Clinical trial NCT04112303
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences
Start date: 2019-10-16; Completion date: 2021-06-25
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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

Detailed description:

Arms: arm 1: Participants received SOF/VEL (400/100 mg) orally once daily for up to 12 weeks.
Interventions: intervention 1: SOF/VEL
Intervention descriptions: intervention 1: Tablets administered orally once daily

Protocol documents:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director: 
Gilead Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3 Multicenter, Open-Label Study to Investigate the Efficacy 
and Safety of SofosbuvirNelpatasvir Fixed-Dose Combination for 
12 Weeks in Subjects with Chronic HCV Infection and Compensated 
Cinhosis 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
This is a non-IND study 
Not Applicable 
Not Available 
Hepatitis C Vims Infection 
GS-US-342-5531 
Name: 
IPIPD 
Telephone: 
IPPU 
Fax: 
IPIPD 
Email: 
IPPU 
Name: 
IPIPD 
Telephone: 
IPPU 
Fax: 
IPIPD 
Mobile: 
IPIPD 
Email: 
IPIPU 
Original: 
03 July 2019 
CONFIDENTIALITY STATEMENT 
The info1mation contained in this document, paiiicularly unpublished data, is the prope1iy or 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 Boai·d or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational drng 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 necessaiy to obtain infonned consent from those 
persons to whom the drng may be administered. 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 2
03 July 2019
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 ..............................................................................................................................................13
1.1.
Background ............................................................................................................................................13
1.2.
Sofosbuvir/Velpatasvir Fixed-Dose Combination .................................................................................13
1.2.1.
General Information .............................................................................................................14
1.2.2.
Clinical Trials of SOF/VEL FDC.........................................................................................14
1.3.
Rationale for This Study ........................................................................................................................15
1.4.
Rationale for Dose Selection of SOF/VEL FDC....................................................................................15
1.5.
Risk/Benefit Assessment for the Study..................................................................................................15
1.6.
Compliance ............................................................................................................................................16
2.
OBJECTIVES.....................................................................................................................................................17
3.
STUDY DESIGN................................................................................................................................................18
3.1.
Study Design..........................................................................................................................................18
3.2.
Study Treatments ...................................................................................................................................18
3.3.
Duration of Treatment............................................................................................................................18
3.4.
Stopping Rules and Discontinuation Criteria.........................................................................................18
3.4.1.
Toxicity-Based Stopping Criteria.........................................................................................19
3.4.2.
Virologic Response-Based Treatment Stopping Criteria .....................................................20
4.
SUBJECT POPULATION..................................................................................................................................21
4.1.
Number of Subjects and Subject Selection ............................................................................................21
4.2.
Inclusion Criteria....................................................................................................................................21
4.3.
Exclusion Criteria...................................................................................................................................22
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................25
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................25
5.2.
Description and Handling of SOF/VEL FDC ........................................................................................25
5.2.1.
Formulation..........................................................................................................................25
5.2.2.
SOF/VEL FDC Packaging and Labeling..............................................................................25
5.2.3.
SOF/VEL FDC Storage and Handling .................................................................................25
5.3.
Dosage and Administration of SOF/VEL FDC......................................................................................25
5.4.
Prior and Concomitant Medications.......................................................................................................26
5.5.
Study Drug Adherence and Accountability for SOF/VEL FDC ............................................................27
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................27
6.
STUDY PROCEDURES ....................................................................................................................................28
6.1.
Subject Enrollment.................................................................................................................................28
6.1.1.
Screening Visit .....................................................................................................................28
6.1.2.
Day 1 Assessments...............................................................................................................30
6.2.
Treatment Assessments (± 3 days).........................................................................................................31
6.2.1.
Week 1 (± 3 days) ................................................................................................................31
6.2.2.
Week 2 (± 3 days) ................................................................................................................31
6.2.3.
Weeks 4 and 8 (± 3 days) .....................................................................................................32
6.2.4.
Week 12 (± 3 days) ..............................................................................................................32


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 3
03 July 2019
6.3.
Posttreatment Assessments (± 5 days) ...................................................................................................33
6.3.1.
Posttreatment Week 4 (± 5 days)..........................................................................................33
6.3.2.
Posttreatment Weeks 12 and 24 (± 5 days) ..........................................................................34
6.4.
Assessments for Premature Discontinuation from Study.......................................................................34
6.5.
Early Termination (ET)..........................................................................................................................34
6.6.
Unscheduled Visit ..................................................................................................................................35
6.7.
Procedures and Specifications................................................................................................................35
6.7.1.
Clinical Laboratory Analytes ...............................................................................................35
6.7.2.
Medical History....................................................................................................................36
6.7.3.
Complete Physical Examination...........................................................................................36
6.7.4.
Vital Signs............................................................................................................................36
6.7.5.
12-Lead ECG........................................................................................................................36
6.7.6.
Creatinine Clearance ............................................................................................................37
6.7.7.
HCV Resistance Sample ......................................................................................................37
6.7.8.
HBV DNA Sample...............................................................................................................37
6.7.9.
Pregnancy Testing................................................................................................................37
6.7.10.
IL28B Testing ......................................................................................................................37
6.8.
End of Study...........................................................................................................................................37
6.9.
Post Study Care......................................................................................................................................38
7.
ADVERSE EVENTS..........................................................................................................................................39
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................39
7.1.1.
Adverse Events.....................................................................................................................39
7.1.2.
Serious Adverse Events........................................................................................................39
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................40
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................40
7.2.1.
Assessment of Causality for Study Drug and Procedures ....................................................40
7.2.2.
Assessment of Severity ........................................................................................................41
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead:......................................................................................................................41
7.4.
Gilead Reporting Requirements.............................................................................................................42
7.5.
Special Situations Reports......................................................................................................................43
7.5.1.
Definitions of Special Situations..........................................................................................43
7.5.2.
Instructions for Reporting Special Situations.......................................................................43
8.
STATISTICAL CONSIDERATIONS................................................................................................................46
8.1.
Analysis Objectives and Endpoints........................................................................................................46
8.1.1.
Analysis Objectives..............................................................................................................46
8.1.2.
Primary Endpoint .................................................................................................................46
8.1.3.
Secondary Endpoint .............................................................................................................46
8.2.
Analysis Conventions.............................................................................................................................47
8.2.1.
Analysis Sets ........................................................................................................................47
8.3.
Data Handling Conventions ...................................................................................................................47
8.4.
Demographic Data and Baseline Characteristics ...................................................................................48
8.5.
Efficacy Analysis ...................................................................................................................................49
8.5.1.
Primary Analysis..................................................................................................................49
8.5.2.
Secondary Analyses .............................................................................................................49
8.6.
Safety Analysis.......................................................................................................................................49
8.6.1.
Extent of Exposure...............................................................................................................50
8.6.2.
Adverse Events.....................................................................................................................50
8.6.3.
Laboratory Evaluations ........................................................................................................50
8.6.4.
Other Safety Evaluations......................................................................................................51
CCI


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 4
03 July 2019
8.7.
Sample Size............................................................................................................................................51
8.7.1.
Justification for Performance Threshold ..............................................................................51
8.7.2.
Determination of Sample Size on Basis of Threshold..........................................................51
9.
RESPONSIBILITIES..........................................................................................................................................53
9.1.
Investigator Responsibilities ..................................................................................................................53
9.1.1.
Good Clinical Practice..........................................................................................................53
9.1.2.
Financial Disclosure.............................................................................................................53
9.1.3.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................53
9.1.4.
Informed Consent.................................................................................................................53
9.1.5.
Confidentiality......................................................................................................................54
9.1.6.
Study Files and Retention of Records ..................................................................................54
9.1.7.
Case Report Forms...............................................................................................................55
9.1.8.
Investigational Medicinal Product Accountability and Return.............................................56
9.1.9.
Inspections............................................................................................................................56
9.1.10.
Protocol Compliance............................................................................................................56
9.2.
Sponsor Responsibilities ........................................................................................................................56
9.2.1.
Protocol Modifications.........................................................................................................56
9.2.2.
Study Report and Publications .............................................................................................57
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................57
9.3.1.
Payment Reporting...............................................................................................................57
9.3.2.
Access to Information for Monitoring..................................................................................57
9.3.3.
Access to Information for Auditing or Inspections ..............................................................58
9.3.4.
Study Discontinuation..........................................................................................................58
10.
REFERENCES ...................................................................................................................................................59
11.
APPENDICES ....................................................................................................................................................61
Appendix 1.
Investigator Signature Page....................................................................................................62
Appendix 2.
Study Procedures Table..........................................................................................................63
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............65
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................88
LIST OF IN-TEXT TABLES
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................26


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 5
03 July 2019
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive 
Foster City, CA 94404
Study Title: 
A Phase 3 Multicenter, Open-Label Study to Investigate the Efficacy 
and Safety of Sofosbuvir/Velpatasvir Fixed-Dose Combination for 
12 Weeks in Subjects with Chronic HCV Infection and Compensated 
Cirrhosis
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
This is a non-IND study
Not Applicable
Not Available
Study Centers 
Planned:
Approximately 20 centers in Japan
Objectives:
The primary objectives of this study are as follows:

To evaluate the antiviral efficacy of therapy with 
sofosbuvir/velpatasvir (SOF/VEL) fixed-dose combination (FDC) 
for 12 weeks as measured by the proportion of subjects with 
sustained virologic response 12 weeks after cessation of treatment 
(SVR12)

To evaluate the safety and tolerability by review of the 
accumulated safety data
The secondary objectives of this study are as follows: 

To determine the proportion of subjects who attain SVR at 4 and 
24 weeks after cessation of treatment (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the emergence of viral resistance to SOF and VEL 
during treatment and after cessation of treatment
Study Design:
This is a multicenter, open-label study in subjects with chronic 
hepatitis C virus (HCV) infection and compensated cirrhosis. 
Approximately 36 subjects will be enrolled and treated with 
SOF/VEL FDC for 12 weeks. Subjects may have HCV of any 
genotype; based on the HCV genotype (GT) distribution in Japan, it is 
expected that approximately 70% of subjects will be GT1, and 
approximately 30% of subjects will be non-GT1. Subjects may be 
either treatment-naive or treatment-experienced with IFN-based 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 6
03 July 2019
treatments.
Number of Subjects 
Planned:
Approximately 36 subjects
Target Population:
Patients with chronic HCV infection and compensated cirrhosis.
Duration of 
Treatment:
Subjects will be treated for 12 weeks
Diagnosis and Main 
Eligibility Criteria:
Chronic HCV-infected male and non-pregnant/non-lactating female 
subjects, aged 18 years or older.
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days prior to 
the Day 1 visit. The screening window can be extended up to 42 days 
in extenuating circumstances.
Study visits will occur at Screening, Day 1, and on-treatment at the 
end of Weeks 1, 2, 4, 8, and 12.
Following the last dose of study drug, all subjects will complete 
posttreatment Week 4, 12 and 24 visits.
Screening assessments will include medical history, physical 
examination, height, weight, vital signs, 12-lead electrocardiogram 
(ECG), adverse events (AEs) related to screening procedures, 
concomitant medications, liver imaging to exclude hepatocellular 
carcinoma (HCC) within 4 months of Day 1, safety laboratory tests 
(including hematology, chemistry, coagulation, urinalysis), HCV 
RNA, serum β-hCG (females of child bearing potential only), serum 
FSH (only for women of any age with amenorrhea of ≥ 12 months, 
[refer to Appendix 4]), HCV genotype, serology (HIV, HCV, HBV), 
hemoglobin A1c (HbA1c), and assessment of the presence of 
cirrhosis (including FibroTest®).
On-treatment assessments include physical examination, weight, vital 
signs, 12-lead ECG, AEs, concomitant medications, pregnancy 
prevention counseling, review of study drug adherence and drug 
accountability, study drug dispensing, safety laboratory tests 
(including hematology, chemistry, coagulation), HCV RNA, HCV 
resistance samples, HBV DNA sample, urine pregnancy tests 
(females of child bearing potential only), and IL28B genotyping.
Posttreatment assessments include weight, vital signs, AEs and 
concomitant medications, pregnancy prevention counseling, safety 
laboratory tests (including hematology and chemistry), HCV RNA, 
HCV resistance samples, HBV DNA, and urine pregnancy tests 
(females of childbearing potential only).


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 7
03 July 2019
Test Product, Dose, 
and Mode of 
Administration:
SOF/VEL fixed dose combination (FDC) is manufactured as a 
400/100 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:
AEs and safety laboratory tests will be collected throughout the study.
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using COBAS® Ampliprep/ COBAS® TaqMan® HCV 
Quantitative Test, version 2.0. 
Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all enrolled 
and treated subjects.
In the primary efficacy analysis, the SVR12 rate in the Full Analysis 
Set (FAS) will be compared to a performance threshold rate of 78% 
using the two-sided exact one-sample binomial test at significance 
level of 0.05. In addition, a point estimate with a two-sided 95% exact 
confidence interval using the binomial distribution (Clopper-Pearson 
method) will be constructed for the SVR12 rate.
Secondary efficacy endpoints include SVR4, SVR24, and the 
proportion of subjects with virologic failure.
All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation [SD], median, 1st quartile [Q1], 
3rd quartile [Q3], minimum, maximum). All categorical endpoints 
will be summarized by the number and percentage of subjects who 
meet the endpoint definition.
Safety endpoints will be analyzed by the number and percentage of 
subjects with events or abnormalities for categorical values or 
8-number summary (n, mean, SD, median, Q1, Q3, minimum, 
maximum) for continuous data.
Different studies have reported SVR12 rates for compensated 
cirrhotic subjects infected with HCV in Japanese populations. The 
SVR12 performance threshold of 78% for this study is determined as 
clinically relevant by referring to results in the confirmatory studies 
of approved DAA products in Japan. Among these studies, the 
average lower bound of the exact 95% confidence interval is 78%. 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 8
03 July 2019
Based on this, a performance threshold of 78% was established for 
the primary efficacy endpoint. A success for the primary endpoint 
will be claimed if the following criterion is met: point estimate of 
SVR12 is statistically significantly higher than 78% by a two-sided 
exact one-sample binomial test at significance level 0.05, ie, p-value 
for the hypothesis testing for superiority is ≤ 0.05.
This study intends to enroll patients who have compensated cirrhosis. 
A sample size of approximately 36 compensated cirrhotic Japanese 
subjects in the study will provide > 80% power to demonstrate 
superiority to a performance threshold of 78%, assuming an expected 
SVR12 rate of 96% with 12 weeks of SOF/VEL therapy (based on a 
two-sided exact one-sample binomial test of superiority at a 
significance level of 0.05). This expected 96% SVR12 rate represents 
a clinically relevant response for compensated cirrhotic patients, who 
are at risk of PI-based liver toxicity and currently have no 
highly-effective PI-free pan-genotypic treatment options.
This study will be conducted in accordance with the guidelines of ICH Good Clinical Practice 
(GCP), and J-GCP (Ministerial Ordinance on Good Clinical Practice for Drugs), and all 
applicable regulatory requirements, including archiving of essential documents.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 9
03 July 2019
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
° C
degrees Celsius
° F
degrees Fahrenheit
Ab
antibody
ABW
actual body weight
AE(s)
adverse event(s)
ALT
alanine aminotransferase (also SGPT)
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase (also SGOT)
ASV
asunaprevir
BMI
body mass index
BCV
beclabuvir
CFR
Code of Federal Regulations
CI
confidence interval
ClCr
creatinine clearance
CPT
Child-Pugh-Turcotte
CRO
contract (or clinical) research organization
CSR
clinical study report
DAA
direct-acting antiviral
DCV
daclatasvir
dL
Deciliter
DNA
deoxyribonucleic acid 
EBR
elbasvir
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eg
example given
eSAE
electronic serious adverse event
ESLD
end stage liver disease
Et al
(Latin) and others
ET
early termination
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
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


