females of child-bearing potential only


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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


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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.  


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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 to <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-342-1521
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 79
12 February 2016
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


SOF/VEL FDC
Protocol GS-US-342-1521
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 80
12 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


SOF/VEL FDC
Protocol GS-US-342-1521
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 81
12 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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-342-1521
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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12 February 2016
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-342-1521
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 83
12 February 2016
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-342-1521
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 84
12 February 2016
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 
(eg, 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 
(eg, 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 
(eg, tamponade) OR Urgent 
intervention indicated


SOF/VEL FDC
Protocol GS-US-342-1521
Final
Gilead Sciences, Inc. 
Original
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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, eg, 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, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, 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-342-1521
Final
Gilead Sciences, Inc. 
Original
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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-342-1521
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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12 February 2016
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-342-1521
Final
Gilead Sciences, Inc. 
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12 February 2016
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 [eg, 
tube feeding or total 
parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, 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 (eg, sepsis or 
perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences (eg, 
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 (eg, 
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


SOF/VEL FDC
Protocol GS-US-342-1521
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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12 February 2016
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
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
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 (eg, 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 (eg, 
IV fluids)
Life-threatening 
consequences (eg, 
hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences (eg, 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 (eg, 
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 (eg, 
hypotensive shock)


SOF/VEL FDC
Protocol GS-US-342-1521
Final
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Original
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (eg, 
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 (eg, 
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 
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


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Gilead Sciences, Inc. 
Original
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)


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Original
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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 (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, 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


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Protocol GS-US-342-1521
Final
Gilead Sciences, Inc. 
Original
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12 February 2016
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


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Final
Gilead Sciences, Inc. 
Original
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12 February 2016
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 [eg, 
tube feeding or total parenteral 
nutrition]


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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 (eg, upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment (eg, 
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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Gilead Sciences, Inc. 
Original
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ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, 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 
(eg, 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 
(eg, 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 
(eg, myxedema coma)
Lipoatrophy (eg, 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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Original
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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 (eg, 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 (eg, 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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Final
Gilead Sciences, Inc. 
Original
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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)
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 VEL 
have demonstrated no adverse effect on fertility or embryo-fetal development. 
However, the risks of treatment with SOF/VEL FDC during pregnancy in humans have not been 
evaluated. Please refer to the latest version of the investigator’s brochure for additional 
information.
3)
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 urine pregnancy test at Screening 
and on the Baseline/Day 1 visit prior to enrollment.  A pregnancy test will be also performed at 
the week 12 and 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 FDC.

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.
Or


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
Consistent and correct use of 1 of the following methods of birth control listed below. 
— Intrauterine device (IUD) 
— Intrauterine hormone-releasing system (IUS) 
— Tubal sterilization
— Essure micro-insert system 
— Vasectomy in the male partner 
— Barrier methods (one female barrier and one male barrier must be used in combination)

Female barriers: Diaphragm with spermicide or Cervical cap with spermicide

Male barriers: Male condom (with or without 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 FDC.
4)
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 FDC 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.
5)
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.


