Clinical trial NCT04211909
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences
Start date: 2020-01-03; Completion date: 2020-11-12
Enrollment: 87 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

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) and Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX ) FDC in participants with chronic HCV infection.

Detailed description:

Arms: arm 1: Participants with chronic HCV infection (genotype 1 or 2), who are treatment-naive or treatment-experienced with interferon (IFN)-based treatments will receive SOF/VEL for 12 weeks. arm 2: Participants with chronic HCV infection (genotype 1), who are treatment-experienced with nonstructural protein 5A (NS5A) direct-acting antiviral (DAA)-based treatments of at least 4 weeks duration will receive SOF/VEL/VOX for 12 weeks.
Interventions: intervention 1: SOF/VEL intervention 2: SOF/VEL/VOX
Intervention descriptions: intervention 1: 400/100 mg FDC tablet orally once daily. intervention 2: 400/100/100 mg FDC tablet orally once daily.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3b Multicenter, Open-Label Study to Investigate the 
Efficacy and Safety of Sofosbuvir/Velpatasvir Fixed-Dose 
Combination and Sofosbuvir/Velpatasvir/Voxilaprevir Fixed-Dose 
Combination for 12 Weeks in Subjects with Chronic HCV 
Infection
Sponsor:
Gilead Sciences, Inc.
IND No.:
This is a non-IND study
Clinical Trials.gov 
Identifier:
Not Applicable
EudraCT No.:
Not Available
Indication:
Hepatitis C Virus Infection
Protocol ID:
Contact Information:
GS-US-342-5532
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List.
Protocol Version/Date:
Original:
25 June 2019
Amendment 1: 04 Oct 2019
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee. The information is only to be 
used by you in connection with authorized clinical studies of the investigational drug 
described in the protocol. You will not disclose any of the information to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessary to obtain 
informed consent from those persons to whom the drug may be administered.
(r) GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................9
1.
INTRODUCTION ..............................................................................................................................................13
1.1.
Background ............................................................................................................................................13
1.2.
Sofosbuvir/Velpatasvir Fixed-Dose Combination (FDC) and 
Sofosbuvir/Velpatasvir/Voxilaprevir FDC.............................................................................................14
1.2.1.
General Information .............................................................................................................14
1.2.2.
Clinical Trials of SOF/VEL FDC and SOF/VEL/VOX FDC...............................................15
1.2.3.
Clinical Pharmacology .........................................................................................................15
1.3.
Rationale for This Study ........................................................................................................................16
1.4.
Rationale for Dose Selection..................................................................................................................16
1.4.1.
Rationale for Dose Selection for SOF/VEL FDC.................................................................16
1.4.2.
Rationale for Dose Selection of SOF/VEL/VOX FDC ........................................................16
1.5.
Risk/Benefit Assessment for the Study..................................................................................................17
1.6.
Compliance ............................................................................................................................................17
2.
OBJECTIVES.....................................................................................................................................................18
3.
STUDY DESIGN................................................................................................................................................19
3.1.
Study Design and Study Treatments ......................................................................................................19
3.2.
Duration of Treatment............................................................................................................................19
3.3.
Stopping Rules and Discontinuation Criteria.........................................................................................19
3.3.1.
Toxicity Based Stopping Criteria.........................................................................................20
3.3.2.
Virologic Response Based Treatment Stopping Criteria......................................................21
4.
SUBJECT POPULATION..................................................................................................................................22
4.1.
Number of Subjects and Subject Selection ............................................................................................22
4.2.
Inclusion Criteria....................................................................................................................................22
4.3.
Exclusion Criteria...................................................................................................................................24
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................26
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................26
5.2.
Description and Handling of SOF/VEL FDC and SOF/VEL/VOX FDC ..............................................26
5.2.1.
Formulation..........................................................................................................................26
5.2.2.
Packaging and Labeling .......................................................................................................26
5.2.3.
Storage and Handling...........................................................................................................27
5.3.
Dosage and Administration of SOF/VEL FDC and SOF/VEL/VOX FDC............................................27
5.3.1.
Dosing and Administration of SOF/VEL FDC (Cohort 1)...................................................27
5.3.2.
Dosing and Administration of SOF/VEL/VOX FDC (Cohort 2).........................................28
5.4.
Prior and Concomitant Medications.......................................................................................................28
5.5.
Study Drug Adherence and Accountability for SOF/VEL FDC and SOF/VEL/VOX FDC..................30
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................30
6.
STUDY PROCEDURES ....................................................................................................................................31
6.1.
Subject Enrollment.................................................................................................................................31
6.1.1.
Screening Visit .....................................................................................................................31
6.1.2.
Day 1 Assessments...............................................................................................................33
6.2.
Treatment Assessments (± 3 Days)........................................................................................................34


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6.2.1.
Week 1 (± 3 Days) ...............................................................................................................34
6.2.2.
Week 2 (± 3 Days) ...............................................................................................................34
6.2.3.
Weeks 4 and 8 (± 3 Days) ....................................................................................................35
6.2.4.
Week 12 (± 3 Days)..............................................................................................................36
6.3.
Posttreatment Assessments ....................................................................................................................37
6.3.1.
Posttreatment Week 4 (± 5 Days).........................................................................................37
6.3.2.
Posttreatment Week 12 (± 5 Days).......................................................................................37
6.4.
Assessments for Premature Discontinuation from Study.......................................................................38
6.5.
Early Termination ..................................................................................................................................38
6.6.
Unscheduled Visit ..................................................................................................................................39
6.7.
Procedures and Specifications................................................................................................................39
6.7.1.
Clinical Laboratory Analytes ...............................................................................................39
6.7.2.
Pharmacokinetic (PK) Sampling ..........................................................................................40
6.7.3.
Medical History....................................................................................................................40
6.7.4.
Complete Physical Examination...........................................................................................40
6.7.5.
Vital Signs............................................................................................................................41
6.7.6.
12-Lead ECG........................................................................................................................41
6.7.7.
Creatinine Clearance ............................................................................................................41
6.7.8.
HCV Resistance Sample ......................................................................................................41
6.7.9.
HBV DNA Sample...............................................................................................................42
6.7.10.
Pregnancy Testing................................................................................................................42
6.7.11.
IL28B Testing ......................................................................................................................42
6.8.
End of Study...........................................................................................................................................42
6.9.
Poststudy Care........................................................................................................................................42
7.
ADVERSE EVENTS..........................................................................................................................................43
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................43
7.1.1.
Adverse Events.....................................................................................................................43
7.1.2.
Serious Adverse Events........................................................................................................43
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................44
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................44
7.2.1.
Assessment of Causality for Study Drug and Procedures ....................................................44
7.2.2.
Assessment of Severity ........................................................................................................45
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO: ........................................................................................................45
7.4.
Gilead Reporting Requirements.............................................................................................................47
7.5.
Special Situations Reports......................................................................................................................47
7.5.1.
Definitions of Special Situations..........................................................................................47
7.5.2.
Instructions for Reporting Special Situations.......................................................................48
8.
STATISTICAL CONSIDERATIONS................................................................................................................50
8.1.
Analysis Objectives and Endpoints........................................................................................................50
8.1.1.
Analysis Objectives..............................................................................................................50
8.1.2.
Primary Endpoint .................................................................................................................50
8.1.3.
Secondary Endpoint .............................................................................................................50
8.2.
Analysis Conventions.............................................................................................................................51
8.2.1.
Analysis Sets ........................................................................................................................51
8.2.2.
Data Handling Conventions .................................................................................................51
8.3.
Demographic Data and Baseline Characteristics ...................................................................................53
8.4.
Efficacy Analysis ...................................................................................................................................53
8.4.1.
Primary Analysis..................................................................................................................53
8.4.2.
Secondary Analyses .............................................................................................................53
8.5.
Safety Analysis.......................................................................................................................................54


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8.5.1.
Extent of Exposure...............................................................................................................54
8.5.2.
Adverse Events.....................................................................................................................54
8.5.3.
Laboratory Evaluations ........................................................................................................55
8.5.4.
Other Safety Evaluations......................................................................................................55
8.6.
Pharmacokinetic Analysis......................................................................................................................55
8.7.
Sample Size............................................................................................................................................55
8.8.
Data Monitoring Committee ..................................................................................................................55
8.9.
Endpoint Adjudication Committee.........................................................................................................55
9.
RESPONSIBILITIES..........................................................................................................................................56
9.1.
Investigator Responsibilities ..................................................................................................................56
9.1.1.
Good Clinical Practice..........................................................................................................56
9.1.2.
Financial Disclosure.............................................................................................................56
9.1.3.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................56
9.1.4.
Informed Consent.................................................................................................................56
9.1.5.
Confidentiality......................................................................................................................57
9.1.6.
Study Files and Retention of Records ..................................................................................57
9.1.7.
Case Report Forms...............................................................................................................58
9.1.8.
Investigational Medicinal Product Accountability and Return.............................................59
9.1.9.
Inspections............................................................................................................................59
9.1.10.
Protocol Compliance............................................................................................................59
9.2.
Sponsor Responsibilities ........................................................................................................................59
9.2.1.
Protocol Modifications.........................................................................................................59
9.2.2.
Study Report and Publications .............................................................................................60
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................60
9.3.1.
Payment Reporting...............................................................................................................60
9.3.2.
Access to Information for Monitoring..................................................................................60
9.3.3.
Access to Information for Auditing or Inspections ..............................................................61
9.3.4.
Study Discontinuation..........................................................................................................61
10.
REFERENCES ...................................................................................................................................................62
11.
APPENDICES ....................................................................................................................................................63
Appendix 1.
Investigator Signature Page....................................................................................................64
Appendix 2.
Study Procedures Table..........................................................................................................65
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............67
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................90
LIST OF IN-TEXT TABLES
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................29


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc
333 Lakeside Drive 
Foster City, CA 94404, USA
Study Title: 
A Phase 3b Multicenter, Open-Label Study to Investigate the 
Efficacy and Safety of Sofosbuvir/Velpatasvir Fixed-Dose 
Combination and Sofosbuvir/Velpatasvir/Voxilaprevir Fixed-Dose 
Combination for 12 Weeks in Subjects with Chronic HCV Infection
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
This is a non-IND study 
Not Applicable
Not Available
Study Centers 
Planned:
Approximately 25 Centers in Korea
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 and sofosbuvir/velpatasvir/voxilaprevir
(SOF/VEL/VOX) 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 weeks after cessation of treatment (SVR4)

To evaluate the proportion of subjects with virologic failure

To evaluate the emergence of viral resistance to SOF, VEL and
VOX during treatment and after cessation of treatment


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Study Design:
This is a multicenter, open-label study in subjects with chronic 
Hepatitis C Virus (HCV) infection.
Cohort 1: Approximately 50 subjects with chronic HCV infection, 
genotype 1 or 2, will be enrolled and treated with SOF/VEL FDC 
for 12 weeks.  Subjects may be treatment-naïve or treatment-
experienced with Interferon (IFN)-based treatments.
Cohort 2: Approximately 30 subjects with chronic HCV infection,
genotype 1, will be enrolled and treated with SOF/VEL/VOX FDC 
for 12 weeks.  Subjects will be treatment-experienced with NS5A 
direct acting antiviral (DAA)-based treatments.
Number of Subjects 
Planned:
Approximately 80 subjects
Target Population:
Treatment-naïve and Treatment-experienced adults with chronic 
HCV infection with HCV genotype 1 or 2.
Duration of 
Treatment:
Subjects in both cohorts 1 and 2 will be treated for 12 weeks
Diagnosis and Main 
Eligibility Criteria:
Chronic HCV-infected male and non-pregnant/non-lactating female 
subjects, aged 19 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 and Week 12 visits.
Screening assessments will include medical history, physical 
examination, height, weight, vital signs, 12-lead electrocardiogram 
(ECG), adverse events (AEs) related to screening procedures, prior 
and concomitant medications, liver imaging to exclude 
hepatocellular carcinoma (HCC) within 4 months of Day 1 for 
subjects with cirrhosis and within 6 months of Day 1 for subjects 
without cirrhosis, safety laboratory tests (including hematology, 
chemistry, coagulation, urinalysis), HCV RNA, serum β-hCG 
(females of childbearing 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 or 
absence of cirrhosis (including FibroTest®).