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 10
03 July 2019
GLE
glecaprevir
GS-7977
sofosbuvir, formerly PSI-7977
GSI
Gilead Sciences, Inc.
GT
Genotype
GZR
grazoprevir
h
hour
H2
histamine
Hb
hemoglobin 
HbA1c
hemoglobin A1c 
HBcAb
HBV core antibody
HBsAb
HBV surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDPE
high density polyethylene 
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
HMG-CoA
3-hydroxy-3-methyl-glutaryl coenzyme A
IB
investigator brochure
ICF
informed consent form 
ICH
International Conference on Harmonization
IEC
independent ethics committee
IFN
interferon
ie
in essence
IL28B
interleukin-28B gene
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
INR
international normalized ratio of prothrombin time
IRB
institutional review board
IU
International Units
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IWRS
interactive web response system
J-GCP
Ministerial Ordinance on Good Clinical Practice for Drugs
JSH
Japan Society of Hepatology
kg
kilogram
kPA
kilopascal
L
liter


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 11
03 July 2019
LAM
lactational amenorrhea method
LDV
ledipasvir
LLOQ
lower limit of quantification
LLT
lower-level term
MCV
mean corpuscular volume or mean cell volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MGB
minor groove binder
MHLW
Ministry of Health, Labour and Welfare
mL
milliliter
mm3
cubic millimeter
mmHg
millimeters mercury
n
number
NS (3/4A/5A/5B)
non-structural protein
PCR
polymerase chain reaction
PI
protease inhibitor
PIB
pibrentasvir
PK
pharmacokinetic
PPIs
proton-pump inhibitors
PT
preferred term or prothrombin time
Q1
quartile 1
Q3
quartile 3
RAS
resistance associated substitutions
RBC
red blood cell count
RBV
ribavirin
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SAE
serious adverse event
Scr
serum creatinine (mg/dL)
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SNP
single nucleotide polymorphism
SOC
standard of care
SOF
sofosbuvir, formerly GS-7977
SOP
standard operating procedure
SSR
special situation report
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
sustained virologic response
SVR12
sustained virologic response 12 weeks after cessation of treatment


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 12
03 July 2019
SVR24
sustained virologic response 24 weeks after cessation of treatment
SVR4
sustained virologic response 4 weeks after cessation of treatment
TND
target not detected
ULN
upper limit of normal
US
United States
WBC
white blood cell
VEL
velpatasvir
β-hCG
β-human chorionic gonadotropin
μg
microgram


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 13
03 July 2019
1.
INTRODUCTION
1.1.
Background
With published HCV prevalence estimates from blood-donor and subgroup-based studies on the 
order of 1-1.9% in Japan {Sievert 2011}, it is estimated that there are approximately
1.3-2.4 million people chronically infected with HCV. An estimated 70% of HCV patients in 
Japan are infected with genotype (GT) 1b, and 25% to 30% with GT 2a or 2b {Sievert 2011}.
The highest prevalence rates of HCV antibodies in first-time blood donor studies have been 
reported in the 50-59 year (1.8%) and 60-69 year (3.4%) age groups {Tanaka 2004}. 
Consequently, the majority of Japanese patients with chronic hepatitis C are elderly 
(average age ~ 70 years) and are more likely to be treatment-experienced and have progressive 
liver disease. Comorbid conditions (eg, diabetes and cardiovascular disease) are also common in 
this population. and it is estimated that approximately 15-30% of patients with chronic hepatitis 
C will go on to develop complications, including liver cirrhosis, HCC, and end stage liver 
disease (ESLD) {Thein 2008}. 
In Japan, ledipasvir/sofosbuvir (LDV/SOF), SOF + ribavirin (RBV), elbasvir (EBR) + 
grazoprevir (GZR), glecaprevir/pibrentasvir (GLE/PIB), and beclabuvir/daclatasvir/asunaprevir 
(BCV/DCV/ASV) are currently approved and recommended as the first-line standard of care 
(SOC) for the treatment of HCV. Per the Japan Society of Hepatology (JSH) guidelines, the 
choice of HCV treatment regimen is to be based on the patient's HCV genotype, prior treatment 
history and cirrhosis status.
Patients that are treatment naïve with compensated cirrhosis are recommended to be treated with 
12 weeks of LDV/SOF, EBR + GZR or GLE/PIB for GT1 or with 12 weeks of SOF+RBV, 
GLE/PIB or LDV/SOF for GT2. These have been recommended as the first-line SOC in the JSH 
treatment guidelines as they are highly efficacious and well-tolerated (GT1: 100%, GT2: 93% to 
100%) {Akuta 2012, Kawaoka 2011, Sakamoto 2011}.
Although recent treatment advances have begun to address several of the unmet needs in the 
treatment of HCV infection in Japan, resulting in a 20% reduction in chronic hepatitis C 
infection rate over a 3 year period, the number of HCV patients with compensated cirrhosis 
(estimated to be 40,000) over the same period remained unchanged suggesting that despite the 
availability of highly efficacious treatment, there is a high rate of progression to cirrhosis in the 
Japanese population {Ito 2016}.
1.2.
Sofosbuvir/Velpatasvir Fixed-Dose Combination
Sofosbuvir (SOF) is a nucleotide analog HCV NS5B polymerase inhibitor. Velpatasvir (VEL) is 
a pangenotypic HCV NS5A inhibitor. 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 14
03 July 2019
1.2.1.
General Information
Please refer to the current Investigator’s Brochure (IB) for additional information on SOF/VEL
FDC, 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.
Clinical Trials of SOF/VEL FDC
1.2.2.1.
GS-US-342-4019 SOF/VEL+/-RBV for 12 Weeks in Japanese subjects with 
Chronic HCV Infection and Decompensated Cirrhosis
This Phase 3 study included 102 subjects with chronic HCV and decompensated cirrhosis who 
were randomized to be treated with SOF/VEL with or without RBV for 12 weeks. All subjects 
completed the full 12 weeks of treatment with SOF/VEL+/-RBV. 57% were treatment naive, 
78% and 20% had genotype 1 and 2 HCV infection, respectively, and 77% and 20% had Child-
Pugh-Turcotte (CPT) class B and C cirrhosis, respectively, at baseline. Overall, 61% of patients 
were female and the mean age was 66 years (range 41–83). Rates of SVR12 were 92% (47/51) in 
each group. Among patients who achieved SVR12, 26% had improved CPT class from baseline 
to posttreatment week 12. Most adverse events (AEs) were consistent with clinical sequelae of 
advanced liver disease or known toxicities of ribavirin. Four patients (8%) who received 
SOF/VEL and seven (14%) who received SOF/VEL plus ribavirin experienced a serious AE. 
The results from this study formed the basis for registration of SOF/VEL (Epclusa®) in Japan for 
the treatment of chronic HCV infection with decompensated cirrhosis {Takehara 2019}.
1.2.2.2.
GS-US-342-3921 SOF/VEL+ RBV for 12 or 24 Weeks in Japanese subjects with 
Chronic Genotype 1 or 2 HCV Infection Who Have Previously Failed a 
Direct-Acting Antiviral-Containing Regimen
This Phase 3 study included 117 subjects with chronic HCV who failed a direct-acting antiviral 
(DAA) based regimen who were treated with SOF/VEL with RBV for 12 or 24 weeks. All but 
one subject completed the full treatment duration with SOF/VEL+RBV. 81% had HCV genotype 
1 infection, 33% had cirrhosis, and 95% had NS5A resistance associated substitutions (RAS) at 
baseline. Overall, SVR12 rates were 97% (58/60; 95% CI 88–100%) with 24 weeks of treatment 
and 82% (47/57; 95% CI 70–91%) with 12 weeks. For HCV genotype 1 and 2 infected patients, 
the SVR12 rates with 24 weeks of treatment were 98% and 92%, respectively. For patients with 
NS5A RASs at baseline, 85% (46/54) in the 12-week group and 96% (54/56) in the 24-week 
group achieved SVR12. The most common adverse events were upper respiratory tract viral 
infection, anemia, and headache. Three (2.6%) patients discontinued treatment because of 
adverse events. The results from this study formed the basis for registration of SOF/VEL 
(Epclusa®) + RBV in Japan for the treatment of chronic HCV infection who failed a direct-acting 
antiviral (DAA) based regimen {Izumi 2018}.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 15
03 July 2019
1.3.
Rationale for This Study
As patients with asymptomatic compensated cirrhosis are at high risk of developing clinical 
signs of decompensation such as portal hypertension and variceal bleeds {D'Amico 2006}, there 
remains a need in Japan for a protease inhibitor (PI)-free HCV treatment regimen that is safe and 
effective for both compensated and decompensated HCV patients. 
SOF/VEL FDC is already approved for use in decompensated patients and DAA failure patients 
with or without compensated cirrhosis in Japan, and the aim of this study is to examine the safety 
and efficacy of SOF/VEL FDC in Japan for DAA naïve compensated cirrhotic patients. This has 
the potential to offer a simplified, safe, and effective PI-free HCV treatment option without the 
need to distinguish between compensated and decompensated cirrhosis.
1.4.
Rationale for Dose Selection of SOF/VEL FDC
Subjects in this study will be administered SOF/VEL FDC, a co-formulation of SOF 400 mg and 
VEL 100 mg that is approved in the US, EU and other regions as Epclusa® for the treatment of 
HCV infection in adults. In addition, this co-formulation is already approved in Japan for HCV 
infected subjects with decompensated cirrhosis or those who are DAA failures with or without 
compensated cirrhosis.
In the Phase 3 ASTRAL 1-3 studies (GS-US-342-1138, GS-US-342-1139, GS-US-342-1140), 
treatment of HCV infected subjects without cirrhosis or with compensated cirrhosis for 12 weeks 
with SOF/VEL FDC 400/100 mg was well tolerated and resulted in high SVR12 rates. In the 
global ASTRAL-4 (GS-US-342-1137) study and in the identical Phase 3 Japanese study
(GS-US-342-4019), treatment of HCV-infected subjects with decompensated CPT class B and C
cirrhosis with SOF/VEL FDC 400/100 mg for 12 weeks was well tolerated and resulted in high 
SVR12 rates across all HCV genotypes. 
These data support evaluation of SOF/VEL FDC 400/100 mg in this phase 3 study in 
Japanese patients with compensated cirrhosis. Refer to the SOF/VEL FDC Investigator’s 
Brochure for additional information.
1.5.
Risk/Benefit Assessment for the Study
This study will provide information of the safety and efficacy of the combination of SOF/VEL
FDC for 12 weeks in Japanese patients with compensated cirrhosis.
The safety profile of SOF/VEL FDC has been established in 3,345 subjects, including the Phase 
3 studies, Phase 2 studies and Phase 1 studies in subjects with compensated and decompensated 
cirrhosis. The safety of SOF/VEL FDC has also been established in 219 Japanese patients. No 
clinical safety issues specifically related to the combination of SOF/VEL FDC have been 
identified to date. Overall, SOF/VEL FDC for 12 weeks was safe and well tolerated in patients 
with or without cirrhosis.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 16
03 July 2019
During the conduct of the study, the sponsor together with the investigator will perform ongoing 
safety reviews.
In summary, safety and efficacy of SOF/VEL FDC for 12 weeks has been evaluated in subjects 
with compensated and decompensated cirrhosis and without cirrhosis.
1.6.
Compliance
This study will be conducted in accordance with the guidelines of ICH Good Clinical Practice 
(GCP), and J-GCP (Ministerial Ordinance on Good Clinical Practice for Drugs), and all 
applicable regulatory requirements, including archiving of essential documents.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 17
03 July 2019
2.
OBJECTIVES
The primary objectives of this study are:

To evaluate the antiviral efficacy of therapy with SOF/VEL fixed-dose combination (FDC) 
for 12 weeks as measured by the proportion of subjects with sustained virologic response 
12 weeks after cessation of treatment (SVR12)

To evaluate the safety and tolerability by review of the accumulated safety data
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 18
03 July 2019
3.
STUDY DESIGN
3.1.
Study Design
This is a multicenter, open-label study evaluating efficacy and safety of SOF/VEL FDC in 
subjects with chronic HCV and compensated cirrhosis.
Subjects may have HCV of any genotype, and based on the HCV genotype (GT) distribution in 
Japan, it is expected that approximately 70% of subjects will be GT1, and approximately 30% of 
subjects will be non-GT1. Subjects may be either treatment-naïve or treatment-experienced with 
IFN-based treatments.
3.2.
Study Treatments
Approximately 36 subjects will be enrolled to be treated with SOF/VEL FDC.
3.3.
Duration of Treatment
Subjects will be treated for 12 weeks.
The total time to complete all study visits is approximately 40 weeks (42 weeks for those 
requiring an extension of the Screening period):

28 days (4 weeks) screening period

12 weeks study treatment period

24 weeks posttreatment period
3.4.
Stopping Rules and Discontinuation Criteria
If a subject discontinues study dosing (for example, as a result of an adverse event [AE]), every 
attempt should be made to keep the subject in the study and continue to perform the required 
study-related follow-up procedures (see Section 6.3). If this is not possible or acceptable to the 
subject or investigator, the subject may be withdrawn from the study.
There is no option for SOF/VEL FDC dose reduction.
Subjects who permanently discontinue SOF/VEL FDC should complete an Early Termination 
(ET) visit. For subjects who have completed an ET visit, the posttreatment Weeks 4, 12, and 24
visits will be completed after the last dose of the study drug. When medically feasible, the 
medical monitor must be consulted prior to subject discontinuation. 
Study drug must be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 19
03 July 2019

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Virologic failure (as defined in Section 3.4.2)

Pregnancy of female subject (refer to Appendix 4)

Significant protocol violation that impacts subject safety

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason

Subject noncompliance

Discontinuation of the study at the request of Gilead, regulatory agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)
3.4.1.
Toxicity-Based Stopping Criteria
The Medical Monitor must be consulted prior to dose discontinuation of SOF/VEL FDC unless 
the investigator believes that immediate action is warranted to ensure the continued safety of the 
subject.
Due to a clinical or laboratory event, administration of study drug may be discontinued. There is 
no option for SOF/VEL FDC dose reduction. If SOF/VEL FDC is stopped due to toxicity, it 
must not be restarted. In these cases that study drug is discontinued permanently, the subject 
must complete an ET visit. Posttreatment Week 4, 12, and 24 visits must also be scheduled, 
4, 12, and 24 weeks from the last dose of study drug.
Subjects who meet any of the following laboratory criteria must stop all study drug:

Elevation of ALT and/or AST above the upper limit of normal and > 5x Day 1 or nadir, 
confirmed by immediate repeat testing

Abnormal elevation of ALT > 3 x Day 1 and total bilirubin > 2 x ULN, confirmed by 
immediate repeat testing

Elevation of ALT > 15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event or laboratory abnormality assessed (and confirmed by immediate 
repeat testing) as related to SOF/VEL FDC 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 20
03 July 2019
3.4.2.
Virologic Response-Based Treatment Stopping Criteria
The following on-treatment Virologic Response-based Treatment Stopping Criteria will be 
utilized:

