Clinical trial NCT02722837
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences
Start date: 2016-04-04; Completion date: 2017-09-13
Enrollment: 119 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to evaluate the efficacy, safety, and tolerability of treatment with sofosbuvir/velpatasvir (SOF/VEL) fixed-dose combination (FDC) for 12 weeks in participants 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 administered orally once daily

Protocol documents:
SAP_002.pdf: 
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Prot_001.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3, Open-label Study to Investigate the Efficacy and Safety of 
SofosbuvirNelpatasvir Fixed Dose Combination for 12 weeks in 
Subjects with Chronic Hepatitis C Vims (HCV) infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
This is a non-IND study 
2015-003001-42 
Not Available 
Hepatitis C Vims Infection 
GS-US-342-1522 
Gilead Study Director: 
Name: 
PPD 
t-'t-'U 
PPD 
t-'t-'U 
Gilead Medical 
Monitor: 
Telephone: 
Fax: 
Email: 
Name: 
Phone: 
Mobile: 
Fax: 
E-mail: 
Protocol Version/Date: 
Original: 
Amendment 1 
Anu Osinusi, MD 
PPD 
J 
t-'t-'U 
I 
PPD 
._____, 
PPD 
I 
17 July 2015 
03 December 2015 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pruiicularly unpublished data, is the prope1iy or 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 infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessruy to obtain infonned consent from those 
persons to whom the dmg may be administered. 


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 2
03 December 2015
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS......................................................................9
1.
INTRODUCTION ..............................................................................................................................................12
1.1.
Background ............................................................................................................................................12
1.2.
Sofosbuvir/Velpatasvir Fixed Dose Combination..................................................................................13
1.2.1.
General Information .............................................................................................................13
1.2.2.
Additional Clinical Pharmacology Study.............................................................................13
1.3.
Rationale for This Study ........................................................................................................................15
1.4.
Rationale for Dose Selection..................................................................................................................16
1.5.
Risk/Benefit Assessment for the Study..................................................................................................17
1.6.
Compliance ............................................................................................................................................17
2.
OBJECTIVES.....................................................................................................................................................18
3.
STUDY DESIGN................................................................................................................................................19
3.1.
Endpoints ...............................................................................................................................................19
3.2.
Study Design..........................................................................................................................................19
3.3.
Study Treatments ...................................................................................................................................19
3.4.
Visit Schedule ........................................................................................................................................19
3.5.
HCV Virologic Response-Based Treatment Stopping Criteria..............................................................20
3.6.
Treatment Discontinuation Criteria........................................................................................................20
3.7.
Biomarker Testing..................................................................................................................................21
3.7.1.
Biomarker Samples for Optional Future Research...............................................................21
3.7.2.
Biomarker Samples for Optional Pharmacogenomic Research............................................21
4.
SUBJECT POPULATION..................................................................................................................................23
4.1.
Number of Subjects and Subject Selection ............................................................................................23
4.2.
Inclusion Criteria....................................................................................................................................23
4.3.
Exclusion Criteria...................................................................................................................................25
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................27
5.1.
Enrollment and Study Drug supply........................................................................................................27
5.2.
Description and Handling of SOF/VEL FDC ........................................................................................27
5.2.1.
Formulation..........................................................................................................................27
5.2.2.
Packaging and Labeling .......................................................................................................27
5.2.3.
Storage and Handling...........................................................................................................27
5.2.4.
Dosage and Administration of SOF/VEL FDC....................................................................28
5.3.
Prior and Concomitant Medications.......................................................................................................28
5.4.
Accountability for SOF/VEL FDC.........................................................................................................29
5.4.1.
Investigational Medicinal Product Return or Disposal.........................................................30
6.
STUDY PROCEDURES ....................................................................................................................................31
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................31
6.2.
Pretreatment Assessments......................................................................................................................31
6.2.1.
Screening Visit (Day -28 to Day 0)......................................................................................31
6.2.2.
Day 1 Assessments...............................................................................................................33
6.3.
Treatment Assessments (± 3 days).........................................................................................................34


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 3
03 December 2015
6.4.
Week 12 (± 3 days) or Early Termination (ET) .....................................................................................34
6.5.
Unscheduled Visit ..................................................................................................................................35
6.6.
Post-Treatment Assessments (5 days).................................................................................................35
6.6.1.
Post treatment Week 4 (± 5 days).........................................................................................36
6.6.2.
Post treatment Weeks 12 and 24 (± 5 days) .........................................................................36
6.7.
End of Study...........................................................................................................................................36
6.8.
Procedures and Specifications................................................................................................................37
6.8.1.
Clinical Laboratory Analytes ...............................................................................................37
6.8.2.
Medical History....................................................................................................................37
6.8.3.
Complete Physical Examination...........................................................................................38
6.8.4.
Vital Signs............................................................................................................................38
6.8.5.
Creatinine Clearance ............................................................................................................38
6.8.6.
12-Lead ECGs......................................................................................................................38
6.8.7.
Viral RNA Sequencing / Phenotyping Sample.....................................................................39
6.8.8.
Health Related Quality of Life Survey (HRQoL).................................................................39
6.8.9.
Pregnancy Testing................................................................................................................39
7.
TOXICITY MANAGEMENT............................................................................................................................40
7.1.
Subject Stopping Rules ..........................................................................................................................40
8.
ADVERSE EVENTS..........................................................................................................................................41
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................41
8.1.1.
Adverse Events.....................................................................................................................41
8.1.2.
Serious Adverse Events........................................................................................................41
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................42
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................42
8.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................42
8.2.2.
Assessment of Severity ........................................................................................................43
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................43
8.4.
Gilead Reporting Requirements.............................................................................................................44
8.5.
Special Situations Reports......................................................................................................................45
8.5.1.
Definitions of Special Situations..........................................................................................45
8.5.2.
Instructions for Reporting Special Situations.......................................................................45
9.
STATISTICAL CONSIDERATIONS................................................................................................................48
9.1.
Analysis Objectives and Endpoints........................................................................................................48
9.1.1.
Analysis Objectives..............................................................................................................48
9.1.2.
Primary Endpoint .................................................................................................................48
9.1.3.
Secondary Endpoint .............................................................................................................48
9.1.4.
Safety Endpoints ..................................................................................................................48
9.1.5.
Other Endpoints of Interest ..................................................................................................49
9.2.
Analysis Conventions.............................................................................................................................49
9.2.1.
Analysis Sets ........................................................................................................................49
9.3.
Data Handling Conventions ...................................................................................................................49
9.4.
Demographic Data and Baseline Characteristics ...................................................................................50
9.5.
Efficacy Analysis ...................................................................................................................................51
9.5.1.
Primary Analysis..................................................................................................................51
9.5.2.
Secondary Analyses .............................................................................................................51
9.6.
Safety Analysis.......................................................................................................................................51
9.6.1.
Extent of Exposure...............................................................................................................51
9.6.2.
Adverse Events.....................................................................................................................52
9.6.3.
Laboratory Evaluations ........................................................................................................52


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 4
03 December 2015
9.6.4.
Other Safety Evaluations......................................................................................................53
9.7.
Sample Size............................................................................................................................................53
10.
RESPONSIBILITIES..........................................................................................................................................54
10.1.
Investigator Responsibilities ..................................................................................................................54
10.1.1.
Good Clinical Practice..........................................................................................................54
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................54
10.1.3.
Informed Consent.................................................................................................................54
10.1.4.
Confidentiality......................................................................................................................55
10.1.5.
Study Files and Retention of Records ..................................................................................55
10.1.6.
Case Report Forms...............................................................................................................56
10.1.7.
Investigational Medicinal Product Accountability and Return.............................................57
10.1.8.
Inspections............................................................................................................................57
10.1.9.
Protocol Compliance............................................................................................................57
10.2.
Sponsor Responsibilities ........................................................................................................................57
10.2.1.
Protocol Modifications.........................................................................................................57
10.2.2.
Study Report and Publications .............................................................................................58
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................58
10.3.1.
Payment Reporting...............................................................................................................58
10.3.2.
Access to Information for Monitoring..................................................................................58
10.3.3.
Access to Information for Auditing or Inspections ..............................................................59
10.3.4.
Study Discontinuation..........................................................................................................59
11.
REFERENCES ...................................................................................................................................................60
12.
APPENDICES ....................................................................................................................................................62
Appendix 1.
Investigator Signature Page....................................................................................................63
Appendix 2.
Study Procedures Table..........................................................................................................64
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............66
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................89
LIST OF IN-TEXT TABLES
Table 1-1.
Preliminary NGMN, NG, EE, and VEL Plasma PK Parameters Following 
Administration of NGM/EE alone or with VEL.....................................................................14
Table 1-2.
Preliminary Summary of LH, FSH, and Progesterone Concentrations Following 
Administration of NGM/EE alone or with VEL.....................................................................15
Table 5-1.
List of Disallowed /Use with Caution Medications................................................................29
Table 9-1.
SVR 12 Rates and Associated 95% Confidence Intervals......................................................53


SOFNELFDC 
Protocol GS-US-342-1522 
Gilead Sciences, Inc. 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
Final 
Amendment 1 
Study Title: 
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 Vims (HCV) infection 
IND Number: 
This is a non-IND study 
EudraCT Number: 
2015-003001-42 
Clinical Trials.gov 
Identifier: 
Not Available 
Study Centers Planned: 
Approximately 12 sites in the Russian Federation and Sweden 
Objectives: 
The primruy objectives of this study ru·e: 
CONFIDENTIAL 
• 
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 prop01iion of subjects with sustained viral response 
12 weeks after cessation of treatment (SVR12) 
• 
To evaluate the safety and tolerability of treatment with 
SOFIVEL for 12 weeks 
The secondruy objectives of this study ru·e: 
• 
To detennine the prop01iion of subjects who attain SVR at 4 and 
24 weeks after cessation of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during 
treatment and after cessation of treatment 
• 
To evaluate the emergence of viral resistance to SOF and VEL 
during u·eatment and after cessation of u·eatment 
The explorat01y objectives of this study are: 
I 
Page5 
03 December 2015 


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 6
03 December 2015
Study Design:
Multi-center, open-label study. Approximately 120 subjects with 
chronic HCV will be enrolled. 
All subjects will receive SOF/VEL FDC once daily for 12 weeks.
Sub study:
Pharmacogenomics (PG) Substudy
In consenting participants, a PG blood sample should be drawn at 
the Baseline/Day 1 visit. If not obtained at Baseline/Day1 visit, the 
sample may be drawn at any time during the study.
Number of Subjects 
Planned:
Approximately 120 subjects
Target Population:
Chronic hepatitis C virus (HCV) infected adults. 
Duration of 
Treatment:
12 Weeks
Diagnosis and Main 
Eligibility Criteria:
Chronic hepatitis C virus (HCV) infected adults. Up to 
approximately 20% of subjects may have cirrhosis at baseline and 
up to approximately 20% may be treatment-experienced. 
Sections 4.2 and 4.3 of the protocol contain detailed Inclusion and 
Exclusion criteria.
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the 
Baseline/Day 1 visit. 
All subjects will complete the following study visits: Screening, 
Baseline/Day 1, on-treatment visits at the end of Weeks 1, 2, 4, 8, 
and 12. All subjects will complete the post treatment Week 4 visit. 
Subjects who achieve SVR4 will complete post treatment Week 12 
and Week 24 visits unless confirmed viral relapse occurs. Viral 
breakthrough or relapse must be confirmed.  
Screening assessments will include physical examination, medical 
history, height, weight, vital signs, 12-lead ECG, adverse events 
related to screening procedures, concomitant medications, safety 
laboratory tests (including hematology, chemistry, and coagulation), 
HCV RNA, HCV genotype, serology (HIV, HCV, HBV), 
hemoglobin A1c (HbA1c), assessment of the presence or absence of 
cirrhosis, imaging for HCC, serum β-hCG (females of child bearing 
potential only), urinalysis and urine drug screen.