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Test Product, Dose, 
and Mode of 
Administration: 
On-treatment assessments include physical examination, weight, 
vital signs, 12-Lead ECGs, AEs, concomitant medications, 
pregnancy prevention com1seling, review of study drug adherence 
and drug accom1tability, study drugs dispensing, safety laboratory 
tests (including hematology, chemistry, coagulation), HCV RNA, 
HCV resistance samples, HBV DNA sample ( only for HBcAb 
positive subjects at Screening), phannacokinetic samples, urine 
pregnancy tests (females of childbearing potential only), and IL28B 
genotyping. 
Posttreatment assessments include weight, vital signs, AEs, 
concomitant medications, pregnancy prevention counseling, safety 
laboratory tests (including hematology and chemistry), HCV RNA, 
HCV resistance samples, HBV DNA sample ( only for HBcAb 
positive subjects at Screening), and urine pregnancy tests (females 
of childbearing potential only). 
Cohort 1: SOFNEL FDC is manufactured as a 400/100 mg FDC 
tablet for oral administration. Subjects will take 1 tablet daily with 
or without food. 
Cohort 2: SOFNELN OX FDC is manufactured as a 
400/100/100 mg FDC tablet for oral administration. Subjects will 
take 1 tablet daily with food. 
Reference Therapy, 
None 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
Phannacokinetics: 
CONFIDENTIAL 
AEs and safety laboratory tests will be collected throughout the 
study. 
Efficacy will be evaluated using scheduled assessments of HCV 
RNA perfonned using COBAS® Ampliprep/ COBAS® TaqMan® 
HCV Quantitative Test, version 2.0. 
A single PK blood sample will be collected at Weeks 2, 4, 8, 12, 
and Early Tennination (if applicable) for all subjects. 
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Statistical Methods: 
The primary efficacy endpoint for the study is SVR12 in all enrolled 
and treated subjects. No hypothesis testing will be perfonned. 
Secondary efficacy endpoints include SVR4. 
Continuous endpoints (except for safety endpoints) will be 
summarized using an 8-number summary (n, mean, standard 
deviation [SD], median, Ql, Q3, minimum, and maximum) by 
cohort. Categorical endpoints will be smmnarized by number and 
percentage of subjects who meet the endpoint definition by cohort. 
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnonnalities for categorical values or 
8-number smmnary (n, mean, standard deviation, median, Ql, Q3, 
minimmn, and maximmn) for continuous data by cohort. 
For Cohort 1, with approximately 50 subjects enrolled into the 
study, the 2-sided 95% exact confidence interval (CI) using the 
binomial distribution (Clopper-Pearson method) of the SVR12 rate 
will be from 86.3% to 99.5%, assuming the expected SVR12 rate is 
95%. 
For Cohort 2, with approximately 30 subjects enrolled into the 
study, the 2-sided 95% exact CI using the binomial distribution 
(Clopper-Pearson method) of the SVR12 rate will be from 82.8% to 
99.9%, assmning the expected SVR12 rate is 95%. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential docmnents. 
CONFIDENTIAL 
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
°C
degrees Celsius
°F
degrees Fahrenheit
Ab
antibody
ABW
actual body weight
AE(s)
adverse event(s)
ALT
alanine aminotransferase (also SGPT)
aPTT
activated partial thromboplastin time
AST
ASV
aspartate aminotransferase (also SGOT)
asunaprevir
BMI
CCDS
body mass index
Company Core Data Sheet
CFR
Code of Federal Regulations
CI
confidence interval
ClCr
creatinine clearance
CRO
contract research organization
CSR
clinical study report
DAA
direct-acting antiviral
DCV
daclatasvir
Dl
DSV
Deciliter
dasabuvir
EBR
elbasvir
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eg
example given
eSAE
electronic serious adverse event
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
GLE
glecaprevir
GSI
Gilead Sciences, Inc.
GT
Genotype


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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
i.e.
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
IVDU
intrauterine hormone-releasing system
Intravenous Drug Use
IWRS
interactive web response system
kg
kilogram
kPA
kilopascal
L
liter
LAM
lactational amenorrhea method
LDV
ledipasvir
LLOQ
lower limit of quantification
LLT
lower-level term
MCV
mean corpuscular volume or mean cell volume


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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)
OBV
OAT
non-structural protein
ombitasvir
organic anion transporter 
PCR
polymerase chain reaction
PI
protease inhibitor
PIB
pibrentasvir
PK
pharmacokinetic
PPIs
proton-pump inhibitors
PT
PTV
preferred term or prothrombin time
paritaprevir
Q1
quartile 1
Q3
quartile 3
RBC
red blood cell count
RBV
ribavirin
RNA
RTV
ribonucleic acid
ritonavir
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
System organ class 
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
SVR4
sustained virologic response 4 weeks after cessation of treatment
TND
target not detected


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ULN
upper limit of normal
US
United States
WBC
white blood cell
VEL
VOX
Velpatasvir
Voxilaprevir
β-hCG
β-human chorionic gonadotropin
μg
microgram


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1.
INTRODUCTION
1.1.
Background
In Korea, chronic HCV infection is one of the leading causes of chronic liver disease and 
hepatocellular carcinoma (HCC) {Kwon 2019}. The prevalence of HCV in South Korea has 
been reported to be 0.78% {Kim 2013}. HCV infection accounts for 10.4% of causative disease 
of HCC, which makes it the 2nd major cause following Hepatitis B Virus (HBV) infection 
{Hwang 2010}. The age-standardized prevalence of HCV antibody (HCV Ab) in patients greater 
than 40 years of age is reported to be on the order of 1.3% which equates to around 193,000 
people {Shin 2006}. The prevalence of HCV infection increases with age and peaks in those 
aged 60 years and older, since the majority of infections occurred via contaminated blood 
transfusions prior to the introduction of blood-donor HCV Ab screening in 1991 {Lim 2009}
{Suh 2006}. 
Since the decline of transfusion related hepatitis C, the majority of new infections are behavior-
related. Of particular note is the practice of acupuncture for chronic illnesses including joint 
disease, and pain sequelae of trauma. Shin, et al reported results of a case study in which 34.1% 
of men and 62.9% of women in rural Korea reported multiple acupuncture procedures with the 
associated risk of HCV infection being 38% for men and 55% for women {Shin 2006}. 
Additionally, more recent study reports that history of blood transfusion and intravenous drug 
use (IVDU) were found in only 14.3% and 5.6% of the cohort, respectively, suggesting that the
majority of patients may have been infected through other settings, such as cosmetics or in 
healthcare {Kwon 2019}. The predominant HCV genotypes (GT) in Korea are GT-1b and GT-2a 
which are roughly present in equal proportions and combined account for around 80-90% of 
infections {Kwon 2019}, {Kwon 2019}, {Shin 2006}. 
As of today, the direct-acting antivirals (DAAs) sofosbuvir (SOF), ledipasvir/sofosbuvir
(LDV/SOF), daclatasvir (DCV), asunaprevir (ASV), ombitasvir (OBV)/paritaprevir
(PTV)/ritonavir (RTV), dasabuvir (DSV), elbasvir (EBR)/grazoprevir (GZR), and glecaprevir
(GLE)/pibrentasvir (PIB) are approved in Korea for treatment of chronic HCV {The Korean 
Association for the Study of the Liver (KASL) 2018}. Despite the availability of these highly 
efficacious DAA regimens with high SVR rates, there is still an unmet medical need for patients 
with chronic HCV in Korea. First, as stated above, the elderly population represents the majority 
of the patient pool, and they are faced with increasing number of comorbidities and co-
medications which may have significant and complex interactions with currently available DAAs 
{The Korean Association for the Study of the Liver (KASL) 2018}. Secondly, protease 
inhibitors (PIs) are contraindicated in patients with decompensated cirrhosis due to toxicity from 
increased drug concentrations in the liver {The Korean Association for the Study of the Liver 
(KASL) 2018}. Currently, the only PI-free regimen approved for treating patients with 
decompensated cirrhosis in Korea is indicated for GT1 patients. Lastly, there is a small, but 
significant group of patients who were treated with the DAA regimen of daclatasvir and 
asunaprevir following its early approval in Korea that subsequently failed treatment due to the 


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low efficacy of the combination. As the treatment regimen included an NS5A inhibitor, these 
patients currently do not have a suitable treatment option {Kwon 2019}.
These unmet needs can largely be resolved with SOF/VEL FDC, a pangenotypic PI-free regimen
and SOF/VEL/VOX FDC, a DAA retreatment regimen that is efficacious in patients that failed 
an NS5B, NS5A or PI combination.
Therefore, the aim of this study is to examine the safety and efficacy of SOF/VEL FDC and 
SOF/VEL/VOX FDC in Korean patients.
1.2.
Sofosbuvir/Velpatasvir Fixed-Dose Combination (FDC) and 
Sofosbuvir/Velpatasvir/Voxilaprevir FDC
SOF/VEL FDC is a co-formulation of SOF 400 mg and VEL 100 mg into a single tablet.
SOF/VEL/VOX FDC is a co-formulation of SOF 400 mg, VEL 100 mg, and VOX 100 mg into a 
single tablet.
Sofosbuvir (SOF) is a nucleotide analog HCV NS5B polymerase inhibitor. 
Velpatasvir (VEL) is a pangenotypic HCV NS5A inhibitor. 
Voxilaprevir (VOX) is a NS3/4A protease inhibitor with potent antiviral activity against 
genotypes 1 to 6 HCV. 
Epclusa® (SOF/VEL FDC) was first approved in the United States on 28 June 2016 and is 
currently approved in 75 countries as of 10 April 2019. Cumulative patient exposure to Epclusa®
since first marketing approval is estimated to be 64,339 patient-years of treatment as of 27 
December 2018. This estimate is based on sales data, which generally overestimate patient 
exposure because stocks of drug are accumulated by distributors and pharmacies.
Vosevi® (SOF/VEL/VOX FDC) was first approved in the United States on 18 July 2017 and is 
currently approved in 44 countries as of 07 May 2019. Cumulative patient exposure to Vosevi®
since first marketing approval is estimated to be 3,677 patient-years of treatment as of 17 January 
2019. This estimate is based on sales data, which generally overestimate patient exposure 
because stocks of drug are accumulated by distributors and pharmacies.
1.2.1.
General Information
For further information on SOF/VEL FDC (Epclusa®) and on SOF/VEL/VOX FDC (Vosevi®), 
refer to the current Investigator’s Brochures and the individual components for each, including:

In-vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology


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
Clinical Experience
1.2.2.
Clinical Trials of SOF/VEL FDC and SOF/VEL/VOX FDC
Two Phase 3 studies, GS-US-342-1138 (ASTRAL-1) and GS-US-342-1139 (ASTRAL-2), 
evaluated the efficacy and safety of SOF/VEL FDC in subjects with genotype 1a, 1b, 2, 4, 5, 6 
HCV infection, without cirrhosis or with compensated cirrhosis.
Refer to the SOF/VEL FDC Investigator’s Brochure for additional information.
Two Phase 3 studies, POLARIS-1 (GS-US-367-1171) and POLARIS-4 (GS-US-367-1170)
evaluated the efficacy and safety of SOF/VEL/VOX FDC in DAA-experienced subjects with 
genotypes 1-6 with chronic HCV infection, without cirrhosis or with compensated cirrhosis.
Refer to the SOF/VEL/VOX FDC Investigator’s Brochure for additional information.
1.2.3.
Clinical Pharmacology 
The PK of SOF and VEL in Asian subjects has been extensively studied in dedicated Phase 1
studies (GS-US-334-0111 and GS-US-367-1905), and phase 2 and 3 studies in the SOF/VEL 
clinical program, as part of Asian subject subpopulations.
These data have indicated that there is no clinically meaningful effect of Asian race on the PK of
SOF, its metabolites GS-566500 and GS-331007, or VEL, and supported the approval of 
Sovaldi® (SOF), Harvoni® (LDV/SOF FDC), and Epclusa (SOF/VEL FDC) in China.
The PK of SOF, its metabolites GS-566500 and GS-331007, VEL, and VOX were assessed in
healthy Japanese subjects in the Phase 1 study GS-US-367-1905. The results of this analysis 
demonstrate that there was no clinically significant impact of Asian race on the PK of SOF, its 
metabolites, VEL, or VOX.
Additionally, the PK of SOF, GS-331007, VEL, and VOX were analyzed in the SOF/VEL/VOX
clinical program, in which a substantial number of Asian subjects were enrolled. The results of
these analyses demonstrate no clinically significant impact of Asian race on the population PK 
model-based exposures of SOF, GS-331007, VEL, or VOX compared with a predominantly 
Caucasian reference population. Importantly, race was not identified as a clinically meaningful 
covariate in the population PK models for SOF, GS-331007, VEL, or VOX.
Collectively, these data demonstrate no clinically significant differences in the PK of SOF, its
metabolites, VEL, or VOX in healthy and HCV-infected Asian and non-Asian subjects, and they
support the use of SOF/VEL FDC, and SOF/VEL/VOX FDC for the treatment of HCV-infected 
Korean patients.


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1.3.
Rationale for This Study
The population for Cohort 1 will be subjects with chronic HCV Genotype 1 or 2 who are either 
treatment-naïve or treatment-experienced with IFN-based treatments. As a large proportion of 
the Korean HCV population are elderly there is a need for a highly efficacious regimen that is 
PI-free and has a favorable direct drug interaction (DDI) profile. Therefore, this study aims to 
examine the safety and efficacy of 12 weeks of SOF/VEL, a PI-free, pangenotypic regimen, in a 
Korean population. 
The population for Cohort 2 will be subjects with chronic HCV infection without cirrhosis or 
with compensated cirrhosis and who have previously not achieved SVR following treatment with 
an NS5A DAA agent. With the increasing use of NS5A inhibitors with or without NS5B 
inhibitors, the unmet medical need for effective retreatment options for the few patients who fail 
these regimens will increase. This study will examine the safety and efficacy of SOF/VEL/VOX 
for 12 weeks for these patients in Korea. 
1.4.
Rationale for Dose Selection 
1.4.1.
Rationale for Dose Selection for SOF/VEL FDC
Subjects in Cohort 1 of 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 the Phase 3 ASTRAL 1-3 studies (GS-US-342-1138, GS-US-342-1139, GS-US-342-1140), 
treatment of HCV infected subjects infected without cirrhosis or with compensated cirrhosis for 
12 weeks with SOF/VEL FDC was well tolerated and resulted in high SVR12 rates.
Refer to the SOF/VEL FDC Investigator’s Brochure for additional information.
1.4.2.
Rationale for Dose Selection of SOF/VEL/VOX FDC
Subjects in Cohort 2 of this study will be administered SOF/VEL/VOX FDC, a co-formulation 
of SOF 400 mg, VEL 100 mg and VOX 100 mg that is approved in the US and other markets as 
Vosevi® for the treatment of HCV infection in adults.
In the POLARIS-1 study, treatment with SOF/VEL/VOX FDC for 12 weeks in subjects with 
HCV infected subjects with Genotype 1, NS5A-inhibitor experienced without cirrhosis or with 
compensated cirrhosis (POLARIS-1) was highly efficacious and well tolerated.  
Refer to the SOF/VEL/VOX FDC Investigator’s Brochure for additional information.