Confirmed HCV RNA ≥ LLOQ after 2 consecutive HCV RNA < LLOQ

Confirmed > 1 log10 increase in HCV RNA from nadir

HCV RNA ≥ LLOQ through 8 weeks of treatment
Confirmation, when required, should be performed as soon as possible and must occur no later 
than 2 weeks after an initial observation indicating virologic failure during the on-treatment 
phase. 
Subjects who terminate study drug early due to virologic failure as defined above will complete 
the Early Termination (ET) visit and all posttreatment visits.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 21
03 July 2019
4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 36 chronic HCV infected male and non-pregnant female subjects, ages 18 or 
older, with compensated cirrhosis at Screening will be enrolled in this study.
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 give informed consent prior to any study specific procedures being 
performed. If subject is a minor, legal representative will provide consent.
2) Male or female, age 18 years at Screening
3) Body weight ≥ 40 kg at Screening
4) Quantifiable HCV RNA (≥lower limit of quantitation [LLOQ]) at Screening
5) Chronic HCV infection (≥ 6 months prior to Screening) documented by prior medical history 
or liver biopsy.
6) Confirmation of cirrhosis by any one of the following methods:
a) Liver biopsy showing cirrhosis (eg, Metavir score = 4 or Ishak score 5)
b) Fibroscan within 4 months of Day 1 showing cirrhosis or results > 12.5 kPa
c) FibroTest® score of > 0.75 at Screening (only in the absence of liver biopsy or 
availability of Fibroscan)
7) HCV treatment status defined as one of the following, and with medical records that include 
sufficient detail to allow for categorization as follows:
a) HCV treatment-naive: Subject has had no prior exposure to any IFN, RBV, or other 
approved or experimental HCV-specific direct-acting antiviral agents.
b) HCV treatment-experienced: Subject has had prior treatment with an approved or 
experimental IFN-containing regimen with or without NS3/4A protease inhibitors. Note:
See Exclusion Criterion #5: if treatment-experienced, prior exposure to any direct-acting 
antiviral agent targeting the HCV NS5A or NS5B is prohibited.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 22
03 July 2019
8) If treatment-experienced, the most recent HCV treatment must have completed at least 
8 weeks prior to Screening
9) Liver imaging (eg, ultrasound or CT scan, at the discretion of the investigator) performed 
within 4 months of Day 1 to exclude hepatocellular carcinoma (HCC) 
10) 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.
11) 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.
12) Male subjects must agree and refrain from sperm donation during treatment and until at least 
30 days after the last dose SOF/VEL FDC. Female subjects must also refrain from egg 
donation and in vitro fertilization during treatment and until at least 30 days after the 
last dose of SOF/VEL FDC.
13) Lactating females must agree to discontinue nursing before the study drug is administered
and through at least 30 days after the last dose of study drug.
14) Subject must be of generally good health, with the exception of chronic HCV infection, as 
determined by the investigator.
15) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments, including all required posttreatment
visits.
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 or currently under evaluation for a potentially clinically 
significant illness (other than HCV) or any other major medical disorder that may 
interfere with subject treatment, assessment, or compliance with the protocol
b) Gastrointestinal disorder or postoperative condition that could interfere with the 
absorption of the study drug
c) Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy
d) Any current or past clinical evidence of decompensated liver disease (eg, ascites, hepatic 
encephalopathy, or variceal bleeding).
e) Solid organ transplantation


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 23
03 July 2019
f)
Significant pulmonary disease
g) Unstable cardiac disease or significant cardiac event within one year prior to Screening
h) Porphyria 
i)
History of clinically significant hemoglobinopathy (eg, sickle cell disease, thalassemia)
j)
Psychiatric hospitalization, suicide attempt and/or a period of disability as a result of their 
psychiatric illness within the last 2 years of Screening
k) Malignancy within the 5 years prior to Screening with the exception of specific cancers 
that are cured by surgical resection (basal cell skin cancer, etc.). Subjects under 
evaluation for possible malignancy are not eligible
l)
Prior or current hepatocellular carcinoma (HCC)
m) Significant drug allergy (such as anaphylaxis or hepatotoxicity)
2) Infection with human immunodeficiency virus (HIV) at Screening
3) Hepatitis B virus (HBV) surface antigen positive at Screening
4) Screening ECG with clinically significant abnormalities
5) Prior exposure to any HCV NS5A or NS5B inhibitor
6) History of clinically significant medical condition associated with other chronic liver disease 
(eg, hemochromatosis, autoimmune hepatitis, Wilson’s disease, α-1-antitrypsin deficiency, 
alcoholic liver disease, non-alcoholic steatohepatitis or toxin exposure)
7) Pregnant or nursing female or male with pregnant female partner
8) Women who wish to become pregnant or males with female partners who wish to become 
pregnant during study treatment and through 30 days after the last dose SOF/VEL FDC
9) Subjects with any of the following laboratory parameters at Screening:
a) ALT > 10 upper limit of normal (ULN)
b) AST > 10 ULN
c) Direct bilirubin > 1.5 × ULN
d) Platelets < 50,000/L
e) HbA1c > 8.5%


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 24
03 July 2019
f)
Hemoglobin < 10 g/dL
g) Albumin < 3 g/dL
h) International Normalized Ratio of prothrombin time (INR) > 1.5 × ULN unless subject 
has known hemophilia or is stable on an anticoagulant regimen affecting INR
i)
Neutrophil count < 500/L
10) Use of any prohibited concomitant medications as described in Section 5.4 of the Protocol
11) Chronic use of systemically administered immunosuppressive agents (eg, prednisone 
equivalent > 10 mg/day)
12) Known hypersensitivity or contraindication to SOF, VEL, or the metabolites or formulation 
excipients


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 25
03 July 2019
5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
This is a multicenter, open-label study in subjects with chronic HCV infection with compensated 
cirrhosis. No blinding is required.
All subjects will be enrolled to receive SOF/VEL FDC for 12 weeks.
5.2.
Description and Handling of SOF/VEL FDC
5.2.1.
Formulation
The SOF/VEL FDC (400/100 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 FDC tablets contain copovidone, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene 
glycol, talc, and iron oxide red.
5.2.2.
SOF/VEL FDC Packaging and Labeling
SOF/VEL FDC (400/100 mg) tablets are packaged in white, high density polyethylene (HDPE) 
bottles. Each bottle contains 28 tablets and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, aluminum-faced liner.
SOF/VEL FDC bottles to be distributed to centers in Japan shall be labeled for clinical use to 
meet applicable requirements of the J-GCP (Ministerial Ordinance on Good Clinical Practice for 
Drugs).
5.2.3.
SOF/VEL FDC Storage and Handling
SOF/VEL FDC tablets should be stored below 30 C (86 F).
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF/VEL FDC tablets.
5.3.
Dosage and Administration of SOF/VEL FDC
SOF/VEL FDC tablet is to be administered once daily with or without food. Each subject must 
be given instructions to maintain approximately the same daily dosing interval between study 
drug doses.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 26
03 July 2019
If a subject does not take the SOF/VEL FDC dose at the usual time, it may be taken up to 
18 hours later; however, no more than one tablet should be taken on any calendar day. The 
subject should resume the standing dosing schedule on the next day.
Study drug should not be cut or split. SOF/VEL FDC tablets will be provided by Gilead Sciences 
for all subjects.
5.4.
Prior and Concomitant Medications
All concomitant medications taken within 30 days prior to Screening, up to and including 
30 days after the last dose of study drug, need to be recorded in the source documents and 
electronic case report form (eCRF) (including all blood products). 
Investigational agents or devices for any indication are prohibited from 28 days prior to the 
Day 1 visit through the end of study drug dosing.
Concomitant use of certain medications or herbal/natural supplements (such as moderate to 
potent inducers of drug transporters or metabolizing enzymes, eg, P-gp, CYP2B6, CYP2C8, or 
CYP3A) with the study drug may result in pharmacokinetic interactions resulting in increases or 
decreases in exposure of the study drug or these medications.
Investigators should refer to the product/package inserts of other medications for 
recommendations or contraindications related to their use.
Table 5-1 below contains examples of medications that are prohibited from 21 days prior to 
Day 1 through the end of treatment and those medications which may be used with caution. The 
use of amiodarone is prohibited from 60 days prior to Day 1 through the end of treatment.
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton- Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsb
Phenytoin, Carbamazepine, Phenobarbital
Antimycobacterialsb
Rifampicin
Rifabutin
Cardiac Medicationsc 
Amiodaroned
Digoxine
Herbal/Natural 
Supplementsb
St. John’s Wort
HMG-CoA Reductase 
Inhibitorsf
Rosuvastatin (≤10 mg/day), Atorvastatin
Other
Bosentanb, Modafinilb, Sulfasalazinec, 
Methotrexatec
Dabigatran etexilateg
a
Proton pump inhibitor (PPI) doses comparable with omeprazole 20mg can be administered with SOF/VEL FDC when 
SOF/VEL FDC is administered with food and taken 4 hours before the PPI. H2-receptor antagonists must not exceed a dose 
of 40 mg famotidine or equivalent and can be taken simultaneously with SOF/VEL FDC and/or staggered by 12 hours. 
Antacids that directly neutralize stomach acid may not be taken within 4 hours (before or after) of SOF/VEL FDC
administration.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 27
03 July 2019
b
May result in a decrease in the concentration of study drug.
c
May result in an increase in the concentration of study drug and/or concomitant medications.
d
May result in symptomatic bradycardia. Mechanism is not currently known. The use of amiodarone is prohibited from 
60 days prior to Day 1 through the end of treatment.
e
Monitor for signs and symptoms of digoxin toxicity.
f
Use with SOF/VEL FDC 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. Rosuvastatin may be coadministered at a 
dose that does not exceed 10 mg.
g
As dabigatran exposure may increase when coadministered with SOF/VEL FDC, clinical monitoring for signs of bleeding 
and anemia is recommended, in addition to monitoring patients using coagulation testing.
Medications for disease conditions excluded from the protocol (eg, HIV infection) are not listed 
under this Concomitant Medication section and are disallowed in the study.
Should subjects have a need to initiate treatment with any excluded concomitant medication, the 
Medical Monitor must be consulted prior to initiation of the new medication. In instances where 
an excluded medication is initiated prior to discussion with the Sponsor, the Investigator must 
notify Gilead as soon as he/she is aware of the use of the excluded medication.
5.5.
Study Drug Adherence and Accountability for SOF/VEL FDC
The investigator or designee (ie pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgement of receipt of each shipment 
of study drug (quantity and condition). All used and unused study drug dispensed to subjects 
must be returned to the site.
SOF/VEL FDC accountability records will be provided to each study site to:

Record the lot number, expiration date (if necessary)

Record the date received and quantity of study drug kits

Record the date, subject number and the study drug kit number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
Refer to Section 9.1.8 for information on return and disposal of study drug.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 28
03 July 2019
6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. 
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment 
Entry into screening does not guarantee enrollment into the study. In order to manage the total 
trial enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or trial-wide at any time.
6.1.1.
Screening Visit
Subjects will be screened within 28 days before Day 1 visit to determine eligibility for 
participation in the study. The screening window can be extended up to 42 days for subjects in 
extenuating circumstances with sponsor approval. A single retest of screening labs is permitted 
only if there is reason to believe the retest value will be within accepted parameters if the initial
value was due to a sample processing error or due to an extenuating circumstance such as an 
intercurrent infection. 
The following will be performed and documented at screening:

Obtain written informed consent

Determine inclusion and exclusion eligibility

Obtain medical history (refer to Section 6.7.2), including:
Hepatitis C treatment history, if applicable 
■
Regimen (s)
■
Dates of previous treatment(s)
■
Response to previous treatment (i.e. nonresponder, relapse, discontinuation including 
reason)

Complete physical examination (refer to Section 6.7.3)

Obtain height and weight

Obtain vital signs (refer to Section 6.7.4)


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 29
03 July 2019

Perform 12-Lead ECG (refer to Section 6.7.5)

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form.

Obtain details of prior and concomitant medications

Liver biopsy and/or Fibroscan results (if available)

Diagnostic imaging (eg, ultrasound or CT scan, at the discretion of the Investigator) should 
be performed to exclude the presence of hepatocellular carcinoma (HCC). Imaging must be 
performed within 4 months of Day 1.

Obtain blood samples for tests:
Hematology
Chemistry
Coagulation tests
HCV RNA
Serum β-hCG pregnancy test for females of childbearing potential only
Serum follicle stimulating hormone (FSH) (only for women of any age with amenorrhea 
of ≥ 12 months [refer to Appendix 4])
HCV Genotype
HCV antibody, HIV antibody, HBV surface antigen (HBsAg), HBV surface antibody 
(HBsAb), HBV core antibody (HBcAb)
HbA1c
Fibrotest®

Obtain urine sample for:
Urinalysis

A single retest of Screening labs is 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 an extenuating circumstance such as intercurrent 
illness.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 30
03 July 2019
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for enrollment into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (eCRF). All 
other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF. 
See Section 7 Adverse Events for additional details.
6.1.2.
Day 1 Assessments
An Interactive Web Response System (IWRS) will be employed to manage subject enrollment. 
The following Day 1 tests and procedures must be performed prior to enrollment and 
dosing/dispensation of study drug:

Determine inclusion and exclusion eligibility (refer to Sections 4.2 and 4.3)

Perform complete physical examination (refer to Section 6.7.3)

Obtain weight

Obtain vital signs (refer to Section 6.7.4)

Perform 12-Lead ECG (refer to Section 6.7.5)

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counseling

Obtain blood samples for tests:
Hematology
Chemistry
Coagulation tests
HCV RNA
IL28B Genotype
HCV resistance samples

Obtain urine sample for:
Pregnancy test for females of childbearing potential only


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 31
03 July 2019
When ready to administer study drug to the subject:

Dispense study drug as directed by the IWRS

Instruct the subject on the packaging, storage, and administration of study drug

Instruct the subject on how to complete the subject diary

Observe the subject taking the first dose of study drug. 
6.2.
Treatment Assessments (± 3 days)
On-treatment visits will be performed at the end of Weeks 1, 2, 4, 8, and 12 for all subjects.
Study drug will be reconciled at every post-Day 1 visit by the investigator in order to monitor the 
subject’s adherence with the study drug.
6.2.1.
Week 1 (± 3 days)
The following procedures/assessments are to be completed at the end of Week 1:

Obtain vital signs (refer to Section 6.7.4)

Assessment of AEs and concomitant medications

Assess adherence with study drug dosing regimen including pill count
6.2.2.
Week 2 (± 3 days)
The following procedures/assessments are to be completed at the end of Week 2:

Obtain vital signs (refer to Section 6.7.4)

Assessment of AEs and concomitant medications

Assess adherence with study drug dosing regimen including pill count

Obtain blood samples for tests:
Hematology
Chemistry
HCV RNA
HCV resistance samples
HBV DNA Sample


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 32
03 July 2019
6.2.3.
Weeks 4 and 8 (± 3 days)
The following procedures/assessments are to be completed at the end of Weeks 4 and 8:

Obtain vital signs (refer to Section 6.7.4)

Assessment of AEs and concomitant medications

Assess adherence with study drug dosing regimen including pill count

Dispense study drug as directed by the IWRS (Week 4 only)

Obtain blood samples for tests:
Hematology
Chemistry
HCV RNA
HCV resistance samples
HBV DNA Sample

Obtain urine sample for:
Pregnancy test for females of childbearing potential only
6.2.4.
Week 12 (± 3 days)
The following procedures/assessments are to be completed at the end of Week 12:

Perform complete physical examination (refer to Section 6.7.3)

Obtain weight

Obtain vital signs (refer to Section 6.7.4)

Assessment of AEs and concomitant medications

Perform 12-Lead ECG (refer to Section 6.7.5)

Conduct pregnancy prevention counseling

Assess adherence with study drug dosing regimen including pill count

Collect any remaining study drug from the subject 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 33
03 July 2019

Obtain blood samples for tests:
Hematology
Chemistry
Coagulation tests
HCV RNA
HCV resistance samples
HBV DNA Sample

Obtain urine sample for:
Pregnancy test for females of childbearing potential only
6.3.
Posttreatment Assessments (± 5 days)
The posttreatment Weeks 4, 12, and 24 visits should be timed from the date of last administration 
of study drug for all subjects, regardless of whether they are a virologic failure or discontinued 
study drug early.
6.3.1.
Posttreatment Week 4 (± 5 days)
The following procedures/assessments are to be completed for all subjects, 4 weeks after taking 
the last dose of study drug:

Obtain vital signs (refer to Section 6.7.4)

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counseling

Obtain blood samples for tests:
Hematology
Chemistry
HCV RNA
HCV resistance sample
HBV DNA Sample

Obtain urine sample for:
Pregnancy test for females of childbearing potential only (refer to Section 6.7.9)


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 34
03 July 2019
6.3.2.
Posttreatment Weeks 12 and 24 (± 5 days)
The following procedures/assessments are to be completed for all subjects, 12 and 24 weeks after 
taking the last dose of study drug:

Obtain weight

Obtain vital signs (refer to Section 6.7.4)

Obtain blood samples for tests:
HCV RNA
HCV resistance sample
6.4.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 3.4, Stopping Rules and Discontinuation Criteria). If this 
is not possible or acceptable to the subject or investigator, the subject may be withdrawn from 
the study.
6.5.
Early Termination (ET)
For subjects who have completed an ET visit, the posttreatment Weeks 4, 12, and 24 follow-up 
visits will be scheduled after the last dose of the study drug.
When medically feasible, the medical monitor must be consulted prior to subject discontinuation.
The following procedures/assessments are to be completed at an Early Termination visit:

Perform complete physical examination (refer to Section 6.7.3)

Obtain weight

Obtain vital signs (refer to Section 6.7.4)