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Original
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6)
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 FDC. 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 7.5.2.1.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3, Open-label Study to Investigate the Efficacy and 
Safety of Sofosbuvir/Velpatasvir Fixed Dose Combination 
for 12 weeks in Subjects with Chronic Hepatitis C Virus 
(HCV) infection
Name of Test Drug:
Sofosbuvir/Velpatasvir
Study Number:
GS-US-342-1521
Protocol Version (Date):
Original: 12 February 2016
Analysis Type:
SVR12
Analysis Plan Version:
1.0
Analysis Plan Date:
14 March 2018
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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GS-US-342-1521 Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN..............................................................................................................................1
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
1.
INTRODUCTION ................................................................................................................................................6
1.1.
Study Objectives ......................................................................................................................................6
1.2.
Study Design............................................................................................................................................6
1.3.
Sample Size and Power............................................................................................................................6
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................7
2.1.
Data Monitoring Committee ....................................................................................................................7
2.2.
Final Analysis ..........................................................................................................................................7
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES..............................................................................8
3.1.
Analysis Sets............................................................................................................................................8
3.1.1.
All Enrolled Analysis Set.......................................................................................................8
3.1.2.
Full Analysis Set ....................................................................................................................8
3.1.3.
Safety Analysis Set.................................................................................................................8
3.2.
Subject Grouping .....................................................................................................................................8
3.3.
Examination of Subject Subsets...............................................................................................................8
3.4.
Multiple Comparisons..............................................................................................................................9
3.5.
Missing Data and Outliers........................................................................................................................9
3.5.1.
Missing Data ..........................................................................................................................9
3.5.2.
Outliers.................................................................................................................................10
3.6.
Data Handling Conventions and Transformations .................................................................................10
3.7.
Visit Windows........................................................................................................................................11
3.7.1.
Definition of Study Day .......................................................................................................11
3.7.2.
Analysis Windows................................................................................................................11
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis 
Window................................................................................................................................12
4.
SUBJECT DISPOSITION ..................................................................................................................................14
4.1.
Subject Enrollment and Disposition.......................................................................................................14
4.2.
Extent of Exposure.................................................................................................................................14
4.2.1.
Duration of Exposure to Study Drug....................................................................................15
4.2.2.
Adherence to Study Drug.....................................................................................................15
4.3.
Protocol Deviations................................................................................................................................16
5.
BASELINE CHARACTERISTICS....................................................................................................................17
5.1.
Demographics ........................................................................................................................................17
5.2.
Other Baseline Characteristics ...............................................................................................................17
5.3.
Medical History......................................................................................................................................18
6.
EFFICACY ANALYSES ...................................................................................................................................19
6.1.
Primary Efficacy Endpoint.....................................................................................................................19
6.1.1.
Definition of the Primary Efficacy Endpoint .......................................................................19
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint....................................................19
6.1.3.
Primary Analysis of the Primary Efficacy Endpoint ............................................................19
6.1.4.
Subgroup Analysis of the Primary Efficacy Endpoint .........................................................19
6.2.
Secondary Efficacy Endpoints ...............................................................................................................20


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6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................20
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................20
6.3.
Changes From Protocol-Specified Efficacy Analyses............................................................................20
7.
SAFETY ANALYSES........................................................................................................................................21
7.1.
Safety Endpoints ....................................................................................................................................21
7.2.
Adverse Events and Deaths....................................................................................................................21
7.2.1.
Adverse Event Dictionary ....................................................................................................21
7.2.2.
Adverse Event Severity........................................................................................................21
7.2.3.
Relationship of Adverse Events to Study Drug....................................................................21
7.2.4.
Serious Adverse Events........................................................................................................21
7.2.5.
Treatment-Emergent Adverse Events...................................................................................21
7.2.5.1.
Definition of Treatment Emergent..................................................................21
7.2.5.2.
Incomplete Dates ............................................................................................22
7.2.6.
Summaries of Adverse Events and Deaths...........................................................................22
7.3.
Laboratory Evaluations ..........................................................................................................................23
7.3.1.
Summaries of Numeric Laboratory Results .........................................................................24
7.3.2.
Graded Laboratory Values ...................................................................................................24
7.3.2.1.
Treatment-Emergent Laboratory Abnormalities.............................................24
7.3.2.2.
Summaries of Laboratory Abnormalities........................................................24
7.4.
Body Weight, Height, and Vital Signs...................................................................................................25
7.5.
Prior and Concomitant Medications.......................................................................................................25
7.6.
Other Safety Measures ...........................................................................................................................26
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................26
8.
REFERENCES ...................................................................................................................................................27
9.
SOFTWARE.......................................................................................................................................................28
10.
SAP REVISION..................................................................................................................................................29
11.
APPENDICES ....................................................................................................................................................30
Appendix 1.
Schedule of Assessments........................................................................................................31
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................12
Table 3-2.
Analysis Windows for Posttreatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................12


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GS-US-342-1521 Statistical Analysis Plan
Version 1.0
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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatine kinase
CRF
case report form
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
DAA
direct acting antiviral
DILI
drug-induced liver injury
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
FDC
fixed dose combination
Gilead
Gilead Sciences, Inc.
GT
genotype (viral)
Hb
hemoglobin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
IFN
interferon
INR
international normalized ratio of prothrombin time
LLOQ
lower limit of quantification
LLT
lower-level term
MedDRA
Medical Dictionary for Regulatory Activities
Peg-IFN
pegylated interferon
PP
per protocol
PT
preferred term
Q1
first quartile
Q3
third quartile
RBV
ribavirin
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SI (units)
International system of units
SOC
system organ class
SOF
Sofosbuvir
SVR
sustained virologic response


