A Phase 3 Multicenter, Open-Label Study to Investigate the Efficacy and Safety of Sofosbuvir/Velpatasvir Fixed-Dose Combination for 12 Weeks in Subjects With Chronic HCV Infection and Compensated Cirrhosis
Phase: PHASE3
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences

Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director: 
Gilead Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3 Multicenter, Open-Label Study to Investigate the Efficacy 
and Safety of SofosbuvirNelpatasvir Fixed-Dose Combination for 
12 Weeks in Subjects with Chronic HCV Infection and Compensated 
Cinhosis 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
This is a non-IND study 
Not Applicable 
Not Available 
Hepatitis C Vims Infection 
GS-US-342-5531 
Name: 
IPIPD 
Telephone: 
IPPU 
Fax: 
IPIPD 
Email: 
IPPU 
Name: 
IPIPD 
Telephone: 
IPPU 
Fax: 
IPIPD 
Mobile: 
IPIPD 
Email: 
IPIPU 
Original: 
03 July 2019 
CONFIDENTIALITY STATEMENT 
The info1mation contained in this document, paiiicularly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Boai·d or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational drng described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaiy to obtain infonned consent from those 
persons to whom the drng may be administered. 

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

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

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

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

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

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Test Product, Dose, 
and Mode of 
Administration:
SOF/VEL fixed dose combination (FDC) is manufactured as a 
400/100 mg FDC tablet for oral administration. Subjects will take 
1 tablet daily with or without food.
Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for 
Evaluation:
Safety:
AEs and safety laboratory tests will be collected throughout the study.
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using COBAS® Ampliprep/ COBAS® TaqMan® HCV 
Quantitative Test, version 2.0. 
Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all enrolled 
and treated subjects.
In the primary efficacy analysis, the SVR12 rate in the Full Analysis 
Set (FAS) will be compared to a performance threshold rate of 78% 
using the two-sided exact one-sample binomial test at significance 
level of 0.05. In addition, a point estimate with a two-sided 95% exact 
confidence interval using the binomial distribution (Clopper-Pearson 
method) will be constructed for the SVR12 rate.
Secondary efficacy endpoints include SVR4, SVR24, and the 
proportion of subjects with virologic failure.
All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation [SD], median, 1st quartile [Q1], 
3rd quartile [Q3], minimum, maximum). All categorical endpoints 
will be summarized by the number and percentage of subjects who 
meet the endpoint definition.
Safety endpoints will be analyzed by the number and percentage of 
subjects with events or abnormalities for categorical values or 
8-number summary (n, mean, SD, median, Q1, Q3, minimum, 
maximum) for continuous data.
Different studies have reported SVR12 rates for compensated 
cirrhotic subjects infected with HCV in Japanese populations. The 
SVR12 performance threshold of 78% for this study is determined as 
clinically relevant by referring to results in the confirmatory studies 
of approved DAA products in Japan. Among these studies, the 
average lower bound of the exact 95% confidence interval is 78%. 

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

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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
aspartate aminotransferase (also SGOT)
ASV
asunaprevir
BMI
body mass index
BCV
beclabuvir
CFR
Code of Federal Regulations
CI
confidence interval
ClCr
creatinine clearance
CPT
Child-Pugh-Turcotte
CRO
contract (or clinical) research organization
CSR
clinical study report
DAA
direct-acting antiviral
DCV
daclatasvir
dL
Deciliter
DNA
deoxyribonucleic acid 
EBR
elbasvir
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eg
example given
eSAE
electronic serious adverse event
ESLD
end stage liver disease
Et al
(Latin) and others
ET
early termination
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed-dose combination
FSH
Follicle-stimulating hormone
g
grams
GCP
Good Clinical Practice

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

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

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SVR24
sustained virologic response 24 weeks after cessation of treatment
SVR4
sustained virologic response 4 weeks after cessation of treatment
TND
target not detected
ULN
upper limit of normal
US
United States
WBC
white blood cell
VEL
velpatasvir
β-hCG
β-human chorionic gonadotropin
μg
microgram