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 7
03 December 2015
On-treatment assessments include adverse events (AEs), 
concomitant medications, study medication pill count, physical 
examination, weight, vital signs, safety laboratory tests, IL28B 
genotyping ( Day 1), HCV RNA, and urine pregnancy tests 
(females of child bearing potential only). 
Single 12-lead ECGs will be collected at Baseline/Day 1 (prior to 
study drug administration) and at Week 1 and Week 12 or End of 
Treatment.  At the time of ECG collection, printed copies (paper) 
will be reviewed by qualified study staff (as determined by the 
Investigator) and compared to the subject’s Baseline ECG as part of 
routine safety monitoring.
Post-treatment assessments include AEs, concomitant medications, 
vital signs, safety laboratory tests, HCV RNA, and urine pregnancy 
tests (females of child bearing potential only).
Health Related Quality of Life (HRQoL) survey SF-36 will be 
completed at Baseline/Day 1, On-treatment Week 4 and Week 12 or 
Early Termination (if applicable), and post treatment Week 4, and 
12 (if applicable).
Samples for HCV RNA sequencing/phenotyping will be collected at 
Day 1 and every visit thereafter. 
For subjects who provide their additional and specific consent, an 
optional blood sample will be collected at the Baseline/Day 1 visit 
for PG (this sample may be drawn after Baseline/Day 1 if 
necessary).
At the following visits an optional plasma sample may be collected 
and archived for future use: Baseline/Day 1 and Week 12 or ET 
visit. Subjects may opt out of archive sample collection.
Test Product, Dose, and 
Mode of 
Administration:
SOF/VEL fixed dose combination (FDC) is manufactured as a 
400 mg/100 mg FDC tablet for oral administration. Subjects will 
take 1 tablet daily with or without food.
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 using the COBAS® AmpliPrep®/COBAS®
TaqMan® HCV Quantitative Test, v2.


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 8
03 December 2015
Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all enrolled 
and treated subjects. No hypothesis testing will be performed.
Secondary efficacy endpoints include SVR4 and SVR24.
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) by 
stratification within group (as appropriate). All categorical 
endpoints will be summarized by 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.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 9
03 December 2015
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)
DDI
drug-drug interaction
dL
deciliter
DSPH
Drug Safety and Public Health
ECG
electrocardiogram
eCRF
electronic case report form(s)
ESA
erythropoiesis stimulating agent
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 
GCSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GS-7977
formerly PSI-7977
GSI
Gilead Sciences, Inc.


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 10
03 December 2015
GT
genotype (viral)
Hb
Hemoglobin
HbA1c
hemoglobin A1c
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
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
mg
milligram
mIU
milli international units
mL
milliliter
mmHg
millimeters mercury
ng
nanogram
ng•h/mL
nanograms times hours per milliliter
NG
norgestrel
NGM
norgestimate 
NGM/EE
norgestimate/ethinyl estradiol
NGMN
norelgestromin


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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 
PPI
proton pump inhibitor
PT
preferred term or prothrombin time 
QD
once daily (use only in tables)
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
TPO
thrombopoietin
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 {28346}. In the United States (US), approximately 
2.7 million people have chronic HCV infection {28338} and HCV infection causes over 
15,000 deaths each year {20446}, 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 
{28339}. Successful treatment of chronic HCV infection reduces the need for liver transplant, the 
incidence of HCC and overall mortality {25891}. 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 {27503}.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 {28583}, 
{28585}, {28587}.
Most current HCV drug development effort focuses on GT1 HCV infection as this is the most 
prevalent HCV genotype in developed countries {32174}. 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
SOF/ velpatasvir (VEL) fixed-dose combination (SOF/VEL FDC) combines two HCV specific 
direct acting antivirals (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 VEL100 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 for Phase 3 evaluation that has demonstrated 
similar exposure of each component compared to co-administration of the single agents.  
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.
Additional Clinical Pharmacology Study
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 OC 
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 
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. 


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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 {13886}, 
{24911}. VEL exposures were consistent with historical data (Studies GS-US-281-0115, 
GS-US-342-0104).
Table 1-1.
Preliminary 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)
0.89 (0.85, 0.94)
Cmax (pg/mL)
1650 (16.8)
1600 (13.7)
0.97 (0.90, 1.04)
Ctau (pg/mL)
454 (18.5)
416 (14.3)
0.92 (0.86, 0.98)
Norgestrel
AUCtau (pg•h/mL)
47,000 (34.4)
43,000 (32.4)
0.91 (0.73, 1.14)
Cmax (pg/mL)
2410 (30.6)
2330 (31.5)
0.96 (0.80, 1.17)
Ctau (pg/mL)
1760 (34.4)
1640 (35.7)
0.92 (0.74, 1.15)
Ethinyl Estradiol
AUCtau (pg•h/mL)
666 (30.7)
686 (27.3)a
1.06 (0.98, 1.14)
Cmax (pg/mL)
57.5 (27.3)
80.0 (28.4)a
1.42 (1.28, 1.58)
Ctau (pg/mL)
14.8 (39.3)
12.4 (43.9)a
0.84 (0.77, 0.92)
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 {25217}, {25218}, {25219}. Follicle stimulating hormone was lower or 
within the expected range for the ovulatory phase {25218}. 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.
Preliminary 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 (2.9, 12.7)
9.3 (5.4, 14.4)
FSH (mIU/mL)
3.6 (2.0, 5.9)
2.6 (2.2, 5.1)
Progesterone (ng/mL)
0.24 (0.17, 0.39)
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. 
1.3.
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 120 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.
In Russia, the prevalence of HCV is estimated to be 4.1% {32174}, or approximately 4.9 million 
adults positive for antibody to-HCV. Although GT1 is the most common genotype in Russia, 
with a prevalence estimated at 55%, GT3 accounts for approximately 35% and GT2 for 
approximately 8% of infections {32174}. Anti-HCV prevalence is lower in Sweden (0.7% of 
adults) and the most common genotypes are similar to Russia: 45% GT1, 34% GT3, 19% GT2, 
and 2% GT4 {32174}. A single pangenotypic regimen would be of benefit for these diverse HCV 
populations. 
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. 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.


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Phase 2 evaluation of SOF + VEL demonstrated that co-administration of the single agents for 
8 or 12 weeks was well tolerated and resulted in high SVR rates across a broad range of HCV 
genotypes. In the Phase 2 study GS-US-342-0102, administration of SOF 400mg + VEL 100mg 
for 12 weeks to treatment-naïve subjects without cirrhosis with genotype 1, 2, 3, 4, or 6 HCV 
infection resulted in SVR12 rate of 100% (28/28), 100% (10/10), 93% (25/27), 86% (6/7), and 
100% (5/5), respectively. In addition, one treatment naïve subject with genotype 5 HCV 
infection administered SOF +VEL 25mg for 12 weeks achieved SVR12. The GS-US-342-0109 
study evaluated SOF + VEL with and without RBV in populations of patients considered more 
difficult to cure, including subjects who had failed a prior interferon based regimen and those 
with cirrhosis. Administration of SOF 400mg + VEL 100 mg for 12 weeks resulted in SVR12 
rates of 88% (23/26) and 100% (27/27) in treatment experienced subjects with genotype 3 HCV 
infection with and without cirrhosis, respectively. Administration of SOF 400mg + VEL 100mg 
for 12 weeks resulted in an SVR4 rates of 100% (27/27) in subjects with genotype 1 HCV 
infection who had failed prior treatment with a protease inhibitor with Peg-IFN/RBV. Seven of 
these 27 subjects had cirrhosis. 
The Phase 2 data suggest that SOF +VEL 100mg has the potential to cure HCV infected patients 
across a broad range of HCV genotypes, when administered for 12 weeks without RBV and 
regardless of prior treatment experience or cirrhosis status. The co-formulation of SOF/VEL
(400 mg/100 mg) adds to the simplicity of the regimen in allowing for a once daily pill. 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 Russia 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.  
1.4.
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
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, has been selected for co-formulation with VEL into a fixed-dose combination tablet.
VEL 100 mg has been 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 and evaluation in this study 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. 


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The favorable safety and efficacy profiles of SOF 400 mg and VEL 100 mg support further 
evaluation of this combination in clinical development.
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 over the current standard of care 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 clinical safety issues 
specifically related to SOF have been identified to date. 
The safety profile of SOF/VEL has not been established. The safety profile of SOF + VEL 25mg 
or VEL 100mg administered for 8 or 12 weeks has been established in over 800 subjects in 
Phase 2 studies. The safety profile of the proposed therapeutic regimen of SOF 400mg and VEL
100mg administered for 12 weeks has been established in 237 subjects enrolled in Phase 2 
studies. No clinical safety issues specifically related to 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 {28583}, {28585}, {28587}.
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 
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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OBJECTIVES 
The prima1y objectives of this study are: 
Final 
Amendment 1 
• 
To evaluate the efficacy of treatment with SOFNEL fixed dose combination (FDC) for 
12 weeks in subjects with chronic HCV infection as measmed by the prop01iion of subjects 
with sustained viral response 12 weeks after cessation of treatment (SVR12) 
• 
To evaluate the safety and tolerability of treatment with SOFNEL for 12 weeks 
The secondmy objectives of this study m·e: 
• 
To determine the prop01iion of subjects who attain SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA dming treatment and after cessation of 
treatment 
• 
To evaluate the emergence of viral resistance to SOF and VEL dming treatment and after 
cessation of treatment 
The explorat01y objectives of this study are: 
PPO 
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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoints of this study are:

Primary efficacy endpoint is SVR12 in all enrolled subjects after 12 weeks of SOF/VEL
treatment

Primary safety endpoint  is Safety and tolerability after 12 weeks of SOF/VEL treatment  and 
AE leading to drug discontinuation 
Secondary endpoints of this study are:

SVR4 and SVR24 in all enrolled subjects after 12 weeks of SOF/VEL treatment

Kinetics of HCV virus 

Emergence of the viral resistance after 12 weeks of treatment and resistance associated 
variants
3.2.
Study Design
This is a multi-center, 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.
3.3.
Study Treatments
Approximately 120 subjects will be enrolled to receive: SOF/VEL (400 mg/100 mg) once daily 
for 12 weeks.
Up to 20% of subjects enrolled in the study may have cirrhosis at baseline and up to 
approximately 20% may be treatment-experienced.
3.4.
Visit Schedule 
All subjects will complete the following study visits: Screening, Day 1, On-Treatment visits at 
the end of Weeks 1, 2, 4, 8, and 12, and Post-Treatment Visits at Weeks 4, 12, and 24 following 
the last dose of study drug. Subjects who achieve SVR4 will complete post treatment Week 12 
and Week 24 visits unless confirmed viral relapse occurs. Viral breakthrough or relapse must be 
confirmed
Screening assessments will be completed within 28 days of the Day 1 Visit. The screening 
window can be extended to 42 days prior to Day 1 in extenuating circumstances with sponsor 
approval.  


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The assessments performed at each visit are described in Section 6 and Appendix 2.
3.5.
HCV Virologic Response-Based Treatment Stopping Criteria
The following on-treatment HCV virologic response-based treatment stopping criteria will be 
utilized:

Confirmed HCV RNA ≥ LLOQ after 2 consecutive HCV RNA < LLOQ

Confirmed > 1 log10 increase from nadir

HCV RNA ≥ LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible and must occur no later than 2 weeks after 
an initial observation indicating virologic failure. 
All subjects will complete the post treatment Week 4 visit. Subjects who achieve SVR4 will 
complete post treatment Week 12 and Week 24 visits unless confirmed viral relapse occurs.
3.6.
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:

Unacceptable toxicity, as defined in Section 7.1 of the protocol, or toxicity that, in the 
judgment of the investigator, compromises the ability to continue study-specific procedures 
or is considered to not be in the subject’s best interest

Pregnancy of female subject

Efficacy failure as defined in Section 3.5

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 Early Termination 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 
visit. 


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Biomarker Testing 
3.7. 
3.7.1. 
Biomarker Samples for Optional Future Research 
PPD 
3.7.2. 
Biomarker Samples for Optional Pharmacogenomic Research 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 120 chronic HCV subjects will be enrolled in this study with up to approximately 
20% of subjects having cirrhosis at baseline and up to approximately 20% being
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 104 IU/mL at Screening.
4) HCV genotype 1, 2, 3, 4, 5, 6 assessed at Screening by the Central Laboratory. 
5) Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy.
6) 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.  
Subject must not have discontinued the prior regimen that resulted in virologic 
failure due to an adverse event.
The subject’s medical records must include sufficient detail of prior virologic failure to 
allow for categorization of prior response (See Section 6.2.1), as either:
(1) Non-Responder: Subject did not achieve undetectable HCV RNA levels while on 
treatment, or 
(2) Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during 
treatment or within 4 weeks of the end of treatment but did not achieve SVR.