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TEAE
treatment-emergent adverse events
TFLs
tables, figures, and listings
ULN
upper limit of normal
VEL
Velpatasvir
WBC
white blood cell count
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-342-1521. This SAP is based on the study protocol dated 12 February 2016
and the electronic case report form (eCRF).This SAP will be finalized before database 
finalization. Any changes made after the finalization of the SAP will be documented in the CSR.
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate the efficacy of treatment with SOF/VEL FDC for 12 weeks in subjects with
chronic HCV infection 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 FDC for 12 weeks.
1.2.
Study Design
This is a multicenter, open-label study to evaluate the safety, tolerability, and antiviral efficacy 
of SOF/VEL FDC for 12 weeks in subjects with chronic HCV infection. Subjects with or without 
cirrhosis will be enrolled.
Approximately 125 subjects with chronic HCV infection will be enrolled in the study and all 
subjects will receive SOF/VEL FDC once daily for 12 weeks. Approximately 20% of subjects 
may be treatment experienced, and up to 20% of subjects may have compensated cirrhosis at 
baseline.
The total time to complete all study visits is up to approximately 28 weeks, including the 
following periods:

28-day (4-week) screening period

12-week treatment period

Up to 12-week posttreatment period
1.3.
Sample Size and Power
A sample size of 125 subjects will provide 95% power to detect an improvement in SVR12 rate 
from 85% to 95% using a two-sided exact one-sample binomial test at a significance level of 
0.05.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee
This study does not have a data monitoring committee (DMC).
2.2.
Final Analysis
After all subjects have completed through the posttreatment Week 12 visit or have prematurely 
discontinued from the study, the final analysis of the data will be performed once all outstanding 
data queries have been resolved, and the database has been cleaned and finalized.


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3.
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 with reasons for exclusion.
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all subjects enrolled in the study after screening.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all enrolled subjects who took at least 1 dose of study drug. 
The study drug in this study is SOF/VEL FDC (400/100 mg).
This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug.
This is the primary analysis set for safety analyses.
3.2.
Subject Grouping
Generally speaking, efficacy analyses will be performed on the FAS. Subjects will be grouped by
HCV genotype (GT1a, GT1b, GT1 (total), GT2, GT3, GT4, GT5, GT6, Indeterminate, and 
Total). For subjects with missing or mixed genotype or indeterminate genotype 1 subtype 
determined by LiPA 2.0 at enrollment, further Sanger sequencing will be performed to determine 
their HCV genotype and subtype. The analysis of HCV RNA less than the lower limit of 
quantitation (< LLOQ) at the end of treatment and during the posttreatment (ie, SVR) follow-up 
period will be performed on the FAS by genotype as described above.
For analyses based on other analysis sets, such as the Safety Analysis Set, data will be 
summarized based on the treatment subjects received.
3.3.
Examination of Subject Subsets
The primary efficacy endpoint will be examined using the following subsets:


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
Age (< 65 years, 65 years)

Sex (male, female)

Baseline body mass index BMI (<25 kg/m2 , ≥25 kg/m2)

HCV genotype and subtype

Cirrhosis (presence, absence, missing)

Baseline HCV RNA (< 800,000 IU/mL, ≥ 800,000 IU/mL)

Baseline alanine aminotransferase (ALT) (≤1.5 × upper limit of normal [ULN], 
> 1.5 × ULN)

prior HCV treatment experience (treatment naïve, treatment experienced)

Prior HCV treatment for treatment-experienced subjects (Peg-IFN + RBV and Other)

Response to prior HCV treatment (non-responder, relapse/breakthrough, early treatment 
discontinuation) for treatment experienced subjects

Adherence to study regimen (<80%, ≥80%)
3.4.
Multiple Comparisons
Adjustments for multiplicity will not be made because no statistical testing will be performed in 
this study.
3.5.
Missing Data and Outliers
3.5.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified.
For missing last dose date of study drug, imputation rules are described in Section 3.7.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in 
Section 7.2.5.2, and for prior and concomitant medications in Section 7.5.
For analyses of categorical HCV RNA data, missing posttreatment week 12 HCV RNA data will
have the missing data imputed.
If a posttreatment week 12 HCV RNA data point is missing and is preceded and followed in time 
by values that are less than the lower limit of quantitation (LLOQ) target not detected (TND) 
(ie, “< LLOQ TND”), then the missing data point will be set to “< LLOQ TND”. If a data point 
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“< LLOQ detected” and followed by “< LLOQ TND”, or preceded by “< LLOQ TND” and 
followed by “< LLOQ detected”, 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).
For 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.
3.5.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analyses.
3.6.
Data Handling Conventions and Transformations
By-subject listings will be presented for all subjects in the Safety Analysis Set 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 will be used for analyses and 
presentation in listings. If a subject was not dosed with study drug, the date the informed consent 
was signed will be used instead of the first dose date of study drug. “01 January” will be used for 
the unknown birth day and month for the purpose of age calculation.
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 to this 
rule is any value reported as < 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).
The COBAS®AmpliPrep/COBAS® TaqMan® HCV Quantitative Test v2.0 was used to determine 
HCV RNA results in this study. The LLOQ of the assay is 15 IU/mL.