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

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1.2.1.
General Information
Please refer to the current Investigator’s Brochure (IB) for additional information on SOF/VEL
FDC, and the individual components, including:

In-vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.2.2.
Clinical Trials of SOF/VEL FDC
1.2.2.1.
GS-US-342-4019 SOF/VEL+/-RBV for 12 Weeks in Japanese subjects with 
Chronic HCV Infection and Decompensated Cirrhosis
This Phase 3 study included 102 subjects with chronic HCV and decompensated cirrhosis who 
were randomized to be treated with SOF/VEL with or without RBV for 12 weeks. All subjects 
completed the full 12 weeks of treatment with SOF/VEL+/-RBV. 57% were treatment naive, 
78% and 20% had genotype 1 and 2 HCV infection, respectively, and 77% and 20% had Child-
Pugh-Turcotte (CPT) class B and C cirrhosis, respectively, at baseline. Overall, 61% of patients 
were female and the mean age was 66 years (range 41–83). Rates of SVR12 were 92% (47/51) in 
each group. Among patients who achieved SVR12, 26% had improved CPT class from baseline 
to posttreatment week 12. Most adverse events (AEs) were consistent with clinical sequelae of 
advanced liver disease or known toxicities of ribavirin. Four patients (8%) who received 
SOF/VEL and seven (14%) who received SOF/VEL plus ribavirin experienced a serious AE. 
The results from this study formed the basis for registration of SOF/VEL (Epclusa®) in Japan for 
the treatment of chronic HCV infection with decompensated cirrhosis {Takehara 2019}.
1.2.2.2.
GS-US-342-3921 SOF/VEL+ RBV for 12 or 24 Weeks in Japanese subjects with 
Chronic Genotype 1 or 2 HCV Infection Who Have Previously Failed a 
Direct-Acting Antiviral-Containing Regimen
This Phase 3 study included 117 subjects with chronic HCV who failed a direct-acting antiviral 
(DAA) based regimen who were treated with SOF/VEL with RBV for 12 or 24 weeks. All but 
one subject completed the full treatment duration with SOF/VEL+RBV. 81% had HCV genotype 
1 infection, 33% had cirrhosis, and 95% had NS5A resistance associated substitutions (RAS) at 
baseline. Overall, SVR12 rates were 97% (58/60; 95% CI 88–100%) with 24 weeks of treatment 
and 82% (47/57; 95% CI 70–91%) with 12 weeks. For HCV genotype 1 and 2 infected patients, 
the SVR12 rates with 24 weeks of treatment were 98% and 92%, respectively. For patients with 
NS5A RASs at baseline, 85% (46/54) in the 12-week group and 96% (54/56) in the 24-week 
group achieved SVR12. The most common adverse events were upper respiratory tract viral 
infection, anemia, and headache. Three (2.6%) patients discontinued treatment because of 
adverse events. The results from this study formed the basis for registration of SOF/VEL 
(Epclusa®) + RBV in Japan for the treatment of chronic HCV infection who failed a direct-acting 
antiviral (DAA) based regimen {Izumi 2018}.

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

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

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2.
OBJECTIVES
The primary objectives of this study are:

To evaluate the antiviral efficacy of therapy with SOF/VEL fixed-dose combination (FDC) 
for 12 weeks as measured by the proportion of subjects with sustained virologic response 
12 weeks after cessation of treatment (SVR12)

To evaluate the safety and tolerability by review of the accumulated safety data
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure