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7) 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) FibroTest® score > 0.75 AND an AST:platelet ratio index (APRI) > 2 during 
Screening
iii) Fibroscan® with a result of >12.5 kPa 
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) FibroTest score ≤ 0.48 AND APRI ≤ 1 performed during Screening
iii) Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Day 1
In the absence of a definitive diagnosis of presence or absence of cirrhosis by FibroTest,
APRI using the above criteria, a liver biopsy or Fibroscan is required. Liver biopsy results 
will supersede FibroTest, APRI or Fibroscan results and be considered definitive.
8) Liver imaging within 6 months of Day 1 is required only in cirrhotic patients to exclude 
hepatocellular carcinoma (HCC).
9) Females of childbearing potential (as defined in Appendix 4) must have a negative serum 
pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to enrollment.
10) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in
Appendix 4.
11) Lactating females must agree to discontinue nursing before the study drug is administered.
12) Subject must be of generally good health, with the exception of chronic HCV infection, as 
determined by the Investigator.
13) 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; 
subjects currently under evaluation for a potentially clinically-significant illness (other 
than HCV) are also excluded 
b) Gastrointestinal disorder or post-operative condition that could interfere with the 
absorption of the study drug
c) Clinical hepatic decompensation (ie, ascites, encephalopathy or variceal hemorrhage)
d) Solid organ transplantation
e) Significant pulmonary disease, significant cardiac disease or porphyria
f)
Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of 
their psychiatric illness within the last 5 years. Subjects with psychiatric illness (without 
the prior mentioned conditions) that is well-controlled on a stable treatment regimen for 
at least 6 months prior to Day 1 or has not required medication in the last 12 months may 
be included. 
g) Malignancy within the 5 years prior to screening, with the exception of specific cancers 
that have been cured by surgical resection (basal cell skin cancer, etc).  Subjects under 
evaluation for possible malignancy are not eligible.
h) Significant drug allergy (such as anaphylaxis or hepatotoxicity).
2) Screening ECG with clinically significant abnormalities
3) Any of the following laboratory parameters at screening: 
a) ALT > 10 the upper limit of normal  (ULN)
b) AST > 10 ULN
c) Direct bilirubin > 1.5 ULN
d) Platelets < 50,000/L
e) HbA1c > 8.5% 


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f)
Creatinine clearance (CLcr) < 60 mL /min as calculated by the Cockcroft-Gault equation 
{2202}
g) Hemoglobin < 11 g/dL for female subjects; < 12 g/dL for male subjects.
h) Albumin < 3 g/dL 
i)
INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR
4) Prior exposure to SOF or other nucleotide analogue HCV NS5B inhibitor or any HCV NS5A 
inhibitor
5) Pregnant or nursing female or male with pregnant female partner 
6) Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, alfa-1 
antitrypsin deficiency, cholangitis).
7) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
8) Clinically-relevant alcohol or drug abuse within 12 months of screening. A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator.
9) Use of any prohibited concomitant medications as described in Section 5.3.
10) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone 
equivalent > 10 mg/day).
11) 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 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:

Hematologic stimulating agents (eg, erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Chronic systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (eg, infliximab)

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), Atorvastatin, 
Simvastatin, Pravastatin, Pitavastatin, 
Fluvastatin, Lovastatin
Other
Modafinil b, Sulfasalazinec, Methotrexatec
a
The 21 day washout period does not apply to proton pump inhibitors (PPIs), which can be taken up to 7 days before Day 1. 
H2-receptor antagonists must not exceed a dose of 20 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. Monitor for signs and 
symptoms of muscle weakness or myopathy, including rhabdomyolysis.
Medications for disease conditions excluded from the protocol (eg, HIV-1 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 EOT visit. 
5.4.1.
Investigational Medicinal Product Return or Disposal
Please refer to Section 10.1.7 for Investigational Medicinal Product Accountability and Return.


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6.
STUDY PROCEDURES
Study procedures to be conducted for each subject enrolled in the study are presented in tabular 
form in Appendix 2 and described briefly in the text that follows. All eligible subjects will 
complete Screening, Day 1, On-Treatment visits at the end of Weeks 1, 2, 4, 8, and 12, and Post 
Treatment Visits at Weeks 4, 12, and 24, as appropriate. Subjects who achieve SVR4 will 
complete post treatment Week 12 and Week 24 visits unless confirmed viral relapse occurs. 
Viral breakthrough or relapse must be confirmed
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 for 
12 weeks. 
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit (Day -28 to Day 0)
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
— A separate informed consent will be required from subjects participating in the PG
sub-study

Obtain medical history, including information on prior HCV treatment history 
— If treatment experienced, record the duration of the prior treatment and the type of
interferon and/or ribavirin or DAA administered 
— Record whether the subject had a Non-response or Relapse/Breakthrough during prior 
treatment as defined in inclusion criterion #6 (Section 4.2)

Obtain demographic information

Perform complete physical examination including vital signs, body weight, and height

Perform 12-lead ECG


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
Obtain details on AEs related to screening procedures (See Section 8 for details)

Obtain details of concomitant medications

Obtain blood samples for 
— Hematology and chemistry tests
— Coagulation tests
— HCV RNA (quantitative) 
— HCV genotype 
— Fibrotest
— HCV antibody, HIV 1/2 antibody, and HBV surface antigen (HBsAg)
— HbA1c
— Serum β-human chorionic gonadotropin (-hCG) pregnancy test, for females of 
childbearing potential only

Obtain urine sample for
— Urinalysis
— Drug screen

Determine cirrhosis status
— If the presence of cirrhosis cannot be determined based on medical history or screening 
lab tests, biopsy or Fibroscan® should be performed 
— 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 28-42 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).  


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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 2).
At the Day 1 visit, complete the following:

Confirm eligibility

Perform complete physical examination, including vital signs and body weight

Perform 12-lead ECG

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counseling

Obtain blood samples for:
— Hematology and chemistry
— Coagulation tests
— HCV RNA(quantitative)
— Viral RNA sequencing / phenotyping 
— IL28B genotype 
— Biomarker archive sample (for subjects who have not opted out)
— Pharmacogenomic testing (for subjects who have consented to participate in the PG
substudy)

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

Health Related Quality of life survey, SF-36


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6.3.
Treatment Assessments (± 3 days)
The following treatment procedures/assessments are to be completed at the end of Weeks 1, 2, 4,
and 8, for all subjects (see Appendix 2).

Obtain vital signs

Perform 12-lead ECG (at Week 1 only)

Assessment of AEs and concomitant medications

Obtain blood samples for:
— Hematology & chemistry
— HCV RNA
— Viral RNA sequencing / phenotyping sample

Obtain urine sample for -hCG pregnancy test for females of childbearing potential only
(Weeks 4,and 8 )

Conduct pregnancy prevention counseling at Week 4 only

Review study drug compliance and drug administration instructions with subject
— Reconcile study drug administration using pill counts

Dispense study drugs as directed by the IWRS ( Weeks 4 and 8 only)

Health Related Quality of life survey, SF-36 ( Week 4 only)
6.4.
Week 12 (± 3 days) or Early Termination (ET) 
If a subject discontinues treatment early for any reason they should complete the Early 
Termination Visit assessments then the Post-Treatment Week 4 visit (4 weeks following the last 
dose of the study drug) should be completed (see Appendix 2).
The following procedures/assessments are to be completed at the Week 12 /Early termination 
Visit as applicable:

Perform complete physical examination

Obtain body weight

Obtain vital signs


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
Perform 12-lead ECG

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Obtain blood samples for:
— Hematology & chemistry
— Coagulation tests
— HCV RNA
— Viral RNA sequencing / phenotyping sample
— Biomarker archive sample (for subjects who have not opted out)

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
— Study drug should be returned at this visit

Health Related Quality of life survey, SF-36 
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, but the investigator should 
at a minimum collect AE and concomitant medication information. At all unscheduled visits 
initiated for the purpose of confirming virologic failure, a viral RNA sequencing / phenotyping 
sample must be collected.
6.6.
Post-Treatment Assessments (5 days)
All subjects will complete the Post-treatment Week 4 visit. Subjects who achieve SVR4 will 
complete post treatment Week 12 and Week 24 visits unless confirmed viral relapse occurs. The 
Post Treatment visits must be scheduled relative to the date of last administration of study drug
(see Appendix 2).


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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:

Obtain weight and vital signs

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Obtain blood samples for:
— Hematology &chemistry
— HCV RNA
— Viral RNA sequencing / phenotyping sample

Obtain urine sample for:
— β -hCG pregnancy test for females of childbearing potential only

Health-related quality of life questionnaire, SF-36
Subjects with HCV RNA < LLOQ at the post treatment Week 4 visit will return for the post
treatment Week 12 visit.
6.6.2.
Post treatment Weeks 12 and 24 (± 5 days)
The following procedures/assessments are to be completed for post treatment Weeks 12 and 24:

Obtain blood samples for:
— HCV RNA
— Viral RNA Sequencing / Phenotyping Sample

Health Related Quality of life survey, SF-36 (post treatment Week 12 only) 

Subjects with HCV RNA < LLOQ at the post treatment Week 12 visit will return for the post 
treatment Week 24 visit unless confirmed viral relapse occurs.
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.
Subjects are considered to have completed the study after the completion of Post Treatment 
Week 24 visit.


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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, Creatine Kinase , Creatinine, Total Bilirubin (reflex to Direct 
Bilirubin), Glucose, Lipase, Potassium, Sodium, Fibrotest, APRI calculation and Direct Bilirubin 
at Screening only.
Urinalysis: Appearance, Blood, Color, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV and HBV. Serology and/or antigen testing for HIV,
including reflex testing, as necessary. HCV RNA will be measured using the COBAS®
AmpliPrep®/COBAS® TaqMan® HCV Quantitative Test, v2. HCV genotype and subtype will be 
determined using the Siemens VERSANT® HCV Genotype INNO-LiPA 2.0 Assay. Gilead 
reserves the right to use alternate assays for HCV RNA and HCV genotype should the above 
assays become unavailable.
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the 
SNP, rs12979860, with sequence specific forward and reverse primers and allele specific 
fluorescently labeled TaqMan® MGB probes. Gilead reserves the rights to use an alternate assay 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum β-hCG or Urine β-hCG 
Additional Tests: Urine Drug screen (for Amphetamines, Cocaine, Methadone, Opiates) and 
Hemoglobin A1c (HbA1c)
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 
(per Section 6.2.1), will be collected on all subjects during screening.


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6.8.3.
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and 
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological. Assessments by other specialists are not required unless 
medically indicated.
6.8.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.8.5.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} 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)
6.8.6.
12-Lead ECGs
Subjects will be required to rest in a supine position for 5 minutes prior to making a recording.
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities.  On-treatment ECGs should be compared to the subject’s 
baseline as part of routine safety monitoring.  


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6.8.7.
Viral RNA Sequencing / Phenotyping Sample
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
At any unscheduled visit initiated for the purpose of confirming virologic breakthrough, a viral 
sequence analysis plasma sample must be collected.
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual.
6.8.8.
Health Related Quality of Life Survey (HRQoL)
A HRQoL survey, the short form 36 or SF-36 survey, will be completed by subjects at Day 1, 
On-Treatment visit at Weeks 4 and 12; Post-Treatment visits at Weeks 4 and 12 (if applicable),
and Early Termination (if applicable).  The subject should read the questionnaire by 
himself/herself and write/mark answers directly onto the questionnaire.
6.8.9.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every 4 weeks during the 
dosing period and 4 weeks after last dose of study drug (post treatment Week 4). Confirmatory 
serum pregnancy testing should be performed after any positive urine pregnancy test.  


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7.
TOXICITY MANAGEMENT
7.1.
Subject Stopping Rules
Administration of all study medication(s) may be discontinued in the event of a clinical or 
laboratory event. The Gilead Medical Monitor must be consulted prior to dose discontinuation of 
SOF/VEL unless the investigator believes that immediate action is warranted to ensure the 
continued safety of the subject.
There is no option for dose reduction of SOF/VEL. 
Subjects who meet any of the following laboratory criteria must stop the study medication:

Elevation of ALT and/or AST > 5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT > 3 x Day 1 and total bilirubin > 2 x ULN, confirmed by 
immediate repeat testing

Elevation of ALT > 15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event or laboratory abnormality assessed (and confirmed by immediate 
repeat testing) as related to SOF/VEL. 
Refer to Section 3.6 for information regarding discontinuation


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8.
ADVERSE EVENTS 
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
8.1.1.
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, 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 8.5)

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 
eCRF.
8.1.2.
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.
8.1.3.
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 8.1.1 and 8.1.2. 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 Section 8.1.3.
8.2.
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.
8.2.1.
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)
8.2.2.
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.
8.3.
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 (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 4 weeks 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 
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 
consent is signed.
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. 


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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the
eCRF completion guideline. 
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:
Safety_FC@gilead.com
Fax:
+1 650-522-5477

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 eCRF and the event description section of the SAE form.
8.4.
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 


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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. 
8.5.
Special Situations Reports
8.5.1.
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.  
8.5.2.
Instructions for Reporting Special Situations
8.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy.