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1.5.
Risk/Benefit Assessment for the Study
This study will provide information on the safety and efficacy of the combination of SOF/VEL 
FDC for 12 weeks in Korean patients that are treatment-naïve or treatment-experienced with 
IFN-based treatment and SOF/VEL/VOX FDC for 12 weeks in Korean patients that are 
treatment-experienced with NS5A DAA-based treatments.
The safety profile of SOF/VEL FDC has been established in 3,345 subjects, included in the
Phase 3 studies, Phase 2 studies and Phase 1 studies which enrolled subjects with compensated 
and decompensated cirrhosis.  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.  
The safety assessment of SOF/VEL/VOX FDC has been established based on data from Phase 3 
clinical studies in which > 1,000 subjects received SOF/VEL/VOX FDC for 12 weeks. There 
were no patients receiving SOF/VEL/VOX FDC for 12 weeks who permanently discontinued 
treatment due to adverse reactions. Overall, SOF/VEL/VOX FDC for 12 weeks was safe and 
well tolerated in patients for the treatment of chronic HCV infection in adults without cirrhosis 
or with compensated cirrhosis who have failed prior treatment with a HCV DAA.
During the conduct of the study, the sponsor together with the investigator will perform ongoing 
safety reviews.
1.6.
Compliance
This study will be conducted in compliance with this protocol, GCP, and all applicable 
regulatory requirements.


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2.
OBJECTIVES
The primary objectives of this study are:

To evaluate the antiviral efficacy of therapy with sofosbuvir/velpatasvir (SOF/VEL)
fixed-dose combination (FDC) for 12 weeks and sofosbuvir/velpatasvir/voxilaprevir
(SOF/VEL/VOX) 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 weeks after cessation of
treatment (SVR4)

To evaluate the proportion of subjects with virologic failure

To evaluate the emergence of viral resistance to SOF, VEL and VOX during treatment and
after cessation of treatment


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3.
STUDY DESIGN
3.1.
Study Design and Study Treatments
This is a multicenter, open-label study in approximately 80 subjects with chronic HCV infection.
Cohort 1: Approximately 50 subjects with chronic HCV infection, genotype 1 or 2, will be 
enrolled and treated with SOF/VEL FDC for 12 weeks.  Subjects may be treatment-naïve or 
treatment-experienced with IFN-based treatments.
Cohort 2: Approximately 30 subjects with chronic HCV infection, genotype 1, will be enrolled 
and treated with SOF/VEL/VOX FDC for 12 weeks.  Subjects will be treatment-experienced 
with NS5A DAA-based treatments.
3.2.
Duration of Treatment
Subjects in both Cohorts 1 and 2 will be treated for 12 weeks.
The total time to complete all study visits is approximately 28 weeks (30 weeks for those 
requiring an extension to 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

12 weeks posttreatment period
3.3.
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.
When medically feasible, the medical monitor must be consulted prior to subject discontinuation. 
Subjects who permanently discontinue SOF/VEL FDC or SOF/VEL/VOX FDC should complete 
an Early Termination (ET) visit.  For subjects who have completed an ET visit, the posttreatment 
Week 4 and 12 visits will be completed after the last dose of study drug.
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


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
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 3.3.2)

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)
3.3.1.
Toxicity Based Stopping Criteria
The Medical Monitor must be consulted prior to study drug discontinuation of SOF/VEL FDC or 
SOF/VEL/VOX 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 or SOF/VEL/VOX FDC dose reduction. If either SOF/VEL FDC 
or SOF/VEL/VOX 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 and Week 12 visits must also be scheduled, 4 and 12 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 (ULN) 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 and SOF/VEL/VOX FDC


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3.3.2.
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 as described above 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.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 80 adults with chronic HCV infection will be enrolled in this study, including 
approximately 50 subjects in Cohort 1 and approximately 30 subjects in Cohort 2.
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. Criteria apply to all subjects unless otherwise stipulated.
1) Willing and able to provide written informed consent
2) Male or female, age 19 years at Screening
3) Body mass index (BMI) ≥ 18 kg/m2
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) Cohort 1 only: HCV genotype 1 or 2 assessed at Screening by the Central Laboratory, and
HCV treatment status defined as one of the following, with medical records that include
sufficient detail to allow for categorization as follows:
a) HCV treatment-naïve: Subject has had no prior exposure to any IFN, RBV, or other
approved or experimental HCV-specific direct-acting antiviral agents (DAAs).
b) HCV treatment-experienced defined as prior treatment failure to a regimen containing
interferon either with or without RBV that was completed at least 8 weeks prior to Day 1.
Subject must not have discontinued the prior regimen that resulted in virologic failure
due to an adverse event. Note: See Exclusion Criterion #6: prior exposure to any direct
acting antiviral agent targeting the HCV NS5A or NS5B is prohibited.
7) Cohort 2 only: HCV genotype 1, assessed at Screening by the Central Laboratory, and
treatment experienced with a NS5A inhibitor-containing regimen of at least a 4-week
duration
a) The most recent treatment must have been completed at least 8 weeks prior to Screening


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b) Subjects must not have discontinued the most recent regimen due to either an adverse
event or virologic failure due to noncompliance
c) The subject’s medical records must include sufficient detail of prior treatment(s) to
confirm eligibility
8) Cirrhosis Determination:
a) Presence of cirrhosis is defined as any one of the following:
i)
Liver biopsy showing cirrhosis (eg, Metavir score  4 or Ishak score ≥5)
ii) Fibroscan within 4 months of Day 1, showing cirrhosis as reflected by a result > 12.5
kPa
iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score > 0.75 at
Screening
b) Absence of cirrhosis is defined as any one of the following, unless the definition of
cirrhosis has been met:
i)
Liver biopsy within 2 years of Screening showing absence of cirrhosis
ii) Fibroscan within 6 months of Day 1 with a result ≤ 12.5 kPa
iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score ≤ 0.75 at
Screening
9) Liver imaging (eg, ultrasound or CT scan, at the discretion of the investigator) performed
within 4-6 months of Day 1 to exclude hepatocellular carcinoma (HCC) is required:
a) Within 4 months for subjects with cirrhosis
b) Within 6 months for subjects without cirrhosis
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 until at least
30 days after the last dose SOF/VEL FDC or SOF/VEL/VOX FDC.
13) Lactating females must agree to discontinue nursing before study drug is administered.


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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 drugs
c) Difficulty with blood collection and/or poor venous access for the purposes of
phlebotomy
d) Clinical hepatic decompensation (eg, ascites, encephalopathy, variceal hemorrhage,
Child-Pugh-B or C cirrhosis)
e) Solid organ transplantation
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)


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2) Infection with human immunodeficiency virus (HIV) at Screening
3) Hepatitis B virus (HBV) surface antigen positive at Screening
4) Clinically-relevant alcohol or drug abuse within 12 months of Screening. A positive drug
screen will exclude subjects unless it can be explained by a prescribed medication; the
diagnosis and prescription must be approved by the investigator
5) Screening ECG with clinically significant abnormalities
6) Cohort 1 only: Prior exposure to any HCV NS5A or NS5B inhibitor
7) 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)
8) Pregnant or nursing female or male with pregnant female partner
9) 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 or
SOF/VEL/VOX FDC
10) Subjects with any of the following laboratory parameters at screening:
a) ALT  >10 x upper limit of normal (ULN)
b) AST > 10 x ULN
c) Direct bilirubin > 1.5 × ULN
d) Platelets < 50,000/L
e) HbA1c > 8.5%
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
11) Use of any prohibited concomitant medications as described in Section 5.4
12) Chronic use of systemically administered immunosuppressive agents (eg, prednisone
equivalent of > 10 mg/day)
13) Known hypersensitivity or contraindication to sofosbuvir, velpatasvir, voxilaprevir or the
metabolites or formulation excipients


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
This is a multicenter, open-label study in two different subject cohorts with chronic HCV 
infection.  No blinding is required. 
All subjects will be enrolled to receive SOF/VEL FDC (Cohort 1) or SOF/VEL/VOX FDC 
(Cohort 2) for 12 weeks.
5.2.
Description and Handling of SOF/VEL FDC and SOF/VEL/VOX FDC
5.2.1.
Formulation 
5.2.1.1.
Formulation SOF/VEL FDC
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.
5.2.1.2.
Formulation SOF/VEL/VOX FDC
The SOF/VEL/VOX FDC (400/100/100 mg) tablets are beige, capsule-shaped film-coated 
tablets debossed with “GSI” on one side and a “3” on the other side. In addition to the active 
ingredients, SOF/VEL/VOX FDC tablets also contain copovidone, microcrystalline cellulose, 
lactose monohydrate, silicon dioxide, croscarmellose sodium, magnesium stearate, polyvinyl 
alcohol, titanium dioxide, macrogol/polyethylene glycol 3350, talc, iron oxide yellow, iron oxide 
red, and ferrosoferric oxide.
5.2.2.
Packaging and Labeling
5.2.2.1.
Packaging and Labeling SOF/VEL FDC
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 study centers in Korea shall be labeled to meet all 
applicable requirements of the Ministry of Food and Drug Safety (MFDS) guideline to Good 
Manufacturing Practice Annex 11 (Investigational Medicinal Products) and/or local regulations 
as applicable.


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Sufficient quantities of SOF/VEL FDC tablets will be shipped to the investigator or qualified 
designee from Gilead Sciences Clinical Supply Management (or its designee).
5.2.2.2.
Packaging and Labeling SOF/VEL/VOX FDC
SOF/VEL/VOX (400/100/100 mg) FDC tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 tablets, silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap fitted 
with an induction-sealed, aluminum-faced liner.
SOF/VEL/VOX FDC bottles to be distributed to study centers in Korea shall be labeled to meet 
all applicable requirements of the Ministry of Food and Drug Safety (MFDS) guideline to Good 
Manufacturing Practice Annex 11 (Investigational Medicinal Products) and/or local regulations 
as applicable. 
Sufficient quantities of SOF/VEL/VOX FDC tablets will be shipped to the investigator or 
qualified designee from Gilead Sciences Clinical Supply Management (or its designee).
5.2.3.
Storage and Handling
Both study drugs, SOF/VEL FDC and SOF/VEL/VOX FDC tablets, should be stored below 
30 °C(86 °F). Storage conditions are specified on the label.  Until dispensed to the subjects, all 
bottles of study drugs 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, study drugs
should not be stored in a container other than the container in which they are supplied. Keep the 
bottle tightly closed to protect from moisture.
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 and SOF/VEL/VOX
FDC tablets.
5.3.
Dosage and Administration of SOF/VEL FDC and SOF/VEL/VOX FDC
5.3.1.
Dosing and Administration of SOF/VEL FDC (Cohort 1)
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. 
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.


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Study drug should not be cut or split. SOF/VEL FDC tablets will be provided by Gilead Sciences 
for all subjects.
5.3.2.
Dosing and Administration of SOF/VEL/VOX FDC (Cohort 2) 
SOF/VEL/VOX FDC tablet is to be administered once daily with food. Each subject must be 
given instructions to maintain approximately the same daily dosing interval between study drug 
doses. 
If a subject does not take the SOF/VEL/VOX 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/VOX 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 eCRF 
(including all blood products). 
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment.  
a) Hematologic stimulating agents (eg, erythropoiesis-stimulating agents (ESAs); granulocyte
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)
b) Chronic use of systemic immunosuppressants including, but not limited to, corticosteroids
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal
antibodies (eg, infliximab)
c) Investigational agents or devices for any indication
Concomitant use of certain medications or herbal/natural supplements (such as inhibitors or 
moderate to strong inducers of drug transporters or metabolizing enzymes, eg, OATP, P-gp, 
CYP2B6, CYP2C8, or CYP3A) with the study drugs may result in pharmacokinetic interactions 
resulting in increases or decreases in exposure of the study drugs or these medications. 
Table 5-1 below contains examples of medications that are prohibited from 28 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.