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When the calculated IU/mL is within the linear range of the assay, the result will be reported as 
the “<< numeric value>> IU/mL”. This result is referred to in this document as the numeric 
result or as “≥ LLOQ detected” for categorical results.
When HCV RNA is not detected, the result is reported as “HCV RNA not detected” or “target 
not detected”. This result is referred to in this document as “< LLOQ target not detected” or 
“< LLOQ TND.”
When the HCV RNA IU/mL is < LLOQ of the assay, the result is reported as “< 15 IU/mL HCV 
RNA detected.” This result is referred to in this document as “< LLOQ detected”.
The overall category of HCV RNA < LLOQ includes “< LLOQ TND” and “< LLOQ detected.”
For numerical HCV RNA data, values below LLOQ will be set to the LLOQ – 1 IU/mL. HCV 
RNA values returned as “target not detected” will also be set to LLOQ – 1 IU/mL.
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data (eg, log10 scale) or nonparametric analysis 
methods may be used, as appropriate.
3.7.
Visit Windows
3.7.1.
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 for an individual study drug will be the end date on the study drug 
administration eCRF for the record where the “subject permanently discontinued” flag is ‘Yes’. 
The last dose date will be defined as the maximum of the last dose dates of study drugs.
If there are subjects for whom the date of last dose of 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 the 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).
3.7.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.


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In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of study drug. If multiple measurements occur on the same day, the last nonmissing value prior 
to the time of first dose of study drug will be considered as the baseline value. If these 
multiple measurements occur at the same time or the time is not available, the average of these 
measurements (for continuous data) or the worst among these measurements (for categorical 
data) will be considered the baseline value.
HCV RNA, vital signs, and safety laboratory data collected up to the last dose date + 3 days are 
considered 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 3-1.
Table 3-1.
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 12
84
2
98
HCV RNA, vital signs, 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 3-2.
Table 3-2.
Analysis Windows for Posttreatment HCV RNA, Vital Signs and 
Safety Laboratory Data
Nominal 
FUa Visit
HCV RNA
Vital Signs and Safety Laboratory Datab
Nominal FU 
Day
Lower Limit
Upper Limit
Nominal FU 
Day
Lower Limit
Upper Limit
FU-4
NA
NA
NA
28
4
30
FU-12
84
70
146
NA
NA
NA
a
FU-x visit = posttreatment Week-x follow-up visit.
b
Vital signs and safety labs will only be summarized for the FU-4 visit (up to 30 days after last dose).
3.7.3.
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 a single value per analysis window.


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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, the 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 most recent record in the analysis window 
will be selected.
If there are 2 records that are equidistant from the nominal day, the more recent 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).

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 and overall. This summary will 
present the number of subjects screened, 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, 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 from study
Among subjects who completed study treatment and who discontinued study treatment, the 
number and percentage of subjects will be summarized for the subjects who had an HCV RNA 
posttreatment Week 12 assessment.
In addition, the total number of subjects who were enrolled and the number of subjects in each of 
the disposition categories listed above will be depicted in 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 completed 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.


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4.2.1.
Duration of Exposure to Study Drug
The 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 1 decimal place (eg, 4.5 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), 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.
Summaries will be provided by treatment group for the Safety Analysis Set. 
4.2.2.
Adherence to Study Drug
The total number of study drug tablets administered will be summarized using descriptive 
statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum).
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability eCRF using the following formula:







ed
administer
not 
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 tablets administered relative to the total amount of study drug tablets prescribed at 
baseline.
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. If study drug bottles are dispensed on or after the subject first met 
virologic failure criteria, the bottles will not be included in the calculation of adherence. If a 
bottle is dispensed and the bottle is returned empty, 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.