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Refer to Section 8.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (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 
Sections 8.3. 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 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: Safety_FC@gilead.com and Fax: +1 (650) 522-5477.
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 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 
+1 650 522-5477 or email Safety_FC@gilead.com.
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
8.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.


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Refer to Section 8.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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9_ 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Objectives and Endpoints 
9.1.1. 
Analysis Objectives 
The prima1y objectives of this study are: 
Final 
Amendment 1 
• 
To evaluate the efficacy of treatment with SOFNEL 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 SOFNEL for 12 weeks 
The secondmy objectives of this study m·e: 
• 
To detennine the prop01iion of subjects who attain SVR4 and SVR24 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 
• 
To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment 
The explorat01y objectives of this study are: 
PPO 
I 
9.1.2. 
Primary Endpoint 
The prima1y efficacy endpoint is SVR12 in the Full Analysis Set (F AS). 
9.1.3. 
Secondary Endpoint 
Secondary efficacy endpoints include the prop01i ion of subjects with HCV RNA < LLOQ at 4 
and 24 weeks after discontinuation of therapy (SVR4 and SVR24), the prop01iion of subjects 
with HCV RNA < LLOQ on treatment, HCV RNA change from Day 1, and the prop01iion of 
subjects with virologic failure. 
9.1.4. 
Safety Endpoints 
The prima1y safety endpoint is any AE leading to pennanent discontinuation of the study dmg. 
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9.1.5. 
Other Endpoints of Interest 
PD 
9.2. 
Analysis Conventions 
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All individual subject data will be listed as measured. All statistical summaries and analyses will 
be perfonned using SAS® software (SAS Institute, Cruy, North Cru·olina, USA). 
The study dmg in this study is SOFNEL. Last dose of study dmg refers to the last dose of any of 
the study dtugs in a treatment group and will be used in the defmition of treatment-emergent AEs 
and laborat01y abnonnalities as well as the efficacy endpoints of SVR at vru·ious post-treatment 
time points. 
9.2.1. 
Analysis Sets 
9.2.1.1. 
Efficacy 
The analysis set for antiviral activity analyses will be the F AS which include all em olled subjects 
who took at least 1 dose of study dt11g. 
9.2.1.2. 
Safety 
The Safety Analysis Set will include all subjects who took at least 1 dose of study dtug. 
Treatment-emergent data will be analyzed and defmed as data collected from the first dose of 
study dtu g through the date of last dose of study dt11g plus 30 days. 
9.3. 
Data Handling Conventions 
Missing data can have an impact upon the inte1p retation of the trial data. Other than the 
endpoints discussed below, values for missing data will not be imputed. 
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed up to 
the time of the last dose. 
If a data point is missing and is preceded and followed in time by values that ru·e "< LLOQ tru·get 
not detected (TND)", then the missing data point will be set to"< LLOQ TND". If a data point is 
missing and preceded and followed by values that are"< LLOQ detected", or preceded by 
"< LLOQ detected" and followed by "< LLOQ TND", or preceded by"< LLOQ TND" and 
followed by "< LLOQ detected", then the missing value will be set to"< LLOQ detected". In 
these situations the data point will be tenned a bracketed success; othe1w ise, the data point will 
be te1m ed a bracketed failure (ie,:::: LLOQ detected). If a data point is missing and is not 
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bracketed, the missing data point will also be termed a failure (ie, ≥LLOQ detected) except for 
SVR24, which will be imputed according to SVR12 status. Success for SVR12 who have no 
further HCV RNA measurements collected will be counted as a success for SVR24 due to the 
high correlation between these 2 endpoints.
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of adverse 
events according to the treatment received; otherwise, if the subject is not dosed then they 
will be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of 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 Day 1 result 
will be replaced with a screening result, if available. If no pre-treatment laboratory value is 
available, the Day 1 value will be assumed to be normal (ie, no grade [Grade 0]) for the summary 
of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing Day 1 result will be 
replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
calculation of summary statistics for the actual HCV RNA values and the change from Day 1 
values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to 
the logarithmic (base 10) scale (log10 IU/mL).
9.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, self-identified race/ethnicity, and age.
Baseline data will include body mass index, HCV RNA level (log10 IU/mL), HCV genotype, 
IL28B genotype, and additional endpoints as necessary.


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9.5. 
Efficacy Analysis 
9.5.1. 
Primary Analysis 
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The prima1y efficacy endpoint is SVR12 in the F AS. The primruy analysis will be perfonned 
after all emolled subjects have been followed through 12 weeks post-treatment or discontinued 
from study. 
In the prima1y efficacy analysis, the SVR12 rate will be calculated along with the two-sided 95% 
exact confidence interval constmcted using the binomial distribution (Clopper-Peru·son method) 
{20839}. No statistical hypothesis testing will be perf01m ed. 
9.5.2. 
Secondary Analyses 
The proportion of subjects with HCV RNA below the LLOQ over time 
(including SVR endpoints) will be presented in tabulru· and gl'aphical f01m . 
Descriptive summru·ies and listings will be provided for additional efficacy evaluations of the 
prop01iion of subjects who experience virologic failure, HCV RNA actual values and chan e 
from baseline, and other endpoints of interest including PPD 
~------------------------~ 
Exj)loratOiy analyses may be erfonned to assess the relationshi 
9.6. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laborat01y, physical examinations, and vital 
signs measurements at various time points during the study, and by the documentation of AEs. 
The prima1y analysis will be the prop01iion of patients who experienced an AE leading to 
treatment discontinuation. 
All safety data collected on or after the first dose of study dmg administration up to 30 days after 
the last dose of study dmg will be suminru·ized. 
9.6.1. 
Extent of Exposure 
A subject's extent of exposure to study dmg will be generated from the study dmg 
administration page of the CRF. 
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9.6.2.
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 an onset date 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 drug. 
Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC and preferred term) will be provided for:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs

All treatment-related SAEs 

All AEs leading to premature discontinuation of study drug
All AEs collected during the course of the study will be presented in data listings
9.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) at each study visit along with corresponding change from Day 1.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
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. 


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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 Day 1 value will be assumed to be normal (ie, no grade [Grade 0]) for the summary 
of graded abnormality.
All laboratory abnormalities will be included in the listings of laboratory data.
9.6.4.
Other Safety Evaluations
Individual data for vital signs measurements will be listed by subject and summarized by 
incidence of events/abnormalities or descriptive statistical summaries (n, mean, SD, median, Q1, 
Q3, minimum, and maximum), as appropriate.
9.7.
Sample Size
With a sample size of 120, the 95% exact confidence interval for different observed SVR12 rates 
are presented in the Table 9-1 below:
Table 9-1.
SVR 12 Rates and Associated 95% Confidence Intervals
Observed SVR12 rate
2-sided 95% exact CI
80% (96 out of 120) 
72% - 87%
85% (102 out of 120) 
77% - 91%
95% (114 out of 120) 
89% - 98%


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
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, South Africa, 
Washington DC, Seoul, and Brazil), International Conference on Harmonisation (ICH) 
guidelines, or with the laws and regulations of the country in which the research is conducted, 
whichever affords the greater protection to the study subject. These standards are consistent with 
the European Union Clinical Trials Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
10.1.2.
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.
10.1.3.
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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The pharmacogenomics consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
10.1.4.
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. NOTE: The investigator must keep a screening log showing 
codes, names, and addresses for all subjects screened and for all subjects enrolled in the trial.
Subject data will be processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
10.1.5.
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);


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
Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
10.1.6.
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 


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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 
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 10.1.5.
10.1.7.
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.
10.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB /IEC or to regulatory authority or health authority 
inspectors.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.    
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. All substantial protocol modifications will be reviewed and approved by 
the local competent authority in accordance with local requirements prior to implementation of 
any changes. In addition, the investigator must submit all protocol modifications to the IRB or 
IEC in accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented.


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10.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies. 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 10.1.4).
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.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
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.
10.3.2.
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 
eCRF.
The monitor is responsible for routine review of the 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 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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Amendment 1
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10.3.3.
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.
10.3.4.
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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11.
REFERENCES
2202
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41.
13886
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.
20446
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.
20839
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in 
the Case of the Binomial. Biometrika 1934 Dec;26 (4):pp. 404-13.
24911
INTELENCE® (etravirine) tablets for oral use. US Prescribing Information. 
Janssen Pharmaceuticals, Inc. 2008 Titusville NJ. Revised February 2013.
25217
Quest Diagnostics. Progesterone, LC/MS/MS Reference Ranges.  2013:
25218
Quest Diagnostics. FSH and LH Reference Ranges.  2013:
25219
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.
25891
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.
27503
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA. December 2013:
28338
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.
28339
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.
28346
World Health Organization (WHO). Hepatitis C Fact sheet N°164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/#. Accessed: 20 March 2014.  


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28583
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 2014;370 
(20):1889-98.
28585
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 2014;370 (16):1483-93.
28587
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.
32174
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
;61:S45-S57.


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12.
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


SOFNELFDC 
Protocol GS..US-342-1522 
Fmal 
Gilead Sciences, Inc. 
Amendment 1 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
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 
GS-US-342-1522, Amendment 1, 03 Deeember 2015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Anu "'Osmusi, MD (Printed) 
Medical Monitor 
Ysc lf, CLo 1 5 
' 
Date 
PPD 
Signature 
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 descnoed. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
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 enswe 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page63 
03 December 2015 


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Appendix 2.
Study Procedures Table
Screening
(Day -28 to 
Day 0)
Day 1
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)
1
2
4
8
12/ET
4
12
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
X
Physical Examination
X
X
X
Height
X
Weight
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
12-Lead ECGc
X
X
X
X
AEs 
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
X
Health Related Quality of 
Life Survey, SF-36
X
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
Study Drug Dispensinga
X
X
X
Laboratory Assessments
Hematology, Chemistry 
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X


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Screening
(Day -28 to 
Day 0)
Day 1
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)
1
2
4
8
12/ET
4
12
24
HCV RNA
X
X
X
X
X
X
X
X
X
X
Viral SequencingH
X
X
X
X
X
X
X
X
X
Pregnancy Testingd
X
X
X
X
X
X
Urinalysis, 
Urine Drug Screen
X
HCV Genotyping, 
X
HCV, HIV, HBV Serology
X
HbA1c, Cirrhosis assessment 
(Fibrotest and APRI)
X
Optional Archive Samplef
X
X
IL28B
X
Pharmacogenomic Samplee
X
Imaging for Hepatocellular 
Carcinoma (HCC)g
X
a
Day 1 assessments must be performed prior to the first dose of the study drug(s)
b
Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
c
Subjects will be required to rest in a supine position for ≥ 5 minutes prior to making a recording. The investigator (or qualified designee) should review the ECG traces 
recorded in real time for gross abnormalities.
d
For female of child bearing potential only. Serum β-hCG at screening, urine pregnancy test on Day 1 and every 4 weeks on treatment visits.
e
For subjects who provide their additional and specific consent, an optional blood sample will be collected at the Baseline/Day 1 visit for PG (this sample may be drawn after 
Baseline/Day 1 if necessary).
f
Subjects may opt out of archive sample collection.
g
Imaging for HCC in cirrhotic subjects only.
h
Plasma samples will be collected for viral resistance and possible other virology studies


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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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Amendment 1
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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 t o <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


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Amendment 1
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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-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 71
03 December 2015
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
Hypouricemia
Adult and Pediatric
≥ 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
Infant  < 1 Year
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


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 72
03 December 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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.  


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Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 73
03 December 2015
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 
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
≥ 16 years
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-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 74
03 December 2015
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-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 75
03 December 2015
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


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Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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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


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Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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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)


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Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 78
03 December 2015
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-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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03 December 2015
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
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention 
indicated
Life-threatening reduction in 
oral intake


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 80
03 December 2015
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal 
bleeding OR Life-threatening 
consequences (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
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Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 81
03 December 2015
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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Amendment 1
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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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Amendment 1
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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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Amendment 1
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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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Amendment 1
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SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR laryngeal 
edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization (other than ER 
visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight from 
baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  Aggressive 
intervention indicated 
[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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Amendment 1
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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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Amendment 1
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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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Amendment 1
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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 during pregnancy in human 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 serum pregnancy test at Screening 
and a negative pregnancy test on the Baseline/Day 1 visit prior to enrollment.  A pregnancy test 
will be performed at the Post Treatment Week 4 visit.   They must also agree to one of the 
following from Screening until 30 days of the last dose of SOF/VEL.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.


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Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
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)
o
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
o
Male barriers: Male condom (with or without spermicide)
Hormonal methods
o
Oral contraceptives (either combined or progesterone only)
o
Injectable progesterone
o
Implants of levonorgestrel
o
Transdermal contraceptive patch
o
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.
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 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.


