Conditions: Chronic HCV Infection
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 384
Healthy volunteers: no

Brief summary:
The primary objectives of this study are to evaluate the efficacy, safety, and tolerability of treatment with ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) in treatment-naive and treatment-experienced participants with chronic genotype 1 hepatitis C virus (HCV) infection.

Detailed description:

Arms:
arm 1: Treatment-experienced and treatment-naive participants will receive LDV/SOF for 12 weeks.

Interventions: intervention 1: LDV/SOF
Intervention descriptions: intervention 1: 90/400 mg FDC tablet administered orally once daily without regard to food

Protocol document:
Prot_002.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3b, Multicenter, Open-Label Study to Investigate the Efficacy 
and Safety of Sofosbuvir/Ledipasvir Fixed-Dose Combination in 
Treatment-Naive and Treatment-Experienced Subjects with Chronic 
Genotype 1 HCV Infection 
Gilead Sciences, Inc. 
333 Lakeside Dtive 
Foster City, CA 94404, USA 
Not Applicable 
Not Applicable 
NCT02021656 
Hepatitis C Vims Infection 
GS-US-337-0131 
Name: 
Telephone: 
Fax: 
E-mail: 
Original: 
Amendment 1.1 : 
Amendment 2.0: 
Amendment 3.0: 
JennyYan , PhannD 
PPD 
PPD 
t-Jt-JU 
28 May2013 
12 December 2013 
01 August 2014 
12 Febmruy 2016 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, patiicularly unpublished data, is the propetiy or 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 Bom·d or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaty to obtain infonned consent from those 
persons to whom the dm g may be administered. 


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Protocol GS-US-337-0131
Final
Gilead Sciences, Inc.
Amendment 3.0
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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....................................................................12
1.
INTRODUCTION ..............................................................................................................................................16
1.1.
Background ............................................................................................................................................16
1.1.1.
HCV Infection......................................................................................................................16
1.1.2.
HCV Infection in Korea .......................................................................................................17
1.1.3.
HCV Infection in Taiwan.....................................................................................................18
1.1.4.
HCV Infection in China .......................................................................................................19
1.1.5.
Summary ..............................................................................................................................20
1.2.
Sofosbuvir (formerly GS-7977) and Ledipasvir (formerly, GS-5885) Fixed Dose Combination..........20
1.2.1.
General Information .............................................................................................................20
1.2.2.
Summary of Additional Clinical Experience with Sofosbuvir and 
Ledipasvir.............................................................................................................................21
1.3.
Rationale for This Study ........................................................................................................................24
1.4.
Rationale for Dose Selection of SOF/LDV FDC ...................................................................................25
1.5.
Overall Risk/Benefit Assessment...........................................................................................................25
1.6.
Compliance ............................................................................................................................................26
2.
OBJECTIVES.....................................................................................................................................................27
3.
STUDY DESIGN................................................................................................................................................28
3.1.
Endpoints ...............................................................................................................................................28
3.2.
Study Design..........................................................................................................................................28
3.3.
Study Treatment.....................................................................................................................................28
3.4.
Duration of Treatment............................................................................................................................28
3.5.
Discontinuation Criteria.........................................................................................................................29
3.6.
Source Data............................................................................................................................................29
4.
SUBJECT POPULATION..................................................................................................................................30
4.1.
Number of Subjects and Subject Selection ............................................................................................30
4.2.
Inclusion Criteria....................................................................................................................................30
4.3.
Exclusion Criteria...................................................................................................................................32
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................34
5.1.
Randomization and Treatment Codes ....................................................................................................34
5.2.
Description and Handling of Sofosbuvir/Ledipasvir Fixed-Dose Combination.....................................34
5.2.1.
Formulation..........................................................................................................................34
5.2.2.
Packaging and Labeling .......................................................................................................34
5.2.3.
Storage and Handling...........................................................................................................34
5.3.
Dosage and Administration of Sofosbuvir/Ledipasvir FDC ..................................................................35
5.4.
Prior and Concomitant Medications.......................................................................................................35
5.5.
Accountability for SOF/LDV FDC ........................................................................................................36
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................37
6.
STUDY PROCEDURES ....................................................................................................................................38
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................38
6.2.
Pretreatment Assessments......................................................................................................................38
6.2.1.
Screening Visit (Day -28 to Day -1).....................................................................................38


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6.3.
Randomization .......................................................................................................................................40
6.4.
Treatment Assessments..........................................................................................................................40
6.4.1.
Baseline/Day 1 Visit.............................................................................................................40
6.4.2.
Week 1 (3 days) ................................................................................................................41
6.4.3.
Week 2 (3 days) ................................................................................................................41
6.4.4.
Week 4 (3 days) ................................................................................................................42
6.4.5.
Week 6 (3 days) ................................................................................................................43
6.4.6.
Week 8 (3 days) ................................................................................................................43
6.4.7.
Week 10 (3 days) ..............................................................................................................44
6.4.8.
Week 12 (3 days) ..............................................................................................................44
6.4.9.
Early Termination (ET)/Unscheduled Visit .........................................................................45
6.5.
Post-Treatment Assessments..................................................................................................................46
6.5.1.
Post Treatment Week 4 (5 days) .......................................................................................46
6.5.2.
Post Treatment Weeks 12 and 24 (5 days)........................................................................47
6.6.
Procedures and Specifications................................................................................................................47
6.6.1.
Clinical Laboratory Analytes ...............................................................................................47
6.6.2.
Medical History....................................................................................................................48
6.6.3.
Complete Physical Examination...........................................................................................48
6.6.4.
Vital Signs............................................................................................................................49
6.6.5.
Creatinine Clearance ............................................................................................................49
6.6.6.
12-Lead ECGs......................................................................................................................49
6.6.7.
Viral RNA Sequencing / Phenotyping Sample.....................................................................49
6.6.8.
Optional Archive Sample .....................................................................................................50
6.6.9.
Single Pharmacokinetic (PK) Sample ..................................................................................50
6.6.10.
Intensive Pharmacokinetic (PK) Substudy (Korea and Taiwan only) ..................................50
6.6.11.
Pharmacogenomic (PG) Substudy........................................................................................50
6.6.12.
Pregnancy Testing................................................................................................................51
6.6.13.
Health Related Quality of Life Survey.................................................................................51
6.7.
Assessments for Premature Discontinuation from Study.......................................................................51
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................52
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................52
7.1.1.
Adverse Events.....................................................................................................................52
7.1.2.
Serious Adverse Events........................................................................................................52
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................53
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................53
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................54
7.4.
Gilead Reporting Requirements.............................................................................................................55
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................56
7.6.
Subject Stopping Rules ..........................................................................................................................56
7.7.
Special Situations Reports......................................................................................................................57
7.7.1.
Definitions of Special Situations..........................................................................................57
7.7.2.
Instructions for Reporting Special Situations.......................................................................57
8.
STATISTICAL CONSIDERATIONS................................................................................................................59
8.1.
Analysis Objectives and Endpoints........................................................................................................59
8.1.1.
Analysis Objectives..............................................................................................................59
8.1.2.
Primary Endpoint .................................................................................................................59
8.1.3.
Secondary Endpoint .............................................................................................................60
8.1.4.
Other Endpoints of Interest ..................................................................................................60
8.2.
Analysis Conventions.............................................................................................................................60


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8.2.1.
Analysis Sets ........................................................................................................................60
8.3.
Data Handling Conventions ...................................................................................................................61
8.3.1.
Interim Analysis ...................................................................................................................62
8.4.
Demographic Data and Baseline Characteristics ...................................................................................62
8.5.
Efficacy Analysis ...................................................................................................................................62
8.5.1.
Primary Analysis..................................................................................................................62
8.5.2.
Secondary Analysis..............................................................................................................63
8.6.
Safety Analysis.......................................................................................................................................64
8.6.1.
Extent of Exposure...............................................................................................................64
8.6.2.
Adverse Events.....................................................................................................................64
8.6.3.
Laboratory Evaluations ........................................................................................................65
8.7.
Pharmacokinetic Analysis......................................................................................................................65
8.8.
Sample Size............................................................................................................................................65
9.
RESPONSIBILITIES..........................................................................................................................................67
9.1.
Investigator Responsibilities ..................................................................................................................67
9.1.1.
Good Clinical Practice..........................................................................................................67
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................67
9.1.3.
Informed Consent.................................................................................................................68
9.1.4.
Confidentiality......................................................................................................................68
9.1.5.
Study Files and Retention of Records ..................................................................................68
9.1.6.
Case Report Forms...............................................................................................................70
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................70
9.1.8.
Inspections............................................................................................................................70
9.1.9.
Protocol Compliance............................................................................................................70
9.2.
Sponsor Responsibilities ........................................................................................................................71
9.2.1.
Protocol Modifications.........................................................................................................71
9.2.2.
Study Report and Publications .............................................................................................71
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................71
9.3.1.
Access to Information for Monitoring..................................................................................71
9.3.2.
Access to Information for Auditing or Inspections ..............................................................72
9.3.3.
Study Discontinuation..........................................................................................................72
10.
REFERENCES ...................................................................................................................................................73
11.
APPENDICES ....................................................................................................................................................79
Appendix 1.
Investigator Signature Page....................................................................................................80
Appendix 2.
Study Procedures Table..........................................................................................................81
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............85
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................108
Appendix 5.
Calculation of Historical Control SVR12 for Treatment-naïve Korean Subjects and 
for Treatment-naïve Chinese Subjects with Chronic GT-1 HCV Infection..........................110
LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-334-0111 Geometric Least-Squares Mean Ratios (90% Confidence 
Intervals) for Sofosbuvir, GS-566500, GS-331007, and Ledipasvir Primary PK 
Parameters in Japanese versus Caucasian Subjects ................................................................22
Table 1-2.
GS-US-337-0113 Number (and Percentage) of Subjects with SVR12...................................24
Table 5-1.
Disallowed and Concomitant Medications to be used with Caution ......................................36


Sofosbuvir/Ledipasvir FDC
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Amendment 3.0
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 3b, Multicenter, Open-Label Study to Investigate the Efficacy 
and Safety of Sofosbuvir/Ledipasvir Fixed-Dose Combination in 
Treatment-Naïve and Treatment-Experienced Subjects with Chronic 
Genotype 1 HCV Infection
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
Not applicable
Not applicable
NCT02021656  
Study Centers 
Planned:
Approximately 20 sites in China
Approximately 14 sites in Korea 
Approximately 10 sites in Taiwan
Objectives:
The primary objectives of this study are:

To determine the antiviral efficacy of treatment with sofosbuvir 
(SOF)/ledipasvir (LDV) fixed-dose combination (FDC) as 
measured by the proportion of subjects with sustained virologic 
response (SVR) 12 weeks after discontinuation of therapy 
(SVR12, defined as HCV RNA < lower limit of quantification 
[LLOQ] 12 weeks post treatment)

To evaluate the safety and tolerability of SOF/LDV FDC as 
assessed 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 discontinuation of therapy (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during treatment 
and after treatment discontinuation

To evaluate the emergence of viral resistance to SOF and LDV 
during treatment and after treatment discontinuation


Sofosbuvir/Ledipasvir FDC 
Protocol GS-US-337-0131 
Gilead Sciences, Inc. 
Study Design: 
Final 
Amendment 3.0 
The explorat01y objectives of this study are: 
PPO 
I 
Intemational (China, Korea and Taiwan), multicenter, open-label study 
in treatment-naive and treatment-experienced adults with chronic 
genotype 1 HCV infection. 
Approximately 180 u·eatment-naive and 180 treatment-experienced 
subjects will receive treatment with SOF 400 mg/LDV 90 mg fixed 
dose combination (FDC) tablet for 12 weeks. 
It is estimated that approximately 200 subjects will be enrolled in 
China, 80 subjects will be enrolled in Korea, and 80 subjects in 
Taiwan. Within each country approximately 50% (i.e., n~100 or 40) of 
subjects will be u·eatment-naive and 50% will be 
u·eatment-experienced (i.e., n~100 or 40). 
Treatment-naive is defined as having never received u·eatment for 
HCV with any interferon (IFN), ribavirin (RBV), or other approved or 
experimental HCV-specific direct acting antivirals. 
Treatment-experienced is defmed as: 
a) IFN intolerant 
Note: Subjects intolerant of Peg-IFNa+RBV+HCV protease 
inhibitor regimens are included in this category. 
b) Non-response 
c) Relapse/Breakthrough 
Note: For treatment-experienced subjects, prior exposure to 
HCV NS3/NS4A protease inhibitors is permitted. 
Up to 20% of subjects enrolled in the study may have compensated 
cinhosis at Screening. 
Number of 
Approximately 360 subjects 
Subjects Planned: 
Target Population: 
Treatment-naive and u·eatment-experienced, chronic genotype 1 HCV 
infected adults 
Duration of 
12 weeks 
Treatment: 
CONFIDENTIAL 
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Amendment 3.0
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Diagnosis and 
Main Eligibility 
Criteria:
Chronic genotype 1, HCV infected, male and 
non-pregnant/non-lactating female subjects, ages 20 years and older, 
treatment-naïve or treatment-experienced, of whom approximately 
20% may have compensated cirrhosis, may be eligible for the study.
Reference Section 4.2 and 4.3 for detailed Inclusion and Exclusion 
criteria.
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the 
Baseline/Day 1 visit. The screening window can be extended to 
42 days for subjects requiring liver biopsy or additional 
HCV genotyping.
Study visits will occur at Screening, Baseline/Day 1, and on-treatment 
at the end of Weeks 1, 2, 4, 6, 8, 10, and 12. Following the last dose of 
study medication, all subjects will complete 4-Week and 12-Week 
Post-Treatment Visits. Subjects with HCV RNA < LLOQ at the 
12-Week Post-Treatment Visit will also complete a 24-Week 
Post-Treatment Visit unless confirmed viral relapse occurs.
Administration of interferon or any HCV-directed treatment, other than 
the study drug, is prohibited from 12 weeks prior to Screening until 
completion of the final post-treatment follow-up visit.
Screening assessments include physical examination, height, weight, 
vital signs, 12-lead electrocardiogram (ECG), medical history, adverse 
events (AEs), concomitant medications, safety laboratory tests 
(hematology, chemistry, coagulation, urinalysis), HCV RNA, serology 
(HIV, HCV, HBV), hemoglobin A1c (HbA1c), assessment of the 
presence or absence of cirrhosis, liver imaging for HCC 
(cirrhotics only), serum β-hCG (females of child bearing 
potential only), thyroid stimulating hormone (TSH), HCV genotyping, 
IL28B genotyping.
On-treatment assessments include adverse events (AEs), concomitant 
medications, review of study drug adherence, physical examinations, 
vital signs, safety laboratory tests, HCV RNA, pharmacokinetic 
samples, and urine pregnancy tests (females of child bearing 
potential only).
Single 12-lead ECGs will be collected at Screening, Baseline/Day 1 
(prior to study drug administration) and on-treatment visits at the end 
of Weeks 1 and Week 12. 
Weight will be measured at Screening, Baseline/Day 1, on-treatment
visit at the end of Week 12, and post-treatment Weeks 12 and 24 visits 
(as applicable).