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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 by genotype for the Safety Analysis Set. 
Categorical displays will also be provided for the number of subjects who are at least 
80% adherent to the study drug (ie, adherence to study drug is ≥80%).
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 CHARACTERISTICS
5.1.
Demographics
Subject demographics (ie, age, sex, race, and ethnicity) will be summarized for the 
Safety Analysis Set overall using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum,
and maximum) for age and the number and percentage of subjects for age categories (< 65 years, 
≥65 years), 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.
A by-subject demographics listing will be provided by subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include:

Body mass index (BMI; in kg/m2) as a continuous variable and as categories (< 25 kg/m2, 
≥25 kg/m2)

HCV genotype and subtype

Cirrhosis (presence, absence, missing)

Baseline HCV RNA (log10 IU/mL) as a continuous variable and as categories 
(< 800,000 IU/mL, ≥ 800,000 IU/mL)

Baseline ALT (U/L) as a continuous variable and as categories (≤1.5 × ULN, > 1.5 × ULN)

Prior HCV treatment experience (treatment naive, treatment experienced)

Prior HCV treatment for treatment-experienced subjects (Peg-IFN + RBV, Other)

Estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault equation
Estimated glomerular filtration rate will be calculated by the Cockcroft-Gault method: 
eGFRCG (mL/min) = [(140 – age (yrs)) × weight (kg) × (0.85 if female)] / (serum creatinine 
(mg/dL) × 72), where weight is total body mass in kilograms.
These baseline characteristics will be summarized for the Safety Analysis Set by genotype and 
overall using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for 
continuous variables and the numbers and percentages of subjects for categorical variables.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.


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A separate by-subject data listing for cirrhosis determination at screening will be provided for all 
subjects.
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 treatment duration and the prior HCV treatment response.
5.3.
Medical History
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).


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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 of the assay is 15 IU/mL.
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint
In the primary efficacy analysis, the SVR12 rate will be compared to the pre-specified
performance goal of 85% by using a two-sided exact one-sample binomial test at the 0.05
significance level. The null (H0) and alternative (H1) hypotheses used to assess superiority of
SOF/VEL FDC relative to the performance goal of 85% are:

H0: SVR12 rate = 85%

H1: SVR12 rate ≠ 85%
It is difficult to characterize a single historical control rate for all genotypes included in this
study given the different standards of care of each genotype (some of which include interferon), 
and the lack of historical data for genotype 4, 5, and 6 participants. Given these difficulties, 
rather than use a historical control rate as the basis for assessing the primary endpoint, a 
pre-specified performance goal is defined as a benchmark against which the efficacy of 
SOF/VEL FDC will be tested. The benchmark sets a high bar of 85%. The basis for this 
benchmark includes the overall trend toward increasing SVR rates in recent years, the higher 
SVR rates observed with Peg-IFNα + RBV treatment in Asian subjects {Yu 2009} compared 
with other races, and the general appeal of using a fixed clinically relevant threshold as a 
measure of treatment benefit {Weins 2013} of SOF/VEL FDC.
6.1.3.
Primary Analysis of the Primary Efficacy Endpoint
The 2-sided 1-sample exact binomial test will be used to test the statistical hypotheses described 
above. The 2-sided 95% exact confidence interval (CI) and p-value based on the 
Clopper-Pearson method {Clopper 1934} will be provided for the SVR12 rate for total subjects.
6.1.4.
Subgroup Analysis of the Primary Efficacy Endpoint
The point estimates and 95% exact CIs of the SVR12 rates will be displayed by genotype and 
subtype for the subgroups outlined in Section 3.3
A forest plot will graphically present estimates and 95% CIs in SVR12 rates for each of the 
subgroups.


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6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
The secondary efficacy endpoint is the proportion of subjects with virologic failure.

The percentage of subjects with virologic failure as the following:
On-treatment virologic failure

HCV RNA persistently ≥ LLOQ through 12 weeks of treatment (ie, nonresponse)
Relapse

HCV RNA ≥ LLOQ at posttreatment Week 12 having achieved HCV RNA < LLOQ at 
EOT
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
For analyses of HCV RNA < LLOQ at end of treatment and during the posttreatment (SVR) 
follow-up period, subjects will be assigned a value at end of treatment or posttreatment week 12
based on windows specified in Section 3.7.2. Missing values will be imputed based on the 
categorical imputation rules described in Section 3.5.1. The two-sided 95% exact CI based on 
Clopper-Pearson method will be provided for the percentage of subjects with HCV RNA 
< LLOQ at each visit by 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.
Summary statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 IU/mL), by genotype at EOT. Imputation rules described in Section 3.5.1 will be used to 
assign HCV RNA values for missing values at posttreatment week 12 that are bracketed by 
“< LLOQ TND” and/or “< LLOQ detected”. Otherwise, a missing = excluded analysis will be 
performed. 
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 or 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 at EOT HCV RNA measurement; otherwise, the 
denominator will be the number of subjects in the FAS.
6.3.
Changes From Protocol-Specified Efficacy Analyses
There are no planned changes from protocol-specified efficacy analyses.