Assessment of AEs and concomitant medications

Perform 12-Lead ECG (refer to Section 6.7.5)

Conduct pregnancy prevention counseling

Assess adherence with study drug dosing regimen including pill count

Collect any remaining study drug from the subject 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 35
03 July 2019

Obtain blood samples for tests:
Hematology
Chemistry
Coagulation tests
HCV RNA
HCV resistance samples
HBV DNA Sample

Obtain urine sample for:
Pregnancy test for females of childbearing potential only
6.6.
Unscheduled Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments are at the investigator’s discretion as clinically indicated, but the investigator should, 
at a minimum, collect AE and concomitant medication information. At all unscheduled visits 
initiated for the purpose of confirming virologic failure, a HCV resistance sample must be 
collected.
6.7.
Procedures and Specifications
6.7.1.
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, and Basophils, Reticulocyte count and 
mean corpuscular volume (MCV).
Coagulation: INR, Prothrombin Activation %, Prothrombin time (PT), Activated partial 
thromboplastin time (aPTT)
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatine Kinase, Creatinine, Direct Bilirubin, Total Bilirubin, 
Glucose, Lipase, Potassium, Sodium, phosphate, uric acid, FibroTest® (at Screening only)
Urinalysis: Blood, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. Reflex to 
microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV and HBV. HBV DNA (reflex testing done when 
ALT > 2x Day 1 value in subjects who are HBsAb or HBcAb positive at Screening). 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, 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 36
03 July 2019
version 2.0. HCV genotype and subtype will be determined using the Siemens VERSANT®
HCV Genotype INNO-LiPA2.0 Assay. Gilead reserves the right to use alternate assays for HCV 
RNA and HCV genotype should the above assays become unavailable or are not definitive.
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 (if positive, requires immediate confirmation 
with Serum β-hCG), and serum FSH.
6.7.2.
Medical History
Medical history, including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
screening.
6.7.3.
Complete Physical Examination
A physical examination must include source documentation of general appearance, and the 
following body systems: Head, neck, and thyroid; eyes, ears, nose, throat, mouth, and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes; abdomen; skin, hair, nails; 
musculoskeletal; neurological.
6.7.4.
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.
6.7.5.
12-Lead ECG
Subjects will be required to rest in a supine position for 5 minutes prior to making a recording. 
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities. 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 37
03 July 2019
6.7.6.
Creatinine Clearance 
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft 1976} using
actual body weight (ABW).
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)
6.7.7.
HCV Resistance Sample
Plasma samples will be collected at Day 1 and at on-treatment visits at Weeks 2, 4, 8, and 12, 
early termination (if applicable), and all posttreatment visits and may be archived 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.
6.7.8.
HBV DNA Sample
A sample for HBV DNA testing will be collected at on-treatment visits at Weeks 2, 4, 8, and 12 
or early termination (if applicable) and posttreatment week 4. HBV DNA will only be tested 
when ALT > 2x Day 1 value in subjects who are HBsAb or HBcAb positive at Screening.
6.7.9.
Pregnancy Testing
All females of childbearing potential will have a serum pregnancy test at Screening. Urine 
pregnancy testing will occur at Day 1 and every 4 weeks through posttreatment 4. In the event of 
a positive urine pregnancy result, subjects will be instructed to return to the clinic as soon as 
possible for a serum pregnancy test.
6.7.10.
IL28B Testing
A blood sample will be obtained at Day 1 for specific genetic analysis of the rs12979860 
(IL28B) genetic variant. 
6.8.
End of Study
Subjects are considered to have completed the study after the posttreatment Week 24 visit, 
regardless of treatment duration or early termination of study drug.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 38
03 July 2019
6.9.
Post Study Care
No poststudy ongoing care will be provided.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 39
03 July 2019
7.
ADVERSE EVENTS 
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
eCRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 40
03 July 2019

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drug 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.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 41
03 July 2019
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated
with laboratory abnormalities, the event should be graded on the basis of the clinical severity in
the context of the underlying conditions; this may or may not be in agreement with the grading
of the laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events
and Serious Adverse Events to Gilead:
Requirements for collection prior to study drug initiation: After informed consent, but prior to 
initiation of study medication, the following types of events should be reported on the case report 
form (eCRF): All SAEs, and adverse events related to protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days or after last administration of study IMP must be 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 posttreatment follow-up period, must be reported to the 
eCRF database and Gilead Pharmacovigilance & Epidemiology (PVE) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
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 PVE.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 42
03 July 2019
Prior treatment history is collected as part of the study entry criteria and evaluation of individual 
patient characteristics and will not be generating lack of effect reports as this is outside the scope 
of the present clinical study. However, investigators should report any cases of lack of effect that 
they feel appropriate regarding the previous treatment regimen as spontaneous reports to the 
relevant authorities or marketing authorisation holders.

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 PVE 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 PVE: Fax: 
E-mail: 

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
PPD
PPD


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 43
03 July 2019
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Special Situations Reports
7.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of AEs associated with product complaints, occupational exposure with an AE, pregnancy 
reports regardless of an associated AE, and an AE in an infant following exposure from 
breastfeeding.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
Occupational exposure is defined as exposure to a medicinal product as a result of one’s
professional or non-professional occupation.
7.5.2.
Instructions for Reporting Special Situations
7.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after
initiation of study drug(s) and throughout the study, including the post study drug(s) follow-up
period, to Gilead PVE by transmitting electronically and also by sending paper pregnancy report 
form within 24 hours of becoming aware of the pregnancy.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 44
03 July 2019
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (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 
Section 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post study
must be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE 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 PVE. Gilead PVE contact information is as follows: 
Email: 
Fax: 
Pregnancies of female partners of male study subjects exposed to Gilead study drug must also be 
reported and relevant information should be submitted to Gilead PVE using the pregnancy and 
pregnancy outcome forms within 24 hours. Monitoring of the subject should continue until the 
conclusion of the pregnancy. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to 
Gilead PVE, fax number
 or email 
 
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on electronic special situations report form
and transmitted to Gilead PVE within 24 hours of the investigator becoming aware of the
situation. If for any reason it is not possible to record the special situation report (SSR)
information electronically, ie, the eCRF database is not functioning, record the SSR on the paper
special situation reporting form and submit within 24 hours to:
Gilead PVE: Fax: 
Email: 
As soon as it is possible to do so, any SSR reported via paper must be transcribed into the eCRF.
PPD
PPD
PPD
PPD
PPD
PPD


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 45
03 July 2019
Database according to instructions in the eCRF completion guidelines. These reports must 
consist of situations that involve study drug(s) and/or Gilead concomitant medications, but do 
not apply to non-Gilead concomitant medications.
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 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.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 46
03 July 2019
8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are:

To evaluate the antiviral efficacy of therapy with SOF/VEL FDC for 12 weeks as measured 
by the proportion of subjects with sustained virologic response 12 weeks after cessation of 
treatment (SVR12)

To evaluate the safety and tolerability by review of the accumulated safety data
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment
8.1.2.
Primary Endpoint
The primary endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of treatment) in
the Full Analysis Set (FAS) population.
The primary safety endpoint is any AE leading to permanent discontinuation of study drug.
8.1.3.
Secondary Endpoint
The secondary efficacy endpoints include the following:

The proportion of subjects with HCV RNA < LLOQ at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24)

The proportion of subjects with virologic failure


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 47
03 July 2019
 
8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SAS®software (SAS Institute, Cary, North Carolina, USA).
The study drug in this study includes SOF/VEL FDC. Last dose of study drug refers to the last 
dose of SOF/VEL FDC and will be used in the definition of treatment-emergent AEs and 
laboratory abnormalities as well as the efficacy endpoints of SVR at various posttreatment time 
points.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis is defined as the Full Analysis Set (FAS) which 
includes all enrolled subjects who took at least 1 dose of study drug(s).
8.2.1.2.
Safety
The primary analysis set for safety analyses will include all subjects who took at least 1 dose of 
study drug. Treatment-emergent data will be analyzed and defined as data collected from the 
first dose of the study drug through the date of last dose of the study drug plus 30 days.
8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, values for missing data will not be imputed. 
For the analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have
the missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed
up to the time of the last dose.
If a data point is missing and is preceded and followed in time by values that are “< LLOQ 
target not detected (TND),” then the missing data point will be set to “< LLOQ TND.” If a 
data point is missing and preceded and followed by values that are “< LLOQ detected,” or 
preceded by“< LLOQ detected” and followed by “< LLOQ TND,” or preceded by 
“< LLOQ TND” and followed by “< LLOQ detected,” then the missing value will be set to 
“< LLOQ detected.” In these situations the data point will be termed a bracketed success; 
CCI
CCI


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 48
03 July 2019
otherwise, the data point will be termed a bracketed failure (ie, ≥LLOQ detected). If a data point 
is missing and is not bracketed, the missing data point will also be termed a failure (ie, ≥LLOQ 
detected) except for SVR24, which will be imputed according to the SVR12 status. Success for 
SVR12 who have no further HCV RNA measurements collected will be counted as a success for 
SVR24 due to the high correlation between these 2 endpoints.
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject took at least 1 dose of study drug, the subject will be included in a summary of 
AEs according to the treatment received; otherwise, if the subject is not dosed, then they will 
be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pretreatment safety laboratory value is 
available, the baseline value will be assumed to be normal (ie, no grade [Grade 0]) in the 
summary of graded laboratory abnormalities. Values for missing vital signs data will not be 
imputed; however, a missing baseline 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 
baseline values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to 
the logarithmic (base 10) scale (log10 IU/mL).
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, race/ethnicity, and age.
Baseline characteristic data will include a summary of body mass index, HCV RNA level 
(log10 IU/mL), genotype of HCV infection, IL28B genotype, and additional endpoints as 
necessary.


SOFNELFDC 
Protocol GS-US-342-5531 
Gilead Sciences, Inc. 
8.5. 
8.5.1. 
Efficacy Analysis 
Primary Analysis 
Final 
Original 
The prima1y efficacy endpoint for this study will be the propo1tion of subjects with SVR12, 
defined as HCV RNA < LLOQ 12 weeks after cessation of treatment. The primaiy analysis will 
be perfonned after all emolled subjects have been followed through 12 weeks posttreatment or 
discontinued from study. 
In the prima1y efficacy analysis, the SVR12 rate in FAS will be compared to the efficacy 
threshold rate of 78% ( described in Section 8. 7 .1) using a two-sided exact one-sainple binomial 
test at significance level of 0.05: ie, the hypothesis for superiority is as follows: 
HO: SVR12 rate = 78%, 
Hl: SVR12 rate t 78% 
In addition, a point estimate with a two-sided 95% exact confidence interval using the binomial 
distribution (Clopper-Pearson method) will be constructed for the SVR12 rate. 
A success for the primaiy endpoint will be claimed if the following criterion is met: point 
estimate of SVR12 is statistically significantly higher than 78% by a two-sided exact one-sainple 
binomial test at significance level 0.05, ie, p-value for above hypothesis testing for superiority is 
:S 0.05. 
8.5.2. 
Secondary Analyses 
The proportion of subjects with HCV RNA below LLOQ over time (including SVR endpoints) 
will be presented in tabular and graphical fonn. 
Descriptive Sllllllllai·ies and listings will be provided for efficacy evaluation of the proportion of 
subjects who experience virologic failure and additional efficacy evaluations including HCV 
RNA values and change from baseline through end of ti·eatment. 
Details on efficacy analyses will be described in the statistical analysis plan. 
8.6. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laborato1y tests, physical examinations, and 
vital signs measurements and AEs will be documented at vai·ious time points during the study. 
CONFIDENTIAL 
Page49 
03 July 2019 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 50
03 July 2019
All safety data collected, on or after the first dose of the study drug administration up to 30 days
after the last dose of the study drug will be summarized.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to the study drug will be generated from the study drug
administration data. Exposure data will be summarized.
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any AE with an onset date on or after the study drug start date
and no later than 30 days after permanent discontinuation of the study drug; or any AE leading to
premature discontinuation of the study drug
Summaries (number and percentage of subjects) or listings, as appropriate, of treatment-
emergent adverse events (by SOC, and PT) will be provided:

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 (including death)

All treatment-related SAEs

AEs leading to premature discontinuation of the study drug
All AEs collected during the course of the study will be presented in data listings.
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by study visit along with the corresponding change from Baseline/Day 1.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 51
03 July 2019
Graded laboratory abnormalities will be defined using the laboratory toxicity grading defined in 
Appendix 3 of this protocol. The incidence of treatment-emergent laboratory abnormalities, 
defined as values that increase by at least one toxicity grade from Baseline/Day 1 at any time 
postbaseline, up to the date of last dose of study drug plus 30 days will be summarized.
Values for missing safety laboratory data will not be imputed; however, a missing 
Baseline/Day 1 result will be replaced with a screening result, if available. If no pretreatment 
laboratory value is available, the Baseline/Day 1 value will be assumed to be normal (ie, no 
grade [Grade 0]) for the summary of graded laboratory abnormalities.
All laboratory abnormalities will be included in the listings of laboratory data.
8.6.4.
Other Safety Evaluations
Individual data for vital sign measurements will be listed by subject and summarized 
descriptively by descriptive statistical summaries (n, mean, SD, median, Q1, Q3, minimum, and 
maximum), as appropriate. 
8.7.
Sample Size
8.7.1.
Justification for Performance Threshold
Different studies have reported SVR rates for compensated cirrhotic subjects infected with HCV 
in Japanese populations {Asahina 2018, Krishnan 2018, Kumada 2015, Kumada 2016, Kumada 
2017, Mizokami 2015, Omata 2014, Toyota 2017}. The SVR12 performance threshold of 78%
for this study is determined as clinically relevant by referring to results in the confirmatory 
studies of approved DAA products in Japan.
The calculated average of the SVR12 rates for the studies is 96.2% (95% CI: 93.2%-98.2%). The 
point estimates of the SVR12 rates for compensated cirrhotic subjects ranged from 88.9% to 
100% across the eight studies conducted in Japan. Among these studies, the average lower bound 
of the exact 95% confidence interval is 78%. Based on these considerations, a performance 
threshold of 78% was established for the primary efficacy endpoint. A success for the primary 
endpoint will be claimed if the following criterion is met: point estimate of SVR12 is statistically 
significantly higher than 78% by a two-sided exact one-sample binomial test at significance level 
0.05, ie, p-value for the hypothesis testing for superiority is ≤0.05.
8.7.2.
Determination of Sample Size on Basis of Threshold
This study intends to enroll patients who have compensated cirrhosis. A sample size of 
approximately 36 compensated cirrhotic Japanese subjects in the study will provide > 80% 
power to demonstrate superiority to a performance threshold of 78%, assuming an expected 
SVR12 rate of 96% with 12 weeks of SOF/VEL therapy (based on a two-sided exact one-sample 
binomial test of superiority at a significance level of 0.05). This expected 96% SVR12 rate, 
based on the observed SVR12 rate in ASTRAL-1 (GS-US-342-1138) for GT1b compensated 
cirrhotic subjects, represents a clinically relevant response for compensated cirrhotic patients, 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 52
03 July 2019
who are at risk of PI-based liver toxicity and currently have no highly-effective PI-free pan-
genotypic treatment options.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 53
03 July 2019
9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with ICH E6(R2) 
Good Clinical Practices and applicable laws and regulations.
This protocol is to be conducted in accordance with the guidance stipulated in Article 14, 
Paragraph 3 and Article 80-2 of the Law for Ensuring the Quality, Efficacy, and Safety of Drugs 
and Medical Devices, “MHLW Ordinance on Good Clinical Practice” {Ministry of Health and 
Welfare 2013}.
9.1.2.
Financial Disclosure
The investigator and subinvestigators will provide documentation of their financial interest or 
arrangements with Gilead, or proprietary interests in the investigational drug under study. This 
documentation must be provided prior to the investigator’s (and any subinvestigator’s) 
participation in the study. The investigator and subinvestigator agree to notify Gilead of any 
change in reportable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date when the last subject completes the protocol-defined 
activities.
9.1.3.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.4.
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 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 54
03 July 2019
conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or
local requirements. 
9.1.5.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any form 
or biological sample submitted to the Sponsor, IRB or IEC or laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The investigator 
must keep a screening log showing codes, names, and addresses for all subjects screened and for 
all subjects enrolled in the trial. Subject data will be processed in accordance with all applicable 
regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.6.
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, as 
applicable; IRB or 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