Sofosbuvir/Ledipasvir FDC 
Protocol GS-US-337-0131 
Gilead Sciences, Inc. 
Optional 
Substudies: 
CONFIDENTIAL 
Final 
Amendment 3.0 
Health Related Quality of Life (HRQoL) Smvey will be conducted at 
Baseline/Day 1, on-u·eatment visits at the end of Weeks 2, 4, 8, and 12, 
and Post-Treatment Week 4 and 12 visits. 
Pregnancy prevention counseling will be addressed with the subject at 
Baseline/Day 1, on-u·eatment visit at the end of Week 12, and 
post-treatment Week 4 visits. 
Post-u·eatment assessments include AEs, concomitant medications, 
vital signs, safety laborat01y tests, HCV RNA, and mine pregnancy 
tests (females of child bearing potential only). 
Samples for viral RNA sequencing/phenotyping will be collected at 
Baseline/Day 1 and eve1y visit thereafter. Single PK samples will be 
collected dming on-u·eatment visits for PK analysis of study dmg. 
Two archive plasma samples will be collected, one at Baseline/Day 1 
and the second at the end of u·eatment visit for potential futme 
biomarker testing. Subjects will have the opportunity to opt out of the 
archive sample collection. For subjects who provide their additional 
and specific consent, a blood sample will be collected at the 
Baseline/Day 1 visit for human phannacogenomic testing (this sample 
may be drawn after Baseline/Day 1, if necessary). 
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Sofosbuvir/Ledipasvir FDC 
Protocol GS-US-337-0131 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
Phrumacokinetics: 
Statistical Methods: 
CONFIDENTIAL 
PD 
Final 
Amendment 3.0 
SOFILDV is manufactured as a FDC tablet, consisting of 400 mg SOF 
and 90 mg LDV, for oral administr·ation. Subjects will take 1 tablet 
daily with or without food. 
None. 
AEs and safety laborat01y tests will be collected throughout the study 
(through the 4-Week Post-Treatment Visit). 
Efficacy will be evaluated using scheduled assessments ofHCV RNA 
perf01med using COBAS® TaqMan® HCV Test, v2.0 for use with the 
High Pure System or COBAS® AmpliPrep I COBAS® TaqMan 
® _HCV Test, v2.0. 
In China, Korea and Taiwan, a single PK blood srunple will be 
collected at each on-tr·eatment visit for all subjects. PPD 
. If 
conauctea, a target of ~ 10-15 suojects may oe emolled fiom eacli 
country. Serial PK srunples would be collected over 24 hours 
post-dose. The PK of SOF (and its metabolites GS-566500 and 
GS-331007) and LDV will be assessed. 
The primruy efficacy endpoint is SVR12 in all emolled and tr·eated 
subjects with chronic genotype-I HCV infection. The primary endpoint 
will be perf01med on the Full Analysis Set (F AS). 
Treatment-Naive Subjects 
The primruy endpoint will be assessed by comparison of the observed 
SVR12 rate for tr·eatment-nai:ve subjects with HCV GT-1 infection 
from Korea and China versus the historical SVR null rate of 49% and 
57% respectively (as calculated in Appendix 5) using a two-sided exact 
one-sample binomial test. 
In addition, for each region (i.e., China, Korea or Taiwan), Korea plus 
Taiwan, and overall (i.e., China plus Korea plus Taiwan), 
a point-estimate with two-sided 95% exact confidence interval using 
the binomial distr·ibution (Clopper-Peru·son method) will be constructed 
for the SVR12 rate. 
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Amendment 3.0
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A sample size of 40 Korean subjects in the treatment-naïve group will 
provide at least 90% power to detect a 27% improvement in SVR12 
rate from the adjusted historical control rate of 49% using 2-sided 
exact one-sample binomial test at significant level of 0.05.
A sample size of 100 Chinese subjects in the treatment-naïve group 
will provide at least 90% power to detect a 17% improvement in 
SVR12 rate from the historical control rate of 57% using 2-sided exact 
one-sample binomial test at significant level of 0.05.
In addition, with 40 subjects in Korea (or Taiwan), the 2 sided 95% 
exact confidence interval for the SVR12 rate will extend at most 32% 
in length. With 80 subjects (Korea plus Taiwan) in the treatment-naïve 
group, a two-sided 95% exact confidence interval for the SVR12 rate 
will extend at most 23% in length. With 100 subjects in China, the 
2 sided 95% exact confidence interval for the SVR12 rate will extend 
at most 20% in length.
Treatment-Experienced Subjects 
There is no treatment option available in China, Korea or Taiwan for 
treatment-experienced patients with GT-1 infection. In the absence of 
effective antiviral therapy, spontaneous clearance of the HCV is rare. 
Consequently a nominal SVR rate of 5% is assumed for 
treatment-experienced subjects.
No statistical hypothesis testing will be performed in 
treatment-experienced subjects. For each region (i.e., China, Korea or 
Taiwan), Korea plus Taiwan, and overall (i.e., China plus Korea plus
Taiwan), a point-estimate with two-sided 95% exact confidence 
interval using the binomial distribution (Clopper-Pearson method) will 
be constructed for the SVR12 rate.
With 40 subjects in Korea (or Taiwan), the 2 sided 95% exact 
confidence interval for the SVR 12 rate will extend at most 32% in 
length. With 80 subjects (Korea plus Taiwan) in the 
treatment-experienced group, a two-sided 95% exact confidence 
interval for the SVR12 rate will extend at most 23% in length. With 
100 subjects in China, the 2 sided 95% exact confidence interval for 
the SVR12 rate will extend at most 20% in length.
Secondary efficacy endpoints include the proportion of subjects with 
SVR4, SVR24, breakthrough and relapse; and HCV RNA change from 
baseline.


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Final
Gilead Sciences, Inc.
Amendment 3.0
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All continuous endpoints (except safety endpoints) will be summarized 
using an 8-number summary (n, mean, standard deviation, median, 
Q1, Q3, minimum, maximum) by treatment-naïve and 
treatment-experienced subjects for each region and overall. All 
categorical endpoints will be summarized by number and percentage of 
subjects who meet the endpoint definition. 
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnormalities for categorical values or 
8-number summary (n, mean, standard deviation, median, Q1, Q3, 
minimum, maximum) for continuous data.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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Amendment 3.0
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase  (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval 
(tau)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BT
breakthrough
BW
body weight
CFR
Code of Federal Regulations
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
Observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
DAA
Direct acting antiviral
DCV
Daclatasvir
dL
Deciliter
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
ECIRB/IEC
Ethics Committee Institutional Review Board/ Independent Ethics Committee
eCRF
Electronic case report form(s)
Emax
Maximal effect
ESA
Erythropoiesis stimulating agent
eSAE
electronic Serious Adverse Event (system)
ESLD
End Stage Liver Disease
ET
early termination
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration


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Protocol GS-US-337-0131
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 13
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
FDC
Fixed Dose Combination
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GMRs
geometric-least squares means ratios
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular Carcinoma
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
HRQoL
Health Related Quality of Life (Survey)
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN
interferon
IL28B
IL28B gene
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
INR
International Normalized Ratio
IRB
Institutional Review Board
IU
International Units
IUD
Intrauterine Device
IV
Intravenous
IVDA
Intravenous drug abuse
IWRS
Interactive Web Response System
kg
Kilogram
L
Liter
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
LLT
Lower-Level Term 
LTFU
Lost to follow up
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
mL
Milliliter
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
Peg-IFNα
pegylated interferon
PG
Pharmacogenomic
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
PT
Preferred Term
QA
Quality Assurance
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’ formula
RBC
Red blood cell count 
RBV
Ribavirin
RNA
ribonucleic acid
RVR
rapid virologic response 
SAE
serious adverse event
SD
Standard deviation
SF-36
Short-Form-36
SOC
Standard of Care or System Organ Class
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
TE
Treatment-Experienced
TN
Treatment-Naïve
TGV
Tegobuvir
TND
Target not detected
TPO
thrombopoietin
TSH
Thyroid stimulating hormone
t½
An estimate of the terinal elimination half-life of the drug in 
serum/plasma/PBMC, calculated by dividing the natural log of 2 by the terminal 
elimination rate contstant (λz)
ULN
upper limit of the normal range


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
US
United States
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
1.1.1.
HCV Infection
Infection with the hepatitis C virus (HCV) is a serious, progressive, and often life-threatening 
disease affecting approximately 180 million adults worldwide {21360}. The infection, if 
untreated, can result in progressive liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and 
end stage liver disease (ESLD). Transmission of HCV infection is parenteral with the majority of 
infections occurring through administration of contaminated blood products, unsafe medical 
procedures, intravenous drug use or sexual transmission {8076}. The hepatitis C virus is 
classified into six major genotypes (GT), i.e., 1-6, with further division to a subtype level 
(e.g., a, b, c) {21479}. Virologic response rates to currently available therapies vary according to 
host IL28B genotype, baseline levels of HCV RNA and HCV genotype. The distribution of HCV 
genotypes and subtypes varies according to geographic region with the most common HCV 
genotypes in the United States and Europe being GT-1, GT-2 and GT-3. In China GT-1, GT-2 
and GT-6 are generally the most common although regional differences in genotype distribution, 
such as GT-3 in the South, are apparent {24217}. In Korea and Taiwan it is estimated that 
approximately 50% of infections are associated GT-1b and 50% with GT-2a {24218}, {29246}, 
{24215}. Genotypes 4, 5 and 6 are most prevalent in the Middle East, South Africa and 
Southeast Asia respectively {22110}.
Following acute infection approximately 15-20% of patients are able to clear the virus without 
intervention, however around 80% of patients go on to establish chronic hepatitis C {8076}. 
Treatment of chronic infection is currently based upon weekly subcutaneous administration of 
pegylated interferon (Peg-IFNα) with orally administered ribavirin (RBV) for 24 to 48 weeks 
dependent upon genotype and virologic response. In Caucasians, this treatment regimen affords 
sustained virologic response rates (SVR) on the order of 42-46% in treatment-naïve patients with 
GT-1 and 76-82% in patients with GT-2/3 infection {23342}, {23351}. Observed SVR rates using 
the same interferon (IFN)-based treatment regimens are generally higher in Asian patients. This
observation has been largely attributed to a higher proportion of Asian patients (>85%) 
possessing the host IL28B-CC genotype which confers a favorable virologic outcome following 
treatment with IFN-containing regimens {22075}, {24243}, {22156}, {21337}, {22098}. Although 
relatively high SVR rates can be achieved in Asian patients with IFNα+RBV, the safety and 
tolerability of IFN-containing regimens is sub-optimal. Contraindications to IFN preclude its use
by a significant number of patients {22156} while management of adverse effects commonly 
results in dose reductions and may lead to treatment discontinuation. Safety and tolerability are
particularly problematic in an aging population with chronic hepatitis C. Moreover, lower SVR 
rates are also observed in older patients {24406}.
Recently, first generation protease inhibitors (PI) (i.e., telaprevir (TVR) and boceprevir (BCV)) 
have been approved in certain countries for use in patients with GT-1 infection when combined 
with Peg-IFNα+RBV. The Peg-IFNα+RBV+PI regimens have incrementally improved SVR 
rates in GT-1 treatment-naïve patients to approximately 70%; however, they are associated with 


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significant safety and tolerability concerns {17996}, {17492}. Moreover, Peg-IFNα+RBV+PI 
regimens are not currently available in Korea, Taiwan or China and, consequently, patients with 
GT-1 infection who fail to respond to Peg-IFNα +RBV have no current treatment options.
1.1.2.
HCV Infection in Korea
In Korea, chronic HCV infection is one of the leading causes of chronic liver disease and 
hepatocellular carcinoma (HCC) {24211}. The age-standardized prevalence of HCV antibody 
(HCV Ab) in patients greater than 40 years of age is reported to be on the order of 1.3% which 
equates to around 193,000 people {24215}. The prevalence of HCV infection increases with age 
and peaks in those individuals aged 60 years and older {24211}. The majority of infections 
occurred via contaminated blood transfusions prior to the introduction of blood-donor HCV Ab 
screening in 1991 {24216}. Consequently the majority of patients with chronic hepatitis C in 
Korea are elderly {24215} and are more likely to have progressive liver disease. HCV infection is 
more closely associated with HCC in the elderly Korean patients than are HBV infection and 
alcoholism {24210}, {24208}. Since the decline of transfusion-related hepatitis C the majority of 
new infections are behavior-related. Of particular note is the practice of acupuncture for chronic 
illnesses including joint disease, pain, sequelae of trauma and other conditions non-responsive to 
conventional therapies. Shin et al reported results of a case study in which 34.1% of men and 
62.9% of women in rural Korea reported multiple acupuncture procedures with the associated 
risk fraction for HCV infection being 38% for men and 55% for women {24214}. Intravenous 
drug abuse (IVDA) is not thought to be a major contributor to the overall prevalence of 
HCV infection in Korea however this route of infection may contribute in young adults and those 
living in harbor cities on the southern and western coasts {24209}, {24211}. The predominant 
HCV genotypes in Korea are GT-1b and GT-2a which are roughly present in equal proportions 
and combined account for around 80-90% of infections {24216}, {24215}, {24209}. Host IL28B 
genotype has been widely reported as a predictor of virologic response to interferon (IFN)-based 
therapies for chronic HCV infection {22075}. The IL28B-CC genotype which confers a favorable 
virologic outcome to IFN-based therapy predominates in Korea with approximately 80-90% of 
patients with this genotype {24212}, {24238}. Consequently the sustained virologic response 
rates in Korean clinical trials evaluating Peg-IFNα+RBV in treatment-naïve GT-1 infection are 
on the order of 55-70% following 48 weeks of therapy {24211}, {24595}, {24387}, {24385}, 
{24237}, {24404}, {24388} . Although relatively high rates of virologic response are achievable
with Peg-IFNα+RBV in treatment-naïve Korean patients due to the high proportion of IL28B CC 
genotype, Heo et al {24236} recently reported a significant difference in SVR rate observed in a 
clinical trial cohort versus that observed in clinical practice based upon ‘Intention To Treat’ 
(ITT) analysis; 81% (21/26) versus 55% (58/106). Although no difference was observed in the 
SVR rates between the clinical trial cohort and the clinical practice cohort according to per 
protocol analysis, the ITT is important since it more likely reflects the observed SVR in clinical 
practice across the country. The authors attribute the lower ITT SVR rate in the clinical practice 
cohort to decreased adherence to assigned therapy including dose reduction for clinical and 
laboratory adverse events. As previously described, the highest prevalence rates for HCV Ab in 
Korean patients are in those individuals aged 60 years and older. These elderly patients are more 
likely to be treatment-experienced and have progressive liver disease. Comorbid conditions 
(e.g., diabetes and cardiovascular disease) are common in this population and pose significant 