To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment

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

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

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

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 36 chronic HCV infected male and non-pregnant female subjects, ages 18 or 
older, with compensated cirrhosis at Screening will be enrolled in this study.
In order to manage the total study enrollment, Gilead Sciences, Inc., at its sole discretion, may 
suspend screening and/or enrollment at any site or study-wide at any time.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Willing and able to give informed consent prior to any study specific procedures being 
performed. If subject is a minor, legal representative will provide consent.
2) Male or female, age 18 years at Screening
3) Body weight ≥ 40 kg at Screening
4) Quantifiable HCV RNA (≥lower limit of quantitation [LLOQ]) at Screening
5) Chronic HCV infection (≥ 6 months prior to Screening) documented by prior medical history 
or liver biopsy.
6) Confirmation of cirrhosis by any one of the following methods:
a) Liver biopsy showing cirrhosis (eg, Metavir score = 4 or Ishak score 5)
b) Fibroscan within 4 months of Day 1 showing cirrhosis or results > 12.5 kPa
c) FibroTest® score of > 0.75 at Screening (only in the absence of liver biopsy or 
availability of Fibroscan)
7) HCV treatment status defined as one of the following, and with medical records that include 
sufficient detail to allow for categorization as follows:
a) HCV treatment-naive: Subject has had no prior exposure to any IFN, RBV, or other 
approved or experimental HCV-specific direct-acting antiviral agents.
b) HCV treatment-experienced: Subject has had prior treatment with an approved or 
experimental IFN-containing regimen with or without NS3/4A protease inhibitors. Note:
See Exclusion Criterion #5: if treatment-experienced, prior exposure to any direct-acting 
antiviral agent targeting the HCV NS5A or NS5B is prohibited.

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8) If treatment-experienced, the most recent HCV treatment must have completed at least 
8 weeks prior to Screening
9) Liver imaging (eg, ultrasound or CT scan, at the discretion of the investigator) performed 
within 4 months of Day 1 to exclude hepatocellular carcinoma (HCC) 
10) Females of childbearing potential (as defined in Appendix 4) must have a negative serum 
pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to enrollment.
11) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 4.
12) Male subjects must agree and refrain from sperm donation during treatment and until at least 
30 days after the last dose SOF/VEL FDC. Female subjects must also refrain from egg 
donation and in vitro fertilization during treatment and until at least 30 days after the 
last dose of SOF/VEL FDC.
13) Lactating females must agree to discontinue nursing before the study drug is administered
and through at least 30 days after the last dose of study drug.
14) Subject must be of generally good health, with the exception of chronic HCV infection, as 
determined by the investigator.
15) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments, including all required posttreatment
visits.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Current or prior history of any of the following:
a) Clinically significant illness or currently under evaluation for a potentially clinically 
significant illness (other than HCV) or any other major medical disorder that may 
interfere with subject treatment, assessment, or compliance with the protocol
b) Gastrointestinal disorder or postoperative condition that could interfere with the 
absorption of the study drug
c) Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy
d) Any current or past clinical evidence of decompensated liver disease (eg, ascites, hepatic 
encephalopathy, or variceal bleeding).
e) Solid organ transplantation

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

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

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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
This is a multicenter, open-label study in subjects with chronic HCV infection with compensated 
cirrhosis. No blinding is required.
All subjects will be enrolled to receive SOF/VEL FDC for 12 weeks.
5.2.
Description and Handling of SOF/VEL FDC
5.2.1.
Formulation
The SOF/VEL FDC (400/100 mg) tablets are pink, diamond-shaped, film-coated tablets, 
debossed with “GSI” on one side and “7916” on the other side. In addition to the active 
ingredients, the SOF/VEL FDC tablets contain copovidone, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene 
glycol, talc, and iron oxide red.
5.2.2.
SOF/VEL FDC Packaging and Labeling
SOF/VEL FDC (400/100 mg) tablets are packaged in white, high density polyethylene (HDPE) 
bottles. Each bottle contains 28 tablets and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, aluminum-faced liner.
SOF/VEL FDC bottles to be distributed to centers in Japan shall be labeled for clinical use to 
meet applicable requirements of the J-GCP (Ministerial Ordinance on Good Clinical Practice for 
Drugs).
5.2.3.
SOF/VEL FDC Storage and Handling
SOF/VEL FDC tablets should be stored below 30 C (86 F).
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF/VEL FDC tablets.
5.3.
Dosage and Administration of SOF/VEL FDC
SOF/VEL FDC tablet is to be administered once daily with or without food. Each subject must 
be given instructions to maintain approximately the same daily dosing interval between study 
drug doses.