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7.
SAFETY ANALYSES
7.1.
Safety Endpoints
The primary safety endpoint is any AE leading to permanent discontinuation of study drug(s).
7.2.
Adverse Events and Deaths
7.2.1.
Adverse Event Dictionary
Clinical and laboratory 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.
7.2.2.
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.
7.2.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE eCRF to the 
question of “Related to Study Treatment.” Events for which the investigator did not record the 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing from that captured on the 
eCRF.
7.2.4.
Serious Adverse Events
Serious adverse events (SAEs) 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.
7.2.5.
Treatment-Emergent Adverse Events
7.2.5.1.
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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7.2.5.2.
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 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 treatment emergent.
7.2.6.
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

AEs leading to interruption of SOF/VEL

Deaths


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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
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
7.3.
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 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 
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.


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A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology and serum chemistry 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.
7.3.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
for ALT, 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 Week 12 and FU-4

Change from baseline at Week 12 and FU-4
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 the reported number of digits and the SD will be displayed to the reported 
number of digits plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3.
7.3.2.
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.
7.3.2.1.
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. If the 
relevant baseline laboratory value is missing, then any abnormality of at least Grade 1 will be 
considered treatment emergent.
7.3.2.2.
Summaries of Laboratory Abnormalities
Categorical laboratory data will be summarized using the number and percentage of subjects in 
the study with the given response at baseline and each scheduled postbaseline visit.


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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.
7.4.
Body Weight, Height, and Vital Signs
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.
7.5.
Prior and 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 and stopped prior to or on the date of first study 
drug administration

Concomitant medications: any medications taken after the date of first study drug 
administration and up to the last dosing date of study drug. Prior and concomitant 
medications: any medications taken both prior to and on or after the initial study drug dosing 
date and within the treatment period (including the therapeutic reach of a study), or any 
medications taken prior to the baseline visit date with a stop date of “continuing”
Concomitant medications will be summarized by generic name of the drug 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 generic
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 date of the 
first dose of study drug or a start date that is after the date of the last dose of study drug will be 
excluded from a concomitant medication summary. If a partial stop date is entered on the eCRF, 
any medication with the month and year (if day is missing) or year (if day and month are 
missing) prior to the date of the first dose of study drug will be excluded from the concomitant 
medication summary. If a partial start date is entered, then any medication with the month and 


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year (if day is missing) or year (if day and month are missing) after the date of the last dose of 
study drug 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 study drug) will be provided in a by-subject 
listing sorted by subject ID number and administration date 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 planned changes from protocol-specified safety analyses.


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8.
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.
Weins BL, Lystig TC, Berry SM. Recent Statistical Contributions to Medical Device 
Development. Therapeutic Innovation & Regulatory Science 2013:1-8.
Yu ML, Chuang WL. Treatment of chronic hepatitis C in Asia: when East meets West. J 
Gastroenterol Hepatol. 2009;24 (3):336-45.


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9.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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10.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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11.
APPENDICES
Appendix 1.
Schedule of Assessments


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Appendix 1.
Schedule of Assessments
Appendix Table 1.
Screening, On-Treatment Visits
Screening2
(Day -28 to Day 0)
Baseline/Day 1
On-treatment Study Week (± 3 days)
Post-treatment Study Week 
(± 5 days)
Week 4
Week 8
End of Treatment 
Week 12 or ET1
Week 4
Week 12
Written Informed Consent
X
Medical History
X
X
Symptom-Directed Physical 
and Vital Signs if indicated
X
X
X
X
AEs and Concomitant 
Medications
X3
X
X
X
Review of Study Medication 
Compliance
X
Hematology, Chemistry, 
Coagulation
X
X
X
X
HCV RNA
X
X
X
X
HCV Genotyping
X
HIV testing, HCV and HBV 
Serology
X
Archive Sample
X
X
X
Cirrhosis determination
X
Urine Pregnancy Testing4
X
X
X
X
Study Medication Dispensation
X
X
X
1
ET = Early Termination
2
The screening window can be extended to 42 days prior to Day 1 for extenuating circumstances with sponsor approval
3
Concomitant medications and AE related to Screening Procedures only 
4
Females of child-bearing potential only