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challenges to the use of Peg-IFNα+RBV therapy. As this group of patients continues to age the 
proportion of patients with chronic hepatitis C who will develop complications, including liver 
cirrhosis, HCC and ESLD is significant; {22077}. In addition, it is important to consider the 
proportion of patients who are ineligible for, intolerant of, or unwilling to receive 
Peg-IFNα+RBV who have no currently available antiviral treatment options {21256}. This also 
applies to patients who have previously failed to respond to Peg-IFNα+RBV therapy. Although 
Peg-IFNα+RBV can achieve high rates of SVR in treatment-naïve patients with chronic HCV 
infection when assigned therapy is tolerated, there is an unmet medical need for effective, safe, 
well-tolerated, all oral therapies that can be used in an aging patient population in Korea.
1.1.3.
HCV Infection in Taiwan
Taiwan has one of the highest prevalence rates of chronic hepatitis C in North-East Asia. In a 
nationwide survey conducted between 1996 and 2005 involving over 164,000 participants in 
out-reach community-based hepatitis screening programs the HCV seroprevalence was estimated 
to be 4.4% {24235}. The study reported an approximately equal seroprevalence in males (4.5%)
and females (4.3%). Importantly seroprevalence varied geographically with certain areas of 
hyperendemicity such as Miaoli and Chiayi Counties where the age-adjusted seroprevalence was 
reported to be 7.6% and 6.1% respectively. The proportion of subjects with HCV antibodies 
progressively increased after the age of 20 years. The predominant routes of transmission are 
thought to be iatrogenic in nature including history of blood transfusion, medical injections and 
acupuncture {29245}, {29248}. Historically, glucose supplements, vitamins, and treatments for 
minor medical conditions have often been administered by injection. Prior to 1980 reusable 
syringes were commonly used particularly in rural areas with poor sterilization techniques likely 
contributing to the spread of HCV infection. After 1980, the rate of HCV infection was likely
reduced following the introduction of disposable syringes. This may in part explain the higher 
prevalence of HCV infection in the elderly population in Taiwan. It has also been postulated that 
inhabitants of communities with high rates of HCV infection may have been repeatedly exposed 
to a common reservoir of infection contributing to the establishment of hyperendemic areas 
{29245}.
As previously described for Korea, the predominant HCV genotypes in Taiwan are GT-1b and 
GT-2a which are present in similar proportions and account for around 80-90% of all infections 
{29247}, {24218}, {29246}. The IL28B-CC host genotype conferring favorable virologic outcome 
to IFN-based therapy predominates with approximately 80-90% of patients with this genotype 
{22075}, {24241}. As a consequence the SVR rates in Taiwanese clinical trials evaluating 
Peg-IFNα+RBV in GT-1 infection are approximately 49-56% and 76-80% in treatment-naïve 
patients receiving 24 weeks and 48 weeks of treatment respectively {24410}, {24382}. However, 
as previously described in Taiwan the seroprevalence of HCV antibodies increases with age with 
the highest rates observed in those 60 years and older {24235}. The use of currently available 
therapy is problematic in the elderly due to contraindications to IFN and RBV and comorbidities 
such as cardiovascular disease and diabetes. In Taiwan for treatment-naïve patients with GT-1 
infection aged ≥65 years the SVR rate for Peg-IFNα+RBV administered for 48 weeks has been 
reported to be 51.9% {24390}. The elderly patient population is more likely to have progressive 
liver disease and be at higher risk for the development of HCC and ESLD. For GT-1 infection 


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the SVR rates for Taiwanese age-matched patients with HCC (post-curative management) and 
cirrhosis are reported to be 33% and 55% respectively {24240}. The safety, tolerability and 
efficacy of IFN+RBV therapy is suboptimal in this population. Finally, there are no currently 
available treatment options for those patients who are ineligible for, intolerant of, or who have 
previously failed to respond to IFN+RBV therapy.
1.1.4.
HCV Infection in China
Reports indicate that around 2% of the population in China, or approximately 27 million people,
may be infected with the hepatitis C virus {19682},{24217},{25129}. Approximately 68% of 
patients are infected with HCV GT-1b, 14% with GT-2, 4% with GT-3 and 13% with GT-6 
{19682},{24217}. GT-1 and GT-2 infection are generally more common in older patients whereas 
GT-3 and GT-6 are more frequent in younger adults. This observation may be related to the 
mode of HCV transmission, with GT-1/GT-2 commonly acquired through prior blood 
transfusion and GT-3/GT-6 associated with IVDA {25094}.
Risk factors for HCV infection are similar to those reported in other parts of the world {25095}. 
Of note, however, is the reported risk of acquiring transfusion-related HCV infection which is on 
the order of 1 in 40,000-60,000 donations {25093}. Such high rates of transfusion-related 
hepatitis C have been attributed in part to the practice of paid blood donation. Following 
introduction of mandatory HCV screening of blood/blood products in the 1990’s and the 
implementation of the blood donation law in 1998, the incidence of post-transfusion hepatitis C 
has been significantly reduced {24392, 25127}. The association of GT-1 infection with blood 
transfusion and the timing of the new requirements related to blood donation may in part explain 
the higher GT-1 infection rates in the elderly. Since the introduction of blood-bank screening, the 
predominant mode of new HCV infection is now intravenous drug use (IDU). 
The recommended treatment regimen for treatment-naïve patients with HCV GT-1 in China
according to the Chinese Society of Hepatology {24428}is subcutaneous or intramuscular 
administration of IFNα or Peg-IFNα plus orally administered RBV for 24 to 48 weeks according 
to baseline viral load and virologic response. These recommendations are aligned with those by 
the APASL Consensus Committee {24699},{22156}. SVR rates in China for GT-1have been 
reported to be on the order of 44% to 70% {24797}, {13261}, {24391}.
A significant number of patients in China are in the 3rd-4th decade of infection and have 
progressive liver disease. The use of IFNα+RBV therapy in the elderly is problematic. Comorbid 
conditions are common (eg, cardiovascular disease, diabetes, mental anomaly, decreased renal 
function) and may preclude IFNα use {24428} {22156} {24398}. Older patients generally report a 
higher frequency of adverse events and of greater severity compared to younger patients. Lower 
levels of treatment adherence are also observed. These factors contribute to overall lower SVR 
rates observed with IFN-based therapy in the elderly {24390}. As patients continue to age, the 
number developing hepatic complications including cirrhosis, HCC and ESLD will be significant 
{22077}. 
The use of IFNα-based therapy is also problematic in the IVDA population. The risk for 
developing severe IFNα-related psychiatric events including depression, suicidal ideation, 


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cognitive disturbances, psychotic symptoms, fatigue and habit relapse is high. Adherence to 
therapy may be low and effective treatment requires multidisciplinary support {25091}. 
A significant number of patients are ineligible for, or unwilling to undergo treatment with 
IFN-based therapy. For these patients, there are presently no available therapeutic options 
available.
1.1.5.
Summary
There is a need for early intervention and eradication of HCV infection to reduce the burden of 
progressive liver disease including of HCC and ESLD. While early introduction of effective 
antiviral therapy is critical in order to reduce the potential future burden of advanced liver 
disease, safe and effective antiviral therapies that can be used in elderly patients with advanced 
disease is of paramount importance today. Gilead Sciences is developing the all-oral, 
interferon- and ribavirin-free SOF/LDV FDC regimen to address this need in Chinese, Korean 
and Taiwanese patients with chronic genotype-1 HCV infection.
1.2.
Sofosbuvir (formerly GS-7977) and Ledipasvir (formerly, GS-5885) Fixed 
Dose Combination
Sofosbuvir/Ledipasvir fixed dose combination (FDC) combines two HCV specific DAA agents 
into a single tablet for the treatment of chronic HCV infection. More than 2500 subjects have 
received treatment with this combination tablet to date.
Sofosbuvir (SOF), formerly GS-7977, is a nucleotide analog that is a potent and selective 
inhibitor of NS5B-directed HCV replication. Over 4,000 subjects have received SOF containing 
regimens to date, from single doses up to repeat dosing for 24 weeks.
Ledipasvir (LDV), formerly GS-5885, is a novel HCV NS5A inhibitor that has demonstrated 
potent anti-HCV activity against genotype (1a and 1b) HCV infection. More than 1000 HCV 
infected subjects have been dosed with LDV in Phase 2 clinical studies, and over 700 subjects 
have been dosed with LDV for over 12 weeks.
1.2.1.
General Information
For further information on SOF/LDV FDC and the individual components, refer to the 
Investigator’s Brochure (IB) for sofosbuvir/ledipasvir fixed-dose combination including:

In Vitro Anti-HCV Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience


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1.2.2.
Summary of Additional Clinical Experience with Sofosbuvir and Ledipasvir
1.2.2.1.
GS-US-334-0111 Pharmacokinetic Bridging Study in Japanese Subjects
To support the conduct of clinical studies in Japan, a PK bridging study was conducted in 
accordance with ICHE5 to compare the safety, tolerability and PK profile in Japanese and 
Caucasian subjects following single-dose administration of SOF at the 200 mg, 400 mg 
(the intended therapeutic dose) and 800 mg dose levels. This study also evaluated the 
pharmacokinetic parameters of the 400 mg dose of SOF and the 90 mg dose of LDV 
administered as a single dose of the SOF/LDV FDC. This study was conducted in the 
United States.
The study enrolled Japanese and Caucasian subjects with an approximately even distribution of 
healthy males and healthy, non-pregnant, non-lactating females between 18–45 years, inclusive, 
with a body mass index (BMI) 18 ≤ BMI ≤ 30. Japanese subjects must have been born in Japan, 
not lived outside Japan for more than 10 years, could trace maternal and paternal Japanese 
ancestry of parents and grandparents, and their lifestyle, including diet, had not significantly 
changed since leaving Japan. Caucasian subjects must not have been of Japanese or Asian 
descent; those with parents or grandparents born in Japan or in any Asian country were excluded. 
Eligible subjects received one dose of study treatment on Day 1 corresponding to their assigned 
group. Each group comprised 8 Japanese and 8 Caucasian subjects and received SOF at either 
the 200 mg, 400 mg or 800 mg dose levels (Groups 1-3), or 400 mg SOF + 90 mg LDV 
administered as a single dose of the SOF/LDV FDC (Group 4). Safety was assessed by 
evaluation of vital signs, 12-lead ECGs, and adverse events. Plasma and urine samples were 
collected at selected time points to assess the PK of SOF, its metabolites GS-566500 and
GS-331007, and LDV.
SOF and SOF/LDV FDC were well tolerated in this study. 
Pharmacokinetic (plasma) results are in Table 1-1.


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Table 1-1.
GS-US-334-0111 Geometric Least-Squares Mean Ratios 
(90% Confidence Intervals) for Sofosbuvir, GS-566500, GS-331007, 
and Ledipasvir Primary PK Parameters in Japanese versus 
Caucasian Subjects
SOF 200 mg
% GLSM Ratio 
(90% CI)
SOF 400 mg
% GLSM Ratio 
(90% CI)
SOF 800 mg
% GLSM Ratio 
(90% CI)
SOF/LDV FDC 
(400 mg/90 mg)
% GLSM Ratio 
(90% CI)
SOF PK Parameter
AUClast (ng•h/mL)
97.02
(63.62, 147.96)
122.62 
(92.54, 162.47)
106.20 
(82.63, 136.49)
90.52 
(54.44, 150.50)
AUCinf (ng•h/mL)
97.30 
(64.77, 146.16)
121.98 
(92.30, 161.20)
106.27 
(82.84, 136.33)
90.77 
(54.90, 150.07)
Cmax (ng/mL)
101.56 
(62.88, 164.02)
107.05 
(76.31, 150.18)
96.37 
(62.23, 149.23)
93.82
(64.53, 136.42)
GS-566500 PK Parameter
AUClast (ng•h/mL)
158.37 
(119.80, 209.34)
149.64
(117.13, 191.17)
125.17 
(103.74, 151.03)
114.13 
(78.15, 166.67)
AUCinf (ng•h/mL)
153.51 
(117.65, 200.30)
147.47
(116.45, 186.74)
124.39 
(103.30, 149.79)
113.27 
(78.24, 163.98)
Cmax (ng/mL)
154.48 
(116.12, 205.51)
138.62 
(108.12, 177.72)
117.59 
(98.72, 140.06)
130.16 
(93.88, 180.44)
GS-331007 PK Parameter
AUClast (ng•h/mL)
80.29 
(64.62, 99.77)
94.44 
(78.30, 113.90)
82.32 
(71.98, 94.16)
85.63 
(63.56, 115.36)
AUCinf (ng•h/mL)
82.37
(67.59, 100.36)
95.93
(80.14, 114.82)
83.68
(74.25, 94.30)
85.40
(64.04, 113.89)
Cmax (ng/mL)
72.72
(57.86, 91.40)
113.48
(91.12, 141.32)
102.44
(73.52, 142.73)
94.34
(68.03, 130.82)
LDV PK Parameter
AUClast (ng•h/mL)
—
—
—
106.07
(68.95, 163.18)
AUCinf (ng•h/mL)
—
—
—
106.66 
(69.13, 164.59)
Cmax (ng/mL)
—
—
—
125.63 
(83.83, 188.26)
No clinically significant differences in the PK of SOF, its metabolites GS-566500 and 
GS-331007, or LDV were observed between Japanese and Caucasian subjects. The safety and 
pharmacokinetic profiles support the use of SOF 400 mg or SOF/LDV FDC (400 mg/90 mg) in 
Japanese and non-Japanese subjects.


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1.2.2.2.
Phase 3 International Registration Studies with SOF/LDV FDC
The SOF/LDV phase 3 international registration program consists of 3 clinical studies for which 
data are available: GS-US-337-0102 (ION-1), GS-US-337-0109 (ION-2), and GS-US-337-0108 
(ION-3). Studies GS-US-337-0102 and GS-US-337-0109 are evaluating treatment with 
SOF/LDVRBV for 12 or 24 weeks in treatment-naive and treatment-experienced subjects, 
respectively, who are infected with genotype 1 HCV. Both studies enrolled up to 20% of 
HCV-infected subjects who had documented compensated cirrhosis. ION-3 is evaluating 
SOF/LDV±RBV treatment for 8 weeks and SOF/LDV treatment for 12 weeks in noncirrhotic 
treatment-naive subjects with genotype 1 HCV infection.
Across all studies, SOF/LDV demonstrated a high degree of efficacy with point estimates for 
SVR12 > 93% in subjects with genotype 1 HCV infection. The addition of RBV to the 
SOF/LDV regimen did not impact the SVR rate.
Across the SOF/LDV Phase 3 studies, treatment with SOF/LDV was generally safe and well 
tolerated. The 3 most frequently occurring AEs were fatigue, headache, and nausea. A higher 
incidence of each event was reported in subjects receiving SOF/LDV+RBV compared with 
subjects receiving SOF/LDV: fatigue (38.0% vs. 22.2%), headache (26.1% vs. 20.6%), and 
nausea (17.4% vs. 10.4%). The most common Grade 3 or 4 chemistry laboratory abnormalities 
across all treatment groups were increased lipase (1.7%) and increased serum glucose (1.5%). 
In subjects with Grade 3 or 4 increased lipase, no case was associated with clinical signs or 
symptoms of pancreatitis. Among subjects who experienced a Grade 3 or 4 increased serum 
glucose, all subjects had a history of diabetes, were taking diabetes medication, or had glucose 
intolerance (denoted by HbA1c > 6.0% at screening).
1.2.2.3.
Study GS-US-337-0113 SOF/LDV FDC Study in Japan
An open-label, randomized, phase 3b study (GS-US-337-0113) is also being conducted in Japan
to assess the efficacy and safety of 12 weeks of SOF/LDV with or without RBV in 
treatment-naive (TN) and treatment-experienced (TE) subjects with genotype 1 HCV infection. 
A total of 341 subjects (166 treatment-naïve and 175 treatment-experienced) were randomized
(1:1) to receive treatment. The majority of subjects are female (58%), and all are Japanese. The 
majority of subjects have genotype 1b HCV infection (97%), non-CC IL28B alleles (52%), high 
baseline viral load (99% had HCV RNA 5 log10 IU/mL), 22% had liver cirrhosis at baseline, 
and 33% were 65 years of age or older.
SVR12 was achieved by 100% (171/171) of subjects receiving SOF/LDV for 12 weeks and by
98% (167/170) subjects receiving SOF/LDV+RBV for 12 weeks (Table 1-2). The study met its 
primary endpoint of superiority compared to a predefined historical SVR12 rate. Factors that 
have historically been predictive of or associated with lower rates of SVR 
(including age ≥65 years, cirrhosis, and prior treatment failure) had no impact on SVR12 rates in 
this study. Three subjects who received SOF/LDV+RBV did not achieve SVR12: 1 subject 
relapsed after discontinuation of therapy, 1 patient discontinued therapy after 1 week of 
treatment due to rash and 1 patient died during the study.