SOF/VEL FDC
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Amendment 1
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5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study or if they become pregnant within 30 days of the last dose of SOF/VEL. Subjects who 
become pregnant or who suspect that they are pregnant must report the information to the 
investigator and discontinue study drug immediately. Subjects whose partner has become 
pregnant or suspects she is pregnant must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 8.5.2.1.

Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3, Open-label Study to Investigate the Efficacy and Safety of 
SofosbuvirNelpatasvir Fixed Dose Combination for 12 weeks in 
Subjects with Chronic Hepatitis C Vims (HCV) infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
This is a non-IND study 
2015-003001-42 
Not Available 
Hepatitis C Vims Infection 
GS-US-342-1522 
Gilead Study Director: 
Name: 
PPD 
t-'t-'U 
PPD 
t-'t-'U 
Gilead Medical 
Monitor: 
Telephone: 
Fax: 
Email: 
Name: 
Phone: 
Mobile: 
Fax: 
E-mail: 
Protocol Version/Date: 
Original: 
Anu Osinusi, MD 
PPD 
J 
t-'t-'U 
I 
PPD 
._____, 
PPD 
I 
17 July 2015 
CONFIDENTIALITY STATEMENT 
The inf01m ation contained in this document, particularly unpublished data, is the prope1iy 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 infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessruy to obtain infonned consent from those 
persons to whom the dmg may be administered. 


SOF/VEL FDC
Protocol GS-US-342-1522
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Original
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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......................................................................9
1.
INTRODUCTION ..............................................................................................................................................12
1.1.
Background ............................................................................................................................................12
1.2.
Sofosbuvir/Velpatasvir Fixed Dose Combination..................................................................................13
1.2.1.
General Information .............................................................................................................13
1.2.2.
Additional Clinical Pharmacology Study.............................................................................13
1.3.
Rationale for This Study ........................................................................................................................15
1.4.
Rationale for Dose Selection..................................................................................................................16
1.5.
Risk/Benefit Assessment for the Study..................................................................................................17
1.6.
Compliance ............................................................................................................................................17
2.
OBJECTIVES.....................................................................................................................................................18
3.
STUDY DESIGN................................................................................................................................................19
3.1.
Endpoints ...............................................................................................................................................19
3.2.
Study Design..........................................................................................................................................19
3.3.
Study Treatments ...................................................................................................................................19
3.4.
Visit Schedule ........................................................................................................................................19
3.5.
HCV Virologic Response-Based Treatment Stopping Criteria..............................................................20
3.6.
Treatment Discontinuation Criteria........................................................................................................20
3.7.
Biomarker Testing..................................................................................................................................21
3.7.1.
Biomarker Samples for Optional Future Research...............................................................21
3.7.2.
Biomarker Samples for Optional Pharmacogenomic Research............................................21
4.
SUBJECT POPULATION..................................................................................................................................23
4.1.
Number of Subjects and Subject Selection ............................................................................................23
4.2.
Inclusion Criteria....................................................................................................................................23
4.3.
Exclusion Criteria...................................................................................................................................25
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................27
5.1.
Enrollment and Study Drug supply........................................................................................................27
5.2.
Description and Handling of SOF/VEL FDC ........................................................................................27
5.2.1.
Formulation..........................................................................................................................27
5.2.2.
Packaging and Labeling .......................................................................................................27
5.2.3.
Storage and Handling...........................................................................................................27
5.2.4.
Dosage and Administration of SOF/VEL FDC....................................................................28
5.3.
Prior and Concomitant Medications.......................................................................................................28
5.4.
Accountability for SOF/VEL FDC.........................................................................................................29
5.4.1.
Investigational Medicinal Product Return or Disposal.........................................................30
6.
STUDY PROCEDURES ....................................................................................................................................31
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................31
6.2.
Pretreatment Assessments......................................................................................................................31
6.2.1.
Screening Visit (Day -28 to Day 0)......................................................................................31
6.2.2.
Day 1 Assessments...............................................................................................................33
6.3.
Treatment Assessments (± 3 days).........................................................................................................34


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6.4.
Week 12 (± 3 days) or Early Termination (ET) .....................................................................................34
6.5.
Unscheduled Visit ..................................................................................................................................35
6.6.
Post-Treatment Assessments (5 days).................................................................................................35
6.6.1.
Post treatment Week 4 (± 5 days).........................................................................................36
6.6.2.
Post treatment Weeks 12 and 24 (± 5 days) .........................................................................36
6.7.
End of Study...........................................................................................................................................36
6.8.
Procedures and Specifications................................................................................................................37
6.8.1.
Clinical Laboratory Analytes ...............................................................................................37
6.8.2.
Medical History....................................................................................................................37
6.8.3.
Complete Physical Examination...........................................................................................38
6.8.4.
Vital Signs............................................................................................................................38
6.8.5.
Creatinine Clearance ............................................................................................................38
6.8.6.
12-Lead ECGs......................................................................................................................38
6.8.7.
Viral RNA Sequencing / Phenotyping Sample.....................................................................39
6.8.8.
Health Related Quality of Life Survey (HRQoL).................................................................39
6.8.9.
Pregnancy Testing................................................................................................................39
7.
TOXICITY MANAGEMENT............................................................................................................................40
7.1.
Subject Stopping Rules ..........................................................................................................................40
8.
ADVERSE EVENTS..........................................................................................................................................41
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................41
8.1.1.
Adverse Events.....................................................................................................................41
8.1.2.
Serious Adverse Events........................................................................................................41
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................42
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................42
8.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................42
8.2.2.
Assessment of Severity ........................................................................................................43
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................43
8.4.
Gilead Reporting Requirements.............................................................................................................44
8.5.
Special Situations Reports......................................................................................................................45
8.5.1.
Definitions of Special Situations..........................................................................................45
8.5.2.
Instructions for Reporting Special Situations.......................................................................45
9.
STATISTICAL CONSIDERATIONS................................................................................................................48
9.1.
Analysis Objectives and Endpoints........................................................................................................48
9.1.1.
Analysis Objectives..............................................................................................................48
9.1.2.
Primary Endpoint .................................................................................................................48
9.1.3.
Secondary Endpoint .............................................................................................................48
9.1.4.
Safety Endpoints ..................................................................................................................48
9.1.5.
Other Endpoints of Interest ..................................................................................................49
9.2.
Analysis Conventions.............................................................................................................................49
9.2.1.
Analysis Sets ........................................................................................................................49
9.3.
Data Handling Conventions ...................................................................................................................49
9.4.
Demographic Data and Baseline Characteristics ...................................................................................50
9.5.
Efficacy Analysis ...................................................................................................................................51
9.5.1.
Primary Analysis..................................................................................................................51
9.5.2.
Secondary Analyses .............................................................................................................51
9.6.
Safety Analysis.......................................................................................................................................51
9.6.1.
Extent of Exposure...............................................................................................................51
9.6.2.
Adverse Events.....................................................................................................................52
9.6.3.
Laboratory Evaluations ........................................................................................................52


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9.6.4.
Other Safety Evaluations......................................................................................................53
9.7.
Sample Size............................................................................................................................................53
10.
RESPONSIBILITIES..........................................................................................................................................54
10.1.
Investigator Responsibilities ..................................................................................................................54
10.1.1.
Good Clinical Practice..........................................................................................................54
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................54
10.1.3.
Informed Consent.................................................................................................................54
10.1.4.
Confidentiality......................................................................................................................55
10.1.5.
Study Files and Retention of Records ..................................................................................55
10.1.6.
Case Report Forms...............................................................................................................56
10.1.7.
Investigational Medicinal Product Accountability and Return.............................................57
10.1.8.
Inspections............................................................................................................................57
10.1.9.
Protocol Compliance............................................................................................................57
10.2.
Sponsor Responsibilities ........................................................................................................................57
10.2.1.
Protocol Modifications.........................................................................................................57
10.2.2.
Study Report and Publications .............................................................................................58
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................58
10.3.1.
Payment Reporting...............................................................................................................58
10.3.2.
Access to Information for Monitoring..................................................................................58
10.3.3.
Access to Information for Auditing or Inspections ..............................................................59
10.3.4.
Study Discontinuation..........................................................................................................59
11.
REFERENCES ...................................................................................................................................................60
12.
APPENDICES ....................................................................................................................................................62
Appendix 1.
Investigator Signature Page....................................................................................................63
Appendix 2.
Study Procedures Table..........................................................................................................64
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............66
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................90
LIST OF IN-TEXT TABLES
Table 1-1.
Preliminary NGMN, NG, EE, and VEL Plasma PK Parameters Following 
Administration of NGM/EE alone or with VEL.....................................................................14
Table 1-2.
Preliminary Summary of LH, FSH, and Progesterone Concentrations Following 
Administration of NGM/EE alone or with VEL.....................................................................15
Table 5-1.
List of Disallowed /Use with Caution Medications................................................................29
Table 9-1.
SVR 12 Rates and Associated 95% Confidence Intervals......................................................53


SOFNELFDC 
Protocol GS-US-342-1522 
Gilead Sciences, Inc. 
PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
Final 
Original 
Study Title: 
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 Vims (HCV) infection 
IND Number: 
This is a non-IND study 
EudraCT Number: 
2015-003001-42 
Clinical Trials.gov 
Identifier: 
Not Available 
Study Centers Planned: 
Approximately 12 sites in the Russian Federation and Sweden 
Objectives: 
The primruy objectives of this study ru·e: 
CONFIDENTIAL 
• 
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 prop01iion of subjects with sustained viral response 
12 weeks after cessation ofu·eatment (SVR12) 
• 
To evaluate the safety and tolerability of u·eatment with 
SOFIVEL for 12 weeks 
The secondruy objectives of this study ru·e: 
• 
To detennine the prop01iion of subjects who attain SVR at 4 and 
24 weeks after cessation ofu·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during 
u·eatlnent and after cessation of u·eatment 
• 
To evaluate the emergence of viral resistance to SOF and VEL 
during u·eatment and after cessation of u·eatment 
The explorat01y objectives of this study are: 
I 
Page5 
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Study Design:
Multi-center, open-label study. Approximately 120 subjects with 
chronic HCV will be enrolled. 
All subjects will receive SOF/VEL FDC once daily for 12 weeks.
Sub study:
Pharmacogenomics (PG) Substudy
In consenting participants, a PG blood sample should be drawn at 
the Baseline/Day 1 visit. If not obtained at Baseline/Day1 visit, the 
sample may be drawn at any time during the study.
Number of Subjects 
Planned:
Approximately 120 subjects
Target Population:
Chronic hepatitis C virus (HCV) infected adults. 
Duration of 
Treatment:
12 Weeks
Diagnosis and Main 
Eligibility Criteria:
Chronic hepatitis C virus (HCV) infected adults. Up to 
approximately 20% of subjects may have cirrhosis at baseline and 
up to approximately 20% may be treatment-experienced. 
Sections 4.2 and 4.3 of the protocol contain detailed Inclusion and 
Exclusion criteria.
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the 
Baseline/Day 1 visit. 
All subjects will complete the following study visits: Screening, 
Baseline/Day 1, on-treatment visits at the end of Weeks 1, 2, 4, 8, 
and 12. All subjects will complete the post treatment Week 4 visit. 
Subjects who achieve SVR4 will complete post treatment Week 12 
and Week 24 visits unless confirmed viral relapse occurs. Viral 
breakthrough or relapse must be confirmed.  
Screening assessments will include physical examination, medical 
history, height, weight, vital signs, 12-lead ECG, adverse events 
related to screening procedures, concomitant medications, safety 
laboratory tests (including hematology, chemistry, and coagulation), 
HCV RNA, HCV genotype, serology (HIV, HCV, HBV), 
hemoglobin A1c (HbA1c), assessment of the presence or absence of 
cirrhosis, imaging for HCC, serum β-hCG (females of child bearing 
potential only), urinalysis and urine drug screen.