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Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
(SOF/VEL FDC and 
SOF/VEL/VOX FDC, unless 
specified)
Use with Caution
Cohort 1
(SOF/VEL FDC)
Use with Caution 
Cohort 2 
(SOF/VEL/VOX FDC)
Acid Reducing Agents
Proton- Pump 
Inhibitorsa, H2-Receptor 
Antagonistsb, Antacidsc
Proton- Pump Inhibitorsa, 
H2-Receptor 
Antagonistsb, Antacidsc
Anticoagulants
Dabigatran Etexilated
Anticonvulsantse
Phenytoin, Carbamazepine, 
Phenobarbital
Antimycobacterialse
Rifampicin, Rifabutin, 
Rifapentineg
Cardiac Medicationsf
Amiodaroneg
Digoxinh
Digoxinh
Herbal/Natural 
Supplementse
St. John’s Wort, Echinacea, 
Milk thistle (i.e., silymarin), 
Chinese herb sho-saiko-to (or 
Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsi
Pitavastatin or Rosuvastatin
(Disallowed with 
SOF/VEL/VOX FDC)
Atorvastatinj,
Rosuvastatin (≤10 
mg/day) j
Atorvastatink, 
Fluvastatink, Lovastatink, 
Pravastatin (<40 
mg/day)j, Simvastatink
Immunosuppressants
Cyclosporine (Disallowed with 
SOF/VEL/VOX FDC)f
Other
Bosentanb, Modafinil b, 
Sulfasalazinec, , Methotrexatec
a
Proton pump inhibitors (PPIs) doses comparable with omeprazole 20mg can be administered with SOF/VEL FDC (when 
SOF/VEL FDC is administered with food) or with SOF/VEL/VOX FDC. The 28 day washout period does not apply to PPIs, 
which can be taken up to 7 days before Day 1
b
H2 receptor antagonists (H2RAs) must not exceed a dose of 40 mg famotidine or equivalent and can be taken 
simultaneously with SOF/VEL FDC or SOF/VEL/VOX FDC and/or staggered by 12 hours. The 28 day washout period 
does not apply to H2RAs, which can be taken up to 7 days before Day 1. 
c
Antacids that directly neutralize stomach acid may not be taken within 4 hours (before or after) of SOF/VEL FDC or 
SOF/VEL/VOX FDC administration.
d
Administration of SOF/VEL/VOX FDC with dabigatran etexilate results in increased concentrations of dabigatran. Clinical 
monitoring of dabigatran is recommended when coadministered with SOF/VEL/VOX FDC.  Refer to dabigatran etexilate 
prescribing information for dose modification recommendations in the setting of moderate renal impairment.
e
May result in a decrease in the concentration of study drugs.
f
May result in an increase in the concentration of study drugs and/or concomitant medications
g
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
h
Monitor for signs and symptoms of digoxin toxicity.
i
Use with SOF/VEL FDC of SOF/VEL/VOX FDC may result in increased concentrations of HMG CoA Reductase 
Inhibitors.  The 28 day washout period does not apply to HMG CoA Reductase Inhibitors, which can be taken up to the day 
before Day 1.
j
Monitor for signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis.
k
Coadministration with SOF/VEL/VOX FDC may increase the concentrations of atorvastatin, fluvastatin, lovastatin, and 
simvastatin.  Increased statin concentrations may increase the risk of myopathy, including rhabdomyolysis.  Use the lowest 
approved statin dose.  If higher doses are needed, use the lowest necessary statin dose based on a risk/benefit assessment.


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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 and 
SOF/VEL/VOX FDC 
The investigator or designee (i.e. pharmacist) is responsible for ensuring adequate accountability 
of all used and unused IMP. This includes acknowledgement of receipt of each shipment of IMP 
(quantity and condition). All used and unused IMP dispensed to subjects must be returned to the 
site.
SOF/VEL FDC and SOF/VEL/VOX 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 IMP kits.

Record the date, subject number and the IMP 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 and SOF/VELNOX FDC 
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6. 
STUDY PROCEDURES 
Final 
Amendment I 
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular fonn in Appendix 2 and described in the text that follows. 
The investigator must docmnent any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO). 
6.1. 
Subject Enrollment 
Entry into screening does not guarantee enrolhnent into the study. In order to manage the total 
trial enrolhnent, 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 the Day 1 visit to detennine eligibility for 
participation in the study. The Screening window can be extended up to 42 days in extenuating 
circumstances with sponsor approval. A single retest of screening labs is pennitted 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 circmnstance such as an intercurrent 
infection. 
The following will be perfonned and documented at screening: 
I 
• 
Detennine inclusion and exclusion eligibility 
• 
Obtain medical history (refer to Section 6.7.3), including: 
Hepatitis C treatment history, if applicable 
Regimen(s) 
Dates of previous treatment(s) 
Response to previous treatment 
o Nonresponder: Subject did not achieve m1detectable HCV RNA while on 
treatment. 
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○
Relapse/Breakthrough: Subject achieved undetectable HCV RNA during
treatment or within 4 weeks of the end of treatment, but did not achieve SVR
○
Discontinuation for any reason

Obtain details of prior and concomitant medications

Complete physical examination (refer to Section 6.7.4)

Obtain height and weight

Obtain vital signs (refer to Section 6.7.5)

Perform 12-Lead ECG (refer to Section 6.7.6)

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 for subjects with cirrhosis and within 6 months of Day 1
for subjects without cirrhosis.

Record any serious adverse events and all adverse events related to protocol mandated
procedures occurring after signing of the consent form.

Obtain blood samples for test:
Hematology
Chemistry
Coagulation tests
HCV RNA
HCV Genotype
HCV antibody, HIV antibody, HBV surface antigen (HBsAg), HBV surface antibody
(HBsAb), HBV core antibody (HBcAb)
HbA1c
Serum β-hCG pregnancy test for females of childbearing potential (refer to
Section 6.7.10)
Serum FSH (only for women of any age with amenorrhea of ≥ 12 months (refer to
Appendix 4)
Fibrotest® 


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
Obtain a Urine sample for:
Urinalysis
Urine drug screen
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 28 Days after screening for enrollment into the study. The Screening window can 
be extended up to 42 days in extenuating circumstances with sponsor approval.
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 6.7.4)

Obtain weight

Obtain vital signs (refer to Section 6.7.5)

Perform 12-Lead ECG (refer to Section 6.7.6)

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counseling

Obtain blood samples for tests:
Hematology
Chemistry
Coagulation tests


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HCV RNA
HCV resistance samples (refer to Section 6.7.8)
IL28B Genotype (refer to Section 6.7.11)

Obtain urine sample for:
Pregnancy test for females of childbearing potential only (refer to Section 6.7.10)
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

Observe the subject taking the first dose of study drug
Note: SOF/VEL/VOX FDC to be taken with food.
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, or qualified designee, 
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 6.7.5)

Perform 12 Lead ECG (refer to section 6.7.6)

Assessment of AEs and concomitant medications

Review of study drug adherence and 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 6.7.5)

Assessment of AEs and concomitant medications

Review of study drug adherence and dosing regimen including pill count


SOF/VEL FDC and SOF/VELNOX FDC 
Protocol GS-US-342-5532 
Gilead Sciences, Inc. 
• 
Obtain blood sample for tests: 
I 
Hematology 
Chemistry 
Coagulation tests 
HCVRNA 
HCV resistance samples 
HBV DNA Sample ( only for HBcAb positive subjects at Screening) 
Single PK (refer to Section 6.7.2.1) 
6.2.3. 
Weeks 4 and 8 (± 3 Days) 
Final 
Amendment I 
The following procedures/assessments are to be completed at the end of Week 4 and Week 8: 
• 
Obtain vital signs (refer to Section 6.7.5) 
• 
Assessment of AEs and concomitant medications 
• 
Review of study drug adherence and dosing regimen including pill com1t 
• 
Dispense study drug as directed by the IWRS (Week 4 only) 
• 
Obtain blood sample for tests: 
Hematology 
Chemistry 
Coagulation tests 
HCVRNA 
HCV resistance samples 
HBV DNA Sample ( only for HBcAb positive subjects at Screening) 
Single PK (refer to Section 6.7.2.1) 
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• 
Obtain urine sample for: 
Final 
Amendment I 
Pregnancy test for females of childbearing potential only (refer to Section 6. 7 .10) 
6.2.4. 
Week 12 (± 3 Days) 
The following procedures/assessments are to be completed at the end of Week 12: 
• 
Perfonn complete physical examination (see Section 6.7.4) 
• 
Obtain weight 
• 
Obtain vital signs (refer to Section 6.7.5) 
• 
Perfonn 12-Lead ECG (refer to section 6.7.6) 
• 
Assessment of AEs and concomitant medications 
• 
Conduct pregnancy prevention counseling 
• 
Review of study drug adherence and dosing regimen including pill count 
• 
Collect any remaining study drug from the subject 
• 
Obtain blood sample for tests: 
Hematology 
Chemistry 
Coagulation tests 
HCVRNA 
HCV resistance samples 
HBV DNA Sample ( only for HBcAb positive subjects at Screening) 
Single PK (refer to Section 6.7.2.1) 
• 
Obtain urine sample for: 
Pregnancy test for females of childbearing potential only (refer to Section 6. 7.10) 
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6.3.
Posttreatment Assessments
The posttreatment Weeks 4 and 12 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 6.7.5)

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counseling

Obtain blood samples for tests:
Hematology
Chemistry
HCV RNA
HCV resistance samples
HBV DNA Sample (only for HBcAb positive subjects at Screening)

Obtain urine sample for:
Pregnancy test for females of childbearing potential only (refer to Section 6.7.10)
6.3.2.
Posttreatment Week 12 (± 5 Days)
The following procedures/assessments are to be completed for all subjects, 12 weeks after taking 
the last dose of study drug:

Obtain weight

Obtain vital signs (refer to Section 6.7.5)

Obtain blood samples for tests:
Chemistry
HCV RNA


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HCV resistance samples
HBV DNA Sample (only for HBcAb positive subjects at Screening)
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 3.3, 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
For subjects who have completed an ET visit, the posttreatment Week 4 and 12 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:

Complete physical examination (refer to Section 6.7.4)

Obtain weight

Obtain vital signs (refer to Section 6.7.5)

Perform 12-Lead ECG (refer to Section 6.7.6)

Assessment of AEs and concomitant medications

Conduct pregnancy prevention counseling

Review of study drug adherence and dosing regimen including pill count

Collect any remaining study drug from the subject

Obtain blood samples for tests:
Hematology
Chemistry
Coagulation tests
HCV RNA
HCV resistance samples


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HBV DNA Sample (only for HBcAb positive subjects at Screening)
Single PK (refer to Section 6.7.2.1)

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: International Normalized Ratio (INR), Prothrombin time (PT), Activated partial 
thromboplastin time (aPTT)
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatine Kinase, Creatinine, 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 including HBsAb, HBsAg, or HBcAb. HBV 
DNA (reflex testing done when ALT > ULN or > Day 1 value in subjects who are 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, 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.


SOF/VEL FDC and SOF/VELNOX FDC 
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Amendment I 
IL28B genotype will be detennined 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 detennination should the above assay become m1available. 
Pregnancy Tests: Serum P-hCG or Urine P-hCG (if positive, requires immediate confinnation 
with Serum P-hCG) and serum FSH. 
6.7.2. 
6.7.2.1. 
Pharmacokinetic (PK) Sampling 
Single PK Samples 
Single PK blood samples will be collected for all subjects at Weeks 2, 4, 8, 12, and Early 
Tennination (if applicable) and archived for PK analysis of SOF (and its metabolites GS-566500 
and GS-331007), VEL, and VOX (as appropriate). The exact time the study drug was taken and 
whether or not the study drug was taken with food on PK assessment days will be recorded in the 
source docmnents and eCRF. 
-
6.7.3. 
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 
screenmg. 
6.7.4. 
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. 
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6.7.5. 
Vital Signs 
Final 
Amendment I 
Assessment of vital signs will include measurement ofresting 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 1mnHg mark on the manometer or to 
the nearest whole nmnber on an automatic device. 
6.7.6. 
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 abnonnalities. 
6.7.7. 
Creatinine Clearance 
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft 1976} using 
actual body weight (ABW). 
Male: 
Female: 
CLcr (mL/min) 
[140 - age (years)] x ABW(kg) 
72 X Ser 
CLer (mL/min) 
[140 - age (years)] x ABW(kg) x 0.85 
72 X Ser 
Ser 
serum creatinine (mg/dL) 
6.7.8. 
HCV Resistance Sample 
Plasma samples will be collected at Day 1 and at on-treatment visits at Weeks 2, 4, 8, and 12, 
Early Tennination (if applicable), and all posttreatment visits and may be archived for viral 
sequence anal sis. At an m1scheduled visit initiated for the purpose of 
· 
· 
· 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
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6.7.9.
HBV DNA Sample
A sample for HBV DNA testing will be collected only for HBcAb positive subjects at Screening
at on-treatment visits at Weeks 2, 4, 8 and 12 or early termination (if applicable) and 
posttreatment weeks 4 and 12. HBV DNA will only be tested when ALT > ULN or > Day 1 
value in these subjects.
6.7.10.
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 Week 4 and at 
Early Termination, 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.
6.7.11.
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 12 visit, 
regardless of treatment duration or early termination of study drug.
6.9.
Poststudy Care
No poststudy ongoing care will be provided.


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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


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately
life-threatening or result in death or hospitalization but may jeopardize the subject or may
require intervention to prevent one of the other outcomes constituting SAEs. Medical and
scientific judgment must be exercised to determine whether such an event is a reportable
under expedited reporting rules. Examples of medically important events include intensive
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or
convulsions that do not result in hospitalization; and development of drug dependency or
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal
product will be considered a medically important event and subject to expedited reporting
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (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 (i.e., 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
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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated
with laboratory abnormalities, the event should be graded on the basis of the clinical severity in
the context of the underlying conditions; this may or may not be in agreement with the grading
of the laboratory abnormality. 
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO:
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 after last administration of study IMP, and they 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 (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead Pharmacovigilance & Epidemiology (PVE) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead PVE.
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 authorization 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, i.e., 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.
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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations (CFR), the EU Clinical Trials Directive (2001/20/EC) and relevant updates, 
and other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Special Situations Reports
7.5.1.
Definitions of Special Situations
Special situation reports (SSR) 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).