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Table 1-2.
GS-US-337-0113 Number (and Percentage) of Subjects with SVR12
Treatment-Naive
Treatment-Experienced
SOF/LDV
12 Weeks
(N=83)
SOF/LDV+RBV
12 Weeks
(N=83)
SOF/LDV
12 Weeks
(N=88)
SOF/LDV+RBV
12 Weeks
(N=87)
Overall SVR12
83/83 (100%)
80/83 (96%)
88/88 (100%)
87/87 (100%)
Treatment with SOF/LDV±RBV was generally well tolerated. Most AEs were mild or moderate 
in severity. The addition of RBV to the SOF/LDV treatment regimen resulted in increased rate of 
observed AEs (64% of subjects who received SOF/LDV and 75% of those who received 
SOF/LDV+RBV). The most commonly reported AEs in the RBV-free group were 
nasopharyngitis, headache, and malaise. The most commonly reported AEs in the 
SOF/LDV+RBV group were nasopharyngitis, anemia, headache and rash. Nasopharyngitis was 
thought to be related to the winter season during which the study took place. Two subjects, both 
in the SOF/LDV+RBV group, permanently discontinued study treatment due to an AE.
Consistent with the expected toxicity profile of RBV, decreases from baseline in hemoglobin and 
lymphocytes, and increases in reticulocytes and platelets and total bilirubin were observed in the 
SOF/LDV+RBV 12 Week group.
1.3.
Rationale for This Study
This Phase 3b study is designed to evaluate the efficacy and safety of the SOF/LDV FDC tablet 
administered for 12 weeks in treatment-naïve and treatment-experienced subjects with chronic 
genotype 1 HCV infection. Up to 20% of subjects enrolled in the study may have compensated 
cirrhosis at screening.
As previously described in Sections 1.1.2 and 1.1.3 in there is a significant unmet medical need 
in China, Korea and Taiwan for simple, well-tolerated, IFN-free, all-oral antiviral regimens for 
the treatment of chronic HCV infection.  The current standard of care (Peg-IFNα+RBV) for these 
patients in China, Korea and Taiwan is associated with significant toxicity, with many patients 
unwilling to be treated with these regimens. There also exists substantial numbers of patients 
who cannot receive Peg-IFNα due to relative or absolute contraindications {20450}, {17893}, 
{17893}, {15573}{15573}, {17892}, {3291}.
Gilead has developed an FDC consisting of SOF with LDV, 2 well-tolerated, potent, once-daily 
antiviral agents in late phase clinical development. Based on Phase 2 data, the SOF/LDV FDC 
has the potential to be a simple and highly effective all-oral, once daily treatment regimen for 
chronic genotype 1 HCV infection, after 12 weeks of treatment.
In the Phase 3 ION studies, the same SOF/LDV FDC regimen proposed for this study in China, 
Korea and Taiwan was evaluated in patients with HCV GT-1 infection. SVR12 rates following 
SOF/LDV for 12 weeks greater than 93% were observed in treatment-naïve subjects with and 
without cirrhosis (Studies GS-US-337-0102, GS-US-337-0108).  In treatment-experienced 


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subjects in GS-US-337-0109, the SVR12 rate was 94% (n=102/109) overall, with 95% of 
subjects without cirrhosis achieving SVR12 and 86% of those with cirrhosis achieving SVR12. 
In Japanese subjects with chronic genotype 1 HCV infection, the SVR12 rate was 100% in both 
treatment naïve (n=83) and treatment-experienced (n=88) patients following treatment with 
SOF/LDV for 12 weeks.
Current data for the SOF/LDV FDC indicates the regimen to be safe, well-tolerated and 
associated with high degrees of antiviral efficacy, supporting the conduct of the proposed 
Phase 3 study in Chinese, Korean and Taiwanese subjects with GT-1 chronic hepatitis C.
1.4.
Rationale for Dose Selection of SOF/LDV FDC
Gilead has developed a fixed-dose combination (FDC) tablet consisting of SOF 400 mg with 
LDV 90 mg, 2 well-tolerated, potent, once-daily antiviral agents. SOF 400 mg is the marketed 
dose of SOF in the US and Europe for the treatment of HCV-infection and as such, has been 
selected for co-formulation with LDV. LDV 90 mg was selected for co-formulation with SOF 
based on safety, PK and antiviral activity data (studies GS-US-256-0102 and GS-US-248-0120). 
Study GS-US-256-0102 established the anti-HCV activity of LDV and indicated that the 
exposures achieved following administration of the 30 mg dose provides >95% of maximal 
antiviral response in GT 1a HCV infected subjects. It was also observed that 30 mg or greater of 
LDV likely provided coverage of some drug related mutations that doses less than 30 mg did not, 
based on an analysis of NS5A mutants that arose in response to exposure to LDV. Therefore, 
30 mg and 90 mg of LDV were selected for further clinical evaluation. In Study 
GS-US-248-0120, 30 mg of LDV was compared to 90 mg of LDV, on a background of 3 other 
antivirals, vedroprevir (VDV, formerly GS-9451, PI), tegobuvir (formerly GS-9190, NNI), and 
RBV. Based on a breakthrough rate in the 90 mg arms of 12% compared to a 27% breakthrough 
rate in the 30 mg arm, 90 mg LDV was selected for further clinical development.
The fixed-dose combination tablet (FDC) of sofosbuvir/ledipasvir 400 mg/90 mg with or without 
RBV has demonstrated favorable safety and efficacy profiles in over 2500 HCV-infected 
subjects across different patient populations in Phase 2 and 3 trials. These doses represent the 
proposed marketed doses of ledipasvir and sofosbuvir that are currently under regulatory review 
in the US, EU and certain other countries worldwide.
1.5.
Overall Risk/Benefit Assessment
The SOF/LDV FDC product combines a potent HCV nucleotide NS5B inhibitor and a potent 
HCV NS5A inhibitor. 
The potential benefits of SOF/LDV FDC for the treatment of chronic HCV are:

Greater antiviral efficacy (i.e., rapid and durable eradication of HCV) compared to the 
current standard of care (Peg-IFNα +RBV)

A reduction in the AEs currently associated with the use of Peg-IFNα+RBV


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
A simple, well-tolerated regimen to replace the current complex, response-guided Peg-IFNα
+RBV regimens.

The potential benefit of a shortened SOF/LDV FDC therapy of 12 weeks is a decrease in the 
burden of treatment for both patients and physicians, through a reduction in the overall 
number of patient visits.
The safety profile of SOF includes more than 3000 chronic HCV-infected subjects that have 
been administered over 12 weeks of SOF in combination with a DAA, Peg-IFNα, with or 
without RBV. No clinical safety issues related to SOF have been identified to date. The safety 
profile of LDV includes over 1000 chronic HCV-infected subjects, of whom over 700 have been 
administered more than 12 weeks of LDV, which was given in combination with other DAAs, 
Peg-IFNα, with or without RBV. No clinical safety issues related to LDV have been identified to 
date.
Furthermore, there is no expectation of significant overlapping or new, unexpected toxicities 
upon administration of SOF/LDV together as an FDC. To date, the SOF/LDV FDC ± RBV has 
been administered to over 2500 HCV infected subjects in phase 2/3 trials. No clinical safety 
issues related to the SOF/LDV FDC have been identified to date.
During the conduct of the study the Sponsor will perform ongoing safety data review.
In summary, there is no currently approved all-oral treatment available for HCV-infected 
patients. This study will support the registration of the SOF/LDV FDC in treatment-naïve and 
treatment-experienced Chinese, Korean and Taiwanese subjects with chronic genotype 1 HCV 
infection including those with compensated cirrhosis.
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2. 
OBJECTIVES 
The prima1y objectives of this study are: 
Final 
Amendment 3.0 
• 
To determine the antiviral efficacy of treatment with sofosbuvir (SOF)/ledipasvir (LDV) 
fixed-dose combination (FDC) as measured by the prop01tion of subjects with sustained 
virologic response (SVR) 12 weeks after discontinuation of therapy (SVR12, defmed as 
HCV RNA < lower limit of quantitation [LLOQ] 12 weeks post treatment) 
• 
To evaluate the safety and tolerability of SOF ILDV FDC as assessed by review of the 
accumulated safety data 
The secondmy objectives of this study are as follows: 
• 
To detennine the prop01tion of subjects who attain SVR at 4 and 24 weeks after 
discontinuation of therapy (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after treatment 
discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV during treatment and after 
treatment discontinuation 
The explorat01y objectives of this study are: 
PPO 
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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoints of this study are:

The primary efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after discontinuation 
of therapy) in the Full Analysis Set (FAS) population.

The primary safety endpoint is any AE leading to permanent discontinuation of study drug.
Secondary endpoints of this study include:

Secondary efficacy endpoints include the proportion of subjects with: HCV RNA < LLOQ at 
4 and 24 weeks after discontinuation of therapy (SVR4 and SVR24); viral breakthrough; 
relapse; and HCV RNA change from baseline.
3.2.
Study Design
This will be an international (China, Korea and Taiwan), multicenter, open-label study in 
treatment-naïve and treatment-experienced adults with chronic genotype 1 HCV infection.
It is estimated that approximately 200 subjects will be enrolled in China, 80 subjects will be 
enrolled in Korea and 80 subjects in Taiwan for a total of 360 enrolled subjects. Within each
country approximately 50% (i.e., n~100 or 40) of subjects will be treatment-naïve and 50% will 
be treatment-experienced (i.e., n~100 or 40).
Up to 20% of subjects enrolled in the study may have compensated cirrhosis at Screening.
3.3.
Study Treatment
Approximately 180 treatment-naïve and 180 treatment-experienced subjects will receive 
treatment with SOF 400 mg/LDV 90 mg fixed dose combination (FDC) tablet for 12 weeks.
3.4.
Duration of Treatment
All subjects will complete screening, on-treatment, and post-treatment assessments. Screening 
assessments will be completed within 28 days of the Baseline/Day 1 visit or within 42 days if a 
liver biopsy or additional HCV genotyping is required. All subjects will receive treatment for 
12 weeks. All subjects will complete a 4-week and 12-week Post-Treatment visit. Subjects with 
HCV RNA < LLOQ at the 12-Week Post-Treatment visit will also complete a 24-Week 
Post-Treatment visit unless confirmed viral relapse occurs.
The assessments performed at each visit are described in Section 6.


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3.5.
Discontinuation Criteria 
When medically feasible, the Medical Monitor must be consulted prior to the premature 
discontinuation of treatment in a given subject.
Study drug must be discontinued in the following instances:

Unacceptable toxicity, as defined in Section 7 of the protocol, or toxicity that, in the 
judgment of the investigator, compromises the ability to continue study-specific procedures 
or is considered to not be in the subject’s best interest

Pregnancy of female subject
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 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.
All subjects will complete the 4-Week and 12-Week Post-treatment visits. Subjects with 
HCV RNA < LLOQ at the 12-week Post-treatment visit will return for the 24-week 
Post-treatment visit, unless confirmed viral relapse occurs. Study drug may be discontinued in 
the following instances:

Significant protocol violation

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason

Discontinuation of the study at the request of Gilead, regulatory agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)
If a subject meets discontinuation criteria during treatment, an Early Termination (ET) visit will 
be required (Section 6.4.9). Following completion of the Early Termination visit, all subjects 
must complete the 4-week and 12-week Post-Treatment visits. All patients with 
HCV RNA < LLOQ at the 12-week Post-Treatment visit must return to the clinic for 24-week 
Post Treatment assessments, unless confirmed viral relapse occurs.
3.6.
Source Data
A Health Related Quality of Life survey, Short-Form-36 (SF-36) will be completed by subjects 
at various timepoints during the study and be used as source data. The subject should read the 
questionnaire by himself/herself and write/mark answers directly onto the questionnaire.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 360 subjects will be enrolled in this study with approximately 
180 treatment-naïve subjects and approximately 180 treatment-experienced subjects. Up to 
20% of subjects enrolled in the study may have compensated cirrhosis at screening.
In order to manage the total study enrollment, Gilead Sciences, Inc., at its sole discretion, may 
suspend screening and/or enrollment at any site or study-wide at any time.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Willing and able to provide written informed consent
2) Male or female, age 20 years
3) Body weight 40 kg
4) HCV RNA 104 IU/mL at Screening
5) Ability to categorize as treatment-naïve or treatment-experienced, defined below:
a) HCV treatment-naïve, as defined as no prior exposure to any IFN, or other approved or 
experimental HCV-specific direct-acting antiviral agent; OR
b) HCV treatment-experienced with medical records that include sufficient detail of prior 
IFN-based treatment to allow for categorization of prior response as either:
i)
Intolerant:  Subject discontinued treatment due to development or significant 
worsening of an adverse event associated with HCV treatment.
ii) Non-Response: Subject did not achieve undetectable HCV RNA levels while on 
treatment
iii) Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during 
treatment or within 4 weeks of the end of treatment, but did not achieve a sustained 
virologic response (SVR)
Treatment-experienced subjects must not have discontinued prior treatment due to non-
compliance with treatment.
6) Genotype 1 HCV at Screening as determined by the Central Laboratory. Any non-definitive 
results will exclude the subject from study participation
7) Confirmation of chronic HCV infection documented by either:
a) A positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping 
test at least 6 months prior to the Baseline/Day 1 visit, or


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b) A liver biopsy performed prior to the Baseline/Day 1 visit with evidence of chronic HCV 
infection
8) Cirrhosis determination [up to 20% of subjects enrolled in the study may have compensated 
cirrhosis]: 
a) Cirrhosis is defined as any one of the following, below. Meeting any of these criteria will 
categorize the subject as cirrhotic.
i)
Liver biopsy showing cirrhosis (e.g. Metavir score = 4 or Ishak score 5)
ii) Fibroscan indicative of cirrhosis as evidenced by a result > 12.5 kPa
b) Absence of cirrhosis is defined as any one of the following:
i)
Liver biopsy within 2 years prior to Screening showing absence of cirrhosis
ii) Fibroscan within 6 months prior to Baseline/Day 1 with a result of ≤ 12.5 kPa
9) Liver imaging within 6 months of Baseline/Day 1 to exclude hepatocellular carcinoma 
(HCC) is required in patients with cirrhosis
10) Screening ECG without clinically significant abnormalities
11) Subjects must have the following laboratory parameters at screening: 
a) ALT 10 the upper limit of normal  (ULN)
b) AST 10 ULN
c) Direct bilirubin 1.5 ULN
d) Platelets  50,000/µL
e) HbA1c 8.5%
f)
Creatinine clearance (CLcr) 50 mL /min, as calculated by the Cockcroft-Gault equation 
{2202}
g) Hemoglobin  11 g/dL for female subjects; 12 g/dL for male subjects.
h) Albumin 3g/dL 
i)
INR ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR.
12) 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 Baseline/Day 1 prior to 
enrollment.