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

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

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

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
Perform 12-Lead ECG (refer to Section 6.7.5)

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form.

Obtain details of prior and concomitant medications

Liver biopsy and/or Fibroscan results (if available)

Diagnostic imaging (eg, ultrasound or CT scan, at the discretion of the Investigator) should 
be performed to exclude the presence of hepatocellular carcinoma (HCC). Imaging must be 
performed within 4 months of Day 1.

Obtain blood samples for tests:
Hematology
Chemistry
Coagulation tests
HCV RNA
Serum β-hCG pregnancy test for females of childbearing potential only
Serum follicle stimulating hormone (FSH) (only for women of any age with amenorrhea 
of ≥ 12 months [refer to Appendix 4])
HCV Genotype
HCV antibody, HIV antibody, HBV surface antigen (HBsAg), HBV surface antibody 
(HBsAb), HBV core antibody (HBcAb)
HbA1c
Fibrotest®

Obtain urine sample for:
Urinalysis

A single retest of Screening labs is permitted only if there is reason to believe the retest value 
will be within accepted parameters, for example, if the initial exclusionary value was either 
due to a sample processing error or due to an extenuating circumstance such as intercurrent 
illness.

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

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

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

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

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

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
Obtain blood samples for tests:
Hematology
Chemistry
Coagulation tests
HCV RNA
HCV resistance samples
HBV DNA Sample

Obtain urine sample for:
Pregnancy test for females of childbearing potential only
6.6.
Unscheduled Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments are at the investigator’s discretion as clinically indicated, but the investigator should, 
at a minimum, collect AE and concomitant medication information. At all unscheduled visits 
initiated for the purpose of confirming virologic failure, a HCV resistance sample must be 
collected.
6.7.
Procedures and Specifications
6.7.1.
Clinical Laboratory Analytes
Hematology: Hematocrit, Hemoglobin (Hb), Platelet count, Red blood cell count (RBC), 
White blood cell count (WBC) with differential (absolute and percentage) including 
Lymphocytes, Monocytes, Neutrophils, Eosinophils, and Basophils, Reticulocyte count and 
mean corpuscular volume (MCV).
Coagulation: INR, Prothrombin Activation %, Prothrombin time (PT), Activated partial 
thromboplastin time (aPTT)
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatine Kinase, Creatinine, Direct Bilirubin, Total Bilirubin, 
Glucose, Lipase, Potassium, Sodium, phosphate, uric acid, FibroTest® (at Screening only)
Urinalysis: Blood, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. Reflex to 
microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV and HBV. HBV DNA (reflex testing done when 
ALT > 2x Day 1 value in subjects who are HBsAb or HBcAb positive at Screening). Serology 
and/or antigen testing for HIV, including reflex testing as necessary. HCV RNA will be 
measured using the COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, 

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version 2.0. HCV genotype and subtype will be determined using the Siemens VERSANT®
HCV Genotype INNO-LiPA2.0 Assay. Gilead reserves the right to use alternate assays for HCV 
RNA and HCV genotype should the above assays become unavailable or are not definitive.
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the 
SNP, rs12979860, with sequence specific forward and reverse primers and allele specific 
fluorescently labeled TaqMan® MGB probes. Gilead reserves the rights to use an alternate assay 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum β-hCG or Urine β-hCG (if positive, requires immediate confirmation 
with Serum β-hCG), and serum FSH.
6.7.2.
Medical History
Medical history, including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
screening.
6.7.3.
Complete Physical Examination
A physical examination must include source documentation of general appearance, and the 
following body systems: Head, neck, and thyroid; eyes, ears, nose, throat, mouth, and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes; abdomen; skin, hair, nails; 
musculoskeletal; neurological.
6.7.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for ≥5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.7.5.
12-Lead ECG
Subjects will be required to rest in a supine position for 5 minutes prior to making a recording. 
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities. 