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 55
03 July 2019

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.7.
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 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 56
03 July 2019
stored in the audit trail of the system. Prior to database lock (or any interim time points as 
described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
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 (eg, data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.6.
9.1.8.
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, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.9.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs, or to regulatory authority or health authority 
inspectors.
9.1.10.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 57
03 July 2019
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 or IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead in an abstract, manuscript, or presentation form or the study has been completed at 
all study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.5).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 58
03 July 2019
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 59
03 July 2019
10.
REFERENCES
Akuta N, Suzuki F, Seko Y, Kawamura Y, Sezaki H, Suzuki Y, et al. Association of IL28B 
Genotype and Viral Response of Hepatitis C Virus Genotype 2 to Interferon Plus 
Ribavirin Combination Therapy. J Med Virol 2012;84 (10):1593-9.
Asahina Y, Itoh Y, Ueno Y, Matsuzaki Y, Takikawa Y, Yatsuhashi H, et al. Ledipasvir-
Sofosbuvir for Treating Japanese Patients with Chronic Hepatitis C Virus 
Genotype 2 Infection. Liver Int 2018;38:1552-61.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in 
cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44 (1):217-31.
Ito S, Kanto T, Yatsuhashi H, J. T, Sato Y. Investigation of actual condition of medical costs in 
liver cirrhosis and liver cancer patients due to hepatitis B or C infection. MHLW 
Research Report. [Japanese].  2016.
Izumi N, Takehara T, Chayama K, Yatsuhashi H, Takaguchi K, Ide T, et al. Sofosbuvir-
velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 hepatitis C 
who failed direct-acting antivirals. Hepatol Int 2018;12 (4):356-67.
Kawaoka T, Hayes CN, Ohishi W, Ochi H, Maekawa T, Abe H, et al. Predictive value of the 
IL28B polymorphism on the effect of interferon therapy in chronic hepatitis C 
patients with genotypes 2a and 2b. J Hepatol 2011;54 (3):408-14.
Krishnan P, Schnell G, Tripathi R, Beyer J, Reisch T, Dekhtyar T, et al. Integrated Resistance 
Analysis of CERTAIN-1 and CERTAIN-2 Studies in Hepatitis C Virus-Infected 
Patients Receiving Glecaprevir and Pibrentasvir in Japan. Antimicrob Agents 
Chemother 2018;62 (2).
Kumada H, Chayama K, Rodrigues L, Jr., Suzuki F, Ikeda K, Toyoda H, et al. Randomized 
phase 3 trial of ombitasvir/paritaprevir/ritonavir for hepatitis C virus genotype 1b-
infected Japanese patients with or without cirrhosis. Hepatology 2015;62 
(4):1037-46.
Kumada H, Suzuki F, Suzuki Y, Toyota J, Karino Y, Chayama K, et al. Randomized 
Comparison of Daclatasvir + Asunaprevir Versus Telaprevir + 
Peginterferon/Ribavirin in Japanese Hepatitis C Virus Patients. J Gastroenterol 
Hepatol 2016;31:14-22.
Kumada H, Suzuki Y, Karino Y, Chayama K, Kawada N, Okanoue T, et al. The Combination of 
Elbasvir and Grazoprevir for the Treatment of Chronic HCV Infection in Japanese 
Patients: A Randomized Phase II/III Study. J Gastroenterol 2017;52:520-33.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 60
03 July 2019
Ministry of Health and Welfare. Ministerial Ordinance on Good Clinical Practice for Drugs. 
Ordinance of the Ministry of Health and Welfare No. 28 of March 27, 1997 (As 
last amended by the Ordinance of Ministry of Health, Labour and Welfare No. 
161 of December 28, 2012). Provisional Translation as of March 2013.
Mizokami M, Yokosuka O, Takehara T, Sakamoto N, Korenaga M, Mochizuki H, et al. 
Ledipasvir and sofosbuvir fi xed-dose combination with and without ribavirin for 
12 weeks in treatment-naive and previously treated Japanese patients with 
genotype 1 hepatitis C: an open-label, randomised, phase 3 trial. Available at 
http://dx.doi.org/10.1016/S1473-3099(15)70099-X. Lancet 2015.
Omata M, Nishiguchi S, Ueno Y, Mochizuki H, Izumi N, Ikeda F, et al. Sofosbuvir plus ribavirin 
in Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 
3 trial. J Viral Hepat 2014;21 (11):762-8.
Sakamoto N, Nakagawa M, Tanaka Y, Sekine-Osajima Y, Ueyama M, Kurosaki M, et al. 
Association of IL28B variants with response to pegylated-interferon alpha plus 
ribavirin combination therapy reveals intersubgenotypic differences between 
genotypes 2a and 2b. J Med Virol 2011;83 (5):871-8.
Sievert W, Altraif I, Razavi HA, Abdo A, Ahmed EA, Alomair A, et al. A systematic review of 
hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int 2011;31 
Suppl 2:61-80.
Takehara T, Sakamoto N, Nishiguchi S, Ikeda F, Tatsumi T, Ueno Y, et al. Efficacy and Safety 
of Sofosbuvir-Velpatasvir With or Without Ribavirin in HCV-Infected Japanese 
Patients with Decompensated Cirrhosis: An Open-Label Phase 3 Trial. J 
Gastroenterol 2019;54:87-95.
Tanaka J, Kumagai J, Katayama K, Komiya Y, Mizui M, Yamanaka R, et al. Sex- and age-
specific carriers of hepatitis B and C viruses in Japan estimated by the prevalence 
in the 3,485,648 first-time blood donors during 1995-2000. Intervirology 2004;47 
(1):32-40.
Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in 
chronic hepatitis C virus infection: a meta-analysis and meta-regression. 
Hepatology 2008;48 (2):418-31.
Toyota J, Karino Y, Suzuki F, Ikeda F, Ido A, Tanaka K, et al. 
Daclatasvir/Asunaprevir/Beclabuvir Fixed-Dose Combination in Japanese 
Patients with HCV genotype 1 Infection. J Gastroenterol 2017;52:385-95.


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 61
03 July 2019
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


SOFNELFDC 
Protocol GS-US-342-5531 
Final 
Gilead Sciences, Inc. 
Original 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3 Multicenter, Open-Label Study to Investigate the Efficacy and Safety of 
SofosbuvirNelpatasvir Fixed-Dose Combination for 12 Weeks in Subjects with Chronic HCV 
Infection and Compensated Cirrhosis 
GS-US-342-5531, Original, 03 July 2019 
;;~~I has been approved by Gilead Scienl PD s4)narure documents I 
~PD 
] (Printed) 
Signature 
PPD 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
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 drug and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 62 
03 July 2019 


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 63
03 Jul 2019
Appendix 2.
Study Procedures Table
Screening
Day 1a
Treatment Week
(3 days)
Posttreatment Week 
(5 days)
1
2
4
8
12/ETb
4
12
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
Height
X
Weight
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
12-Lead ECGd
X
X
X
Adverse Events and Concomitant Medicationse
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling
X
X
X
Imaging for HCCf
X
Review of Study Drug Adherence and Drug 
Accountabilityg
X
X
X
X
X
Study Drug Dispensingh
X
X
Laboratory Assessments
Hematology, Chemistry 
X
X
X
X
X
X
X
Coagulation (Prothrombin activation %, PT, 
aPTT and INR)
X
X
X
Urinalysis
X
HCV RNA
X
X
X
X
X
X
X
X
X
HCV resistance samples
X
X
X
X
X
X
X
X


SOF/VEL FDC
Protocol GS-US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 64
03 Jul 2019
Screening
Day 1a
Treatment Week
(3 days)
Posttreatment Week 
(5 days)
1
2
4
8
12/ETb
4
12
24
HBV DNA samplei
X
X
X
X
X
Serum or Urine Pregnancy Testj
X
X
X
X
X
X
Serum FSHk
X
HCV Genotyping
X
IL28B Genotype
X
HCV Ab, HIV Ab, HBsAg, HBsAb, HBcAb
X
HbA1c
X
FibroTest®
X
a
Day 1 assessments must be performed prior to dosing.
b
ET = early termination.
c
Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
d
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. 
e
Adverse events and concomitant medications will be collected up to 30 days after the last dose of all study drug.
f
Liver imaging (eg, ultrasound or CT scan, at the discretion of the investigator) should be performed to exclude the presence of hepatocellular carcinoma (HCC) in all subjects 
within 4 months of Day 1.
g
Study drug will be reconciled at every post- Day 1 visit by the investigator in order to monitor the subject’s adherence with the study drug. Subjects must be instructed to 
bring back all bottles of study drug in the original container at every post- Day 1 visit through the end of treatment.
h
The interactive web response system (IWRS) will provide direction on the specifics of each subject’s study drug dispensing.
i
Reflex testing done only when ALT > 2x Day 1 value in subjects who are HBsAb or HBcAb positive at Screening.
j
All females of childbearing potential will have a serum pregnancy test at Screening. Urine pregnancy testing will occur at Day 1 and every 4 weeks through posttreatment 
Week 4. In the event of a positive urine pregnancy result, subjects will be instructed to return to the clinic as soon as possible for a serum pregnancy test. 
k
Women of any age with amenorrhea of ≥ 12 months (see Appendix 4).


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 65
03 Jul 2019
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 
≥ 7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 66
03 Jul 2019
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 67
03 Jul 2019
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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.
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L
2.0 to <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 68
03 Jul 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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
.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


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 69
03 Jul 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to 1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63 to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
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


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 70
03 Jul 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
Adult and Pediatric
≥ 1 year
Infant < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
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


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 71
03 Jul 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to 4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs. Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 72
03 Jul 2019
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-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 73
03 Jul 2019
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-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 74
03 Jul 2019
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
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 


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 75
03 Jul 2019
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
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-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 76
03 Jul 2019
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-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 77
03 Jul 2019
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-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 78
03 Jul 2019
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-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 79
03 Jul 2019
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
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 80
03 Jul 2019
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


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 81
03 Jul 2019
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)


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 82
03 Jul 2019
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


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 83
03 Jul 2019
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-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 84
03 Jul 2019
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-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 85
03 Jul 2019
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-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 86
03 Jul 2019
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-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
Page 87
03 Jul 2019
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–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 88
03 July 2019
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 the initiation of puberty (Tanner stage 2) 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. In 
addition, women of any age with amenorrhea of ≥12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of SOF have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies of SOF 
have demonstrated no adverse effect on fertility or embryo-fetal development.
Data from clinical pharmacokinetic interaction studies of VEL have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies of VEL 
have demonstrated no adverse effect on fertility or embryo-fetal development. 
However, the risks of treatment with SOF/VEL FDC during pregnancy in humans have not been 
evaluated. Please refer to the latest version of the Investigator’s Brochure for additional 
information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable 
effective contraceptive measure. They must have a negative serum pregnancy test at Screening 
and a negative urine pregnancy test on the Day 1 visit prior to enrollment. Pregnancy tests will 
be performed every 4 weeks throughout duration of trial including posttreatment Week 4 visit. In 
the event of a delayed menstrual period (over one month between menstruations), a pregnancy 
test must be performed to rule out pregnancy. This is even true for women of childbearing 
potential with infrequent or irregular periods. They must also agree to one of the following from 
Screening until 30 days after the last dose of SOF/VEL FDC.


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 89
03 July 2019

Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom from the date of Screening until 30 
days after the last dose of SOF/VEL FDC. 
Intrauterine device (IUD) with a failure rate of <1% per year
Intrauterine hormone-releasing system (IUS) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
(unapproved in Japan)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Barrier methods (one female barrier and one male barrier must be used in combination)
■
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
(unapproved in Japan)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone (unapproved in Japan)
■
Implants of levonorgestrel (unapproved in Japan)
■
Transdermal contraceptive patch (unapproved in Japan)
■
Contraceptive vaginal ring (unapproved in Japan)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of SOF/VEL FDC.
3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use
condoms until 30 days after the last dose of SOF/VEL FDC 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 FDC.


SOF/VEL FDC
Protocol GS–US-342-5531
Final
Gilead Sciences, Inc. 
Original
CONFIDENTIAL
Page 90
03 July 2019
Male subjects must also refrain from sperm donation during treatment and until at least 30 days 
after the last dose of SOF/VEL FDC.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM). Female condom and male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study or within 30 days of last study 
drug dose must report the information to the investigator.
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.5.2.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3 Multicenter, Open-Label Study to Investigate the 
Efficacy and Safety of Sofosbuvir/Velpatasvir Fixed-Dose 
Combination for 12 Weeks in Subjects with Chronic HCV 
Infection and Compensated Cirrhosis
Name of Test Drug:
SOF/VEL FDC 
Study Number:
GS-US-342-5531 
Protocol Version (Date):
Original: 03 July 2019 
Analysis Type:
Posttreatment Week 12 Analysis
Posttreatment Week 24 Analysis
Analysis Plan Version:
1.0 
Analysis Plan Date:
12 April 2021 
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
[r) GILEAU 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 2
12 April 2021
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ...............................................................................................................................1
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TABLES ....................................................................................................................................................3
LIST OF ABBREVIATIONS.........................................................................................................................................4
1.
INTRODUCTION..................................................................................................................................................6
1.1.
Study Objectives........................................................................................................................................6
1.2.
Study Design .............................................................................................................................................6
1.3.
Sample Size and Power .............................................................................................................................7
2.
TYPE OF PLANNED ANALYSIS........................................................................................................................8
2.1.
Data Monitoring Committee......................................................................................................................8
2.2.
Interim Analyses........................................................................................................................................8
2.2.1.
Posttreatment Week 12 Analysis (Primary Analysis) .............................................................8
2.3.
Posttreatment Week 24 Analysis (Final Analysis)....................................................................................8
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES...............................................................................9
3.1.
Analysis Sets .............................................................................................................................................9
3.1.1.
All Enrolled Analysis Set ........................................................................................................9
3.1.2.
Full Analysis Set......................................................................................................................9
3.1.3.
Safety Analysis Set..................................................................................................................9
3.2.
Subject Grouping.......................................................................................................................................9
3.3.
Examination of Subject Subgroups .........................................................................................................10
3.4.
Multiple Comparisons .............................................................................................................................10
3.5.
Missing Data and Outliers.......................................................................................................................10
3.5.1.
Missing Data..........................................................................................................................10
3.5.2.
Outliers ..................................................................................................................................11
3.6.
Data Handling Conventions and Transformations ..................................................................................11
3.7.
Visit Windows.........................................................................................................................................12
3.7.1.
Definition of Study Day ........................................................................................................12
3.7.2.
Analysis Visit Windows........................................................................................................13
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................14
4.
SUBJECT DISPOSITION ...................................................................................................................................16
4.1.
Subject Enrollment and Disposition........................................................................................................16
4.2.
Extent of Exposure ..................................................................................................................................17
4.2.1.
Duration of Exposure to Study Drug.....................................................................................17
4.2.2.
Adherence to Study Drug ......................................................................................................17
4.3.
Protocol Deviations .................................................................................................................................18
4.4.
Assessment of COVID-19 Impact...........................................................................................................19
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19.....................................................19
4.4.2.
Protocol Deviations Due to COVID-19 ................................................................................19
4.4.3.
Missed and Virtual Visits due to COVID-19 ........................................................................19
5.
BASELINE CHARACTERISTICS .....................................................................................................................20
5.1.
Demographics..........................................................................................................................................20
5.2.
Other Baseline Characteristics ................................................................................................................20
5.3.
Medical History.......................................................................................................................................21
6.
EFFICACY ANALYSES.....................................................................................................................................22