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13) 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.
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.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Current or prior history of any of the following:
a) Clinically-significant illness (other than HCV) or any other major medical disorder that 
may interfere with subject treatment, assessment or compliance with the protocol; 
subjects currently under evaluation for a potentially clinically-significant illness (other 
than HCV) are also excluded.  
b) Gastrointestinal disorder or post-operative condition that could interfere with the 
absorption of the study drug. 
c) Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy.
d) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).
e) Solid organ transplantation.
f)
Significant pulmonary disease, significant cardiac disease or porphyria.
g) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of 
their psychiatric illness within the last 5 years. Subjects with psychiatric illness
(without the prior mentioned conditions) that is well-controlled on a stable treatment 
regimen for at least 12 months prior to Baseline/Day 1 or has not required medication in 
the last 12 months may be enrolled. 
h) 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.
i)
Significant drug allergy (such as anaphylaxis or hepatotoxicity). 
2) If treatment-naïve, prior exposure to approved or experimental HCV-specific direct-acting 
antiviral agent(s). If treatment-experienced, prior exposure to approved or experimental 
HCV-specific direct-acting antiviral agent(s) other than NS3/4A protease inhibitors is
prohibited.


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3) Pregnant or nursing females.
4) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency, cholangitis).
5) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
6) Donation or loss of more than 400 mL blood within 2 months prior to Baseline/Day 1.
7) Use of any prohibited concomitant medications as described in Section 5.4.
8) Administration of interferon or any HCV-directed treatment, other than the study drug, is 
prohibited from 12 weeks prior to Screening until completion of the final post-treatment 
follow-up visit.
9) Chronic use of systemically administered immunosuppressive agents 
(e.g., prednisone equivalent > 10 mg/day), azathioprine or monoclonal antibodies such as 
infliximab.
10) Known hypersensitivity to SOF, LDV, or formulation excipients. 


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Treatment Codes
This is an open-label, non-randomized study. Every subject will receive SOF/LDV FDC tablet 
for 12 weeks. An Interactive Web Response System (IWRS) will be employed to manage subject 
enrollment and study drug dispensation.
5.2.
Description and Handling of Sofosbuvir/Ledipasvir Fixed-Dose Combination 
5.2.1.
Formulation
Sofosbuvir (SOF)/ledipasvir (LDV) fixed-dose combination (FDC) tablets are orange, diamond-
shaped, film-coated tablets containing 400 mg of SOF and 90 mg of LDV. The tablets are 
debossed with “GSI” on one side and “7985” on the other side. The SOF/LDV FDC tablets
contain the following inactive ingredients: lactose monohydrate, copovidone, microcrystalline 
cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, FD&C yellow # 6 /sunset yellow 
FCF aluminum lake.
5.2.2.
Packaging and Labeling
Sofosbuvir (SOF)/ledipasvir (LDV) fixed-dose combination (FDC) tablets are packaged in 
white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets (Korea and 
Taiwan) or 28 tablets (China only) and a silica gel desiccant canister or sachet and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner.
All labels for SOF/LDV FDC bottles to be distributed to study centers in participating countries 
shall be labeled to meet all applicable requirements of the US Food and Drug Administration 
(FDA) and local regulations as applicable.
Sufficient quantities of SOF/LDV FDC tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Materials & Logistics (or its designee).
5.2.3.
Storage and Handling
Sofosbuvir (SOF)/ledipasvir (LDV) FDC bottles should be stored at controlled room temperature 
until required for administration. Controlled room temperature is defined as 25 C; excursions 
are permitted between 15 C and 30 C.
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the Investigational Medicinal Product (IMP) 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 


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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/LDV FDC.
5.3.
Dosage and Administration of Sofosbuvir/Ledipasvir FDC 
Sofosbuvir/Ledipasvir 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 IMP doses. In order to maintain compliance with the treatment regimen, SOF/LDV 
FDC should be administered at approximately the same time each day.
For missed dose(s) of study medication, subjects should be instructed to take the missed dose(s) 
of IMP as soon as possible during the same day.  Subjects should be cautioned never to double 
the next dose with a missed dose of IMP under any circumstances.
5.4.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to Screening, up to and including the date of 
the visit four weeks after discontinuation of study treatment need to be recorded in the source 
documents and electronic case report form(s) (eCRFs).
Administration of interferon or any HCV-directed treatment, other than the study drug, is 
prohibited from 12 weeks prior to Screening until completion of the final post-treatment 
follow-up visit.
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Baseline/Day 1 visit through the end of treatment:

Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO mimetics)

Chronic use of systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or 
monoclonal antibodies (e.g., infliximab)

Investigational agents or devices for any indication
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters ie, P-gp) with study drug may result in pharmacokinetic interactions resulting 
in increases or decreases in exposure of study drug.  
The use of amiodarone is prohibited from 60 days prior to Baseline/Day 1 through the end of 
treatment.


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Examples of representative medications which are prohibited from 21 days prior to 
Baseline/Day 1 through the end of treatment are listed below:
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
Anticonvulsantsc
Phenobarbital, phenytoin, 
carbamazepine, oxcarbazepine
Antimycobacterialsc
Rifabutin, rifapentine, rifampin
Cardiac Medications
Amiodaronee
Digoxin b
Herbal/Natural Supplementsc
St. John’s Wort, Echinacea, milk 
thistle (ie, silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-
Tang)
HMG-CoA Reductase Inhibitorsd
Rosuvastatin
a
It is recommended to separate antacid and SOF/LDV FDC administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from SOF/LDV FDC at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with SOF/LDV FDC. Proton-pump inhibitors should not be taken before SOF/LDV FDC.
b
Co-administration of SOF/LDV FDC with digoxin may increase the concentration of digoxin. Caution is warranted and 
therapeutic concentration monitoring of digoxin is recommended when co-administered with SOF/LDV FDC. 
c
May result in a decrease in the concentrations of study drugs.
d
Use with study drug may result in an increase in the concentration of rosuvastatin, which is associated with increased risk of
myopathy, including rhabdomyolysis.
e
May result in symptomatic bradycardia. Mechanism is not currently known. The use of amiodarone is prohibited from 
60 days prior to Baseline/Day 1 through the end of treatment.
Medications for disease conditions excluded from the protocol (eg, HIV-1 infection, 
active cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study. 
5.5.
Accountability for SOF/LDV FDC
The investigator is responsible for ensuring adequate accountability of all used and unused IMP.
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). 
All used and unused IMP dispensed to subjects must be returned to the site.
SOF/LDV FDC accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits.

Record the date, subject number, subject initials, the IMP kit number dispensed.

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.


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Subjects must be instructed to bring back all bottles of study medication in the original container 
at every post-baseline study visit through the end of treatment.
Study medication will be reconciled using medication pill counts at every post-baseline visit by 
the investigator or designee (e.g., pharmacist, study coordinator) in order to monitor the subject’s 
adherence with the medication regimen. 
5.5.1.
Investigational Medicinal Product Return or Disposal
Please refer to Section 9.1.7 for Investigational Medicinal Product Accountability and Return.


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6.
STUDY PROCEDURES
Study visits will occur at Screening, Baseline/Day 1, and on-treatment at the end of Weeks 1, 2, 
4, 6, 8, 10, and 12. All subjects will complete 4-week and 12-week Post-Treatment visits. In 
addition, all subjects with HCV RNA < LLOQ at the 12-week Post-Treatment visit will complete 
a 24-week Post-Treatment visit unless confirmed viral relapse occurs. The end of study will 
occur at the 12-week or 24-week Post-Treatment visit according to virologic response.
Administration of interferon or any HCV-directed treatment, other than the study drug, is 
prohibited from 12 weeks prior to Screening until completion of the final post-treatment 
follow-up visit.
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. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
Information on the specific laboratory parameters to be measured and clinical assessments to be 
performed are provided below.
6.1.
Subject Enrollment and Treatment Assignment
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit (Day -28 to Day -1)
Screening assessments will be completed within 28 days of the Baseline/Day 1 visit. The 
screening window can be extended to 42 days for subjects requiring liver biopsy or additional 
HCV genotype testing. 
Subjects will be screened to determine eligibility for participation in the study. The following 
will be performed and documented at screening:

Obtain signed informed consent
A separate informed consent will be required from subjects participating in the intensive 
pharmacokinetic and/or pharmacogenomic sub-studies.

Determine inclusion eligibility (Reference Section 4.2 and 4.3)
If the presence of cirrhosis is determined, then appropriate diagnostic imaging 
(e.g., CT or Ultrasound) should be performed to exclude the presence of hepatocellular 
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
Obtain medical history (Reference Section 6.6.2)

Perform complete physical examination

Obtain body height and weight

Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature)

Perform 12-lead ECG

Assessment of AEs and concomitant medications 

Obtain blood samples for tests 
Hematology & Chemistry
Coagulation tests
HCV RNA
Serum -hCG pregnancy test for females of childbearing potential only
IL28B genotype 
Determination of genotype and subtype of HCV infection
HCV antibody, HIV 1/2 antibody, and HBV surface antigen (HBsAg)
HbA1c
TSH

Obtain urine sample for:
Urinalysis
Record any adverse events occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 28-42 days after screening for entry 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 non-serious adverse 
events related to protocol-mandated procedures on the adverse events case report form 


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(CRF/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 
CRF/eCRF.  See Section 7 Adverse Events and Toxicity Management for additional details.
6.3.
Randomization
This is a non-randomized study. An Interactive Web Response System (IWRS) will be employed 
to manage subject enrollment and study drug dispensation.
6.4.
Treatment Assessments
6.4.1.
Baseline/Day 1 Visit
The following baseline tests and procedures must be completed prior to dosing/dispensing:

Confirm eligibility

Perform complete physical examination

Obtain body weight

Obtain vital signs

Perform 12-lead ECG

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Subject completes Health Related Quality of Life Survey, SF-36

Obtain blood samples for:
Hematology & Chemistry
Coagulation tests
HCV RNA
Viral RNA Sequencing / Phenotyping Sample
Archive Sample (for subjects that have not opted out)
Pharmacogenomic testing (for subjects who have consented to participate in the 
Pharmacogenomic Substudy)


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
Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Drug Administration
Dispense study drugs 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 drugs and record the time of first dose.
6.4.2.
Week 1 (3 days)
The following procedures/assessments are to be completed at the end of Week 1.

Obtain vital signs

Perform 12-lead ECG

Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Single PK Sample
Viral RNA Sequencing / Phenotyping Sample

Complete medication pill count and review patient diary data with subject
6.4.3.
Week 2 (3 days)
The following procedures/assessments are to be completed at the end of Week 2:

Obtain vital signs

Assessment of AEs and concomitant medications

Subject completes Health Related Quality of Life Survey, SF-36


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
Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Single PK Sample
Viral RNA Sequencing / Phenotyping Sample 
If applicable at Week 2, collect serial PK substudy samples (for subjects who have 
consented to participate in the PK substudy)

Complete medication pill count and review dosing diary data with subject
6.4.4.
Week 4 (3 days)
The following procedures/assessments are to be completed at the end of Week 4:

Obtain vital signs

Assessment of AEs and concomitant medications

Subject completes Health Related Quality of Life Survey, SF-36

Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Single PK Sample
Viral RNA Sequencing / Phenotyping Sample 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only
If applicable at Week 4, collect serial PK substudy samples (for subjects who have 
consented to participate in the PK substudy)

Complete medication pill count and review patient diary data with subject

Dispense study drugs as directed by the IWRS


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6.4.5.
Week 6 (3 days)
The following procedures/assessments are to be completed at the end of Week 6.

Obtain vital signs

Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Single PK Sample
Viral RNA Sequencing / Phenotyping Sample 

Complete medication pill count and review patient diary data with subject
6.4.6.
Week 8 (3 days)
The following procedures/assessments are to be completed at the end of Week 8:

Obtain vital signs

Assessment of AEs and concomitant medications

Subject completes Health Related Quality of Life Survey, SF-36

Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Single PK Sample
Viral RNA Sequencing / Phenotyping Sample

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Complete medication pill count and review patient diary data with subject

Dispense study drugs as directed by the IWRS


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6.4.7.
Week 10 (3 days)
The following procedures/assessments are to be completed at the end of Week 10.

Obtain vital signs

Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Single PK Sample
Viral RNA Sequencing / Phenotyping Sample

Complete medication pill count and review patient diary data with subject
6.4.8.
Week 12 (3 days)
The following procedures/assessments are to be completed at the end of Week 12:

Perform complete physical examination

Obtain body weight

Obtain vital signs

Perform 12-lead ECG

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Subject completes Health Related Quality of Life Survey, SF-36

Obtain blood samples for:
Hematology & Chemistry
Coagulation tests
HCV RNA
Single PK Sample


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Viral RNA Sequencing / Phenotyping Sample
Archive Sample (for subjects that have not opted out)

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Complete medication pill count and review patient diary data with subject
6.4.9.
Early Termination (ET)/Unscheduled Visit 
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments at the unscheduled visits are at the investigator’s discretion. At all unscheduled 
visits initiated for the purpose of confirming virologic failure, a Viral RNA
Sequencing / Phenotyping Sample must be collected.
The Sponsor (e.g. Medical Monitor and Clinical Program Manager)/ CRO must be informed, as 
soon as possible, when a subject prematurely discontinues treatment. The primary reason for 
premature treatment discontinuation must be provided to the Sponsor/ CRO.
If a subject discontinues treatment early for any reason then the following assessments for the 
Early Termination (ET) Visit must be performed:

Perform complete physical examination

Obtain body weight

Obtain vital signs

Perform 12-lead ECG

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Subject completes a Health Related Quality of Life Survey, SF-36

Obtain blood samples for:
Hematology & Chemistry
Coagulation tests
HCV RNA


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Single PK Sample
Viral RNA Sequencing / Phenotyping Sample
Archive Sample (for subjects that have not opted out)

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Complete medication pill count and review dosing diary data with subject
6.5.
Post-Treatment Assessments
All subjects must complete the Post-Treatment Week 4 and Week 12 visits. For subjects who 
have completed an ET visit, the post-treatment Week 4 and Week 12 follow-up visits will be 
scheduled at 4 and 12 weeks after the last dose of study drug. All subjects with 
HCV RNA < LLOQ at the 12-week Post-Treatment visit will also complete the 24-week 
Post-Treatment visit, unless viral relapse is determined.
6.5.1.
Post Treatment Week 4 (5 days)
The following procedures/assessments are to be completed for all subjects, 4 Weeks after taking 
the last dose of study drug:

Obtain vital signs

Assessment of AEs and concomitant medications

Pregnancy prevention counseling 

Subject completes a Health Related Quality of Life Survey, SF-36

Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Viral RNA Sequencing / Phenotyping Sample 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only
All subjects, including those who prematurely discontinue study drug, must return for 
Post Treatment Visit at Week 12.


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6.5.2.
Post Treatment Weeks 12 and 24 (5 days)
The following procedures/assessments are to be completed for the Post-treatment Week 12 and 
24 Visits:

Obtain body weight

Obtain vital signs

Subject completes a Health Related Quality of Life Survey, SF-36 (Post treatment Week 12 
only)

Obtain blood samples for:
HCV RNA
Viral RNA Sequencing / Phenotyping Sample 
Subjects with HCV RNA < LLOQ at the Post-Treatment Week 12 Visit will return at the 
post-treatment Week 24 Visit. 
6.6.
Procedures and Specifications
6.6.1.
Clinical Laboratory Analytes
Hematology: Hematocrit, Hemoglobin (Hb), Platelet count, Red blood cell count (RBC), 
White blood cell count (WBC) with differential (absolute and percentage) including 
Lymphocytes, Monocytes, Neutrophils, Eosinophils, Basophils, Reticulocyte count and MCV.
Coagulation: INR, Prothrombin time (PT), Activated partial thromboplastin time (APTT).
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct Bilirubin), 
Direct Bilirubin at Screening only, Glucose, Lipase, Potassium, Sodium; Gamma-glutamyl 
transferase (GGT) at Baseline only.
Urinalysis: Appearance, Blood, Color, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV, HBV and HIV. HCV RNA will be measured using the 
COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System or COBAS® AmpliPrep 
/ COBAS® TaqMan® HCV Test, v2.0. HCV genotype and subtype will be determined using the 
Siemens VERSANTHCV Genotype INNO-LiPA 2.0 Assay. Gilead reserves the right to use 
alternate assays for HCV RNA and HCV genotype should the above assays become unavailable 
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 


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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 -hCG or Urine -hCG (if positive, requires immediate confirmation 
with Serum -hCG)
Additional Tests: Hemoglobin A1c (HbA1c), and TSH (reflex free T4).
6.6.2.
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. Additionally, for treatment naïve subjects, any relative or absolute contraindications to 
interferon treatment (“IFN ineligible”) should be identified. Information related to 
HCV infection will also be collected.
For treatment-experienced subjects, obtain HCV treatment history, in order to categorize the 
patient as either IFN-intolerant, non-responder or relapse/breakthrough, defined as:

IFN-intolerant:  Subjects considered to be IFN-intolerant must (according to investigator 
judgment) have sufficiently recovered from IFN-related clinical adverse events and/or 
laboratory abnormalities prior to Screening. In addition, all other protocol eligibility criteria 
must be met.