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6.7.6.
Creatinine Clearance 
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft 1976} using
actual body weight (ABW).
Male:
CLcr (mL/min) = [140 - age (years)] BW(kg)
72 Scr
Female:
CLcr (mL/min) = [140 - age (years)] BW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
6.7.7.
HCV Resistance Sample
Plasma samples will be collected at Day 1 and at on-treatment visits at Weeks 2, 4, 8, and 12, 
early termination (if applicable), and all posttreatment visits and may be archived for viral 
sequence analysis. At any unscheduled visit initiated for the purpose of confirming virologic 
breakthrough, a viral sequence analysis plasma sample must be collected.
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual.
6.7.8.
HBV DNA Sample
A sample for HBV DNA testing will be collected at on-treatment visits at Weeks 2, 4, 8, and 12 
or early termination (if applicable) and posttreatment week 4. HBV DNA will only be tested 
when ALT > 2x Day 1 value in subjects who are HBsAb or HBcAb positive at Screening.
6.7.9.
Pregnancy Testing
All females of childbearing potential will have a serum pregnancy test at Screening. Urine 
pregnancy testing will occur at Day 1 and every 4 weeks through posttreatment 4. In the event of 
a positive urine pregnancy result, subjects will be instructed to return to the clinic as soon as 
possible for a serum pregnancy test.
6.7.10.
IL28B Testing
A blood sample will be obtained at Day 1 for specific genetic analysis of the rs12979860 
(IL28B) genetic variant. 
6.8.
End of Study
Subjects are considered to have completed the study after the posttreatment Week 24 visit, 
regardless of treatment duration or early termination of study drug.

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6.9.
Post Study 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 (ie, decreased hemoglobin).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drug and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.

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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated
with laboratory abnormalities, the event should be graded on the basis of the clinical severity in
the context of the underlying conditions; this may or may not be in agreement with the grading
of the laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events
and Serious Adverse Events to Gilead:
Requirements for collection prior to study drug initiation: After informed consent, but prior to 
initiation of study medication, the following types of events should be reported on the case report 
form (eCRF): All SAEs, and adverse events related to protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days or after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required posttreatment follow-up period, must be reported to the 
eCRF database and Gilead Pharmacovigilance & Epidemiology (PVE) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead PVE.

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Prior treatment history is collected as part of the study entry criteria and evaluation of individual 
patient characteristics and will not be generating lack of effect reports as this is outside the scope 
of the present clinical study. However, investigators should report any cases of lack of effect that 
they feel appropriate regarding the previous treatment regimen as spontaneous reports to the 
relevant authorities or marketing authorisation holders.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the
eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead PVE within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead PVE: Fax: 
E-mail: 

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
PPD
PPD

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

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

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Database according to instructions in the eCRF completion guidelines. These reports must 
consist of situations that involve study drug(s) and/or Gilead concomitant medications, but do 
not apply to non-Gilead concomitant medications.
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.

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

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8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SAS®software (SAS Institute, Cary, North Carolina, USA).
The study drug in this study includes SOF/VEL FDC. Last dose of study drug refers to the last 
dose of SOF/VEL FDC and will be used in the definition of treatment-emergent AEs and 
laboratory abnormalities as well as the efficacy endpoints of SVR at various posttreatment time 
points.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis is defined as the Full Analysis Set (FAS) which 
includes all enrolled subjects who took at least 1 dose of study drug(s).
8.2.1.2.
Safety
The primary analysis set for safety analyses will include all subjects who took at least 1 dose of 
study drug. Treatment-emergent data will be analyzed and defined as data collected from the 
first dose of the study drug through the date of last dose of the study drug plus 30 days.
8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, values for missing data will not be imputed. 
For the analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have
the missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed
up to the time of the last dose.
If a data point is missing and is preceded and followed in time by values that are “< LLOQ 
target not detected (TND),” then the missing data point will be set to “< LLOQ TND.” If a 
data point is missing and preceded and followed by values that are “< LLOQ detected,” or 
preceded by“< LLOQ detected” and followed by “< LLOQ TND,” or preceded by 
“< LLOQ TND” and followed by “< LLOQ detected,” then the missing value will be set to 
“< LLOQ detected.” In these situations the data point will be termed a bracketed success; 
CCI
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otherwise, the data point will be termed a bracketed failure (ie, ≥LLOQ detected). If a data point 
is missing and is not bracketed, the missing data point will also be termed a failure (ie, ≥LLOQ 
detected) except for SVR24, which will be imputed according to the SVR12 status. Success for 
SVR12 who have no further HCV RNA measurements collected will be counted as a success for 
SVR24 due to the high correlation between these 2 endpoints.
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject took at least 1 dose of study drug, the subject will be included in a summary of 
AEs according to the treatment received; otherwise, if the subject is not dosed, then they will 
be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pretreatment safety laboratory value is 
available, the baseline value will be assumed to be normal (ie, no grade [Grade 0]) in the 
summary of graded laboratory abnormalities. Values for missing vital signs data will not be 
imputed; however, a missing baseline result will be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
calculation of summary statistics for the actual HCV RNA values and the change from 
baseline values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to 
the logarithmic (base 10) scale (log10 IU/mL).
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, race/ethnicity, and age.
Baseline characteristic data will include a summary of body mass index, HCV RNA level 
(log10 IU/mL), genotype of HCV infection, IL28B genotype, and additional endpoints as 
necessary.