SOFNELFDC 
GS-US-342-5531 
Statistical Analysis Plan - Final Analysis 
Version 1.0 
6.1. 
Prirnary Efficacy Endpoint ...................................................................................................................... 22 
6.1.1. 
Definition of the Primary Efficacy Endpoint ........................................................................ 22 
6.1.2. 
Statistical Hypothesis for the Primary Efficacy Endpoint.. ................................................... 22 
6.1.3. 
Primary Analysis of the Primary Efficacy Endpoint.. ........................................................... 22 
6.1.4. 
Subgroup Analysis of the Primary Efficacy Endpoint .......................................................... 22 
6.2. 
Secondary Efficacy Endpoints ................................................................................................................ 23 
6. 2 .1. 
Definition of Secondary Efficacy Endpoints ......................................................................... 23 
6.2.2. 
Anal sis Methods for Seconda 
Efficac End oints ........................................................... 23 
6.4. 
Changes from Protocol-specified Efficacy Analyses .............................................................................. 25 
7. 
SAFETY ANALYSES ......................................................................................................................................... 26 
7 .1. 
Adverse Events and Deaths ..................................................................................................................... 26 
7.1.1. 
Adverse Event Dictionary ..................................................................................................... 26 
7.1.2. 
Adverse Event Severity ......................................................................................................... 26 
7.1.3. 
Relationship of Adverse Events to Study Drng ..................................................................... 26 
7.1.4. 
Serious Adverse Events ......................................................................................................... 26 
7.1.5. 
Treatrnent-Emergent Adverse Events .................................................................................... 26 
7 .1.5.1. 
Definition of Treatment-Emergent Adverse Events ........................................ 26 
7.1.5.2. 
IncornpleteDates ............................................................................................. 27 
7.1.6. 
Summaries of Adverse Events and Deaths ............................................................................ 27 
7.2. 
Laboratory Evaluations ........................................................................................................................... 28 
7.2.1. 
Summaries ofNumeric Laboratory Results .......................................................................... 29 
7.2.2. 
Graded Laboratory Values .................................................................................................... 29 
7 .2.2.1. 
Treatment-Emergent Laboratory Abnormalities ............................................. 30 
7.2.2.2. 
Summaries of Laboratory Abnormalities ........................................................ 30 
7.3. 
Body Weight, Height, and Vital Signs .................................................................................................... 30 
7.4. 
Prior and Concomitant Me.dications ........................................................................................................ 31 
7.5. 
Electrocar·diograrn Results ....................................................................................................................... 31 
7.6. 
Other Safety Measures ............................................................................................................................ 32 
7.7. 
Changes From Protocol-Specified Safety Analyses ................................................................................ 32 
8. 
REFERENCES ..................................................................................................................................................... 33 
9. 
SOFTWARE ......................................................................................................................................................... 34 
10. SAP REVISION ................................................................................................................................................... 35 
11. APPENDICES ...................................................................................................................................................... 36 
Table 1. 
Table 2. 
Table 3. 
CONFIDENTIAL 
LIST OF IN-TABLES 
Analysis Visit Windows for On-treatment HCV RNA, Vita.I Signs and Safety 
Laboratory Data ....................................................................................................................... 13 
Analysis Visit Windows for Posttreatment HCV RNA, Vital Signs and Safety 
Laboratory Data ....................................................................................................................... 14 
Analysis Visit Windows for On-treatment ECG Data ............................................................. 14 
Page3 
12 April 2021 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 4
12 April 2021
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body mass index
CCG
eCRF Completion Guidelines
CI
confidence interval
COVID-19
Coronavirus disease 2019
CRF
case report form
CSR
clinical study report
DMC
data monitoring committee
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
ET
early termination
EOT
End of treatment
FAS
Full Analysis Set
FDC
Fixed-dose combination
FU
Follow-up
GT
Genotype
HCV
hepatitis C virus
HLGT
high-level group term
HLT
high-level term
INR
international normalized ratio
LLT
lower-level term
LLOQ
Lower limit of quantitation
LOQ
Limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
NLP
Natural Language Processing
Peg-INF
Pegylated interferon 
PK
pharmacokinetics
PT
preferred term
Q1, Q3
first quartile, third quartile
RNA
Ribonucleic acid
RR
electrocardiographic interval representing the time measurement between the R wave of one 
heartbeat and the R wave of the preceding heartbeat
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
Standard error
SOC
system organ class


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 5
12 April 2021
SOF
sofosbuvir
SVR
Sustained Virologic Response 
SVRx
sustained virologic response x weeks after cessation of treatment
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
TND
Target not detected
ULN
upper limit of normal
VEL
velpatasvir
WHO
World Health Organization


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 6
12 April 2021
1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-342-5531. This SAP is based on the study protocol dated 03 July 2019 and the 
electronic case report form (eCRF). The SAP will be finalized before SVR 12 database 
finalization. Any changes made after the finalization of the SAP will be documented in the CSR. 
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate the antiviral efficacy of therapy with sofosbuvir/velpatasvir (SOF/VEL) 
fixed-dose combination (FDC) for 12 weeks as measured by the proportion of subjects with 
sustained virologic response 12 weeks after cessation of treatment (SVR12) 

To evaluate the safety and tolerability by review of the accumulated safety data
The secondary objectives of this study are as follows:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 

To evaluate the proportion of subjects with virologic failure 

To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment
1.2.
Study Design
This is a multicenter, open-label study evaluating efficacy and safety of SOF/VEL FDC in 
subjects with chronic HCV infection and compensated cirrhosis. 
Subjects may have HCV of any genotype. Based on the HCV genotype (GT) distribution in 
Japan, it is expected that approximately 70% of subjects will be GT1, and approximately 30% of 
subjects will be non-GT1. Subjects may be either treatment-naive or treatment-experienced with 
interferon (IFN)-based treatments.
Approximately 36 subjects will be enrolled to be treated with SOF/VEL FDC for 12 weeks.
The total time to complete all study visits is approximately 40 weeks (42 weeks for those 
requiring an extension of the Screening period):

28 days (4 weeks) screening period [up to 42 days (6 weeks) for extenuating circumstances 
may be granted] 

12 weeks study treatment period 

24 weeks posttreatment period


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 7
12 April 2021
The schedule of assessment is provided as an appendix to the SAP (Appendix 1).
1.3.
Sample Size and Power
A sample size of approximately 36 compensated cirrhotic Japanese subjects in the study will 
provide > 80% power to demonstrate superiority to a performance threshold of 78%, assuming 
an expected SVR12 rate of 96% with 12 weeks of SOF/VEL therapy (based on a 2-sided exact 
1-sample binomial test of superiority at a significance level of 0.05)


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 8
12 April 2021
2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee 
This study does not have a data monitoring committee (DMC). 
2.2.
Interim Analyses
2.2.1.
Posttreatment Week 12 Analysis (Primary Analysis)
The analysis for the primary endpoint SVR12 will be conducted after all subjects complete the 
posttreatment Week 12 visit or prematurely discontinue from study. All the safety and efficacy 
data through the posttreatment Week 12 visit will be cleaned, finalized, and included for the 
analysis.
2.3.
Posttreatment Week 24 Analysis (Final Analysis)
After all subjects have completed the study, outstanding data queries have been resolved, and the 
database has been cleaned and finalized, the final analysis of the data will be performed.


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 9
12 April 2021
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard error (SE), median, 
first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the Safety Analysis Set and sorted by 
subject ID number, visit date, and time (if applicable). Data collected on log forms, such as AEs, 
will be presented in chronological order within the subject. The treatment group to which 
subjects were initially assigned will be used in the listings. Age, sex at birth, race, and ethnicity 
will be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The number of subjects eligible for each analysis set will be 
provided. Subjects who were excluded from each analysis set will be summarized or provided in 
a by-subject listing with reasons for exclusion. 
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all subjects who received a study subject identification 
number in the study after screening.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all enrolled subjects who took at least 1 dose of study drug 
in this study, which is SOF/VEL FDC. This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. This is the 
primary analysis set for safety analyses. Treatment-emergent data will be analyzed and defined 
as data collected from the first dose of the study drug through the date of last dose of the study 
drug plus 30 days.
3.2.
Subject Grouping
For analyses based on the All Enrolled Analysis Set, FAS, or demographic and baseline 
characteristics tables, subjects will be grouped according to the HCV genotype (GT1 with GT1 
broken down as GT1a and GT1b; non-GT1 with non-GT1 broken down as GT2, GT2a/2c and 
GT2b).


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 10
12 April 2021
3.3.
Examination of Subject Subgroups
Subject subsets within each genotype will also be explored by presumed prognostic baseline 
characteristics for the primary efficacy endpoint, SVR12. The presumed prognostic baseline 
characteristics include the following: 

age (< 65 years, ≥ 65 years)

sex (male, female) 

baseline body mass index (BMI) (< 25 kg/m2, ≥ 25 kg/m2)

IL28B (CC, non-CC; with non-CC further broken down to CT, TT)

baseline HCV RNA (< 800,000 IU/mL, ≥ 800,000 IU/mL) 

baseline alanine aminotransferase (ALT) (≤ 1.5 × upper limit of normal (ULN), 
> 1.5 × ULN) 

prior HCV treatment experience (treatment naive, treatment experienced) 

prior HCV treatment (pegylated interferon [Peg-IFN], Other) for treatment experienced 
subjects 

prior HCV treatment response (non-responder, relapse/breakthrough, early treatment 
discontinuation, met a virologic stopping rule, unknown) for treatment experienced subjects 

study treatment status (completed study treatment, discontinued study treatment)

adherence to study regimen (< 80%, ≥ 80%) 
3.4.
Multiple Comparisons
No multiplicity adjustment will be made for testing because only one test will be performed.
3.5.
Missing Data and Outliers
3.5.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document. 
For missing last dosing date of study drug, imputation rules are described in Section 3.7.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for 
prior and concomitant medications in Section 7.4. 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 11
12 April 2021
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have missing data imputed up to the 
time of the last dose (for on-treatment displays). If the study day associated with the last dosing 
date of the study drug is greater than or equal to the lower bound of a visit window, and the value 
at the visit is missing, then the value will be imputed. If the study day associated with the last 
dosing date is less than the lower bound of a visit window, then the on-treatment value at that 
visit will remain missing. 
If an HCV RNA data point is missing and is preceded and followed in time by values that are 
“< lower limit of quantification (LLOQ) target not detected (TND),” then the missing data point 
will be set to “< LLOQ TND.” If a data point is missing and preceded and followed by values 
that are “< LLOQ detected,” or preceded by “< LLOQ detected” and followed by “< LLOQ 
TND,” or preceded by “< LLOQ TND” and followed by “< LLOQ detected,” then the missing 
value will be set to “< LLOQ detected.” In these situations, the data point will be termed a 
bracketed success; otherwise, the data point will be termed a bracketed failure (ie, ≥ LLOQ 
detected). If a data point is missing and is not bracketed, the missing data point will also be 
termed a failure (ie, ≥ LLOQ detected) except for SVR24, which will be imputed according to 
SVR12 status. Success for SVR12 who have no further HCV RNA measurements collected will 
be counted as a success for SVR24 due to the high correlation between these 2 endpoints.
For the analyses of continuous HCV RNA efficacy data, when and only when a missing HCV 
RNA value is imputed as < LLOQ TND or < LLOQ detected according to the imputation rule 
described above, the corresponding continuous value will be imputed to LLOQ − 1 IU/mL. No 
other imputation will be performed for continuous HCV RNA data. 
3.5.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.6.
Data Handling Conventions and Transformations
By-subject listings will be presented for all subjects in the Safety Analysis Set and sorted by 
subject ID number, visit date, and time (if applicable) unless otherwise specified. Data collected 
on log forms, such as AEs, will be presented in chronological order within subject. 
Age (in years) on the date of the first dose of study drug and sex at birth will be used for analyses 
and presentation in listings.
If a subject was never dosed with study drug, then the date the informed consent was signed will 
be used instead of the first dose date of study drug. For some countries, only birth year is 
collected on the CRF. In those cases, “01 January” will be used for the unknown birth day and 
month for the purpose of age calculation, unless age is captured on the CRF. 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 12
12 April 2021
Non-PK data that are continuous in nature but less than the lower limit of quantitation (LOQ) or 
above the upper limit of quantitation will be imputed as follows: 

A value that is 1unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “ x” (where x is considered the 
LOQ). For example, if the values are reported as < 50 and < 5.0, values of 49 and 4.9, 
respectively, will be used for calculation of summary statistics. An exception for this rule is 
any value reported < 1. For the values reported as < 1 or < 0.1, a value of 0.9 or 0.09, 
respectively, will be used for calculation of summary statistics. 

A value that is 1 unit above the LOQ will be used for calculation of descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the LOQ). Values with 
decimal points will follow the same logic as above. 

The LOQ will be used for calculation of descriptive statistics if the datum is reported in the 
form of “≤ x” or “≥ x” (where x is considered the LOQ).
The COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, v2.0 was used to 
determine HCV RNA results in this study. The LLOQ of the assay is 15 IU/mL. 
When the calculated HCV RNA value is within the linear range of the assay, then the result will 
be report as the “<< numeric value>> IU/mL.” This result will be referred to in this document as 
the numeric result or as “≥ LLOQ detected” for categorical result. 
When HCV RNA is not detected, the result is reported as “No HCV RNA detected” or “target 
not detected”. This result will be referred to in this document as “< LLOQ target not detected” or 
“< LLOQ TND.” 
When the HCV RNA IU/mL is less than LLOQ of the assay, the result is reported as 
“< 15 IU/mL HCV RNA detected.” This result will be referred to in this document as “< LLOQ 
detected.”
The overall category of HCV RNA < LLOQ includes “< LLOQ TND” and “< LLOQ detected.”
For numerical HCV RNA data, values below LLOQ will be set to the LLOQ – 1 IU/mL 
(ie, 14 HCV RNA IU/mL). HCV RNA values returned as “No HCV RNA detected” will also be 
set to 14 IU/mL.
For selected analyses, HCV RNA data (IU/mL) will be transformed to the logarithmic (base 10) 
scale (log10 IU/mL).
3.7.
Visit Windows
3.7.1.
Definition of Study Day
Study day is the day relative to the date of the first dose of study drug. Study Day 1 will be 
defined as the day of first dose of study drug administration. 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 13
12 April 2021
Study day will be calculated from the date of first dose of study drug administration and derived 
as follows: 

For postdose study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date 
The last dose date for the study drug will be the end date on study drug administration eCRF for 
the record where the “subject permanently discontinued” flag is ‘Yes’. 
If there are subjects for whom the date of last study drug is unknown due to the reason that the 
subject was lost to follow-up and not able to be contacted, the date of last dose will be estimated 
using the maximum of nonmissing study drug start or stop dates, visit dates, and laboratory 
collection dates (posttreatment visits and unscheduled visits are not included).
3.7.2.
Analysis Visit Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows. 
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of study drug. 
HCV RNA, vital signs, and safety laboratory data collected up to the last dose date + 3 days are 
considered to be on-treatment data and HCV RNA, vital signs, and safety laboratory data 
collected after the last dose date + 3 days are considered posttreatment data. The analysis 
windows for on-treatment HCV RNA, vital signs and safety laboratory data are provided in 
Table 1. 
Table 1.
Analysis Visit Windows for On-treatment HCV RNA, Vital Signs and 
Safety Laboratory Data 
HCV RNA and Safety Laboratory Data
Vital Signs 𝐃𝐚𝐭𝐚
Nominal 
Visit
Nominal FU 
Day
Lower Limit
Upper Limit
Nominal FU 
Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
1
(none)
1
Week 1
N/A
N/A
N/A
7
2
11
Week 2
14
2
21
14
12
21
Week 4
28
22
42
28
22
42
Week 8
56
43
70
56
43
70
Week 12
84
71
≥ 85
84
71
≥ 85


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 14
12 April 2021
HCV RNA, vital sign, and safety laboratory data collected after the last dose date + 3 days will 
be assigned to the posttreatment follow-up (FU) visit. Visit windows will be calculated from the 
last dose date (ie FU Day = collection date minus the last dose date) as shown in Table 2. 
Table 2.
Analysis Visit Windows for Posttreatment HCV RNA, Vital Signs and 
Safety Laboratory Data 
HCV RNA
Vital Signs and Safety Laboratory 𝐃𝐚𝐭𝐚𝐛
Nominal 
𝐅𝐔𝐚 Visit
Nominal FU 
Day
Lower Limit
Upper Limit
Nominal FU 
Day
Lower Limit
Upper Limit
FU-4
28
21
69
28
4
30
FU-12
84
70
146
NA
NA
NA
FU-24
168
147
210
NA
NA
NA
a
FU-x visit = posttreatment Week-x follow-up visit. 
b
Days are calculated based on last dose date. 
ECG data collected up to the last dose date + 3 days are considered to be on-treatment data. 
Qualitative assessments of whether the ECG is normal or abnormal will be assessed for 
on-treatment data based on the visit windows shown in Table 3. 
Table 3.
Analysis Visit Windows for On-treatment ECG Data 
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 12
84
2
(none)
Note: ECGs are to be collected at screening, baseline, Week 1, and Week 12 or Early Termination. For purposes of analysis, 
baseline value will be the last available value prior to the first dose of study drug and end of treatment value will be the last 
available value on or prior to the last dose date + 3 days.
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, the average (arithmetic mean) will be used for the baseline value. If multiple ECG 
measurements occur on the same day prior to first dose of any study drug, the average will be 
used as baseline for continuous data, regardless of the timing of these multiple ECG 
measurements.