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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 medication and throughout the study, including the post study drug follow-up 
period, to the or Gilead PVE using the pregnancy report form within 24 hours of becoming 
aware of the pregnancy. 
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (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 or 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 drugs 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.
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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, i.e., 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
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 and the eCRF completion guidelines for full instructions on the mechanism of 
special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are as follows:

To evaluate the antiviral efficacy of therapy with SOF/VEL FDC for 12 weeks and
SOF/VEL/VOX FDC for 12 weeks as measured by the proportion of subjects with 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 weeks after cessation of
treatment (SVR4)

To evaluate the proportion of subjects with virologic failure

To evaluate the emergence of viral resistance to SOF, VEL and VOX during treatment and
after cessation of treatment
8.1.2.
Primary Endpoint
The primary efficacy endpoint for the study is SVR12 (HCV RNA < LLOQ 12 weeks after 
discontinuation of study treatment) in the Full Analysis Set (FAS) population.  
The primary safety endpoint is any AE leading to permanent discontinuation of study drugs.  
8.1.3.
Secondary Endpoint
Secondary endpoints include the following:

The proportion of subjects with SVR4 (HCV RNA < LLOQ 4 weeks after discontinuation of
study treatment)

The proportion of subjects with virologic failure

The proportion of subjects with HCV RNA < LLOQ on treatment

HCV RNA change from baseline

ALT normalization


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8.2. 
Analysis Conventions 
Final 
Amendment I 
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be perfonned using SAS®software (SAS Institute, Cary, North Carolina, USA). 
The study drugs in this study include SOFNEL FDC and SOFNELNOX FDC. Last dose of 
study drug refers to the last dose of SOFNEL FDC (Cohort 1) or SOFNELNOX FDC (Cohort 
2) and will be used in the definition of treatment-emergent AEs and laboratory abnonnalities as 
well as the efficacy endpoints of SVR at various post treatment time points. 
8.2.1. 
8.2.1.1. 
Analysis Sets 
Efficacy 
The primary analysis set for efficacy analysis will be the FAS, which includes all enrolled 
subjects who took at least 1 dose of study drug. 
8.2.1.2. 
Safety 
The primary analysis set for safety analyses will be the Safety Analysis Set, which includes all 
subjects who took at least 1 dose of study drug. Treatment-emergent data will be analyzed and 
defined as data collected from the first dose of the study drug through the date of last dose of 
study drug plus 30 days. 
8.2.1.3. 
Phannacokinetics 
The PK Analysis Set will include all subjects who received at least 1 dose of study drug, and 
have at least 1 nomnissing postdose concentration value for the corresponding analyte in plasma. 
The analytes of interest may include SOF (and its metabolites GS-566500 and GS-331007), VEL 
or VOX where applicable. 
8.2.2. 
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. 
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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 tenned a bracketed success; otherwise, the data point will 
be tenned a bracketed failure (i.e., 
LLOQ detected). If a data point is missing and is not 
bracketed, the missing data point will also be tenned a failure (i.e., 
LLOQ detected). 
Where appropriate, safety data for subjects who did not complete the study will be included in 
summary statistics. For example, 
• If a subject took at least 1 dose of study drug, the subject will be included in a summary of 
AEs according to the treatment received; otherwise, if the subject is not dosed, then they will 
be excluded from the summary. 
• If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of 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 
smmnary 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 pre-treatment safety laboratory value 
is available, the baseline value will be assumed to be nonnal (i.e., no grade [Grade O]) in the 
smmnary of graded laboratory abnonnalities. 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 smmnary 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 transfonned to 
the logarithmic (base 10) scale (log,o IU/mL). 
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8.3. 
Demographic Data and Baseline Characteristics 
Final 
Amendment I 
Demographic and baseline characteristics will be smmnarized using standard descriptive 
methods by cohort. 
Demographic data will include sex, self-identified race/ethnicity, and age. 
Baseline characteristics data will include BMI, HCV RNA level (log,o IU/mL), genotype of 
HCV infection, IL28B genotype, and additional endpoints as necessary 
8.4. 
8.4.1. 
Efficacy Analysis 
Primary Analysis 
The primary efficacy endpoint for this study will be the proportion of subjects with SVR12 in all 
enrolled and treated subjects. The primary analysis will be perfonned after all enrolled subjects 
have been followed through 12 weeks posttreatment or discontinued from study. The point 
estimate with a 2-sided 95% exact confidence interval (CI) using the binomial distribution 
(Clopper-Pearson method) will be constructed for the SVR12 rate by cohort. No hypothesis 
testing will be perfonned. 
8.4.2. 
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 smmnaries and listings will be provided for additional efficacy evaluations of the 
proportion of subjects who experience virologic failure, ALT nonnalization, sermn HCV RNA 
actual values and change from baseline. Continuous endpoints will be smmnarized using an 8-
number smmnary (n, mean, standard deviation [SD], median, Ql, Q3, minimum, and maximum) 
by cohort. Categorical endpoints will be smmnarized by number and percentage of subjects who 
meet the endpoint definition by cohort. 
Details on efficacy analyses will be described in the statistical analysis plan. 
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8.5.
Safety Analysis
Safety endpoints will be evaluated by assessment of clinical laboratory tests, physical 
examinations, vital signs measurements at various time points during the study, and by 
documentation of AEs. 
All safety data collected on or after the first dose of study drug administration and up to 30 days 
after the last dose of study drug will be summarized by cohort.
8.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the eCRF. Exposure data will be summarized by cohort. 
8.5.2.
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) coding 
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 
AE will be defined as any AE with an onset date on or after the date of first dose of study drug 
and no later than 30 days after permanent discontinuation of the study drug; or any AE leading to 
premature discontinuation of study drug.
Summaries (number and percentage of subjects) of treatment-emergent AEs (by SOC and PT) 
will be provided by cohort:

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 study drug

AEs leading to interruption of study drug
All AEs collected during the course of the study will be presented in data listings.


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8.5.3. 
Laboratory Evaluations 
Final 
Amendment I 
Selected laboratory data will be smmnarized (n, mean, SD, median, Ql, Q3, minimmn, and 
maximmn) by cohort and study visit along with the corresponding change from baseline. 
Graded laboratory abnonnalities will be defined using the laboratory toxicity grading scheme in 
Appendix 3. The incidence of treatment-emergent laboratory abnonnalities, defined as values 
that increase by at least one toxicity grade from baseline at any time postbaseline, up to the date 
of last dose of study drug plus 30 days will be smnmarized by cohort. 
All laboratory abnonnalities will be included in the listings of laboratory data. 
8.5.4. 
Other Safety Evaluations 
Individual data for 12-lead ECG and vital sign measurements will be listed by subject and 
summarized for each cohort and visit by incidence of events/abnonnalities or by descriptive 
statistical smmnaries (n, mean, SD, median, Ql, Q3, minimmn, and maximmn), for continuous 
data by cohort, as appropriate. 
8.6. 
Pharmacokinetic Analysis 
In the PK analysis set, concentrations of SOF, its metabolites GS-566500 and GS-331007, VEL, 
and VOX (as applicable) in plasma will be detennined using validated bioanalytical assays and 
listed. Details of the analyses will be provided in the phannacokinetic reporting and analysis 
plan. 
8.7. 
Sample Size 
For Cohort 1, with approximately 50 subjects enrolled into the study, the 2-sided 95% exact CI 
using the bino1nial distribution (Clopper-Pearson method) of the SVR12 rate will be from 86.3% 
to 99.5%, assmning the expected SVR12 rate is 95%. 
For Cohort 2, with approximately 30 subjects enrolled into the study, the 2-sided 95% exact CI 
using the bino1nial distribution (Clopper-Pearson method) of the SVR12 rate will be from 82.8% 
to 99.9%, assmning the expected SVR12 rate is 95%. 
8.8. 
Data Monitoring Committee 
No data monitoring committee will be used in this study. 
8.9. 
Endpoint Adjudication Committee 
No Adjudication com1nittee will be used in this study. 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with ICH E6(R2) Good 
Clinical Practices and applicable laws and regulations.
9.1.2.
Financial Disclosure
The investigator and sub-investigators 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 sub-investigator’s) 
participation in the study. The investigator and sub-investigator 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 (ICF), 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 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 
conducting the consent discussion, and also by an impartial witness if required by IRB/IEC or 
local requirements. 


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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, i.e., history, physical examination, and
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled;

Participation in study (including study number);

Study discussed and date of informed consent;


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
Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (i.e., 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 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 captures the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 


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investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (e.g., data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 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 QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.9.
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
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 approval before modifications 
can be implemented.


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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent
of Gilead in an abstract, manuscript, or presentation form or the study has been completed at
all study sites for at least 2 years.

The investigator will submit to Gilead any proposed publication or presentation along with
the respective scientific journal or presentation forum at least 30 days before submission of
the publication or presentation.

No such communication, presentation, or publication will include Gilead’s confidential
information (see Section 9.1.5).
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, e.g., attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them.  The monitor should have access to any subject records needed to 


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verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study.  If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately.  The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time.  Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Hwang JS. A Report: HCC (Hepatocellular Carcinoma) Random Registration Project [Korean]. 
Available at: 
http://www.kasl.org/bbs/skin/guide/download.php?code ency&number 8529.  
2010.
Kim DY, Kim IH, Jeong SH, Cho YK, Lee JH, Jin YJ, et al. A Nationwide Seroepidemiology of 
Hepatitis C Virus Infection in South Korea. Liver Int 2013;33:586-94.
Kwon JH, Song MJ, Jang JW, Bae SH, Choi JY, Yoon SK, et al. Efficacy and Safety of 
Tenofovir Disoproxil Fumarate in Treatment-Naive Patients with Chronic 
Hepatitis B in Korea. Dig Dis Sci 2019.
Lim YS. Current status of liver disease in Korea: hepatitis C. The Korean journal of hepatology 
2009;15 Suppl 6:S25-8.
Shin HR. Epidemiology of hepatitis C virus in Korea. Intervirology 2006;49 (1-2):18-22.
Suh DJ, Jeong SH. Current status of hepatitis C virus infection in Korea. Intervirology 2006;49 
(1-2):70-5.
The Korean Association for the Study of the Liver (KASL). 2017 KASL Clinical Practice 
Guidelines Management of Hepatitis C: Treatment of Chronic Hepatitis C. 
Clinical and Molecular Hepatology 2018;24 (3):169-229.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


SOFN EL FDC and SOFN EUVOX FDC 
Protocol GS-US-342-5532 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment I 
A Phase 3b Multicenter, Open-Label Study to Investigate the Efficacy and Safety of 
SofosbuvirNelpatasvir Fixed-Dose Combination and SofosbuvirN elpatasvirN oxilaprevir Fixed-
Dose Combination for 12 Weeks in Subjects with Chronic HCV Infection 
GS-US-342-5532, Original Protocol, 04 October 2019 
This protocol has been approved by Gilead. The following signature documents this approval. 
PD 
PD 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary details for me 
and my staff to conduct this study as described. I will conduct this study as outlined herein and will make 
a reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead. I will discuss this material with them to ensure that they are fully 
informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
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Appendix 2.
Study Procedures Table
Screening
Day 1a
Treatment Week
(3 days)
Posttreatment Week 
(5 days)
1
2
4
8
12/ETb
4
12
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
Height
X
Weight
X
X
X
X
Vital Signsc
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 
X
X
X
X
X
X
X
Chemistry 
X
X
X
X
X
X
X
X
Coagulation (PT, aPTT and INR)
X
X
X
X
X
X
Urinalysis, Urine drug screen
X
HCV RNA
X
X
X
X
X
X
X
X


SOF/VEL FDC and SOF/VELNOX FDC 
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Amendment I 
Gilead Sciences, Inc. 
a 
b 
C 
d 
e 
f 
g 
h 
k 
HCV resistance samples 
HBV DNA Sample; 
Single PK 
Semm or Urine PregnancyTesti 
Semm FSJ-lk 
HCV Genotyping 
IL28B Genotype 
HCV Ab, HIV Ab, 1-IBsAg, HBsAb, 
HBcAb 
HbA lc 
Fi bro Test® 
Screening 
X 
X 
X 
X 
X 
X 
Day I assessments must be perfom1ed prior to dosing. 
ET 
early tem1ination. 
Day t• 
X 
X 
X 
Vital signs include resting blood pressure, pulse, respiratory rate and temperature. 
1 
2 
X 
X 
X 
Treatment Week 
Posttreatment Week 
(±3 days) 
(±5 days) 
4 
8 
12/ETb 
4 
12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subjects will be re.quired to rest in a supine position for 2:: 5 minutes prior to making a recording. The investigator (or qualified designee) should review the ECG traces 
recorded in real time for clinically significant abnom1alities. 
Adverse events and Concomitant Medications will be collected up to 30 days after the last dose of all study dmgs. 
Liver imaging (eg, ultrasound or CT scan, at the discretion of the investigator) should be perfom1ed to exclude the presence ofhepatocellular carcinoma (HCC) within 
4 months of Day I for subjects with cirrhosis, and within 6 months of Day I for subjects without cirrhosis. 
Study dmgs will be reconciled at every post Day I visit by the investigator in order to monitor the subject's adherence with the study dmgs. Subjects must be instmcted to 
bring back all bottles of study dmgs in the original container at every post Day I visit through the end of treatment. 
The IWRS will provide direction on the specifics of each subject's study dmg dispensing. 
Sample only to be collected for 1-IBcAb positive subjects at Screening. Reflex testing done only when ALT > ULN or > Day I value in these subjects. 
All females of childbearing potential will have a semm pregnancy test at Screening. Urine pregnancy testing will occur at Day I 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 instmcted to return to the clinic as soon as possible for a semm pregnancy 
test. 
r 
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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 
Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 
Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 
≥ 7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN
1.50 to 3.00 ULN
3.00 ULN


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%
# An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L
2.0 t o <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Infant <1 Year
>ULN to 6.0 mEq/L
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL
1.51 to < 1.74 mmolL
< 6.1 mg/dL
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L


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Protocol GS-US-342-5532 
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 71
04 October 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
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


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Protocol GS-US-342-5532 
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 72
04 October 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN
1.5 to 2.5 ULN
2.5 to 5.0 ULN
5.0 ULN
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL
10.0 to 12.0 mg/dL
12.0 to 15.0 mg/dL
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L


SOF/VEL FDC and SOF/VEL/VOX FDC
Protocol GS-US-342-5532 
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 73
04 October 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
** An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention
of grading any result within the LLN and ULN a 0.  