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8.5. 
8.5.1. 
Efficacy Analysis 
Primary Analysis 
Final 
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The prima1y efficacy endpoint for this study will be the propo1tion of subjects with SVR12, 
defined as HCV RNA < LLOQ 12 weeks after cessation of treatment. The primaiy analysis will 
be perfonned after all emolled subjects have been followed through 12 weeks posttreatment or 
discontinued from study. 
In the prima1y efficacy analysis, the SVR12 rate in FAS will be compared to the efficacy 
threshold rate of 78% ( described in Section 8. 7 .1) using a two-sided exact one-sainple binomial 
test at significance level of 0.05: ie, the hypothesis for superiority is as follows: 
HO: SVR12 rate = 78%, 
Hl: SVR12 rate t 78% 
In addition, a point estimate with a two-sided 95% exact confidence interval using the binomial 
distribution (Clopper-Pearson method) will be constructed for the SVR12 rate. 
A success for the primaiy endpoint will be claimed if the following criterion is met: point 
estimate of SVR12 is statistically significantly higher than 78% by a two-sided exact one-sainple 
binomial test at significance level 0.05, ie, p-value for above hypothesis testing for superiority is 
:S 0.05. 
8.5.2. 
Secondary Analyses 
The proportion of subjects with HCV RNA below LLOQ over time (including SVR endpoints) 
will be presented in tabular and graphical fonn. 
Descriptive Sllllllllai·ies and listings will be provided for efficacy evaluation of the proportion of 
subjects who experience virologic failure and additional efficacy evaluations including HCV 
RNA values and change from baseline through end of ti·eatment. 
Details on efficacy analyses will be described in the statistical analysis plan. 
8.6. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laborato1y tests, physical examinations, and 
vital signs measurements and AEs will be documented at vai·ious time points during the study. 
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All safety data collected, on or after the first dose of the study drug administration up to 30 days
after the last dose of the study drug will be summarized.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to the study drug will be generated from the study drug
administration data. Exposure data will be summarized.
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any AE with an onset date on or after the study drug start date
and no later than 30 days after permanent discontinuation of the study drug; or any AE leading to
premature discontinuation of the study drug
Summaries (number and percentage of subjects) or listings, as appropriate, of treatment-
emergent adverse events (by SOC, and PT) will be provided:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs (including death)

All treatment-related SAEs

AEs leading to premature discontinuation of the study drug
All AEs collected during the course of the study will be presented in data listings.
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by study visit along with the corresponding change from Baseline/Day 1.

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

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who are at risk of PI-based liver toxicity and currently have no highly-effective PI-free pan-
genotypic treatment options.