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 15
12 April 2021

For postbaseline values:

The record closest to the nominal day for that visit will be selected except for HCV RNA 
posttreatment follow-up visits, for which the latest record in the analysis window will be 
selected. 

If there are 2 records that are equidistant from the nominal day, the later record will be 
selected. 

If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified. 

If multiple valid nonmissing categorical observations exist in a window, records will be 
selected as follows: 

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on 
the same day, the value with the lowest severity will be selected (eg, normal will be 
selected over abnormal). If multiple ECG measurements occur on the same day prior to 
the first dose of any study drug, the value with the lowest severity will be selected 
regardless of the timing of these multiple ECG measurements.

For postbaseline visits, follow the same rules described above for postbaseline numeric 
observations, except that if there are multiple records on the same day, the most 
conservative value will be selected (eg, abnormal will be selected over normal). 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 16
12 April 2021
4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided for each investigator. The summary will 
present the number and percentage of subjects in the Safety Analysis Set. For each column, the 
denominator for the percentage calculation will be the total number of subjects analyzed for that 
column. 
A summary of subject disposition will be provided by HCV genotype (GT1, GT1 broken down 
[1a, 1b], GT2, GT2 broken down [GT2a/2c, GT2b]) and overall. This summary will present the 
number of subjects screened, the number of subjects enrolled, the number of subjects enrolled 
but never treated, and the number and percentage of subjects in each of the categories listed 
below. 

In Safety Analysis Set 

In FAS 

Completed study treatment

Did not complete study treatment with reasons for premature discontinuation of study 
treatment

Completed study follow-up

Did not complete the study follow-up with reasons for premature discontinuation of study 
follow-up
Among subjects who completed study treatment and who discontinued study treatment, the 
number and percentage of subjects will be summarized for: 

Who had no HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 
Assessment and thereafter) 

Who had HCV posttreatment Week 4 assessment but no HCV posttreatment Week 12 and 
thereafter (With HCV FU-4 but No FU-12 and thereafter) 
If a subject did not have any HCV RNA assessment ≥ 21 days after the last dose of any study 
drug (ie, lower bound of FU-4 visit for HCV RNA data), the subject is categorized as having 
“No HCV FU-4 and thereafter.” If a subject had the HCV FU-4 assessment but did not have any 
HCV RNA assessment ≥ 70 days after the last dose of any study drug (ie, lower bound of FU-12 
visit for HCV RNA data), the subject is categorized as having “With HCV FU-4 but No FU-12 
and thereafter.” 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 17
12 April 2021
In addition, the total number of subjects who were enrolled, and the number of subjects in each 
of the disposition categories listed above will be depicted by a flowchart.
The following by-subject listings will be provided by subject identification (ID) number in 
ascending order to support the above summary tables: 

Disposition for subjects who complete study treatment and study follow up

Disposition for subjects who did not complete study treatment and/or study follow up with 
reasons for premature discontinuation of study treatment and/or study 

Lot number and kit ID (if applicable)
4.2.
Extent of Exposure 
Extent of exposure to study drug will be examined by assessing the total duration of study drug 
exposure and the level of adherence to the study drug regimen specified in the protocol. 
4.2.1.
Duration of Exposure to Study Drug 
Total duration of exposure to study drug will be defined as last dose date minus first dose date 
plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). 
The total duration of exposure to study drug will be summarized using descriptive statistics 
(n, mean, SD, median, Q1, Q3, minimum, and maximum) and using the number of subjects 
(ie, cumulative counts) and percentage of subjects exposed through the following time periods: 
baseline (Day 1), Week 1 (Day 7), Week 2 (Day 14), Week 4 (Day 28), Week 6 (Day 42), 
Week 8 (Day 56), Week 10 (Day 70), and Week 12 (Day 84). A 3-day window is applied to the 
last planned on-treatment visit to match with the protocol-specified visit window, ie, the number 
of subjects exposed through Week 12 will be calculated as the number of subjects who were 
exposed to study drug for at least 81 days. Summaries will be provided for the Safety Analysis 
Set. 
4.2.2.
Adherence to Study Drug
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:
Total Number of Doses Administered =
No. of Tablets Dispensed ―
No. of Tablets Returned
The level of adherence to the study drug regimen will be assessed based on the total amount of 
study drug administered relative to the total amount of study drug prescribed at baseline. 
) 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 18
12 April 2021
The level of adherence will be expressed in percentage using the following formula: 
Level of Adherence (%) =
Total Amount of Study Drug Administered  
Total Amount of Study Drug Prescribed at baseline  × 100
Note: If calculated adherence is greater than 100%, the result will be set to 100%.
In this study, the total amount of SOF/VEL (400/100 mg) prescribed for 12 weeks would require 
84 tablets for each subject. 
Subjects who prematurely discontinue study drug for lack of efficacy (ie, virologic failure) will 
have the total amount of study drug prescribed calculated up to the first date when virologic 
failure criteria were met. For virologic failure confirmed by 2 consecutive measurements, the 
date of the first measurement will be used. If study drug bottles are dispensed on or after the 
subject first met virologic failure criteria, these bottles will not be included in the calculation of 
adherence. If a bottle is dispensed and the bottle is returned empty, then the number of tablets 
returned will be entered as zero. If a bottle is dispensed but not returned (missing), the number of 
tablets taken from that bottle will be counted as zero. 
Descriptive statistics for the level of adherence (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) with the number and percentage of subjects belonging to adherence categories 
(eg, [< 80%, ≥ 80 to < 90%, ≥ 90%]) will be provided for the Safety Analysis Set. Categorical 
displays also will be provided for the number of subjects who are at least 80% adherent to their 
drug regimen (ie, adherence is ≥ 80% for the study drugs).
No inferential statistics will be provided for duration of exposure and adherence to study drug.
A separate by-subject listing of study drug administration and drug accountability will be 
provided by subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations 
Subjects who did not meet the eligibility criteria for study entry but enrolled in the study, will be 
summarized. The summary will present the number and percentage of subjects who did not meet 
at least 1 eligibility criterion and the number of subjects who did not meet specific criteria based 
on the All Enrolled Analysis Set. A by-subject listing will be provided for those subjects who did 
not meet at least 1 eligibility (inclusion or exclusion) criterion. The listing will present the 
eligibility criterion (or criteria if more than 1 deviation) that subjects did not meet and related 
comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation category (eg, nonadherence to study drug, violation of select inclusion/exclusion 
criteria) will be summarized for the All Enrolled Analysis Set. 
(------) 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 19
12 April 2021
4.4.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (2019 nCOV [COVID-19]) pandemic 
which has caused a disruption in the regular visit schedules for this study. Some subjects were 
unable to attend onsite visits due to shelter in place guidelines, site closures, or other reasons. 
This section provides how to handle special situations due to COVID-19 in the analysis.
Adverse events due to COVID-19 will be included in AE analyses if applicable.
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19
A by-subject listing of reasons for premature study drug or study discontinuation due to 
COVID-19 will be created for the enrolled analysis set.
4.4.2.
Protocol Deviations Due to COVID-19
Similar summary as described in protocol deviations section will be performed for important 
protocol deviations due to COVID-19 for the enrolled analysis set.
A by-subject listing will be provided for subjects with important protocol deviation related to 
COVID-19. A separate listing will be provided for subjects with non-important protocol 
deviation related to COVID-19.
4.4.3.
Missed and Virtual Visits due to COVID-19
A by-subject listing of subjects with missed or virtual visits due to COVID-19 will be provided 
by subject ID number in ascending order.
Information regarding missed or virtual visits due to COVID-19 was collected as free text in the 
CRF comment fields. The determination of missing or virtual visits due to COVID-19 was done 
using Natural Language Processing (NLP) to search the CRF comment fields. A brief description 
of the natural language processing algorithm developed for determining missed and virtual visits 
based on CRF comment text is provided in Appendix 2.


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 20
12 April 2021
5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (i.e. age, sex, race, and ethnicity) will be summarized by HCV 
genotype (GT1, GT1 broken down [1a, 1b], GT2, GT2 broken down [GT2a/2c, GT2b], 
non-GT1) and overall using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) for age and BMI (kg/m2), and using the numbers and percentages of subjects for age 
categories (< 65 years, ≥ 65 years), BMI categories (< 25 kg/m2, ≥ 25 kg/m2), sex, race, and 
ethnicity. Age is calculated in years at the date of initial study drug administration. If a subject 
did not receive study drug after enrollment, the subject’s age will be calculated from the date that 
the subject signed the informed consent form. The summary of demographic data will be 
provided for the Safety Analysis Set.
A by-subject demographic listing, which includes the date the informed consent was signed, will 
be provided by subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include:

body mass index (BMI; in kg/m2) as a continuous variable and as categories (< 25 kg/m2, 
≥ 25kg/m2) 

HCV genotype/subgenotype (GT1 with GT1 broken down as GT1a and GT1b; non-GT1 with 
non-GT1 broken down as GT2, GT2a/2c and GT2b)

IL28B (CC, non-CC; with non-CC further broken down to CT, TT)

baseline HCV RNA (log10 IU/mL) as a continuous variable and as categories 
(< 800,000 IU/mL, ≥ 800,000 IU/mL)

baseline ALT (U/L) as a continuous variable and as categories (≤ 1.5 × ULN, > 1.5 × ULN)

prior HCV treatment experience (treatment naive, treatment experienced)

prior HCV treatment response (non-responder, relapse/breakthrough, early treatment 
discontinuation, met a virologic stopping rule, unknown) for treatment experienced subjects 

prior HCV treatment for treatment experienced subjects (Peg-IFN, Other) 

estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault equation
eGFRCG (mL/min) = [(140 – age (yrs)) × weight (kg) × (0.85 if female)] / (serum creatinine 
(mg/dL) × 72), where weight is total body mass in kilograms.


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 21
12 April 2021
These baseline characteristics will be summarized by HCV genotype (GT1 with GT1 broken 
down as GT1a and GT1b; non-GT1 with non-GT1 broken down as GT2, GT2a/2c and GT2b) 
and the study overall using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) for continuous variables and using the numbers and percentages of subjects for 
categorical variables. The summary of baseline characteristics will be provided for the Safety 
Analysis Set. 
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order. The type of assay used to determine the HCV genotype will also be displayed in 
this listing. 
A separate by-subject data listing for cirrhosis determination will be provided for safety analysis 
set.
A separate by-subject data listing for prior HCV treatment and response will be provided for all 
subjects. The listing will display the prior HCV treatment experience for all subjects as well as 
the prior HCV regimen, the treatment duration, and the prior HCV treatment response for 
treatment experienced subjects.
5.3.
Medical History
General medical history data will be collected at screening and a by-subject listing will be 
provided for the Safety Analysis Set.


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 22
12 April 2021
6.
EFFICACY ANALYSES 
6.1.
Primary Efficacy Endpoint 
6.1.1.
Definition of the Primary Efficacy Endpoint 
The primary efficacy endpoint is SVR12 defined as HCV RNA < LLOQ 12 weeks after 
discontinuation of study drug in the FAS. The COBAS® AmpliPrep/COBAS® TaqMan® HCV 
Quantitative Test, v2.0 will be used to measure HCV RNA. The LLOQ for this assay is 
15 IU/mL. 
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint 
In the primary efficacy analysis, the SVR12 rate in FAS will be compared to the pre-specified 
efficacy threshold of 78% using a 2-sided exact 1-sample binomial test at the 0.05 significance 
level. The null (H0) and alternative (H1) hypotheses used to assess the superiority of SOF/VEL 
relative to the performance goal of 78% as follows: 
H0: SVR12 rate = 78% 
H1: SVR12 rate ≠ 78% 
In addition, a point estimate with a 2-sided 95% exact confidence interval (CI) using the 
binomial distribution (Clopper-Pearson method) {Clopper 1934} will be constructed for the 
SVR12 rate. 
6.1.3.
Primary Analysis of the Primary Efficacy Endpoint 
The 2-sided 1-sample binomial test will be used to test the statistical hypothesis described above. 
The 2-sided 95% exact CI based on the Clopper-Pearson method will be provided for the SVR12 
rate. 
6.1.4.
Subgroup Analysis of the Primary Efficacy Endpoint 
The point estimates and the 2-sided 95% exact CIs of the SVR12 rates will be displayed by 
genotype (GT1 with GT1 broken down as GT1a and GT1b; non-GT1 with non-GT1 broken 
down as GT2, GT2a/2c and GT2b) for each subgroup outlined in Section 3.3. 
The SVR rates will be summarized by categories of early viral response to explore possible early 
on-treatment predictors of SVR12. The relationship between SVR12 and study drug interruption 
may also be explored. 
A Forest plot will graphically present the point estimates and the 2-sided 95% exact CIs of the 
SVR12 rates by HCV genotype for each of the subgroups. 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 23
12 April 2021
6.2.
Secondary Efficacy Endpoints 
6.2.1.
Definition of Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following: 

The proportion of subjects who attain HCV RNA < LLOQ at 4 and 24 weeks after cessation 
of treatment (SVR4 and SVR24) 

The proportion of subjects with virologic failure as the following: 
On-treatment virologic failure 
o
HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ, while on 
treatment, confirmed with 2 consecutive values (note, second confirmation value can 
be posttreatment), or last available on-treatment measurement with no subsequent 
follow up values (ie, breakthrough) 
o
> 1 log10 IL/mL increase in HCV RNA from nadir while on treatment, confirmed 
with 2 consecutive values (note, second conformation value can be posttreatment), 
or last available on-treatment measurement with no subsequent follow up values 
(ie, rebound) 
o
HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (ie, nonresponse) 
Relapse 
o
HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA 
< LLOQ at EOT, confirmed with 2 consecutive values or last available posttreatment 
measurement 
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints 
For analyses of SVR4 and SVR24, subjects will be assigned a value at each visit based on the 
analysis visit windows specified in Section 3.7.2. Missing values will be imputed based on the 
categorical imputation rules described in Section 3.5.1. The 2-sided 95% exact CI based on 
Clopper-Pearson method will be provided for the proportion of subjects who attain SVR4 and 
SVR24 by HCV genotype (GT1 with GT1 broken down as GT1a and GT1b; non-GT1 with non-
GT1 broken down as GT2, GT2a/2c and GT2b). The overall category for “HCV RNA < LLOQ” 
will be split into the following 2 subcategories: “< LLOQ TND” for subjects with target not 
detected and “< LLOQ detected” for subjects with < LLOQ in tabular displays. 
For the virologic failure analysis, a summary table of the number and percentage of subjects with 
SVR12, virologic failure, and Other will be created. This summary will be performed broken 
down by HCV genotype (GT1 with GT1 broken down as GT1a and GT1b; non-GT1 with non-
GT1 broken down as GT2, GT2a/2c and GT2b). All subjects who achieve SVR12 will be 
categorized as SVR12. Virologic failure will be descriptively summarized as “on-treatment 
virologic failure” and relapse (which will be broken down by study drug completed yes/no). 