SOF/VEL FDC and SOF/VEL/VOX FDC
Protocol GS-US-342-5532 
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 74
04 October 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 and SOF/VEL/VOX FDC
Protocol GS-US-342-5532 
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 75
04 October 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 and SOF/VEL/VOX FDC
Protocol GS-US-342-5532 
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 76
04 October 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


SOF/VEL FDC and SOF/VEL/VOX FDC
Protocol GS-US-342-5532 
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Gilead Sciences, Inc.
Amendment 1
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV
block
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc 
interval 0.50 sec OR 
Increase in interval 
0.06 sec above baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc 
interval 0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(eg, anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode 
(associated with a procedure 
of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening 
symptomatic CHF
Life-threatening CHF


SOF/VEL FDC and SOF/VEL/VOX FDC
Protocol GS-US-342-5532 
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak 
flow 25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal 
interference with usual social & 
functional activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities OR Pulse 
oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis 
OR Medical intervention 
indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional 
activities
Disabling visual loss in affected 
eye(s)


SOF/VEL FDC and SOF/VEL/VOX FDC
Protocol GS-US-342-5532 
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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04 October 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 and SOF/VEL/VOX FDC
Protocol GS-US-342-5532 
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 80
04 October 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


SOF/VEL FDC and SOF/VEL/VOX FDC
Protocol GS-US-342-5532 
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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04 October 2019
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal 
bleeding OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference 
with oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening 
consequences (eg, 
hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences (eg, sepsis, 
circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
OR Medical intervention 
indicated 
Symptoms causing inability to 
perform usual social/
functional activities OR 
Operative intervention 
indicated 
Life-threatening 
consequences (eg, 
perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening 
consequences (eg, 
hypotensive shock)


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


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


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


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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic self-
care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional 
activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0
BMD t-score or z-score –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing 
inability to perform usual 
social & functional 
activities
Disabling muscle pain 
causing inability to perform 
basic self-care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain 
with radiographic findings 
OR Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-
care functions


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


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


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


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


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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 of 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. 
Data from clinical pharmacokinetic interaction studies of SOF/VEL/VOX have demonstrated 
that there is no reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity 
studies of VOX have demonstrated no adverse effect on fertility or embryo-fetal development. 
However, the risks of treatment with SOF/VEL FDC or SOF/VEL/VOX FDC during pregnancy 
in humans have not been evaluated. Please refer to the latest version of the Investigator’s 
Brochures for additional information.


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b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable 
effective contraceptive measure. They must have a negative serum pregnancy test at Screening 
and a negative pregnancy test on the Day 1 visit prior to first dose of drug.  Pregnancy tests will 
be performed every 4 weeks throughout duration of trial up until and including the 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 or 
SOF/VEL/VOX FDC.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable
method of contraception only when it is in line with the subject’s preferred and usual
lifestyle.
Or

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 or SOF/VEL/VOX 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)
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
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring


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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 or SOF/VEL/VOX 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 or SOF/VEL/VOX 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 or 
SOF/VEL/VOX FDC.
Male subjects must also refrain from sperm donation during treatment and until at least 30 days 
after the last dose of SOF/VEL FDC or SOF/VEL/VOX FDC.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM).  Female condom and male 
condom should not be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of 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.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3b Multicenter, Open-Label Study to Investigate the
Efficacy and Safety of Sofosbuvir/Velpatasvir Fixed-Dose
Combination and Sofosbuvir/Velpatasvir/Voxilaprevir 
Fixed-Dose Combination for 12 Weeks in Subjects with 
Chronic HCV Infection
Name of Test Drug:
SOF/VEL FDC and SOF/VEL/VOX FDC
Study Number:
GS-US-342-5532
Protocol Version (Date):
Amendment 1: 04 Oct 2019
Analysis Type:
Final analysis
Analysis Plan Version:
1.0
Analysis Plan Date:
10 December 2020
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(fJ GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TABLES...................................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
PHARMACOKINETIC ABBREVIATIONS................................................................................................................5
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.
Final Analysis ..........................................................................................................................................8
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES..............................................................................9
3.1.
Analysis Sets............................................................................................................................................9
3.1.1.
All Enrolled Analysis Set.......................................................................................................9
3.1.2.
Full Analysis Set ....................................................................................................................9
3.1.3.
Safety Analysis Set.................................................................................................................9
3.1.4.
Pharmacokinetic (PK) Analysis Set .......................................................................................9
3.2.
Subject Grouping ...................................................................................................................................10
3.3.
Examination of Subject Subgroups........................................................................................................10
3.4.
Multiple Comparisons............................................................................................................................11
3.5.
Missing Data and Outliers......................................................................................................................11
3.5.1.
Missing Data ........................................................................................................................11
3.5.2.
Outliers.................................................................................................................................12
3.6.
Data Handling Conventions and Transformations .................................................................................12
3.7.
Analysis Visit Windows.........................................................................................................................13
3.7.1.
Definition of Study Day .......................................................................................................13
3.7.2.
Analysis Windows................................................................................................................14
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................15
4.
SUBJECT DISPOSITION ..................................................................................................................................16
4.1.
Subject Enrollment and Disposition.......................................................................................................16
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................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..........................................................................................................18
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
CCI-


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6.1.
Primary Efficacy Endpoint.....................................................................................................................22
6.1.1.
Definition of the Primary Efficacy Endpoint .......................................................................22
6.1.2.
Primary Analysis of the Primary Efficacy Endpoint ............................................................22
6.1.3.
Subgroup Analysis of the Primary Efficacy Endpoint .........................................................22
6.2.
Secondary Efficacy Endpoints ...............................................................................................................22
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................22
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................23
6.3.
Changes From Protocol-Specified Efficacy Analyses............................................................................24
7.
SAFETY ANALYSES........................................................................................................................................25
7.1.
Adverse Events and Deaths....................................................................................................................25
7.1.1.
Adverse Event Dictionary ....................................................................................................25
7.1.2.
Adverse Event Severity........................................................................................................25
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................25
7.1.4.
Serious Adverse Events........................................................................................................25
7.1.5.
Treatment-Emergent Adverse Events...................................................................................25
7.1.5.1.
Definition of Treatment-Emergent Adverse Events .......................................25
7.1.5.2.
Incomplete Dates ............................................................................................26
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................26
7.2.
Laboratory Evaluations ..........................................................................................................................27
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................28
7.2.2.
Graded Laboratory Values ...................................................................................................28
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities.............................................29
7.2.2.2.
Summaries of Laboratory Abnormalities........................................................29
7.3.
Body Weight, Height, and Vital Signs...................................................................................................29
7.4.
Prior and Concomitant Medications.......................................................................................................30
7.5.
Electrocardiogram Results .....................................................................................................................30
7.6.
Other Safety Measures ...........................................................................................................................31
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................31
8.
PHARMACOKINETIC ANALYSES ................................................................................................................32
8.1.
Pharmacokinetic Sample Collection ......................................................................................................32
8.3.
Population PK Analysis .........................................................................................................................32
9.
REFERENCES ...................................................................................................................................................34
10.
SOFTWARE.......................................................................................................................................................35
11.
SAP REVISION..................................................................................................................................................36
12.
APPENDICES ....................................................................................................................................................37
LIST OF IN-TABLES
Table 1.
Analysis Windows for On-treatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................14
Table 2.
Analysis Windows for Posttreatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................14
Table 3.
Analysis Windows for On-treatment ECG Data.....................................................................15
Table 4.
Examples of search terms for “COVID-19” and “Virtual” used to identify missed 
and virtual visits. ....................................................................................................................40
Table 5.
Examples of extraneous text terms to eliminate from the comment fields.............................40
CCI


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
COVID-19
Coronavirus disease 2019
CSR
clinical study report
DAA
Direct-acting antiviral
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
FAS
Full Analysis Set
FU
follow up
Hb
hemoglobin
HLT
high-level term
IFN
interferon
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
NLP
natual language processing
PT
preferred term
Q1, Q3
first quartile, third quartile
RBV
ribavirin
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SI (units)
international system of units
SOC
system organ class
SOF
Sofosbuvir (Sovaldi®)
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
VOX
Voxilaprevir
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCtau
area under the concentration versus time curve over the dosing interval
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf, where “Dose” is the dose of the drug
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Cmin
minimum observed concentration of drug
Ctau
observed drug concentration at the end of the dosing interval
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 
2 by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-342-5532. This SAP is based on the study protocol amendment 1 dated 
04 October 2019 and the electronic case report form (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR.
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate the antiviral efficacy of therapy with sofosbuvir/velpatasvir (SOF/VEL) 
fixed-dose combination (FDC) for 12 weeks and sofosbuvir/velpatasvir/voxilaprevir 
(SOF/VEL/VOX) 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 weeks after cessation of 
treatment (SVR4)

To evaluate the proportion of subjects with virologic failure

To evaluate the emergence of viral resistance to SOF, VEL and VOX during treatment and 
after cessation of treatment
1.2.
Study Design
This is a multicenter, open-label study in approximately 80 subjects with chronic HCV infection.
Cohort 1: Approximately 50 subjects with chronic HCV infection, genotype 1 or 2, will be 
enrolled and treated with SOF/VEL FDC for 12 weeks. Subjects may be treatment-naïve or 
treatment-experienced with IFN-based treatments.
Cohort 2: Approximately 30 subjects with chronic HCV infection, genotype 1, will be enrolled 
and treated with SOF/VEL/VOX FDC for 12 weeks. Subjects will be treatment-experienced with 
NS5A DAA-based treatments.


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The total time to complete all study visits is approximately 28 weeks (30 weeks for those 
requiring an extension to 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

12 weeks posttreatment period
The schedule of assessment is provided as an appendix to the SAP (Appendix 1).
1.3.
Sample Size and Power
For Cohort 1, with approximately 50 subjects enrolled into the study, the 2-sided 95% exact 
confidence interval (CI) using the binomial distribution (Clopper-Pearson method) of the SVR12 
rate will be from 86.3% to 99.5%, assuming the expected SVR12 rate is 95%.
For Cohort 2, with approximately 30 subjects enrolled into the study, the 2-sided 95% exact CI 
using the binomial distribution (Clopper-Pearson method) of the SVR12 rate will be from 82.8% 
to 99.9%, assuming the expected SVR12 rate is 95%.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee
This study does not have a data monitoring committee (DMC).
2.2.
Final Analysis
The analysis for the primary efficacy endpoint SVR12 will be conducted when all subjects have 
completed the posttreatment Week 12 visit or have prematurely discontinued from study. All the 
safety and efficacy data through the Posttreatment Week 12 visit will be cleaned, finalized and 
included for the analysis.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard error (SE), median, 
first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the Safety Analysis Set and sorted by 
unique subject ID number (including site ID and 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
and had detectable HCV RNA at baseline. This definition is modified from the definition of FAS 
specified in the protocol, in order to exclude any subject with undetectable HCV RNA at 
baseline from efficacy analyses (see Section 6.3). The study drugs in this study include 
SOF/VEL FDC (Cohort 1) and SOF/VEL/VOX FDC (Cohort 2).
This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. This is the 
primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic (PK) Analysis Set
The PK Analysis Set will include all enrolled subjects who took at least 1 dose of study drug and 
have at least 1 nonmissing concentration value for the corresponding analyte in plasma. This is 
the primary analysis set for all PK analyses. The analytes of interest may include SOF (and its 
metabolites GS-566500 and GS-331007), VEL or VOX where applicable. Within the PK
Analysis Set, those subjects with PK exposure data successfully derived from the population PK 
modeling will be included in the analyses related to PK exposure.