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On-treatment assessments include adverse events (AEs), 
concomitant medications, study medication pill count, physical 
examination, weight, vital signs, safety laboratory tests, IL28B 
genotyping ( Day 1), HCV RNA, and urine pregnancy tests 
(females of child bearing potential only). 
Single 12-lead ECGs will be collected at Baseline/Day 1 (prior to 
study drug administration) and at Week 1 and Week 12 or End of 
Treatment.  At the time of ECG collection, printed copies (paper) 
will be reviewed by qualified study staff (as determined by the 
Investigator) and compared to the subject’s Baseline ECG as part of 
routine safety monitoring.
Post-treatment assessments include AEs, concomitant medications, 
vital signs, safety laboratory tests, HCV RNA, and urine pregnancy 
tests (females of child bearing potential only).
Health Related Quality of Life (HRQoL) survey SF-36 will be 
completed at Baseline/Day 1, On-treatment Week 4 and Week 12 or 
Early Termination (if applicable), and post treatment Week 4, and 
12 (if applicable).
Samples for HCV RNA sequencing/phenotyping will be collected at 
Day 1 and every visit thereafter. 
For subjects who provide their additional and specific consent, an 
optional blood sample will be collected at the Baseline/Day 1 visit 
for PG (this sample may be drawn after Baseline/Day 1 if 
necessary).
At the following visits an optional plasma sample may be collected 
and archived for future use: Baseline/Day 1 and Week 12 or ET 
visit. Subjects may opt out of archive sample collection.
Test Product, Dose, and 
Mode of 
Administration:
SOF/VEL fixed dose combination (FDC) is manufactured as a 
400 mg/100 mg FDC tablet for oral administration. Subjects will 
take 1 tablet daily with or without food.
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 using the COBAS® AmpliPrep®/COBAS®
TaqMan® HCV Quantitative Test, v2.


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Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all enrolled 
and treated subjects. No hypothesis testing will be performed.
Secondary efficacy endpoints include SVR4 and SVR24.
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) by 
stratification within group (as appropriate). All categorical 
endpoints will be summarized by 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.
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)
DDI
drug-drug interaction
dL
deciliter
DSPH
Drug Safety and Public Health
ECG
electrocardiogram
eCRF
electronic case report form(s)
ESA
erythropoiesis stimulating agent
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 
GCSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GS-7977
formerly PSI-7977
GSI
Gilead Sciences, Inc.


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GT
genotype (viral)
Hb
hemoglobin
HbA1c
hemoglobin A1c
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
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
mg
milligram
mIU
milli international units
mL
milliliter
mmHg
millimeters mercury
ng
nanogram
ng•h/mL
nanograms times hours per milliliter
NG
norgestrel
NGM
norgestimate 
NGM/EE
norgestimate/ethinyl estradiol
NGMN
norelgestromin


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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 
PPI
proton pump inhibitor
PT
preferred term or prothrombin time 
QD
once daily (use only in tables)
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
TPO
thrombopoietin
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 {28346}. In the United States (US), approximately 
2.7 million people have chronic HCV infection {28338} and HCV infection causes over 
15,000 deaths each year {20446}, 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 
{28339}. Successful treatment of chronic HCV infection reduces the need for liver transplant, the 
incidence of HCC and overall mortality {25891}. 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 {27503}.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 {28583}, 
{28585}, {28587}.
Most current HCV drug development effort focuses on GT1 HCV infection as this is the most 
prevalent HCV genotype in developed countries {32174}. 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
SOF/ velpatasvir (VEL) fixed-dose combination (SOF/VEL FDC) combines two HCV specific 
direct acting antivirals (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 VEL100 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 for Phase 3 evaluation that has demonstrated 
similar exposure of each component compared to co-administration of the single agents.  
The development of SOF/VEL may have a major impact on 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.
Additional Clinical Pharmacology Study
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 OC 
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 
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. 


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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 {13886}, 
{24911}. VEL exposures were consistent with historical data (Studies GS-US-281-0115, 
GS-US-342-0104).
Table 1-1.
Preliminary 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)
0.89 (0.85, 0.94)
Cmax (pg/mL)
1650 (16.8)
1600 (13.7)
0.97 (0.90, 1.04)
Ctau (pg/mL)
454 (18.5)
416 (14.3)
0.92 (0.86, 0.98)
Norgestrel
AUCtau (pg•h/mL)
47,000 (34.4)
43,000 (32.4)
0.91 (0.73, 1.14)
Cmax (pg/mL)
2410 (30.6)
2330 (31.5)
0.96 (0.80, 1.17)
Ctau (pg/mL)
1760 (34.4)
1640 (35.7)
0.92 (0.74, 1.15)
Ethinyl Estradiol
AUCtau (pg•h/mL)
666 (30.7)
686 (27.3)a
1.06 (0.98, 1.14)
Cmax (pg/mL)
57.5 (27.3)
80.0 (28.4)a
1.42 (1.28, 1.58)
Ctau (pg/mL)
14.8 (39.3)
12.4 (43.9)a
0.84 (0.77, 0.92)
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
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 


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phases, respectively {25217}, {25218}, {25219}. Follicle stimulating hormone was lower or 
within the expected range for the ovulatory phase {25218}. 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.
Preliminary 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 (2.9, 12.7)
9.3 (5.4, 14.4)
FSH (mIU/mL)
3.6 (2.0, 5.9)
2.6 (2.2, 5.1)
Progesterone (ng/mL)
0.24 (0.17, 0.39)
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. 
1.3.
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 120 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.
In Russia, the prevalence of HCV is estimated to be 4.1% {32174}, or approximately 4.9 million 
adults positive for antibody to-HCV. Although GT1 is the most common genotype in Russia, 
with a prevalence estimated at 55%, GT3 accounts for approximately 35% and GT2 for 
approximately 8% of infections {32174}. Anti-HCV prevalence is lower in Sweden (0.7% of 
adults) and the most common genotypes are similar to Russia: 45% GT1, 34% GT3, 19% GT2, 
and 2% GT4 {32174}. A single pangenotypic regimen would be of benefit for these diverse HCV 
populations. 
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. 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.


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Phase 2 evaluation of SOF + VEL demonstrated that co-administration of the single agents for 
8 or 12 weeks was well tolerated and resulted in high SVR rates across a broad range of HCV 
genotypes. In the Phase 2 study GS-US-342-0102, administration of SOF 400mg + VEL 100mg 
for 12 weeks to treatment-naïve subjects without cirrhosis with genotype 1, 2, 3, 4, or 6 HCV 
infection resulted in SVR12 rate of 100% (28/28), 100% (10/10), 93% (25/27), 86% (6/7), and 
100% (5/5), respectively. In addition, one treatment naïve subject with genotype 5 HCV 
infection administered SOF +VEL 25mg for 12 weeks achieved SVR12. The GS-US-342-0109 
study evaluated SOF + VEL with and without RBV in populations of patients considered more 
difficult to cure, including subjects who had failed a prior interferon based regimen and those 
with cirrhosis. Administration of SOF 400mg + VEL 100 mg for 12 weeks resulted in SVR12 
rates of 88% (23/26) and 100% (27/27) in treatment experienced subjects with genotype 3 HCV 
infection with and without cirrhosis, respectively. Administration of SOF 400mg + VEL 100mg 
for 12 weeks resulted in an SVR4 rates of 100% (27/27) in subjects with genotype 1 HCV 
infection who had failed prior treatment with a protease inhibitor with Peg-IFN/RBV. Seven of 
these 27 subjects had cirrhosis. 
The Phase 2 data suggest that SOF +VEL 100mg has the potential to cure HCV infected patients 
across a broad range of HCV genotypes, when administered for 12 weeks without RBV and 
regardless of prior treatment experience or cirrhosis status. The co-formulation of SOF/VEL
(400 mg/100 mg) adds to the simplicity of the regimen in allowing for a once daily pill. 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 Russia 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.  
1.4.
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
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, has been selected for co-formulation with VEL into a fixed-dose combination tablet.
VEL 100 mg has been 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 and evaluation in this study 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. 


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The favorable safety and efficacy profiles of SOF 400 mg and VEL 100 mg support further 
evaluation of this combination in clinical development.
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 over the current standard of care 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 clinical safety issues 
specifically related to SOF have been identified to date. 
The safety profile of SOF/VEL has not been established. The safety profile of SOF + VEL 25mg 
or VEL 100mg administered for 8 or 12 weeks has been established in over 800 subjects in 
Phase 2 studies. The safety profile of the proposed therapeutic regimen of SOF 400mg and VEL
100mg administered for 12 weeks has been established in 237 subjects enrolled in Phase 2 
studies. No clinical safety issues specifically related to 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 {28583}, {28585}, {28587}.
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 
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.


SOFNELFDC 
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2-
OBJECTIVES 
The prima1y objectives of this study are: 
Final 
Original 
• 
To evaluate the efficacy of treatment with SOFNEL fixed dose combination (FDC) for 
12 weeks in subjects with chronic HCV infection as measmed by the prop01iion of subjects 
with sustained viral response 12 weeks after cessation of treatment (SVR12) 
• 
To evaluate the safety and tolerability of treatment with SOFNEL for 12 weeks 
The secondmy objectives of this study m·e: 
• 
To determine the prop01iion of subjects who attain SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA dming treatment and after cessation of 
treatment 
• 
To evaluate the emergence of viral resistance to SOF and VEL dming treatment and after 
cessation of treatment 
The explorat01y objectives of this study are: 
PPO 
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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoints of this study are:

Primary efficacy endpoint is SVR12 in all enrolled subjects after 12 weeks of SOF/VEL
treatment

Primary safety endpoint  is Safety and tolerability after 12 weeks of SOF/VEL treatment  and 
AE leading to drug discontinuation 
Secondary endpoints of this study are:

SVR4 and SVR24 in all enrolled subjects after 12 weeks of SOF/VEL treatment

Kinetics of HCV virus 

Emergence of the viral resistance after 12 weeks of treatment and resistance associated 
variants
3.2.
Study Design
This is a multi-center, 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.
3.3.
Study Treatments
Approximately 120 subjects will be enrolled to receive: SOF/VEL (400 mg/100 mg) once daily 
for 12 weeks.
Up to 20% of subjects enrolled in the study may have cirrhosis at baseline and up to 
approximately 20% may be treatment-experienced.
3.4.
Visit Schedule 
All subjects will complete the following study visits: Screening, Day 1, On-Treatment visits at 
the end of Weeks 1, 2, 4, 8, and 12, and Post-Treatment Visits at Weeks 4, 12, and 24 following 
the last dose of study drug. Subjects who achieve SVR4 will complete post treatment Week 12 
and Week 24 visits unless confirmed viral relapse occurs. Viral breakthrough or relapse must be 
confirmed
Screening assessments will be completed within 28 days of the Day 1 Visit. The screening 
window can be extended to 42 days prior to Day 1 in extenuating circumstances with sponsor 
approval.  


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The assessments performed at each visit are described in Section 6 and Appendix 2.
3.5.
HCV Virologic Response-Based Treatment Stopping Criteria
The following on-treatment HCV virologic response-based treatment stopping criteria will be 
utilized:

Confirmed HCV RNA ≥ LLOQ after 2 consecutive HCV RNA < LLOQ

Confirmed > 1 log10 increase from nadir

HCV RNA ≥ LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible and must occur no later than 2 weeks after 
an initial observation indicating virologic failure. 
All subjects will complete the post treatment Week 4 visit. Subjects who achieve SVR4 will 
complete post treatment Week 12 and Week 24 visits unless confirmed viral relapse occurs.
3.6.
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:

Unacceptable toxicity, as defined in Section 7.1 of the protocol, or toxicity that, in the 
judgment of the investigator, compromises the ability to continue study-specific procedures 
or is considered to not be in the subject’s best interest

Pregnancy of female subject

Efficacy failure as defined in Section 3.5

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 Early Termination 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 
visit. 


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3.7. 
3.7.1. 
Biomarker Samples for Optional Future Research 
PPD 
3.7.2. 
Biomarker Samples for Optional Pharmacogenomic Research 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 120 chronic HCV subjects will be enrolled in this study with up to approximately 
20% of subjects having cirrhosis at baseline and up to approximately 20% being
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 104 IU/mL at Screening.
4) HCV genotype 1, 2, 3, 4, 5, 6 assessed at Screening by the Central Laboratory. 
5) Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy.
6) 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.  
Subject must not have discontinued the prior regimen that resulted in virologic 
failure due to an adverse event.
The subject’s medical records must include sufficient detail of prior virologic failure to 
allow for categorization of prior response (See Section 6.2.1), as either:
(1) Non-Responder: Subject did not achieve undetectable HCV RNA levels while on 
treatment, or 
(2) Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during 
treatment or within 4 weeks of the end of treatment but did not achieve SVR.