SOFNELFDC 
GS-US-342-5531 
Statistical Analysis Plan - Final Analysis 
Version 1.0 
Subjects who do not achieve SVR12 and do not meet criteria for virologic failure will be 
categorized as "Other." The denominator for relapse will be the number of subjects who had 
HCV RNA < LLOQ on their last obse1ved on-treatment HCV RNA measurement; othe1w ise, the 
denominator will be the number of subjects in the FAS. Virologic outcomes will also be 
provided by prior HCV treatment experience on FAS overall and by HCV genotype. 
A concordance table between SVR12 and SVR24 will be provided by HCV genotype (GTl with 
GTl broken down as GTla and GTl b; non-GTl with non-GTl broken down as GT2, GT2a/2c 
and GT2b) and overall on FAS who had obse1ved HCV RNA measurements at both 
posttreatment Week 12 and posttreatment Week 24 visits. 
In addition, a summaiy table of the number and percentage of subjects with HCV RNA < LLOQ 
and LLOQ at the posttreatment follow-up visit ( obse1ved and imputed, with reasons for 
imputed) will be provided for each posttreatment follow-up visit overall and by HCV genotype. 
The 2-sided 95% Clopper-Peai·son exact Cls will be presented for the overall propo1iion of 
subjects with HCV RNA < LLOQ. 
-
I 
I 
I -
CONFIDENTIAL 
Page 24 
12 April 2021 


SOFNELFDC 
GS-US-342-5531 
Statistical Analysis Plan - Final Analysis 
6.4. 
Changes from Protocol-specified Efficacy Analyses 
There are no planned changes from protocol-specified efficacy analyses. 
CONFIDENTIAL 
Page 25 
Version 1.0 
12 April 2021 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 26
12 April 2021
7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA System organ class (SOC), high-level group term (HLGT), high-level term (HLT), 
preferred term (PT), and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria 
specified in the protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings. the most severe 
will be considered (for sorting purpose only) in data presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE case report form 
(CRF) to the question of “Related to Study Treatment.” Events for which the investigator did not 
record the relationship to study drug will be considered to be related to study drug for summary 
purposes. However, by-subject data listings will show the relationship as missing from that 
captured on the CRF.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Drug Safety and 
Public Health Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events 
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 27
12 April 2021
7.1.5.2.
Incomplete Dates
If the onset date of AE is incomplete, then the month and year (or year alone if month is not 
recorded) of onset determine whether an AE is treatment emergent, as long as the AE stop date is 
not prior to the first dose date of study drug. The event is considered treatment emergent if both 
of the following 2 criteria are met: 

The AE onset and end dates are the same as or after the month and year (or year) of the 
first dose date of study drug 

The AE onset date is the same as or before the month and year (or year) of 30th day after the 
date of the last dose of study drug 
An AE with a completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dose date of study drug, will be considered to be treatment-emergent.
7.1.6.
Summaries of Adverse Events and Deaths 
A brief high-level summary of TEAEs will be provided by the number and percentage of 
subjects who had the following: any AE, any AE of Grade 3 or above, any AE of Grade 2 or 
above, any treatment-related AE, any treatment-related AE of Grade 3 or above, any treatment-
related AE of Grade 2 or above, any SAE, any treatment-related SAE, any AE that led to 
premature discontinuation of the study drug, any AE that led to interruption of the study drug. 
All deaths (including those that are treatment emergent and those that are not treatment 
emergent) observed during the study will also be summarized and included in this table. 
Adverse event summaries will provide the number and percentage of subjects with TEAEs by 
SOC and PT on the Safety Analysis Set as follows: 

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs (including death)

All treatment-related SAEs

AEs leading to premature discontinuation of the study drug

AEs leading to interruption of the study drug


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 28
12 April 2021
Multiple events will be counted once only per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and then by PT in order of descending 
incidence of the pooled treatment groups within each SOC. In summaries by severity grade, the 
most severe grade will be used for those AEs that occurred more than once in an individual 
subject during the study. 
In addition to the above summary tables, TEAEs will also be summarized by PT only, in order of 
descending incidence within the pooled treatment group for: 

AEs that occurred in at least 5% of subjects 

AEs of Grade 3 or above

All treatment-related AEs

All SAEs

AEs leading to premature discontinuation of study drug

AEs leading to interruption of the study drug 
In addition to the summaries described above, data listings will be provided for the following: 

All AEs

AEs of Grade 3 or above

SAEs

Deaths

AEs leading to premature discontinuation of the study drug

AEs leading to interruption of study drug
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to last dose of any study drug plus 30 days 
for subjects who have permanently discontinued study drug. The analysis will be based on values 
reported in conventional units. When values are below the LOQ, they will be listed as such, and 
the closest imputed value will be used for the purpose of calculating summary statistics. For 
example, if “< 0.2” was recorded, a value of 0.1 will be used for the purpose of calculating 
summary statistics; if “< 0.1” was recorded, a value of 0.09 will be used for the purpose of 
calculating summary statistics. 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 29
12 April 2021
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
Gilead Grading Scale for Severity of AEs and Laboratory Abnormalities will be flagged in the 
data listings, as appropriate. 
No inferential statistics will be generated.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
for ALT, AST, total bilirubin, alkaline phosphatase, white blood cell (WBC) counts, neutrophils, 
lymphocytes, hemoglobin, platelets, reticulocytes, and international normalized ratio (INR) as 
follows: 

Baseline values

Values at each postbaseline visit

Change from baseline at each postbaseline visit 
A baseline laboratory value will be defined as the final assessment performed on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
will be displayed to reported number of digits, SD to reported number of digits plus 1. 
Median (Q1, Q3) of the observed values for ALT, AST, total bilirubin, alkaline phosphatase, 
hemoglobin, reticulocytes, WBC, neutrophils, lymphocytes, and platelets will be plotted using a 
line plot by visit. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3. 
The number of subjects with hemoglobin < 10 g/dL and < 8.5 g/dL at any postbaseline visits 
(up to 30 days after the last dose of any study drug) will be summarized.
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of AEs and Laboratory Abnormalities will be used for 
assigning toxicity grades to laboratory results for analysis as Grade 0, Grade 1 (mild), Grade 2 
(moderate), Grade 3 (severe), or Grade 4 (potentially life threatening). Grade 0 includes all 
values that do not meet criteria for an abnormality of at least Grade 1. Some laboratory tests have 
laboratory toxicity criteria for both increased and decreased levels; analyses for each direction 
(ie, increased, decreased) will be presented separately. 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 30
12 April 2021
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 1 
toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug. 
If the relevant baseline laboratory value is missing, then any abnormality of at least Grade 1 will 
be considered treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit. 
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by analyte; subjects will be categorized according to the most 
severe postbaseline abnormality grade for a given analyte: 

Graded laboratory abnormalities 

Grade 3 or above laboratory abnormalities 
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dose for the laboratory parameter of 
interest. 
A by-subject listing of treatment-emergent Grade 3 or above laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the analyte of interest, with all applicable 
severity grades or abnormal flags displayed. 
7.3.
Body Weight, Height, and Vital Signs
Vital signs (systolic and diastolic blood pressure [mmHg] and pulse [beats/min]) at each visit, 
and change from baseline at each visit will be summarized for the Safety Analysis Set using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum). The baseline 
value will be defined as the last available value collected on or prior to the date/time of first dose 
of study drug. Change from baseline to a postbaseline visit will be defined as the postbaseline 
value minus the baseline value. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3). No inferential statistics will be generated. 
A by-subject listing of vital signs (systolic and diastolic blood pressure [mmHg], pulse 
[beats/min], respiration [breaths/min], and body temperature [°C]) will be provided by subject ID 
number and visit in chronological order. In the same manner, a separate by-subject listing of 
body weight, height, and BMI will be provided. 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 31
12 April 2021
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary. The medications will be categorized 
as prior, concomitant, or both using the following definitions: 

Prior medications: any medications taken prior to the initial study drug dosing date

Concomitant medications: any medications initially taken on or after the initial study drug 
dosing date and within the study drug’s treatment period (including study drug’s therapeutic 
reach) 

Prior and concomitant medications: any medications taken both prior to and on or after the 
initial study drug dosing date and within the study drug’s treatment period (including study 
drug’s therapeutic reach); or any medications taken prior to the Baseline visit date with a stop 
date of “continuing” 
Concomitant medications will be summarized by preferred name using the number and 
percentage of subjects for each treatment group. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary of concomitant medications will be ordered by 
descending frequency of preferred names. For drugs with the same frequency, sorting will be 
done alphabetically. 
Summaries will be based on the Safety Analysis Set. No inferential statistics will be generated. 
For purposes of analysis, any medication with a stop date that is on or prior to the initial study 
drug dosing date or start date that is after the last study drug dosing date will be excluded from a 
concomitant medication summary. If a partial stop date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) prior to the initial 
study drug dosing date will be excluded from the concomitant medication summary. If a partial 
start date is entered, then any medication with the month and year (if day is missing) or year 
(if day and month are missing) after the study drug stop date will be excluded from the 
concomitant medication summary. Medications with completely missing dates will be included 
in the concomitant medication summary.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and medication administration date in 
chronological order. 
7.5.
Electrocardiogram Results
A shift table of the investigators’ assessments of ECG results at each visit compared with 
baseline values will be presented using the following categories: normal; abnormal, not clinically 
significant; abnormal, clinically significant; missing. The number and percentage of subjects in 
each cross-classification group of the shift table will be presented. Subjects with a missing value 
at baseline or postbaseline will not be included in the denominator for percentage calculation. No 
inferential statistics will be provided. 


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 32
12 April 2021
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order. 
7.6.
Other Safety Measures
A data listing will be provided for subjects who become pregnant during the study. 
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 33
12 April 2021
8.
REFERENCES 
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Biometrika 1934;26 (4):404-13.


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 34
12 April 2021
9.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 35
12 April 2021
10.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 36
12 April 2021
11.
APPENDICES
Appendix 1.
Schedule of Assessments
Appendix 2.
Determining Missing and Virtual Visits due to COVID-19


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 37
12 April 2021
Appendix 1.
Schedule of Assessments
Treatment Week
(3 days)
Posttreatment Week 
(5 days)
Screening
Day 1a
1
2
4
8
12/ETb
4
12
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
Height
X
Weight
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
12-Lead ECGd
X
X
X
X
Adverse Events and Concomitant 
Medicationse
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling
X
X
X
Imaging for HCCf
X
Review of Study Drug Adherence 
and Drug Accountabilityg
X
X
X
X
X
Study Drug Dispensingh
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
X
X
X
Coagulation (Prothrombin 
activation %, PT, aPTT and INR)
X
X
X
Urinalysis
X


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 38
12 April 2021
Treatment Week
(3 days)
Posttreatment Week 
(5 days)
Screening
Day 1a
1
2
4
8
12/ETb
4
12
24
HCV RNA
X
X
X
X
X
X
X
X
X
HCV resistance samples
X
X
X
X
X
X
X
X
HBV DNA Samplei
X
X
X
X
X
Serum or Urine Pregnancy Testj
X
X
X
X
X
X
Serum FSHk
X
HCV Genotyping
X
IL28B Genotype
X
HCV Ab, HIV Ab, HBsAg, 
HBsAb, HBcAb
X
HbA1c
X
FibroTest®
X
a
Day 1 assessments must be performed prior to dosing.
b
ET = early termination.
c
Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
d
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. 
e
Adverse events and Concomitant Medications will be collected up to 30 days after the last dose of all study drugs. 
f
Liver imaging (eg, ultrasound or CT scan, at the discretion of the investigator) should be performed to exclude the presence of hepatocellular carcinoma (HCC) within 4 months of Day 1 for 
subjects with cirrhosis, and within 6 months of Day 1 for subjects without cirrhosis.
g
Study drugs will be reconciled at every post- Day 1 visit by the investigator in order to monitor the subject’s adherence with the study drugs. Subjects must be instructed to bring back all bottles of 
study drugs in the original container at every post- Day 1 visit through the end of treatment.
h
The IWRS will provide direction on the specifics of each subject’s study drug dispensing. 
i
Reflex testing done only when ALT > 2x Day 1 value in subjects who are HBsAb or HBcAb positive at Screening.
j
All females of childbearing potential will have a serum pregnancy test at Screening. Urine pregnancy testing will occur at Day 1 and every 4 weeks through posttreatment Week 4 and at ET 
if applicable. In the event of a positive urine pregnancy result, subjects will be instructed to return to the clinic as soon as possible for a serum pregnancy test. 
k
Women of any age with amenorrhea of ≥ 12 months (see Protocol Appendix 4).


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 0.8
CONFIDENTIAL
Page 39
4 April 2021
Appendix 2.
Determining Missing and Virtual Visits due to COVID-19
This appendix describes the site collection of COVID-19 data as it pertains to missed/virtual 
visits and the data processing algorithm used to determine which visits were missing and which 
visits were virtual.
Data collection
A COVID-19 supplement to the eCRF Completion Guidelines (CCG) was provided by data 
management to instruct clinical trial sites with respect to data entry expectations pertaining to 
scenarios related to the COVID-19 pandemic. If a visit was missed, sites should enter “Visit 
missed due to COVID-19.” If a visit which was to be conducted in-person was conducted 
virtually, sites should enter “Virtual visit due to COVID-19.”
Determination of Missed and Virtual visits
Natural Language Processing (NLP) was used to search the CRF comment fields to identify 
instances of “COVID-19” (or synonyms, see Table X1) and “Virtual” (or synonyms, see 
Table X1). The search terms are maintained in a global lookup and can be modified and/or 
corrected to tune the NLP model. For each comment field the following algorithm was applied:
STEP 1: Eliminate extraneous text from each comment field, e.g. “and”, “or”, “for”, etc. This is 
done using the list of extraneous terms given in Table X2.
STEP 2: Check each of the remaining comment text strings against the “COVID-19” terms and 
“Virtual” terms with the Levenshtein distance, using SAS function COMPGED (Computes a 
generalized edit distance using the Levenshtein operations to compute/summarize the degree of 
difference between two text strings): 
i)
If Levenshtein distance < 149 for any of the “COVID-19” terms then COVIDFL = 1, 
else COVIDFL = 0
ii) If Levenshtein distance < 149 for any of the “Virtual” terms then VIRTFL = 1, 
else VIRTFL = 0
STEP 3: For any comments with COVIDFL = 1, assign “Missed visit” or “Virtual visit as 
follows:
i)
IF COVIDFL =1 and the visit date is missing then result is ‘Missed Visit’
ii) IF COVIDFL =1 and VIRTFL = 1 then result is = ‘Virtual Visit’
iii) Otherwise result is missing


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 0.8
CONFIDENTIAL
Page 40
4 April 2021
Examples of search terms for “COVID-19” and “Virtual” used to identify missed and virtual 
visits.
Table X1.
Search terms for “COVID-19”
Search terms for “Virtual”
COVID19
VIRTUAL
CORONA
TELEMED
CORONAVIRUS
TELEHEALTH
PANDEMIC
TELEPHONE
OUTBREAK
REMOTE
CRISIS
TELEMEDICINE
LOCKDOWN
TELECONSULTATION
QUARANTINE
TELEPHONICALLY
PHONE
HOME VISIT
ZOOM
SHELTER
SKYPE


SOF/VEL FDC
GS-US-342-5531
Statistical Analysis Plan – Final Analysis
Version 0.8
CONFIDENTIAL
Page 41
4 April 2021
Table X2.
Examples of extraneous text terms to eliminate from the comment fields.
a
down
in
she'd
until
about
during
into
she'll
up
above
each
is
she's
very
after
few
it
should
was
again
for
its
so
we
against
from
it's
some
we'd
all
further
itself
such
we'll
am
had
i've
than
were
an
has
let's
that
we're
and
have
me
that's
we've
any
having
more
the
what
are
he
most
their
what's
as
he'd
my
theirs
when
at
he'll
myself
them
when's
be
her
nor
themselves
where
because
here
of
then
where's
been
here's
on
there
which
before
hers
once
there's
while
being
herself
only
these
who
below
he's
or
they
whom
between
him
other
they'd
who's
both
himself
ought
they'll
why
but
his
our
they're
why's
by
how
ours
they've
with
could
how's
ourselves
this
would
did
i
out
those
you
do
i'd
over
through
you'd
does
if
own
to
you'll
doing
i'll
same
too
your
down
i'm
she
under
you're
you've
yourself
yourselves
yours


GS-US-342-5531-SAP-V1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
13-Apr-2021
23:15:05
Clinical Research eSigned
14-Apr-2021
05:55:17
Regulatory Affairs eSigned 14-Apr-2021
15:49:49
PPD
PPD
PPD-