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3.2. 
Subject Grouping 
Version 1.0 
Generally speaking, the efficacy analyses will be perfonned on FAS by treatment group. 
Subjects will be grouped according to the HCV genotype (GT 1 a, GT 1 b, GT 1 total, and GT2) as 
recorded in the clinical database and overall within each treatment group. The safety analyses 
will be perfonned on the Safety Analysis Set by treatment group according to the actual 
treatment that the subjects received. 
For selected analyses, for example, the summary of demographics and baseline characteristics 
and the primary analysis of the primary endpoint, please refer to the relevant sections for the 
detailed description of subject grouping. 
3.3. 
Examination of Subject Subgroups 
Subject subsets within each genotype will also be explored by baseline characteristics for the 
primary efficacy endpoint, SVR12. The baseline characteristics include the following: 
• 
age(< 65 years,~ 65 years) 
• 
sex (male, female) 
• 
Race 
• 
Ethnicity 
• 
baseline body mass index (BMI) (< 30 kg/m2, 
30 kg/m2; < 25 kg/m2, 
25 kg/m2) 
• 
cirrhosis (presence, absence) 
• 
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) (:S 1.5 x upper limit of nonnal (ULN), 
> 1.5 x ULN) 
• 
prior HCV treatment experience (SOFNEL 12 Weeks: treatment naive, treatment 
experienced; SOFNELNOX 12 Weeks: treatment experienced) 
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
prior HCV treatment for treatment experienced subjects (SOF/VEL 12 Weeks: direct acting 
antiviral [DAA] + pegylated interferon [Peg-IFN] + ribavirin [RBV], Peg-IFN + RBV,
Other; SOF/VEL/VOX 12 Weeks: NS5A +/- DAA[s] and Other[s]; with NS5A +/- DAA[s] 
further broken down to NS5A + NS5B, NS5A + NS3 +/- NS5B, and NS5A +/- Other[s])

Response to prior HCV treatment (non-responder , relapse/breakthrough, early treatment 
discontinuation, met a virologic stopping rule not otherwise listed, and unknown) for 
treatment experienced subjects

adherence to study regimen (< 80%, ≥ 80%)

study treatment status (completed study treatment, discontinued study treatment)
3.4.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
3.5.
Missing Data and Outliers
3.5.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 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.
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have missing data imputed up to the 
time of the last dose (for on-treatment displays). If the study day associated with the last dosing 
date of any study drug is greater than or equal to the lower bound of a visit window, and the 
value at the visit is missing, then the value will be imputed. If the study day associated with the 
last dosing date is less than the lower bound of a visit window then the on-treatment value at that 
visit will remain missing. 
If a HCV RNA data point is missing and is preceded and followed in time by values that are 
“< lower limit of quantification (LLOQ) target not detected (TND),” then the missing data point 
will be set to “< LLOQ TND.” If a data point is missing and preceded and followed by values 
that are “< LLOQ detected,” or preceded by “< LLOQ detected” and followed by 
“< LLOQ TND,” or preceded by “< LLOQ TND” and followed by “< LLOQ detected,” then the 
missing value will be set to “< LLOQ detected.” In these situations the data point will be termed 
a bracketed success; otherwise, the data point will be termed a bracketed failure 
(ie, ≥LLOQ detected). If a data point is missing and is not bracketed, the missing data point will 
also be termed a failure (ie, ≥LLOQ detected).


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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 
unique subject ID number, visit date, and time (if applicable) unless otherwise specified. Data 
collected on log forms, such as AEs, will be presented in chronological order within subject. 
Age (in years) on the date of the first dose of study drug and sex at birth will be used for analyses 
and presentation in listings.
If a subject was not dosed with study drug at all, then the date the informed consent was signed 
will be used instead of the first dose date of study drug. 
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ)
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate 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 to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate 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 to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).
COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, v2.0 will be used to determine 
HCV RNA results in this study. The lower limit of quantitation (LLOQ) of the assay is 
15 IU/mL.
When the calculated HCV RNA value is within the linear range of the assay, then the result will 
be reported as the “<< numeric value>> IU/mL.” This result will be referred to in this document 
as the numeric result or as “≥ LLOQ detected” for categorical result.
When HCV RNA is not detected, the result is reported as “No HCV RNA detected” or “target 
not detected”. This result will be referred to in this document as “< LLOQ target not detected” or 
“< LLOQ TND.”


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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." 
Version 1.0 
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 transfonned to the logarithmic (base 10) 
scale (log10 IU/mL). 
3.7. 
Analysis Visit Windows 
3.7.1. 
Definition of Study Day 
Study day will be calculated from the first dosing date of study drug 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 
Therefore, study day 1 is the day of first dose of study drug administration. 
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The last dose date will be the end date on study drug administration eCRF for the record where 
the “subject permanently discontinued” flag is ‘Y’. The last dose date will be defined as the 
maximum of the last dose dates of the study drugs. If there are subjects for whom the date of 
last 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 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 Windows for On-treatment HCV RNA, Vital Signs and 
Safety Laboratory Data
Nominal Visit
Vital Signs
HCV RNA and Safety Laboratory Data
Nominal Day
Lower Limit
Upper Limit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
1
(none)
1
Week 1
7
2
11
NA
NA
NA
Week 2
14
12
21
14
2
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
HCV RNA, vital sign, and safety laboratory data collected after the last dose date + 3 days will 
be assigned to the posttreatment follow-up (FU) visits. Visit windows will be calculated from the 
last dose date (ie, FU Day  collection date minus the last dose date) as shown in Table 2.
Table 2.
Analysis Windows for Posttreatment HCV RNA, Vital Signs and 
Safety Laboratory Data
Nominal 
FUa Visit
HCV RNA
Vital Signs and Safety Laboratory Data b
Nominal FU Day
Lower Limit
Upper Limit
Nominal FU 
Day
Lower Limit
Upper Limit
FU 4
28
21
69
28
4
30
FU 12
84
70
146
NA
NA
NA
a
FU x visit  posttreatment Week x follow up visit.
b
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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 based on the 
visit windows as shown in Table 3.
Table 3.
Analysis Windows for On-treatment ECG Data
Nomial Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 1
7
2
45
Week 12
84
46
87
Note: ECGs are to be collected at screening, baseline, Week 1, and Week 12 or Early Termination. For purposes of analysis,
baseline will be the last available value prior to first dose.
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 nonmissing value on or prior to the first dosing date of study drug will 
be selected, unless specified differently. If there are multiple records with the same time or 
no time recorded on the same day, the baseline value will be the average of the 
measurements for continuous data, or the measurement with the lowest severity (eg, normal 
will be selected over abnormal for safety ECG findings) for categorical data.

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 for 
continuous data and the worse severity will be taken for categorical data, unless 
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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by treatment group for each investigator. For 
each treatment group, the summary will present the number and percentage of subjects in the 
Safety Analysis Set. The denominator for the percentage calculation will be the total number of 
subjects analyzed for that column.
A summary of subject disposition will be provided by genotype and overall for each treatment 
group. This summary will present the number of subjects screened, the number of subjects 
enrolled, the number of subjects not enrolled, the number of subjects enrolled but never treated, 
and the number of subjects in each of the categories listed below.

In Safety Analysis Set

In Full Analysis Set

In PK Analysis Set

Completed study treatment

Did not complete study treatment with reasons for premature discontinuation of study 
treatment

Completed study

Did not complete the study with reasons for premature discontinuation of study
Among subjects who completed study treatment or discontinued study treatment, the number and 
percentage of subjects will be summarized for the following:

Subjects who had no HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 
Assessment and thereafter)

Subjects who had HCV posttreatment Week 4 assessment but no HCV posttreatment 
Week 12 and thereafter (With HCV FU-4 but No FU-12 and thereafter)
If a subject did not have any HCV RNA assessment ≥ 21 days after the last dose of any study 
drug (ie, lower bound of FU-4 visit for HCV RNA data), the subject is categorized as having 
“No HCV FU-4 and thereafter.” If a subject had the HCV FU-4 assessment but did not have any 
HCV RNA assessment ≥ 70 days after the last dose of any study drug (ie, lower bound of 
FU-12 visit for HCV RNA data), the subject is categorized as having “With HCV FU-4 but No 
FU-12 and thereafter.”
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In addition, the total number of subjects who were enrolled, and the number of subjects in each 
of the disposition categories will be depicted by a flowchart.
The following by-subject listings will be provided by unique subject ID number in ascending 
order to support the above summary tables:

Subjects Who Received Study Drug from Specific Batches

Subject disposition
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence relative 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 dosing date minus first dosing 
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
(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), and Week 12 (Day 84). A 3-day window is applied to the last planned 
on-treatment visit to match with the protocol-specified visit window, ie number of subjects 
exposed through Week 12 will be calculated as the number of subjects who were exposed to 
study drug for at least 81 days. Summaries will be provided for the Safety Analysis Set by HCV 
genotype and treatment group. 
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. 
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


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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) or SOF/VEL/VOX (400/100/100 mg) 
prescribed for 12 weeks would require 84 tablets.
Subjects who prematurely discontinue study drug for lack of efficacy (ie, virologic failure) will 
have the total amount of study drug prescribed calculated up to the first date when virologic 
failure criteria were met. For virologic failure confirmed by 2 consecutive measurements, the 
date of the first measurement will be used. If study drug bottles are dispensed on or after the 
subject first met virologic failure criteria, these bottles will not be included in the calculation of 
adherence. If a bottle is dispensed and the bottle is returned empty, then the number of tablets 
returned will be entered as zero. If a bottle is dispensed but not returned (missing), the number of 
tablets taken from that bottle will be counted as zero. 
Descriptive statistics for the level of adherence (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) with the number and percentage of subjects belonging to adherence categories 
(eg, < 80%, ≥ 80 to < 90%, ≥ 90%, at least 80% adherence to study drug) will be provided by 
treatment group for the Safety Analysis Set. 
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 unique 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 by 
treatment group 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 (e.g., eligibility criteria, informed consent) will be summarized by treatment 
group for the All Enrolled Analysis Set. A by-subject listing will be provided for those subjects 
with important protocol deviation. 
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.


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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.
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.
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 unique 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 detailed 
explanation of the algorithm is given in Appendix 2.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, and ethnicity) and baseline characteristics 
(body weight [in kg], height [in cm], body mass index [BMI; in kg/m2]) will be summarized by 
HCV genotype and total for each treatment group. Age, body weight, and height will be 
summarized by descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum). 
Age categories (< 65 years, ≥65 years), sex, race, and ethnicity will be summarized by the 
numbers and percentages of subjects. Age will be calculated in years at the date of the first dose 
of study drug. If a subject did not receive study drug after enrollment, the subject’s age will be
calculated from the date that the subject signed the informed consent form. The summary of 
demographic data will be provided for the Safety Analysis Set.
A by-subject demographic listing, which includes first dose date, will be provided by unique 
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include:

cirrhosis (presence, absence)

IL28B (CC, non-CC; with non-CC further broken down to CT, TT)

baseline HCV RNA 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 (SOF/VEL 12 Weeks: treatment naive, treatment 
experienced; SOF/VEL/VOX 12 Weeks: treatment experienced)

prior HCV treatment for treatment experienced subjects (Cohort 1: direct acting antiviral 
[DAA] + pegylated interferon [Peg-IFN] + ribavirin [RBV], Peg-IFN + RBV, Other[s]; 
Cohort 2: NS5A +/- DAA[s] and Other[s]; with NS5A +/- DAA[s] further broken down to 
NS5A + NS5B, NS5A + NS3 +/- NS5B, and NS5A +/- Other[s])

prior HCV treatment response (non-responder , relapse/breakthrough, early treatment 
discontinuation, met a virologic stopping rule not otherwise listed, and unknown) for 
treatment experienced subjects

estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault equation as a 
continuous variable and as categories (< 90 mL/min, ≥ 90 mL/min)

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.


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These baseline characteristics will be summarized by HCV genotype and total for each treatment 
group. Continuous variables will be summarized using descriptive statistics (n, mean, SD, 
median, Q1, Q3, minimum, and maximum) and categorical variables using the numbers and 
percentages of subjects. 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 unique 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 all subjects at 
screening.
A separate by-subject data listing for prior HCV treatment and response will be provided for all 
treatment experienced subjects. The listing will display the prior HCV regimen(s) and 
treatment(s) including the treatment duration, and the prior HCV treatment response.
5.3.
Medical History
General medical history data will be collected at screening and a by-subject listing will be 
provided for Safety Analysis Set. 


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint is SVR12 defined as HCV RNA < LLOQ 12 weeks after 
discontinuation of study drug in the FAS population. The COBAS® AmpliPrep/COBAS®
TaqMan® HCV Quantitative Test, v2.0 will be used to measure HCV RNA. The LLOQ for this 
assay is 15 IU/mL.
6.1.2.
Primary Analysis of the Primary Efficacy Endpoint
For each treatment group, the point estimate of SVR12 and the 2-sided 95% exact CI based on
the Clopper-Pearson method {Clopper 1934} will be provided by HCV genotype and overall.
6.1.3.
Subgroup Analysis of the Primary Efficacy Endpoint
For each treatment group, the point estimates and the 2-sided 95% exact CIs based on the 
Clopper-Pearson method will be provided for the SVR12 rates by HCV genotype and overall for 
each subgroup outlined in Section 3.3.
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 outlined in Section 3.3. for each 
treatment group.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include the following:

The proportion of subjects with SVR4 (HCV RNA < LLOQ 4 weeks after discontinuation of 
study treatment)

The proportion of subjects with HCV RNA < LLOQ by visit while on treatment

HCV RNA (log10 IU/mL) change from baseline by visit through the end of treatment (EOT)

The proportion of subjects with ALT normalization (defined as ALT > ULN at baseline and 
ALT≤ULN at each visit), presented by study visit.