Non-Responder: Subject did not achieve undetectable HCV RNA levels 
(HCV RNA ≥LLOQ) while on treatment. For Peg-IFNα/IFN/RBV non-responders, subjects 
should be further defined as Null or Partial Responders:
Null Responders: HCV RNA < 2 Log10 reduction during the first 12 weeks of treatment.
Partial Responders: HCV RNA ≥ 2 Log10 reduction during the first 12 weeks of 
treatment.

Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels 
(HCV RNA < LLOQ) during treatment or within 4 weeks of end of treatment, but did not 
achieve a sustained virologic response (SVR).
6.6.3.
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and 
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological. 


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6.6.4.
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.
6.6.5.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} using actual body 
weight (BW). 
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)
6.6.6.
12-Lead ECGs
Subjects will be required to rest in a supine position for 5 minutes prior to making a recording.
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities.  On-treatment ECGs should be compared to the subject’s 
Baseline as part of routine safety monitoring.
6.6.7.
Viral RNA Sequencing / Phenotyping Sample 
Plasma samples will be collected at Baseline/Day 1 and each additional visit for viral sequence 
analysis. At any unscheduled visit initiated for the purpose of confirming virologic breakthrough, 
a plasma sample for viral sequence analysis must be collected. Untested samples may be
archived.
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual.


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6.6.8. 
Optional Archive Sample 
PD 
6.6.9. 
Single Pharmacokinetic (PK) Sample 
Final 
Amendment 3.0 
Single PK blood samples will be collected for all subjects at each on-treatment visit after 
Baseline/Day 1 and archived for PK analysis of SOF (and its metabolites GS-566500 and 
GS-331 007) and LDV. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.6.10. 
Intensive Pharmacokinetic (PK) Substudy (Korea and Taiwan only) 
PPD 
6.6.11. 
Pharmacogenomic (PG) Substudy 
PPD 
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6.6.12. 
Pregnancy Testing 
Final 
Amendment 3.0 
All females of childbearing potential will have urine pregnancy testing eve1y 4 weeks during the 
dosing period and for a minimum of 1 month following the last dose of study dmg. In the event 
of a positive urine pregnancy test result, subjects will be instructed to stop study dmgs 
immediately and retum to the clinic as soon as possible for a confmnat01y semm pregnancy test. 
6.6.13. 
Health Related Quality of Life Survey 
A health related quality oflife survey, SF-36 will be completed by patients at Baseline/Day 1, 
On-ti·eatinent Weeks 2, 4, 8, 12, Post-ti·eatment Weeks 4 and 12, and Early Tennination 
(if applicable). The subject should read the questionnaire by himself/herself and write/mark 
answers directly onto the questionnaire. 
6.7. 
Assessments for Premature Discontinuation from Study 
If a subject discontinues study dosing (for example, as a result of an AE), eve1y attempt should 
be made to keep the subject in the study and continue to perf01m the required study-related 
follow-up and procedures (see Section 6.4.9). If this is not possible or acceptable to the subject 
or investigator, the subject may be withdrawn from the study. 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. AEs may also include pre- or post treatment complications that 
occur as a result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse 
reports, or occupational exposure. Preexisting events that increase in severity or change in nature 
during or as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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


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7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
All SAEs, regardless of causal relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-mandated procedures performed from screening 
onwards.
All AEs, regardless of causal relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP must be reported to the CRF/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 post-treatment follow up 
period.
Investigators are not obligated to actively seek SAEs after post treatment follow-up. However, if 
the investigator learns of any SAEs that occur after study participation has concluded, i.e., after 
the 12-week or 24-week post treatment visit (as applicable) and the event is deemed relevant to 
the use of IMP, he/she should promptly document and report the event to Gilead DSPH.
Gilead DSPH contact information is as follows: Email: Safety_FC@gilead.com and 
Fax: +1 (650) 522-5477.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours as described above.
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.


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CRO and Gilead Sciences Phrumacovigilance Representative contact inf01mation is as follows: 
CRO Phan nacovigilance 
Representative 
(for sites in Korea and Taiwan): 
CRO Phrumacovigilance 
Representative 
(for sites in China): 
CRO Medical Monitor 
(for sites in Korea and Taiwan): 
CRO Medical Monitor 
(for sites in China) 
Gilead Sciences Medical Monitor 
(Back-Up): 
SAE Hotline: 
Korea: 
Taiwan: 
E-mail: 
China: 
E-mail: 
Name: 
Phone: 
Fax: 
E-mail: 
Name: 
Phone: 
Fax: 
E-mail: 
Name: 
Phone: 
Fax: 
E-mail: 
+ 65 6221 8582 
+ 00308 13 2766 
+ 00801 10 4423 
medical_ singapore@pru·exel.com 
Quintiles 
Ph V _ Gilead@quintiles.com 
Viola Yang 
PPD 
PPD 
PPD 
I 
Ian Escudero 
PPD 
PPD 
1-'1-'U 
I 
Chohee Ylm MD 
PPD 
PPD 
1-'1-'U 
I 
• 
For fatal or life-threatening events, copies of hospital case rep01ts, autopsy rep01ts, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occm without personal subject identification, 
maintaining the u·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensme the timely completion of accmate safety 
rep01ts. 
Any medications necessruy for u·eahnent of the SAE must be recorded onto the concomitant 
medication section of the subject's CRF/eCRF and the event description section of the SAE 
f01m. 
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 regulat01y agencies rep01ts of SAEs, serious adverse dmg reactions (SADRs), or 
suspected lmexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulat01y 
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agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. 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.
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).
Severity should be recorded and graded according to the GSI Grading Scale for Severity of AEs 
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.
7.6.
Subject Stopping Rules
The Medical Monitor must be consulted prior to dose discontinuation of SOF/LDV 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/LDV FDC dose reduction. If SOF/LDV FDC is stopped due to toxicity, it 
must not be restarted; if SOF/LDV FDC is discontinued, the subject must complete an ET visit. 
Post-treatment 4-Week and 12-Week visits must also be scheduled, 4 and 12 weeks from the last 
dose of study drug. Subjects with HCV RNA < LLOQ at the 12-week Post-Treatment visit will 
complete the 24-week Post-Treatment visit, unless viral relapse is determined. 
Subjects who meet any of the following laboratory criteria must stop study medication:

Elevation of ALT and/or AST > 5x Baseline/Day 1 or nadir, confirmed by immediate repeat 
testing

Abnormal elevation of ALT > 3 x Baseline/Day 1 and total bilirubin > 2 x ULN, confirmed 
by immediate repeat testing


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
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 as related to SOF/LDV FDC
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, and 
pregnancy reports regardless of an associated AE.  Also includes reports of adverse reactions in 
infants following exposure from breastfeeding, and reports of adverse reactions associated with 
product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure to 
the medicinal product.
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. 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.
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the CRO Pharmacovigilance Representative using the 
pregnancy report form within 24 hours of becoming aware of the pregnancy. 
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.


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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 
the Serious Adverse Events section (Section 7.3). Furthermore, any SAE occurring as an adverse 
pregnancy outcome post study must be reported to the CRO Pharmacovigilance Representative.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to the CRO Pharmacovigilance Representative using 
the pregnancy outcome report form. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead DSPH. Gilead DSPH contact 
information is as follows: Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Pregnancies of female partners of male study subjects exposed to Gilead study drugs must also 
be reported and relevant information should be submitted to the CRO Pharmacovigilance 
Representative using the pregnancy and pregnancy outcome forms within 24 hours. Monitoring 
of the subject’s partner should continue until the conclusion of the pregnancy. If the end of the 
pregnancy occurs after the study has been completed, the outcome should be reported directly to 
Gilead DSPH, fax number +1 650 522-5477 or email Safety_FC@gilead.com.
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to the CRO Pharmacovigilance Representative within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study IMP, 
but do not apply to concomitant medications. Except for situations that result in AEs, special 
situations involving concomitant medications will not be reported. Any inappropriate use of 
medications prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y analysis objectives of this study are: 
Final 
Amendment 3.0 
• 
To detennine the antiviral efficacy of combination treatment with sofosbuvir 
(SOF)/ledipasvir (LDV) fixed-dose combination (FDC) as measmed by the prop01iion of 
subjects with sustained virologic response (SVR) 12 weeks after discontinuation of therapy 
(SVR12, defmed as HCV RNA < lower limit of quantitation [LLOQ] 12 weeks post 
treatment). 
• 
To evaluate the safety and tolerability of SOFILDV FDC as assessed by review of the 
accumulated safety data 
The secondmy objectives of this study m·e as follows: 
• 
To determine the prop01iion of subjects who attain SVR at 4 and 24 weeks after 
discontinuation of therapy (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA dming treatment and after treatment 
discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV dming treatment and after 
treatment discontinuation 
The explorat01y objectives of this study are: 
PPO 
I 
8.1.2. 
Primary Endpoint 
The prima1y efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after discontinuation of 
therapy) in the Full Analysis Set (F AS) population. 
The primary safety endpoint is any AE leading to pennanent discontinuation of study dmg. 
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8.1.3.
Secondary Endpoint
Secondary efficacy endpoints include the proportion of subjects with: HCV RNA < LLOQ at 
4 and 24 weeks after discontinuation of therapy (SVR4 and SVR24); viral breakthrough; relapse; 
and HCV RNA change from baseline.
8.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include ALT normalization; and the health related quality of 
life endpoints.
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).
Last dose of study drug refers to the last dose of SOF/LDV 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 post-treatment time points.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which includes 
subjects who were enrolled and received at least one dose of study drug and have chronic 
genotype (1a, 1b, or mixed 1a/1b) HCV infection. 
8.2.1.2.
Safety
The primary analysis set for safety analyses is defined as subjects who were enrolled and 
received at least one dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of 
study drug through the date of the last dose of study drug plus 30 days.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all subjects who are enrolled and have received at least one dose 
of study drug and for whom concentration data of analytes [SOF, LDV, and metabolite(s), as 
appropriate] are available. The PK analysis set will be used for analyses of general PK.


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8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. In general, values for 
missing data will not be imputed. 
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and is 
immediately preceded and followed in time by values that are deemed successes, then the 
missing data point will be termed a success; otherwise the data point will be termed a failure.
Any subject with missing data due to premature discontinuation of the study will be considered a 
failure at the time points on, or following, the date of discontinuation. If no HCV RNA values 
are obtained after the last dose of study medication, the subject will be considered a treatment 
failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of adverse 
events according to the treatment received; otherwise, if the subject is not dosed then they 
will be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pre-treatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for 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).
PK concentration values below the lower limit of quantitation (BLQ) will be treated as zero for 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing. For the presentation of summary and order statistics, 
if at least 1 subject has a concentration value BLQ for the time point, then the minimum value 
will be displayed as “BLQ”. If more than 50% of the subjects have a concentration data value 


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BLQ for the time point, then the minimum and median values will be displayed as “BLQ”. If all 
subjects have concentration data values BLQ for the time point, then all order statistics 
(minimum, first quartile [Q1], median, third quartile [Q3], maximum) will be displayed as 
“BLQ”.
Exposure parameters that are selected for statistical analysis will be natural log-transformed. 
Concentration values that are BLQ will be excluded for any ratio or natural log-transformed 
statistical analysis.
8.3.1.
Interim Analysis
An interim analysis will be performed after all subjects enrolled from Korea and Taiwan have 
been followed through 12 weeks post-treatment or discontinued from the study to support 
regulatory submissions in these two countries.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment-naive and treatment-experienced subjects.
Demographic summaries will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include a summary of body mass index, HCV RNA level 
(log10 IU/mL), HCV genotype (1a or 1b, or mixed 1a/1b), IL28B genotype, presence/absence of 
cirrhosis, baseline ALT level, and additional endpoints as necessary.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after discontinuation of 
therapy) in the FAS population. The primary analysis will be performed after all enrolled 
subjects have been followed through 12 weeks post-treatment or discontinued from study.
The primary efficacy analysis described below will compare the observed SVR12 rate for the 
investigational regimen (i.e., SOF/LDV FDC for 12 weeks) versus the historical SVR null rate in 
treatment–naïve Korean subjects and in treatment–naïve Chinese subjects, respectively.
In addition, a point estimate with a two-sided 95% exact confidence interval using the binomial 
distribution (Clopper-Pearson method) {20839} will be constructed for the SVR12 rate by 
treatment-naïve and treatment-experienced subjects for each region (i.e., China, Korea or 
Taiwan), Korea plus Taiwan and overall (i.e., China plus Korea plus Taiwan).
Treatment-Naïve Subjects
In the primary efficacy analysis the SVR12 rate from Korea and China will be compared to the 
adjusted historical SVR null rate of 49% in Korea and historical control rate of 57% in China, 
respectively (as calculated in Appendix 5) using a two-sided exact one-sample binomial test. 