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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.
This protocol is to be conducted in accordance with the guidance stipulated in Article 14, 
Paragraph 3 and Article 80-2 of the Law for Ensuring the Quality, Efficacy, and Safety of Drugs 
and Medical Devices, “MHLW Ordinance on Good Clinical Practice” {Ministry of Health and 
Welfare 2013}.
9.1.2.
Financial Disclosure
The investigator and subinvestigators will provide documentation of their financial interest or 
arrangements with Gilead, or proprietary interests in the investigational drug under study. This 
documentation must be provided prior to the investigator’s (and any subinvestigator’s) 
participation in the study. The investigator and subinvestigator agree to notify Gilead of any 
change in reportable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date when the last subject completes the protocol-defined 
activities.
9.1.3.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.4.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 

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conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or
local requirements. 
9.1.5.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any form 
or biological sample submitted to the Sponsor, IRB or IEC or laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The investigator 
must keep a screening log showing codes, names, and addresses for all subjects screened and for 
all subjects enrolled in the trial. Subject data will be processed in accordance with all applicable 
regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.6.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments; CRF and query forms, as 
applicable; IRB or IEC and governmental approval with correspondence; informed consent; drug
records; staff curriculum vitae and authorization forms; and other appropriate documents and 
correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

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
Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.7.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. Subsequent to data entry, a study monitor will perform source data 
verification within the EDC system. Original entries as well as any changes to data fields will be 

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stored in the audit trail of the system. Prior to database lock (or any interim time points as 
described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (eg, data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.6.
9.1.8.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.9.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs, or to regulatory authority or health authority 
inspectors.
9.1.10.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications

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

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

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

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

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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

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

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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
24
Clinical Assessments
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
Height
X
Weight
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
12-Lead ECGd
X
X
X
Adverse Events and Concomitant Medicationse
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling
X
X
X
Imaging for HCCf
X
Review of Study Drug Adherence and Drug 
Accountabilityg
X
X
X
X
X
Study Drug Dispensingh
X
X
Laboratory Assessments
Hematology, Chemistry 
X
X
X
X
X
X
X
Coagulation (Prothrombin activation %, PT, 
aPTT and INR)
X
X
X
Urinalysis
X
HCV RNA
X
X
X
X
X
X
X
X
X
HCV resistance samples
X
X
X
X
X
X
X
X

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

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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
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

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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN

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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects. Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L
2.0 to <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL
1.74 to <1.94 mmolL
6.1 to <7.0 mg/dL
.51 to < 1.74 mmolL
< 6.1 mg/dL
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88 mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10 mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23 mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38 mmol/L
13.5 mg/dL
> 3.38 mmol/L

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to 1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63 to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
Adult and Pediatric
≥ 1 year
Infant < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L

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

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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

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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.

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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 

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

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

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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

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

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

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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (eg, 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (eg, 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting

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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social &
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)

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

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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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Gilead Sciences, Inc. 
Original
CONFIDENTIA
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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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Final
Gilead Sciences, Inc. 
Original
CONFIDENTIA
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03 Jul 2019
GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated
Urinary Tract 
obstruction (eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (eg, septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.

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Original
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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are ≥54 years of age with 
cessation of previously occurring menses for ≥12 months without an alternative cause. In 
addition, women of any age with amenorrhea of ≥12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of SOF have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies of SOF 
have demonstrated no adverse effect on fertility or embryo-fetal development.
Data from clinical pharmacokinetic interaction studies of VEL have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies of VEL 
have demonstrated no adverse effect on fertility or embryo-fetal development. 
However, the risks of treatment with SOF/VEL FDC during pregnancy in humans have not been 
evaluated. Please refer to the latest version of the Investigator’s Brochure for additional 
information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable 
effective contraceptive measure. They must have a negative serum pregnancy test at Screening 
and a negative urine pregnancy test on the Day 1 visit prior to enrollment. Pregnancy tests will 
be performed every 4 weeks throughout duration of trial including posttreatment Week 4 visit. In 
the event of a delayed menstrual period (over one month between menstruations), a pregnancy 
test must be performed to rule out pregnancy. This is even true for women of childbearing 
potential with infrequent or irregular periods. They must also agree to one of the following from 
Screening until 30 days after the last dose of SOF/VEL FDC.

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

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