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
The percentage of subjects with virologic failure as the following:
On-treatment virologic failure
■
HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ, while on 
treatment, confirmed with 2 consecutive values (note, second confirmation value can 
be posttreatment), or last available on-treatment measurement with no subsequent 
follow up values (ie, breakthrough)
■
> 1 log10IU/mL increase in HCV RNA from nadir while on treatment, confirmed with 
2 consecutive values (note, second confirmation value can be posttreatment), or last 
available on-treatment measurement with no subsequent follow up values 
(ie, rebound)
■
HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (ie, nonresponse)
Relapse
■
HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA 
< LLOQ at EOT, confirmed with 2 consecutive values or last available posttreatment 
measurement
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
For analyses of HCV RNA < LLOQ by visit while on treatment and during the posttreatment 
(SVR) follow-up period, subjects will be assigned a value at each visit based on the analysis visit 
windows specified in Section 3.7.2. Missing values will be imputed based on the categorical 
imputation rules described in Section 3.5.1. For each treatment group, the 2-sided 95% exact CI
based on Clopper-Pearson method will be provided for the percentage of subjects with HCV 
RNA < LLOQ at each visit by HCV genotype and total. The overall category for “HCV RNA 
< LLOQ” will be split into the following 2 subcategories: “< LLOQ TND” for subjects with 
target not detected and “< LLOQ detected” for subjects with < LLOQ in tabular displays. 
Graphs for the percentage of subjects with HCV RNA < LLOQ over time during treatment will 
be displayed by HCV genotype and total for each treatment group.
Summary statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 IU/mL), by HCV genotype and total and by visit through EOT for each treatment group. 
Imputation rules described in Section 3.5.1 will be used to assign HCV RNA values for missing 
values at a visit that are bracketed by “< LLOQ TND” and/or “< LLOQ detected”. Otherwise, a 
missing  excluded analysis will be performed. Plots of the mean ± SD and median (Q1, Q3) of 
absolute values and changes from baseline in HCV RNA through EOT will be presented by
HCV genotype and total for each treatment group.


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For the SVR12 endpoint analysis, a summary table of the number and percentage of subjects 
with SVR12, virologic failure, and other will be created. This summary will be presented by 
HCV genotype and overall for each treatment group. All subjects who achieve SVR12 will be 
categorized as SVR12. Virologic failure will be descriptively summarized as “on-treatment 
virologic failure” and relapse (which will be broken down by study drug completed yes/no). 
Subjects who do not achieve SVR12 and do not meet criteria for virologic failure will be 
categorized as “Other.” The denominator for relapse will be the number of subjects who had 
HCV RNA < LLOQ on their last observed on-treatment HCV RNA measurement; otherwise, the 
denominator will be the number of subjects in the FAS. Virologic outcomes will also be 
provided by cirrhosis status and prior HCV treatment experience on FAS by HCV genotype and 
overall for each treatment group.
A table for ALT normalization by visit will use similar methodology to the analyses of HCV 
RNA <LLOQ, but will use a missing  excluded analysis. Only those subjects with ALT greater 
than the ULN range at baseline (defined as the last ALT value collected prior to first dose of 
study drug) will be included in the analysis of ALT normalization. The summary will be 
performedby HCV genotype and overall for each treatment group.
Drug resistant substitutions will be analyzed as part of the Virology Study Report.
6.3.
Changes From Protocol-Specified Efficacy Analyses
The definition of FAS will be modified to “all enrolled subjects who took at least 1 dose of study 
drug and had detectable HCV RNA at baseline” to exclude any subject with undetectable HCV 
RNA at baseline from efficacy analyses. 


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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, and the most 
severe will be considered (for sorting purpose only) in data presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
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 Pharmacovigilance 
and Epidemiology 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 one or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days
after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug.


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing 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 for each treatment group by the number 
and percentage of subjects who had the following: any AE, any AE of Grade 3 or above, any AE 
of Grade 2 or above, any treatment-related AE, any treatment-related AE of Grade 3 or above, 
any treatment-related AE of Grade 2 or above, any SAE, any treatment-related SAE, and any AE 
that led to premature discontinuation of study drug, and any AE that led to interruption of 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 for each treatment group based on the safety analysis set as follows:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs 

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs (including death)

All treatment-related SAEs 

AEs leading to premature discontinuation of study drug

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Multiple events will be counted once only per subject in each summary. Adverse events will be 
summarized and listed in alphabetic order of SOC and then by PT in order of descending 
incidence within each SOC. In summaries by severity grade, the most severe grade will be used 
for those AEs that occurred more than once in an individual subject during the study. 
In addition to the above summary tables, TEAEs will also be summarized by PT only for each 
treatment group, in order of descending incidence for:

All AEs

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 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.
In addition to the summaries described above, data listings with a variable indicating whether the 
event is treatment emergent will be provided for the following:

All AEs

AEs of Grade 3 or above

SAEs

Deaths

AEs leading to premature discontinuation of 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 the last dose of study drug plus 30 days
for subjects who have permanently discontinued study drug. The analysis will be based on values 
reported in conventional units. When values are below the LOQ, they will be listed as such, and 
the closest imputed value will be used for the purpose of calculating summary statistics as 
specified in Section 3.6. Hemolized test results will not be included in the analysis, but they will 
be listed in by-subject laboratory listings.


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A by-subject listing for laboratory test results will be provided by unique 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 Adverse Events and Laboratory Abnormalities will be 
flagged in the data listings, as appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
by treatment group for ALT, aspartate aminotransferase (AST), albumin, total bilirubin, alkaline 
phosphatase, uric acid, white blood cell (WBC) counts, neutrophils, lymphocytes, hemoglobin, 
platelets, reticulocytes, and international normalized ratio (INR), creatinine, and creatinine 
kinase 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 last measurement obtained 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 
values will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
Median (Q1, Q3) of the observed values for ALT, AST, albumin, total bilirubin, alkaline 
phosphatase, WBC, neutrophils, lymphocytes, hemoglobin, platelets, and reticulocytes will be 
plotted using a line plot by treatment group and 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 or < 8.5 g/dL at any postbaseline visits 
(up to 30 days after the last dose of any study drug) will be summarized by treatment group.
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used to assign toxicity grades (0 to 4) to laboratory results for analysis. Grade 0 includes all 
values that do not meet the criteria for an abnormality of at least Grade 1. For laboratory tests 
with criteria for both increased and decreased levels, analyses for each direction (ie, increased, 
decreased) will be presented separately. 


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7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of
last dose of study drug plus 30 days for subjects who permanently discontinued study drug, or all 
available data in the database snapshot for subjects still on treatment at the time of the interim 
analysis. If the relevant baseline laboratory value is missing, then any abnormality of at least 
Grade 1 will be considered treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test and treatment group; subjects will be categorized 
according to the most severe postbaseline abnormality grade for a given lab test:

Graded laboratory abnormalities

Grade 3 or 4 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 dosing date.
A by-subject listing of treatment-emergent Grade 3 or 4 laboratory abnormalities will be 
provided by unique subject ID number and visit in chronological order. This listing will include
all test results that were collected throughout the study for the lab test of interest, with all 
applicable severity grades or abnormal flags displayed.
7.3.
Body Weight, Height, and Vital Signs
Vital signs (systolic and diastolic blood pressure [mmHg], pulse [beats/min]) at each visit, and 
change from baseline at each visit will be summarized for the safety analysis set by treatment 
group 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 by-subject listing of 
body weight, height, and BMI will be provided separately.


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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 and stopped prior to or on the date of first study 
drug administration 

Concomitant medications: any medications initially taken on or after the initial study drug 
dosing date and within the study drug treatment period (including the study drug therapeutic 
reach)
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 administration date in chronological order.
7.5.
Electrocardiogram Results
A Shift table of the investigator’s assessment of ECG results at baseline (normal, abnormal but 
not clinically significant, abnormal and clinically significant, or missing) versus the 
investigotor’s assessment at each on-treatment visit (normal, abnormal but not clinically 
significant, abnormal and clinically significant, or missing) will be presented by treatment group. 
The number and percent of subjects in each cross-classification group will be presented (subjects 
with a missing value at baseline or on-treatment visit will not be included in the denominator for 
percent calculation).
A listing of ECG results including comments regarding clinically significant abnormalities will 
be provided.


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7.6.
Other Safety Measures
A data listing will be provided for subjects who become pregnant during the study.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8. 
PHARMACOKINETIC ANALYSES 
8.1. 
Pharmacokinetic Sample Collection 
A single PK blood sample will be collected at Weeks 2, 4, 8, 12, and Early Tennination 
(if applicable) for all subjects. 
I 
I 
8.3. 
Population PK Analysis 
Version 1.0 
The population PK models for SOF, GS-331007, VEL, and VOX (as applicable) previously 
developed for regulatory submissi.2!l!,SOFNEL US NDA and SOFNELNOX US NDA) will be 
applied to the data collected from-
sparse 
PK sampling of this study. PK 
parameters (ADC.au and Cmax for SOF and GS-331007, and AUC1au, Cmax, Cmin or C.au for VEL 
and VOX) will be estimated from the simulated SOF, GS-331007, VEL, and VOX concentration 
data using the respective population PK models, for all subjects in the PK Analysis Set. The 
population PK model-derived PK parameters will be listed and summarized by treatment group. 
The population PK parameters of SOF, GS-331007, VEL, and VOX (as applicable) will be 
compared to the population PK parameters in the corresponding US NDA population to assess 
the difference in PK exposure between Korean subjects in this study and the overall population. 
The statistical model will include population group as a fixed effect. The following SAS® PROC 
MIXED code will provide the comparison between the population groups and the 90% CI 
calculations for natural log-transfonned PK parameters. 
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proc mixed data poppk method type3;
  where analyte ‘{GS-XXXX}’ and param ‘{AUCtau}’;
  class popgrp;
  model logval
 popgrp;
  lsmeans popgrp / diff;
  estimate “Korea vs USNDA” popgrp 1 -1 / cl alpha  0.1;
  ods output Estimates  LS_Diffs LSMeans  LS_Means CovParms  MSE;
run;
The estimate statement will be used to produce the point estimate and the corresponding 90% CI 
of the difference in PK parameters of interest on a logarithmic scale. The test-to-reference ratio 
and associated 90% CI will be calculated by taking the exponential of the point estimate and the 
corresponding lower and upper limits, which is consistent with the two 1-sided tests approach
{U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER) 2003}, {U.S. Department of Health and Human Services Food 
and Drug Administration Center for Drug Evaluation and Research (CDER) 2001}.
The following tables will be provided:

Individual and Summary of Population PK Model-derived PK Parameters by Treatment 
Group

Summary of Population PK Parameters for SOF/VEL Treated Subjects in 
Study GS-US-342-5532 Compared to the SOF/VEL US NDA Population 

Summary of Population PK Parameters for SOF/VEL/VOX Treated Subjects in 
Study GS-US-342-5532 Compared to the SOF/VEL/VOX US NDA Population
The following listings will be provided:

Population PK model derived PK parameters
A population PK report based on data from this and possibly other studies will be prepared by 
the PK scientist.


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9.
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.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry. Statistical Approaches 
to Establishing Bioequivalence.  January, 2001.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry. Bioavailability and 
Bioequivalence Studies for Orally Administered Drug Products - General 
Considerations (Revision 1).  March, 2003.


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Appendix 1.
Study Procedures Table
Screening
Day 1a
Treatment Week
(3 days)
Posttreatment Week 
(5 days)
1
2
4
8
12/ETb
4
12
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
Height
X
Weight
X
X
X
X
Vital Signsc
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 
X
X
X
X
X
X
X
Chemistry 
X
X
X
X
X
X
X
X
Coagulation (PT, aPTT and INR)
X
X
X
X
X
X
Urinalysis, Urine drug screen
X
HCV RNA
X
X
X
X
X
X
X
X
HCV resistance samples
X
X
X
X
X
X
X


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Statistical Analysis Plan - Final Analysis 
HBV DNA Sample; 
Single PK 
Semm or Urine PregnancyTesti 
Semm FSHk 
I-ICY Genotyping 
IL28B Genotype 
I-ICY Ab, HIV Ab, 1-IBsAg, HBsAb, 
HBcAb 
HbA lc 
Fi bro Test® 
Screening 
X 
X 
X 
X 
X 
X 
a 
Day I assessments must be perfom1ed prior to dosing. 
b 
ET 
early tem1ination. 
Day t• 
X 
X 
c 
Vital signs include resting blood pressure, pulse, respiratory rate and temperature. 
1 
2 
X 
X 
Treatment Week 
(±3 days) 
4 
8 
12/ETb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Version 1.0 
Posttreatment Week 
(±5 days) 
4 
12 
X 
X 
X 
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 abnomrnlities. 
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 perfom1ed to exclude the presence ofhepatocellular carcinoma (HCC) within 4 months of Day I for 
subjects with cirrhosis, and within 6 months of Day I for subjects without cirrhosis. 
g 
Study drugs will be reconciled at every post Day I 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 I visit through the end of treatment. 
h 
The IWRS will provide direction on the specifies of each subject's study drug dispensing. 
Sample only to be collected for HBcAb positive subjects at Screening. Renex testing done only when ALT > ULN or > Day I value in these subjects. 
All females of childbearing potential will have a serum pregnancy test at Screening. Urine pregnancy testing will occur at Day I 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 c linic as soon as possible for a serum pregnancy test. 
k 
Women of an a e with amenorrhea of;:: 12 months see Protocol A 
end ix 4 . 
I° 
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Appendix 2.
Determining Missing and Virtual visits do to COVID-19
This appendix describes the site collection of COVID-19 data as 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 4) and “Virtual” (or synonyms, see
Table 4). 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 5.
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


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Table 4.
Examples of search terms for “COVID-19” and “Virtual” used to 
identify missed and virtual visits.
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
SHELTER
PHONE
HOME VISIT
ZOOM
SKYPE
Table 5.
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


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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


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