Sofosbuvir/Ledipasvir FDC 
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The hypothesis for superiority in Korea is: 
• 
HO: SVRI2 rate = 49%, 
• 
HI: SVRI2 rate :;t 49%. 
The hypothesis for superiority in China is: 
• 
HO: SVRI2 rate = 57%, 
• 
HI: SVRI2 rate :;t 57%. 
Treatment-Experienced Subjects 
Final 
Amendment 3.0 
There is no treatment option available in China, Korea or Taiwan for treatment-experienced 
patients with GT -I infection. In the absence of effective antiviral therapy, spontaneous clearance 
of the HCV is rare. Consequently a nominal SVR rate of 5% is assumed for 
treatment -experienced subjects. 
No statistical hypothesis testing will be perf01med in u·eatment-experienced subjects. For each 
region (i.e., China, Korea or Taiwan), Korea plus Taiwan, and overall (i.e., China plus Korea 
plus Taiwan), a point-estimate with two-sided 95% exact confidence interval using the binomial 
disu·ibution (Clopper-Pearson method) will be constructed for the SVRI2 rate. 
8.5.2. 
Secondary Analysis 
The proportion of subjects with HCV RNA below LLOQ over time (including SVRI2) will be 
presented by u·eatment-naive and u·eatment-experienced subjects for each region 
(i.e., China, Korea or Taiwan), Korea plus Taiwan, and overall (i.e., China plus Korea 
plus Taiwan) in tabular and graphical fonn. 
Descriptive summaries and listings will be provided for additional efficacy evaluations including 
the proportion of subjects who experience virologic failure, AL T nonnalization, semm HCV 
RNA actual values and change from baseline and health related quality of life endpoints. 
Exj)lorat01y analyses may be erfonned to assess PPD 
Details on efficacy analyses will be described in the statistical analysis plan. 
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8.6.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements, at various time points during the study, and by the documentation of AEs.
All safety data collected on or after the first dose of study drug administration up to 30 days after 
the last dose of study drug will be summarized for each region (i.e., China, Korea or 
Taiwan), Korea plus Taiwan, and overall (i.e., China plus Korea plus Taiwan). Safety 
endpoints will be summarized as the number (proportion) of subjects with events or 
abnormalities for categorical data or as an 8-number summary (n, mean, standard deviation, 
median, Q1, Q3, minimum, maximum) for continuous data.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to IMP data will be generated from the IMP 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 new or worsening adverse event that begins on or after the 
date of first dose of IMP up to the date of last dose of IMP plus 30 days.
Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC, HLT, and PT) will be provided:

All AEs,

All study drug-related AEs,

Combined Grade 2, 3 and 4 AEs,

Combined Grade 3 and 4 AEs,

Combined Grade 2, 3 and 4 study drug-related AEs,

Combined Grade 3 and 4 study drug-related AEs,

All AEs that caused permanent discontinuation from study drug,

All AEs that caused change in dose or temporary interruption of study drug,


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
All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
8.6.3.
Laboratory Evaluations
Selected laboratory data (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be 
summarized at study visits along with corresponding change from baseline. 
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
defined in Appendix 3 of this protocol. The incidence of treatment-emergent laboratory 
abnormalities, defined as values that increase by at least one toxicity grade from baseline at any 
time post-baseline up to the date of last dose of study drug plus 30 days will be summarized. If 
baseline data are missing, then any post-baseline graded abnormality (i.e., at least Grade 1) will 
be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
8.7.
Pharmacokinetic Analysis
. Intensive plasma concentrations of the study drug and metabolite(s) over time, if analyzed, will 
be summarized using descriptive statistics. Details of the analysis plan will be provided in the 
statistical analysis plan.  Population PK parameters for the study drugs and metabolite(s), as 
applicable, will be estimated and summarized using descriptive statistics
8.8.
Sample Size
Treatment-Naïve Subjects:
A sample size of 40 Korean subjects in the treatment-naïve group will provide at least 90% 
power to detect a 27% improvement in SVR12 rate from the adjusted historical control rate of 
49% using 2-sided exact one-sample binomial test at significant level of 0.05.
A sample size of 100 Chinese subjects in the treatment-naïve group will provide at least 90% 
power to detect a 17% improvement in SVR12 rate from the historical control rate of 57% using 
2-sided exact one-sample binomial test at significant level of 0.05.
In addition, with 40 subjects in Korea (or Taiwan), the 2 sided 95% exact confidence interval 
will extend at most 32% in length. With 80 subjects (Korea plus Taiwan) in the treatment-naive 
group a two-sided 95% exact confidence interval will extend at most 23% in length. With 
100 subjects in China, the 2 sided 95% exact confidence interval for the SVR12 rate will extend 
at most 20% in length.


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Treatment-Experienced Subjects:
For Treatment Experienced subjects, a confidence interval approach will be used to justify the 
sample size given that our goal is to characterize the SVR rate in a population with limited 
treatment options and not to test a specific hypothesis. With 40 subjects in Korea (or Taiwan), 
the 2 sided 95% exact confidence interval will extend at most 32% in length. With 80 subjects 
(Korea plus Taiwan) in the treatment-experienced group, a two-sided 95% exact confidence 
interval will extend at most 23% in length. With 100 subjects in China, the 2 sided 95% exact 
confidence interval for the SVR12 rate will extend at most 20% in length.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the ECIRB/IEC and/or Regulatory Body has been documented and provided 
as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the ECIRB/IEC and/or Regulatory Body 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.


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9.1.3. 
Informed Consent 
Final 
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The investigator is responsible for obtaining written infonned consent from each individual 
pati icipating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazat·ds of the study and before lmde1iaking any study-related procedures. The 
investigator must use the most cunent IRB- or IEC-approved infonned consent f01m (ICF) for 
documenting written inf01m ed consent. Each infonned consent (or assent as applicable) will be 
appropriately signed and dated by the subject or the subject's legally authorized representative 
and the person conducting the consent discussion, and also b an impa1iial witness if re uired by 
IRB or IEC or local requirements. PPD 
Phatm acogenomic consent f01m will inf01m subjects about phannacogenomic testing and sample 
retention, and their right to receive clinically relevant phatm acogenomic analysis results. 
9.1.4. 
Confidentiality 
The investigator must assure that subjects' anonymity will be strictly maintained and that their 
identities at·e protected from lmauthorized patties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
f01m or biological sample submitted to the Sponsor, IRB [or] IEC, or laborat01y. Laborat01y 
specimens must be labeled in such as way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laborat01y 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 n·ial. Subject data will be processed in accordance 
with all applicable regulations. 
The investigator agrees that all inf01m ation received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study inf01m ation, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This infonnation is not to be disclosed to any third patty (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 fmi her agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third pat·ty or othe1wise into the 
public domain. 
9.1.5. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator's study file, and 
(2) subject clinical source documents. 
The investigator's study file will contain the protocol/ainendments, CRF and que1y f01ms, IRB 
[or] IEC and govemmental approval with con espondence, inf01m ed consent, dmg records, staff 
cmTiculum vitae and authorization fonns, and other appropriate documents and con espondence. 
CONFIDENTIAL 
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The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.


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9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in the 
audit trail of the system. Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will used his/her log in credentials to confirm 
that the forms have been reviewed, and that the entries required per the protocol scheduled of 
events and procedures. System-generated or manual queries will be issued to the investigative 
site staff as data discrepancies are identified by the monitor or internal Gilead staff, who 
routinely review the data for completeness, correctness, and consistency. The site coordinator is 
responsible for responding to the queries in a timely manner, within the system, either by 
confirming the data as correct or updating the original entry, and providing the reason for the 
update (e.g. data entry error). At the conclusion of the trial, Gilead will provide the site with a 
read-only archive copy of the data entered by that site. This archive must be stored in accordance 
with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead (Quality Assurance) QA, the site may destroy used (empty or partially empty) and unused 
IMP supplies in accordance with that site’s approved SOP. A copy of the site’s approved SOP 
will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs [or] IECs, or to regulatory authority or health 
authority inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB [or] 
IEC in accordance with local requirements and receive documented 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 agencies. 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be 
prepared in certain cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead in an abstract, manuscript, or presentation form or the study has been completed at 
all study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.


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9.3.2.
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.
9.3.3.
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.
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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
Appendix 5.
Calculation of Historical Control SVR12 for Treatment-naïve Korean Subjects and 
for Treatment-naïve Chinese Subjects with Chronic GT-1 HCV Infection


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment 3.0 
A Phase 3b, Multicenter, Open-Label Study to Investigate the Efficacy and Safety of 
Sofosbuvir/Ledipasvir Fixed-Dose Combination in Treatment-Naive and Treatment-Experienced 
Subjects with Chronic Genotype 1 HCV Infection 
GS-US-337-0131, Amendment 3.0, 12 February 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Je~y Yang h~nnD CPted) 
PPD 
Study Director 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully infonned about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 80 
12 February 2016 


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Appendix 2.
Study Procedures Table
Table 1.
Screening and On-Treatment Study Visits
Clinical Assessments
Screeninga
On Treatment Period
Day -28
to Day -1
Baseline/
Day 1b
Week 1
(3 days)
Week 2
(3 days)
Week 4
(3 days)
Week 6
(3 days)
Week 8
(3 days)
Week 10
(3 days)
Week 12
(3 days)
ET
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
Liver Imaging (Cirrhotics Only)
X
Height
X
Weight
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
12-lead ECGd
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
Health Related Quality of Life
X
X
X
X
X
X
Hematology & Chemistry
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
Serum HCV RNA
X
X
X
X
X
X
X
X
X
X


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Protocol GS-US-337-0131
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 82
12 February 2016
Clinical Assessments
Screeninga
On Treatment Period
Day -28
to Day -1
Baseline/
Day 1b
Week 1
(3 days)
Week 2
(3 days)
Week 4
(3 days)
Week 6
(3 days)
Week 8
(3 days)
Week 10
(3 days)
Week 12
(3 days)
ET
Single PK Sample
X
X
X
X
X
X
X
X
Viral RNA Sequencing 
/Phenotyping Sample (Plasma)e
X
X
X
X
X
X
X
X
X
Archive Sample j
X
X
X
Serum or Urine Pregnancy Testk
X
X
X
X
X
X
Urinalysis
X
IL28B Genotype, HCV 
Genotype
X
HCV Ab, HIV Ab and HBsAg
X
Hemoglobin A1c, TSH
X
PK Substudy Collectionf
X
X
Single Pharmacogenomic 
Sampleg
X
Review of Study Drug 
Adherence and Drug 
Accountabilityh
X
X
X
X
X
X
X
X
Study Drug Dispensingi
X
X
X
a
The screening window can be extended to 42 days for subjects requiring liver biopsy or additional HCV genotype testing. 
b
Baseline/Day 1 assessments must be performed prior to dosing.
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 gross abnormalities.
e
Serum samples will be collected and stored for potential HCV sequencing and other virology studies.


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Protocol GS-US-337-0131
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
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12 February 2016
f
The optional PK substudy is conducted in Taiwan and Korea only. Subjects that consent to the optional PK substudy will have serial PK samples drawn at Week 2 or Week 4 
visit.  
g
Only for subjects who have provided consent for this sample and testing (Taiwan and Korea only). This sample can be obtained at a subsequent visit if not obtained at Day 1.
h
Study medication and dosing diary, will be reconciled at every post-baseline visit by the investigator or designee in order to monitor the subject’s adherence with the 
medication regimen. 
i
Study Drug will be dispensed per IWRS directions.  Subjects must be instructed to bring back all bottles of study medication(s) in the original container at every post baseline 
study visits through the end of treatment. 
j
Archive plasma samples will be collected at the Baseline/Day 1 visit and at the end of treatment for subjects who have not opted out of sample collection.
k
For female subjects of childbearing potential. In the event of a positive urine test, a serum pregnancy test will be done.


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Amendment 3.0
CONFIDENTIAL
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12 February 2016
Table 2.
Post Treatment Study Visits
Clinical Assessments
Post Treatment Perioda
Post Treatment Week 4
(5 days)
Post Treatment Week 12
(5 days)
Post Treatment Week 24
(5 days)
Weight
X
X
Vital Signsb
X
X
X
Adverse Events
X
Concomitant Medications
X
Pregnancy Prevention Counseling
X
Health Related Quality of Life
X
X
Hematology & Chemistry
X
Serum HCV RNA
X
X
X
Viral Sequencing Sample (Plasma)c
X
X
X
Serum or Urine Pregnancy Testd
X
a
All subjects will complete both 4-week and 12-week Post-Treatment visits regardless of the treatment duration. Subjects with HCV RNA < LLOQ at their 12-week 
Post-Treatment visit will complete a 24-week Post-Treatment visit, unless viral relapse is determined. The end of study will occur at the 24-week Post-Treatment visit. 
b
Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
c
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies. 
d
For female subjects of childbearing potential. In the event of a positive urine test, a serum pregnancy test will be done.


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Protocol GS-US-337-0131
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Amendment 3.0
CONFIDENTIAL
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12 February 2016
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18June2012
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L


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Protocol GS-US-337-0131
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Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
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12 February 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
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
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L


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Final
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Amendment 3.0
CONFIDENTIAL
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12 February 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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
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% 


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Protocol GS-US-337-0131
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Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
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12 February 2016
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 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


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Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
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12 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L


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Protocol GS-US-337-0131
Final
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Amendment 3.0
CONFIDENTIAL
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12 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.14 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 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL


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CONFIDENTIAL
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12 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L
Bicarbonate
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
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
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
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


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Gilead Sciences, Inc.
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12 February 2016
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
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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12 February 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


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


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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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Gilead Sciences, Inc.
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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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Gilead Sciences, Inc.
Amendment 3.0
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12 February 2016
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
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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12 February 2016
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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Gilead Sciences, Inc.
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12 February 2016
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (eg, 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (eg, 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 


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


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


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Gilead Sciences, Inc.
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12 February 2016
MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic self-
care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing 
inability to perform usual 
social & functional activities
Disabling muscle pain causing 
inability to perform basic self-
care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-
care functions


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


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


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


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


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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Background
Non-clinical toxicity studies of sofosbuvir and ledipasvir demonstrated no adverse effect on 
embryo-fetal development. However, there are no clinical studies of sofosbuvir or ledipasvir in 
pregnant women. Please refer to the latest version of the investigator’s brochure for additional 
information.
2) Definition of Female of Childbearing Potential and Contraceptive Requirements for Female 
Subjects (and their male partners)
Women > 54 years of age with cessation for ≥ 12 months of previously occurring menses, or 
women of any age who have had a hysterectomy, or have had both ovaries removed, or have had 
medically documented ovarian failure will be considered to be of non-childbearing potential. 
Women ≤54 years of age (including those with amenorrhea of any duration) who have not had a 
hysterectomy, and have not had both ovaries removed, and have not had medically documented 
ovarian failure will be considered to be of childbearing potential. 
Women of childbearing potential must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on the Baseline/Day 1 visit prior to randomization. They must also 
agree to one of the following from 3 weeks prior to Baseline/Day 1 until 30 days after last dose 
of study drug.

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
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 last dose of study drug: 
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization
vasectomy in male partner
hormone-containing contraceptive:
implants of levonorgestrel


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injectable progesterone
oral contraceptives (either combined or progesterone only)
contraceptive vaginal ring 
transdermal contraceptive patch
3) Contraceptive Requirements for Male Subjects (and their female partners)
All male study participants must agree to consistently and correctly use a condom from the date 
of Screening until 90 days after the last dose of study drug. If their female partner is of child 
bearing potential (as defined above), their female partner must use 1 of the methods of birth 
control listed above from the date of Screening until 90 days after the last dose of study drug. 
Male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of 
study drug. 
4) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they (or their partner) become pregnant at 
any time during the study, or if they become pregnant within 30 days (90 days for partners of 
male subjects) of last study drug dose. Subjects who become pregnant or who suspect that they 
are pregnant must report the information to the investigator and discontinue study drug 
immediately. Subjects whose partner has become pregnant or suspects she is pregnant must 
report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.7.2.1.


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Appendix 5.
Calculation of Historical Control SVR12 for Treatment-naïve Korean 
Subjects and for Treatment-naïve Chinese Subjects with Chronic 
GT-1 HCV Infection
This section details the calculation for the historical control SVR12 rates for treatment-naïve
Korean subjects and for treatment-naïve Chinese subjects with chronic GT-1 HCV infection. 
The historical control calculation for Korea assumes that of the treatment-naïve subjects with 
HCV GT-1 infection to be enrolled in Korea, approximately 60% will have ‘Uncomplicated 
Infection’, ~30% will be ‘Elderly’, and ~10% will be ‘Cirrhotic’. Based on discussions with 
clinical investigators in these countries, these assumptions ensure a conservative estimation of 
the historical SVR rate following Peg-IFNα+RBV in the respective populations. The references 
used for the calculation of the historical control rates are provided in Appendix Table 2 below.
For Korea, the SVR rates among each of the three patient populations are calculated according to 
the reference studies (Appendix Table 2). The overall historical SVR rate is subsequently
calculated as the weighted average of the population-specific rates, with the weight being the 
expected percentages of patients in each population. With these assumptions in mind and using 
the referenced literature, the adjusted historical SVR control rate for the populations in Korea are 
calculated as follows:
Appendix Table 1.
SVR rates following Peg-IFNα+RBV in Treatment-Naïve Korean 
Subjects with GT-1 HCV Infection
Country 
Uncomplicated 
Infection
Elderly
Cirrhotic
Weighted Average
Korea
62.7%
30.8%
24%
62.7% * 0.6 + 30.8% * 0.3 + 24% *0.1= 49%
Therefore, a null adjusted historical SVR rate for this study is 49% following estimation of the 
SVR rate for Korea. 
For China, the historical control rate has been calculated according to the reference studies in 
Appendix Table 3. SVR rates are not reported separately for elderly patients or those with 
cirrhosis in these references. Consequently, the calculated historical SVR rate of 57% has not 
been adjusted by different population.