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7) 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) FibroTest® score > 0.75 AND an AST:platelet ratio index (APRI) > 2 during 
Screening
iii) Fibroscan® with a result of >12.5 kPa 
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) FibroTest score ≤ 0.48 AND APRI ≤ 1 performed during Screening
iii) Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Day 1
In the absence of a definitive diagnosis of presence or absence of cirrhosis by FibroTest,
APRI using the above criteria, a liver biopsy or Fibroscan is required. Liver biopsy results 
will supersede FibroTest, APRI or Fibroscan results and be considered definitive.
8) Liver imaging within 6 months of Day 1 is required only in cirrhotic patients to exclude 
hepatocellular carcinoma (HCC).
9) Females of childbearing potential (as defined in Appendix 4) must have a negative serum 
pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to enrollment.
10) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in
Appendix 4.
11) Lactating females must agree to discontinue nursing before the study drug is administered.
12) Subject must be of generally good health, with the exception of chronic HCV infection, as 
determined by the Investigator.
13) 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; 
subjects currently under evaluation for a potentially clinically-significant illness (other 
than HCV) are also excluded 
b) Gastrointestinal disorder or post-operative condition that could interfere with the 
absorption of the study drug
c) Clinical hepatic decompensation (ie, ascites, encephalopathy or variceal hemorrhage)
d) Solid organ transplantation
e) Significant pulmonary disease, significant cardiac disease or porphyria
f)
Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of 
their psychiatric illness within the last 5 years. Subjects with psychiatric illness (without 
the prior mentioned conditions) that is well-controlled on a stable treatment regimen for 
at least 6 months prior to Day 1 or has not required medication in the last 12 months may 
be included. 
g) Malignancy within the 5 years prior to screening, with the exception of specific cancers 
that have been cured by surgical resection (basal cell skin cancer, etc).  Subjects under 
evaluation for possible malignancy are not eligible.
h) Significant drug allergy (such as anaphylaxis or hepatotoxicity).
2) Screening ECG with clinically significant abnormalities
3) Any of the following laboratory parameters at screening: 
a) ALT > 10 the upper limit of normal  (ULN)
b) AST > 10 ULN
c) Direct bilirubin > 1.5 ULN
d) Platelets < 50,000/L
e) HbA1c > 8.5% 


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f)
Creatinine clearance (CLcr) < 60 mL /min as calculated by the Cockcroft-Gault equation 
{2202}
g) Hemoglobin < 11 g/dL for female subjects; < 12 g/dL for male subjects.
h) Albumin < 3 g/dL 
i)
INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR
4) Prior exposure to SOF or other nucleotide analogue HCV NS5B inhibitor or any HCV NS5A 
inhibitor
5) Pregnant or nursing female or male with pregnant female partner 
6) Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, alfa-1 
antitrypsin deficiency, cholangitis).
7) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
8) Clinically-relevant alcohol or drug abuse within 12 months of screening. A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator.
9) Use of any prohibited concomitant medications as described in Section 5.3.
10) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone 
equivalent > 10 mg/day).
11) 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 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:

Hematologic stimulating agents (eg, erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Chronic systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal 
antibodies (eg, infliximab)

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), Atorvastatin, 
Simvastatin, Pravastatin, Pitavastatin, 
Fluvastatin, Lovastatin
Other
Modafinil b, Sulfasalazinec, Methotrexatec
a
The 21 day washout period does not apply to proton pump inhibitors (PPIs), which can be taken up to 7 days before Day 1. 
H2-receptor antagonists must not exceed a dose of 20 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. Monitor for signs and 
symptoms of muscle weakness or myopathy, including rhabdomyolysis.
Medications for disease conditions excluded from the protocol (eg, HIV-1 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 EOT visit. 
5.4.1.
Investigational Medicinal Product Return or Disposal
Please refer to Section 10.1.7 for Investigational Medicinal Product Accountability and Return.


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6.
STUDY PROCEDURES
Study procedures to be conducted for each subject enrolled in the study are presented in tabular 
form in Appendix 2 and described briefly in the text that follows. All eligible subjects will 
complete Screening, Day 1, On-Treatment visits at the end of Weeks 1, 2, 4, 8, and 12, and Post 
Treatment Visits at Weeks 4, 12, and 24, as appropriate. Subjects who achieve SVR4 will 
complete post treatment Week 12 and Week 24 visits unless confirmed viral relapse occurs. 
Viral breakthrough or relapse must be confirmed
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 for 
12 weeks. 
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit (Day -28 to Day 0)
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
— A separate informed consent will be required from subjects participating in the PG
sub-study

Obtain medical history, including information on prior HCV treatment history 
— If treatment experienced, record the duration of the prior treatment and the type of 
interferon and/or ribavirin or DAA administered 
— Record whether the subject had a Non-response or Relapse/Breakthrough during prior 
treatment as defined in inclusion criterion #6 (Section 4.2)

Obtain demographic information

Perform complete physical examination including vital signs, body weight, and height

Perform 12-lead ECG


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
Obtain details on AEs related to screening procedures (See Section 8 for details)

Obtain details of concomitant medications

Obtain blood samples for 
— Hematology and chemistry tests
— Coagulation tests
— HCV RNA (quantitative) 
— HCV genotype 
— Fibrotest
— HCV antibody, HIV 1/2 antibody, and HBV surface antigen (HBsAg)
— HbA1c
— Serum β-human chorionic gonadotropin (-hCG) pregnancy test, for females of 
childbearing potential only

Obtain urine sample for
— Urinalysis
— Drug screen

Determine cirrhosis status
— If the presence of cirrhosis cannot be determined based on medical history or screening 
lab tests, biopsy or Fibroscan® should be performed 
— 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 28-42 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).  


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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 2).
At the Day 1 visit, complete the following:

Confirm eligibility

Perform complete physical examination, including vital signs and body weight

Perform 12-lead ECG

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counseling

Obtain blood samples for:
— Hematology and chemistry
— Coagulation tests
— HCV RNA(quantitative)
— Viral RNA sequencing / phenotyping 
— IL28B genotype 
— Biomarker archive sample (for subjects who have not opted out)
— Pharmacogenomic testing (for subjects who have consented to participate in the PG
substudy)

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

Health Related Quality of life survey, SF-36


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6.3.
Treatment Assessments (± 3 days)
The following treatment procedures/assessments are to be completed at the end of Weeks 1, 2, 4,
and 8, for all subjects (see Appendix 2).

Obtain vital signs

Perform 12-lead ECG (at Week 1 only)

Assessment of AEs and concomitant medications

Obtain blood samples for:
— Hematology & chemistry
— HCV RNA
— Viral RNA sequencing / phenotyping sample

Obtain urine sample for -hCG pregnancy test for females of childbearing potential only
(Weeks 4,and 8 )

Conduct pregnancy prevention counseling at Week 4 only

Review study drug compliance and drug administration instructions with subject
— Reconcile study drug administration using pill counts

Dispense study drugs as directed by the IWRS ( Weeks 4 and 8 only)

Health Related Quality of life survey, SF-36 ( Week 4 only)
6.4.
Week 12 (± 3 days) or Early Termination (ET) 
If a subject discontinues treatment early for any reason they should complete the Early 
Termination Visit assessments then the Post-Treatment Week 4 visit (4 weeks following the last 
dose of the study drug) should be completed (see Appendix 2).
The following procedures/assessments are to be completed at the Week 12 /Early termination 
Visit as applicable:

Perform complete physical examination

Obtain body weight

Obtain vital signs


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
Perform 12-lead ECG

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Obtain blood samples for:
— Hematology & chemistry
— Coagulation tests
— HCV RNA
— Viral RNA sequencing / phenotyping sample
— Biomarker archive sample (for subjects who have not opted out)

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
— Study drug should be returned at this visit

Health Related Quality of life survey, SF-36 
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, but the investigator should 
at a minimum collect AE and concomitant medication information. At all unscheduled visits 
initiated for the purpose of confirming virologic failure, a viral RNA sequencing / phenotyping 
sample must be collected.
6.6.
Post-Treatment Assessments (5 days)
All subjects will complete the Post-treatment Week 4 visit. Subjects who achieve SVR4 will 
complete post treatment Week 12 and Week 24 visits unless confirmed viral relapse occurs. The 
Post Treatment visits must be scheduled relative to the date of last administration of study drug
(see Appendix 2).


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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:

Obtain weight and vital signs

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Obtain blood samples for:
— Hematology &chemistry
— HCV RNA
— Viral RNA sequencing / phenotyping sample

Obtain urine sample for:
— β -hCG pregnancy test for females of childbearing potential only

Health-related quality of life questionnaire, SF-36
Subjects with HCV RNA < LLOQ at the post treatment Week 4 visit will return for the post
treatment Week 12 visit.
6.6.2.
Post treatment Weeks 12 and 24 (± 5 days)
The following procedures/assessments are to be completed for post treatment Weeks 12 and 24:

Obtain blood samples for:
— HCV RNA
— Viral RNA Sequencing / Phenotyping Sample

Health Related Quality of life survey, SF-36 (post treatment Week 12 only) 

Subjects with HCV RNA < LLOQ at the post treatment Week 12 visit will return for the post 
treatment Week 24 visit unless confirmed viral relapse occurs.
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.
Subjects are considered to have completed the study after the completion of Post Treatment 
Week 24 visit.


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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, Creatine Kinase , Creatinine, Total Bilirubin (reflex to Direct 
Bilirubin), Glucose, Lipase, Potassium, Sodium, Fibrotest, APRI calculation and Direct Bilirubin 
at Screening only.
Urinalysis: Appearance, Blood, Color, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV and HBV. Serology and/or antigen testing for HIV,
including reflex testing, as necessary. HCV RNA will be measured using the COBAS®
AmpliPrep®/COBAS® TaqMan® HCV Quantitative Test, v2. HCV genotype and subtype will be 
determined using the Siemens VERSANT® HCV Genotype INNO-LiPA 2.0 Assay. Gilead 
reserves the right to use alternate assays for HCV RNA and HCV genotype should the above 
assays become unavailable.
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the 
SNP, rs12979860, with sequence specific forward and reverse primers and allele specific 
fluorescently labeled TaqMan® MGB probes. Gilead reserves the rights to use an alternate assay 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum β-hCG or Urine β-hCG 
Additional Tests: Urine Drug screen (for Amphetamines, Cocaine, Methadone, Opiates) and 
Hemoglobin A1c (HbA1c)
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 
(per Section 6.2.1), will be collected on all subjects during screening.


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6.8.3.
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and 
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological. Assessments by other specialists are not required unless 
medically indicated.
6.8.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.8.5.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} 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)
6.8.6.
12-Lead ECGs
Subjects will be required to rest in a supine position for 5 minutes prior to making a recording.
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities.  On-treatment ECGs should be compared to the subject’s 
baseline as part of routine safety monitoring.  


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6.8.7.
Viral RNA Sequencing / Phenotyping Sample
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
At any unscheduled visit initiated for the purpose of confirming virologic breakthrough, a viral 
sequence analysis plasma sample must be collected.
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual.
6.8.8.
Health Related Quality of Life Survey (HRQoL)
A HRQoL survey, the short form 36 or SF-36 survey, will be completed by subjects at Day 1, 
On-Treatment visit at Weeks 4 and 12; Post-Treatment visits at Weeks 4 and 12 (if applicable),
and Early Termination (if applicable).  The subject should read the questionnaire by 
himself/herself and write/mark answers directly onto the questionnaire.
6.8.9.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every 4 weeks during the 
dosing period and 4 weeks after last dose of study drug (post treatment Week 4). Confirmatory 
serum pregnancy testing should be performed after any positive urine pregnancy test.  


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7.
TOXICITY MANAGEMENT
7.1.
Subject Stopping Rules
Administration of all study medication(s) may be discontinued in the event of a clinical or 
laboratory event. The Gilead Medical Monitor must be consulted prior to dose discontinuation of 
SOF/VEL unless the investigator believes that immediate action is warranted to ensure the 
continued safety of the subject.
There is no option for dose reduction of SOF/VEL. 
Subjects who meet any of the following laboratory criteria must stop the study medication:

Elevation of ALT and/or AST > 5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT > 3 x Day 1 and total bilirubin > 2 x ULN, confirmed by 
immediate repeat testing

Elevation of ALT > 15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event or laboratory abnormality assessed (and confirmed by immediate 
repeat testing) as related to SOF/VEL. 
Refer to Section 3.6 for information regarding discontinuation


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8.
ADVERSE EVENTS 
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
8.1.1.
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, 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 8.5)

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 
eCRF.
8.1.2.
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.
8.1.3.
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 8.1.1 and 8.1.2. 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 Section 8.1.3.
8.2.
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.
8.2.1.
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)
8.2.2.
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.
8.3.
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 (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 4 weeks 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 
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 
consent is signed.
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. 


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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the
eCRF completion guideline. 
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:
Safety_FC@gilead.com
Fax:
+1 650-522-5477

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 eCRF and the event description section of the SAE form.
8.4.
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 


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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. 
8.5.
Special Situations Reports
8.5.1.
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.  
8.5.2.
Instructions for Reporting Special Situations
8.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy.


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Refer to Section 8.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (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 
Sections 8.3. 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 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: Safety_FC@gilead.com and Fax: +1 (650) 522-5477.
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 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 
+1 650 522-5477 or email Safety_FC@gilead.com.
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
8.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications.
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.


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Refer to Section 8.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.


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9_ 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Objectives and Endpoints 
9.1.1. 
Analysis Objectives 
The prima1y objectives of this study are: 
Final 
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• 
To evaluate the efficacy of treatment with SOFNEL 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 SOFNEL for 12 weeks 
The secondmy objectives of this study m·e: 
• 
To detennine the prop01iion of subjects who attain SVR4 and SVR24 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment 
• 
To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment 
The explorat01y objectives of this study are: 
PPO 
I 
9.1.2. 
Primary Endpoint 
The prima1y efficacy endpoint is SVR12 in the Full Analysis Set (F AS). 
9.1.3. 
Secondary Endpoint 
Secondary efficacy endpoints include the prop01iion of subjects with HCV RNA < LLOQ at 4 
and 24 weeks after discontinuation of therapy (SVR4 and SVR24), the prop01iion of subjects 
with HCV RNA < LLOQ on treatment, HCV RNA change from Day 1, and the prop01iion of 
subjects with virologic failure. 
9.1.4. 
Safety Endpoints 
The prima1y safety endpoint is any AE leading to pennanent discontinuation of the study dmg. 
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9.1.5. 
Other Endpoints of Interest 
PD 
9.2. 
Analysis Conventions 
Final 
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All individual subject data will be listed as measured. All statistical summaries and analyses will 
be perfonned using SAS® software (SAS Institute, Cruy, North Cru·olina, USA). 
The study dmg in this study is SOFNEL. Last dose of study dmg refers to the last dose of any of 
the study dtugs in a treatment group and will be used in the definition of treatment-emergent AEs 
and laborat01y abnonnalities as well as the efficacy endpoints of SVR at vru·ious post-treatment 
time points. 
9.2.1. 
Analysis Sets 
9.2.1.1. 
Efficacy 
The analysis set for antiviral activity analyses will be the F AS which include all em olled subjects 
who took at least 1 dose of study dt11g. 
9.2.1.2. 
Safety 
The Safety Analysis Set will include all subjects who took at least 1 dose of study dtug. 
Treatment-emergent data will be analyzed and defmed as data collected from the first dose of 
study dtug through the date of last dose of study dt11g plus 30 days. 
9.3. 
Data Handling Conventions 
Missing data can have an impact upon the inte1p retation of the trial data. Other than the 
endpoints discussed below, values for missing data will not be imputed. 
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed up to 
the time of the last dose. 
If a data point is missing and is preceded and followed in time by values that ru·e "< LLOQ tru·get 
not detected (TND)", then the missing data point will be set to"< LLOQ TND". If a data point is 
missing and preceded and followed by values that are"< LLOQ detected", or preceded by 
"< LLOQ detected" and followed by "< LLOQ TND", or preceded by"< LLOQ TND" and 
followed by"< LLOQ detected", then the missing value will be set to"< LLOQ detected". In 
these situations the data point will be tenned a bracketed success; othe1wise, the data point will 
be te1m ed a bracketed failure (ie, :::: LLOQ detected). If a data point is missing and is not 
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bracketed, the missing data point will also be termed a failure (ie, ≥LLOQ detected) except for 
SVR24, which will be imputed according to SVR12 status. Success for SVR12 who have no 
further HCV RNA measurements collected will be counted as a success for SVR24 due to the 
high correlation between these 2 endpoints.
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of adverse 
events according to the treatment received; otherwise, if the subject is not dosed then they 
will be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of 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 Day 1 result 
will be replaced with a screening result, if available. If no pre-treatment laboratory value is 
available, the Day 1 value will be assumed to be normal (ie, no grade [Grade 0]) for the summary 
of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing Day 1 result will be 
replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
calculation of summary statistics for the actual HCV RNA values and the change from Day 1 
values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to 
the logarithmic (base 10) scale (log10 IU/mL).
9.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, self-identified race/ethnicity, and age.
Baseline data will include body mass index, HCV RNA level (log10 IU/mL), HCV genotype, 
IL28B genotype, and additional endpoints as necessary.


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9.5. 
Efficacy Analysis 
9.5.1. 
Primary Analysis 
Final 
Original 
The prima1y efficacy endpoint is SVR12 in the F AS. The primmy analysis will be perfonned 
after all emolled subjects have been followed through 12 weeks post-treatment or discontinued 
from study. 
In the prima1y efficacy analysis, the SVR12 rate will be calculated along with the two-sided 95% 
exact confidence interval constmcted using the binomial distribution (Clopper-Pem·son method) 
{20839}. No statistical hypothesis testing will be perf01med. 
9.5.2. 
Secondary Analyses 
The proportion of subjects with HCV RNA below the LLOQ over time 
(including SVR endpoints) will be presented in tabula~· and graphical f01m. 
Descriptive summm·ies and listings will be provided for additional efficacy evaluations of the 
prop01iion of subjects who experience virologic failure, HCV RNA actual values and chan e 
from baseline, and other endpoints of interest including PPD 
~------------------------~ 
Exj)loratOiy analyses may be erfonned to assess the relationshi 
9.6. 
Safety Analysis 
Safety will be evaluated by assessment of clinicallaborat01y, physical examinations, and vital 
signs measurements at vm·ious time points during the study, and by the documentation of AEs. 
The prima1y analysis will be the prop01iion of patients who experienced an AE leading to 
treatment discontinuation. 
All safety data collected on or after the first dose of study dmg administration up to 30 days after 
the last dose of study dmg will be sUllllnm·ized. 
9.6.1. 
Extent of Exposure 
A subject's extent of exposure to study dmg will be generated from the study dmg 
administration page of the CRF. 
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9.6.2.
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 an onset date 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 drug. 
Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC and preferred term) will be provided for:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs

All treatment-related SAEs 

All AEs leading to premature discontinuation of study drug
All AEs collected during the course of the study will be presented in data listings
9.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) at each study visit along with corresponding change from Day 1.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
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. 


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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 Day 1 value will be assumed to be normal (ie, no grade [Grade 0]) for the summary 
of graded abnormality.
All laboratory abnormalities will be included in the listings of laboratory data.
9.6.4.
Other Safety Evaluations
Individual data for vital signs measurements will be listed by subject and summarized by 
incidence of events/abnormalities or descriptive statistical summaries (n, mean, SD, median, Q1, 
Q3, minimum, and maximum), as appropriate.
9.7.
Sample Size
With a sample size of 120, the 95% exact confidence interval for different observed SVR12 rates 
are presented in the Table 9-1 below:
Table 9-1.
SVR 12 Rates and Associated 95% Confidence Intervals
Observed SVR12 rate
2-sided 95% exact CI
80% (96 out of 120) 
72% - 87%
85% (102 out of 120) 
77% - 91%
95% (114 out of 120) 
89% - 98%


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
10.1.2.
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.
10.1.3.
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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The pharmacogenomics consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
10.1.4.
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. NOTE: The investigator must keep a screening log showing 
codes, names, and addresses for all subjects screened and for all subjects enrolled in the trial.
Subject data will be processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
10.1.5.
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);


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
Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
10.1.6.
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 


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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 
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 10.1.5.
10.1.7.
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.
10.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB /IEC or to regulatory authority or health authority 
inspectors.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
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 or IEC 
in accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented.


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10.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agencies. 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 10.1.4).
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.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
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.
10.3.2.
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 
eCRF.
The monitor is responsible for routine review of the 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 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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10.3.3.
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.
10.3.4.
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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11.
REFERENCES
2202
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41.
13886
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.
20446
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.
20839
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in 
the Case of the Binomial. Biometrika 1934 Dec;26 (4):pp. 404-13.
24911
INTELENCE® (etravirine) tablets for oral use. US Prescribing Information. 
Janssen Pharmaceuticals, Inc. 2008 Titusville NJ. Revised February 2013.
25217
Quest Diagnostics. Progesterone, LC/MS/MS Reference Ranges.  2013:
25218
Quest Diagnostics. FSH and LH Reference Ranges.  2013:
25219
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.
25891
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.
27503
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA. December 2013:
28338
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.
28339
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.
28346
World Health Organization (WHO). Hepatitis C Fact sheet N°164. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/#. Accessed: 20 March 2014.  


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28583
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 2014;370 
(20):1889-98.
28585
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 2014;370 (16):1483-93.
28587
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.
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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
;61:S45-S57.


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12.
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


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
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 
GS-US-342-1522, Original, 17 July 2015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Anu dsinusi, MD (Printed) 
Medical Monitor 
IPPD 
Signature 
~STIGATORSTATEMENT 
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. 
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 
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Appendix 2.
Study Procedures Table
Screening
(Day -28 to 
Day 0)
Day 1
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)
1
2
4
8
12/ET
4
12
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
X
Physical Examination
X
X
X
Height
X
Weight
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
X
12-Lead ECGc
X
X
X
X
AEs 
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
X
Health Related Quality of 
Life Survey, SF-36
X
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
Study Drug Dispensinga
X
X
X


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Screening
(Day -28 to 
Day 0)
Day 1
On-treatment Study Week (± 3 days)
Post treatment 
Study Week (± 5 days)
1
2
4
8
12/ET
4
12
24
Laboratory Assessments
Hematology, Chemistry 
X
X
X
X
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
Viral SequencingH
X
X
X
X
X
X
X
X
X
Pregnancy Testingd
X
X
X
X
X
X
Urinalysis, 
Urine Drug Screen
X
HCV Genotyping, 
X
HCV, HIV, HBV Serology
X
HbA1c, Cirrhosis assessment 
(Fibrotest and APRI)
X
Optional Archive Samplef
X
X
IL28B
X
Pharmacogenomic Samplee
X
Imaging for Hepatocellular 
Carcinoma (HCC)g
X
a
Day 1 assessments must be performed prior to the first dose of the study drug(s)
b
Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
c
Subjects will be required to rest in a supine position for ≥ 5 minutes prior to making a recording. The investigator (or qualified designee) should review the ECG traces 
recorded in real time for gross abnormalities.
d
For female of child bearing potential only. Serum β-hCG at screening, urine pregnancy test on Day 1 and every 4 weeks on treatment visits.
e
For subjects who provide their additional and specific consent, an optional blood sample will be collected at the Baseline/Day 1 visit for PG (this sample may be drawn after 
Baseline/Day 1 if necessary).
f
Subjects may opt out of archive sample collection.
g
Imaging for HCC in cirrhotic subjects only.
h
Plasma samples will be collected for viral resistance and possible other virology studies


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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


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 67
17 July 2015
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


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 68
17 July 2015
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.  


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 69
17 July 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 70
17 July 2015
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-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 71
17 July 2015
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-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 72
17 July 2015
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


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 73
17 July 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 74
17 July 2015
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-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 75
17 July 2015
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-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 76
17 July 2015
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-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 77
17 July 2015
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-342-1522
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-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 79
17 July 2015
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-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 80
17 July 2015
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-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 81
17 July 2015
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-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 82
17 July 2015
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 


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 83
17 July 2015
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 84
17 July 2015
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (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


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 85
17 July 2015
MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic self-
care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing 
inability to perform usual 
social & functional activities
Disabling muscle pain causing 
inability to perform basic self-
care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-
care functions


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 86
17 July 2015
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]


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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17 July 2015
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


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 88
17 July 2015
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


SOF/VEL FDC
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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17 July 2015
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.


SOF/VEL FDC
Protocol GS-GS-US-343-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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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 during pregnancy in human 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 serum pregnancy test at Screening 
and a negative pregnancy test on the Baseline/Day 1 visit prior to enrollment.  A pregnancy test 
will be performed at the Post Treatment Week 4 visit.   They must also agree to one of the 
following from Screening until 30 days of the last dose of SOF/VEL.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.


SOF/5816
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
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17 July 2015
Or

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)
o
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
o
Male barriers: Male condom (with or without spermicide)
Hormonal methods
o
Oral contraceptives (either combined or progesterone only)
o
Injectable progesterone
o
Implants of levonorgestrel
o
Transdermal contraceptive patch
o
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.
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 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.


SOF/5816
Protocol GS-US-342-1522
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 92
17 July 2015
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study or if they become pregnant within 30 days of the last dose of SOF/VEL. Subjects who 
become pregnant or who suspect that they are pregnant must report the information to the 
investigator and discontinue study drug immediately. Subjects whose partner has become 
pregnant or suspects she is pregnant must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 8.5.2.1.