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Appendix Table 2.
Literature References for Historical Control Rate Calculations in 
Korea
SVR Rates in Korea
Population
SVR%
SVR n/N
Reference
GT-1 Treatment Naïve (Peg-IFN/RBV 48 Weeks)
80.8
21/26
{24236}
54.7
58/106
{24236}
62.7
341/543
{26807}
62.2
158/254
{26389}
64.2
104/162
{26389}
66.0
31/47
{26390}
Overall SVR Rate
62.7%
SVR Rates in Korea Elderly
Population
SVR%
SVR n/N
Reference
GT-1 Treatment Naïve (Peg-IFN/RBV 48 weeks)
30.8
4/13
{26390}
Overall SVR Rate
30.8%
SVR Rates in Korea Cirrhotics
Population
SVR%
SVR n/N
Reference
GT-1 Treatment Naïve (Peg-IFN/RBV 48 weeks)
24.0
12/50
{24405}
Overall SVR Rate
24.0%
Appendix Table 3.
Literature References for Historical Control Rate Calculations in 
China
SVR Rates in China
Population
SVR
%
SVR n/N
Reference
GT-1 Treatment Naïve (Peg-IFN/RBV 48 weeks)
70.3
102/145
{24797}
43.9
18/41
{13261}
46.0
58/126
{24391}
Overall SVR Rate
(102+18+58) / (145+41+126) = 57%

SAP_003.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title: 
A Phase 3b, Multicenter, Open-Label Study to Investigate the 
Efficacy and Safety of Sofosbuvir/Ledipasvir Fixed-Dose 
Combination in Treatment-Naïve and Treatment-Experienced 
Subjects with Chronic Genotype 1 HCV Infection 
 
 
Name of Test Drug: 
Ledipasvir/Sofosbuvir Fixed-Dose Combination 
 
 
Study Number: 
GS-US-337-0131 
 
 
Protocol Version/Date: 
Original: 
28 May 2013 
Amendment 1.1: 12 December 2013 
Amendment 2.0: 01 August 2014 
Amendment 3.0: 12 February 2016 
 
 
Analysis Type 
SVR12 and Final Analyses for Subjects from Mainland China 
and from Overall (China plus Korea plus Taiwan) 
 
 
Analysis Plan Version: 
1.0 
 
 
Analysis Plan Date: 
28 July 2017 
 
 
Analysis Plan Author: 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
PPD


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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT-TABLES ........................................................................................................................................ 3 
LIST OF ABBREVIATIONS ........................................................................................................................................ 4 
1. 
INTRODUCTION ................................................................................................................................................ 6 
1.1. 
Study Objectives ...................................................................................................................................... 6 
1.1.1. 
Primary Study Objectives ....................................................................................................... 6 
1.1.2. 
Secondary Study Objectives ................................................................................................... 6 
1.1.3. 
Exploratory Study Objectives ................................................................................................ 6 
1.2. 
Study Design ............................................................................................................................................ 7 
1.2.1. 
Design Configuration, Subject Population and Treatment Groups ........................................ 7 
1.2.2. 
Study Duration ....................................................................................................................... 7 
1.2.3. 
Schedule of Assessments........................................................................................................ 8 
1.3. 
Sample Size and Power ............................................................................................................................ 8 
1.3.1. 
Treatment Naïve Subjects: ..................................................................................................... 8 
1.3.2. 
Treatment Experienced Subjects: ........................................................................................... 8 
2. 
TYPE OF PLANNED ANALYSIS ...................................................................................................................... 9 
2.1. 
Posttreatment Week 4 Analysis ................................................................................................................ 9 
2.2. 
Primary Efficacy Endpoint Analysis ........................................................................................................ 9 
2.3. 
Final Analysis .......................................................................................................................................... 9 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................ 10 
3.1. 
Analysis Sets .......................................................................................................................................... 10 
3.1.1. 
Enrolled Analysis Set ........................................................................................................... 10 
3.1.2. 
Full Analysis Set .................................................................................................................. 10 
3.1.3. 
Safety Analysis Set ............................................................................................................... 10 
3.1.4. 
Pharmacokinetic Analysis Set .............................................................................................. 10 
3.2. 
Subject Groups ....................................................................................................................................... 10 
3.3. 
Strata and Covariates .............................................................................................................................. 10 
3.4. 
Examination of Subject Subsets ............................................................................................................. 11 
3.5. 
Data Handling Conventions and Transformations ................................................................................. 11 
3.6. 
Missing Data and Outliers ...................................................................................................................... 12 
3.6.1. 
Missing Data ........................................................................................................................ 12 
3.6.2. 
Outliers ................................................................................................................................. 13 
3.7. 
Visit Windows ........................................................................................................................................ 13 
3.7.1. 
Definition of Study Day 1, First/Last Dosing Date, and Baseline ........................................ 13 
3.7.2. 
Analysis Windows ................................................................................................................ 14 
3.7.3. 
Selection of Data in the Event of Multiple Records in a Window ....................................... 16 
4. 
SUBJECT DISPOSITION .................................................................................................................................. 17 
4.1. 
Subject Enrollment ................................................................................................................................. 17 
4.2. 
Disposition of Subjects .......................................................................................................................... 17 
4.3. 
Extent of Exposure ................................................................................................................................. 18 
4.3.1. 
Duration of Exposure to Study Drug .................................................................................... 18 
4.3.2. 
Adherence to Study Drug ..................................................................................................... 18 
4.4. 
Protocol Deviations ................................................................................................................................ 19 
5. 
BASELINE DATA ............................................................................................................................................. 20 
5.1. 
Demographics and Baseline Characteristics .......................................................................................... 20 
5.2. 
Medical History ...................................................................................................................................... 21 


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6. 
EFFICACY ANALYSES ................................................................................................................................... 22 
6.1. 
Primary Efficacy Endpoint ..................................................................................................................... 22 
6.1.1. 
Definition of the Primary Efficacy Endpoint ....................................................................... 22 
6.1.2. 
Primary Analysis of the Primary Efficacy Endpoint ............................................................ 22 
6.1.3. 
Subgroup Analysis of the Primary Efficacy Endpoint ......................................................... 23 
6.2. 
Secondary Efficacy Endpoints ............................................................................................................... 23 
6.2.1. 
Definition of Secondary Efficacy Endpoints ........................................................................ 23 
6.2.2. 
Analysis Methods for Secondary Efficacy Endpoints .......................................................... 24 
6.3. 
Exploratory Efficacy Endpoints ............................................................................................................. 25 
6.3.1. 
Definition of Exploratory Efficacy Endpoints ...................................................................... 25 
6.3.2. 
Analysis Methods for Exploratory Efficacy Endpoints ........................................................ 25 
6.4. 
Changes From Protocol-Specified Efficacy Analyses............................................................................ 26 
7. 
SAFETY ANALYSES ........................................................................................................................................ 27 
7.1. 
Adverse Events....................................................................................................................................... 27 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 27 
7.1.2. 
Adverse Event Severity ........................................................................................................ 27 
7.1.3. 
Relationship of Adverse Events to Study Drug .................................................................... 27 
7.1.4. 
Serious Adverse Events ........................................................................................................ 27 
7.1.5. 
Treatment-Emergent Adverse Events ................................................................................... 28 
7.1.6. 
Summaries of Adverse Events and Deaths ........................................................................... 28 
7.2. 
Laboratory Evaluations .......................................................................................................................... 29 
7.2.1. 
Summaries of Numeric Laboratory Results ......................................................................... 30 
7.2.2. 
Graded Laboratory Values ................................................................................................... 30 
7.3. 
Body Weight, Height, BMI and Vital Signs........................................................................................... 31 
7.4. 
Concomitant Medications ...................................................................................................................... 31 
7.5. 
Electrocardiogram Results ..................................................................................................................... 32 
7.6. 
Other Safety Measures ........................................................................................................................... 32 
8. 
PHARMACOKINETIC ANALYSES ................................................................................................................ 33 
9. 
REFERENCES ................................................................................................................................................... 34 
10. SOFTWARE ....................................................................................................................................................... 35 
11. SAP REVISION .................................................................................................................................................. 36 
12. APPENDICES .................................................................................................................................................... 37 
 
Appendix 1. 
Table of Contents for Statistical Tables, Figures, and Listings .............................................. 38 
Appendix 2. 
Schedule of Assessments ........................................................................................................ 44 
Appendix 3. 
Calculation of Historical Control SVR12 for Treatment naïve Chinese Subjects with 
Chronic GT-1 HCV Infection ................................................................................................. 48 
 
 
LIST OF IN-TEXT-TABLES 
Table 3-1. 
On-Treatment Visit Windows for Selected Tests ................................................................... 15 
Table 3-2. 
Post-treatment Visit Windows for Selected Tests .................................................................. 15 
Table 3-3. 
On-Treatment Visit Windows for ECGs ................................................................................ 15 
 


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LIST OF ABBREVIATIONS 
β-hCG 
β-human chorionic gonadotropin 
AE 
adverse event 
ALT 
alanine aminotransferase (also SGPT) 
ANC 
absolute neutrophil count 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase  (also SGOT) 
AUC 
area under the curve 
AUCtau 
area under the plasma concentration versus time curve over the dosing interval (tau) 
BID 
twice a day  
BLQ 
below the lower limit of quantification 
BMI 
body mass index 
BPM 
beats per minute 
BW 
body weight 
CI 
confidence interval 
CLcr 
creatinine clearance 
CRF 
case report form(s) 
CRO 
Contract (or clinical) research organization  
CSR 
clinical study report 
DAA 
Direct acting antiviral 
dL 
Deciliter 
DNA 
deoxyribonucleic acid 
DSPH 
Drug Safety and Public Health 
ECG 
Electrocardiogram 
eCRF 
eGFR 
Electronic case report form(s) 
estimated glomerular filtration rate  
Emax 
maximal effect 
EOT 
End of Treatment 
FDC 
FU 
fixed-dose combination 
follow-up 
HCV 
hepatitis C virus 
HLT 
HLGT 
HRQoL 
H0 
H1 
high level term 
high level group term 
Health-Related Quality of Life 
null hypothesis 
alternative hypothesis 
IFN 
interferon  
INR 
International Normalized Ratio of prothrombin time 
IVRS 
Interactive Voice Response System 
LDV 
Ledipasvir 


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LLT 
lower level term 
LLOQ 
lower limit of quantitation 
MedDRA 
PG 
Medical Dictionary for Regulatory Activities 
Pharmacogenomics 
PK 
pharmacokinetics 
PT 
preferred term 
Q1 
first quartile 
Q3 
third quartile 
RBV 
ribavirin 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SOF 
sofosbuvir 
SVR 
sustained virologic response 
SVRx 
sustained virologic response x weeks after stopping study drug 
TE 
treatment-emergent 
TFLs  
ULN 
VF 
tables, figures, and listings 
upper limit of normal 
virologic failure  
WHO 
World Health Organization 
 


Ledipasvir/Sofosbuvir 
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Statistical Analysis Plan 
L 
INTRODUCTION 
Version 1.0 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in the sunnnaty and analysis of data from Study GS-US-337-0131 for 
Mainland China (hereafter refen ed to as China), and for the study Overall, i.e., China plus other 
regions of Korea and Taiwan. This SAP was based on the protocol amendment 3.0 
12 Febmary 2016. Related documents are the original study protocol, protocol amendments, and 
electronic case report form (eCRF). Any changes made after the fmalization of the SAP will be 
documented in the clinical study rep01t (CSR). Analysis of data for subjects emolled in Korea 
and Taiwan has previously been conducted in accordance with the SAP dated 22 July 2014 and 
rep01ted in an interim CSR dated 10 October 2014. 
1.1. 
Study Objectives 
1.1.1. 
Primary Study Objectives 
• 
To detennine the antiviral efficacy of treatment with ledipasvir (LDV)/sofosbuvir (SOF) 
fixed-dose combination (FDC) as measured by the prop01tion of subjects with sustained 
virologic response (SVR) 12 weeks after discontinuation of therapy (SVR12, defmed as 
HCV RNA < lower limit of quantification [LLOQ] 12 weeks post treatment) 
• 
To evaluate the safety and tolerability of LDV/SOF FDC as assessed by review of the 
accumulated safety data 
1.1.2. 
Secondary Study Objectives 
• 
To detennine the prop01tion of subjects who attain SVR at 4 and 24 weeks after 
discontinuation of therapy (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after treatment 
discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV during treatment and after 
treatment discontinuation 
1.1.3. 
Exploratory Study Objectives 
IT 
I 
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1.2. 
Study Design 
1.2.1. 
Design Configuration, Subject Population and Treatment Groups 
This is an international (China, Korea and Taiwan), multicenter, open-label study in treatment-
naïve and treatment experienced adults with chronic genotype 1 HCV infection. 
Approximately 180 treatment-naïve and 180 treatment experienced subjects will receive 
treatment with LDV/SOF 90/400 mg fixed dose combination (FDC) tablet for 12 weeks. 
Approximately 200 subjects will be enrolled in China, 80 subjects will be enrolled in Korea, and 
80 subjects in Taiwan. Within each country/region approximately 50% (i.e., n~100 or 40) of 
subjects will be treatment-naïve and 50% will be treatment experienced (i.e., n~100 or 40).  
Treatment naïve is defined as having never received treatment for HCV with any interferon 
(IFN), ribavirin (RBV), or other approved or experimental HCV-specific direct acting antivirals. 
Treatment experienced is defined as: 
A) IFN intolerant 
Note: Subjects intolerant of Peg-IFNα + RBV + HCV protease inhibitor regimens are included 
in this category. 
B) Non-response 
C)  Relapse/Breakthrough 
Note: For treatment experienced subjects, prior exposure to HCV NS3/NS4A protease inhibitors 
is permitted. 
Up to 20% of subjects enrolled in the study may have compensated cirrhosis at Screening. 
1.2.2. 
Study Duration 
The total time to complete all study visits is approximately 40 to 42 weeks including: 
• 28 to 42 day (4 to 6 weeks) screening period 
• 12 week treatment period 
• 24 week post-treatment period 


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1.2.3. 
Schedule of Assessments 
The schedule of assessments is provided as an appendix to the SAP (Appendix 2). 
1.3. 
Sample Size and Power 
1.3.1. 
Treatment Naïve Subjects:  
A sample size of 100 Chinese subjects in the treatment naïve group will provide at least 90% 
power to detect a 17% improvement in SVR12 rate from the historical control rate of 57% using 
2-sided exact one-sample binomial test at significant level of 0.05. With 100 subjects in China, 
the two-sided 95% exact confidence interval for the SVR12 rate will extend at most 20% in 
length. 
1.3.2. 
Treatment Experienced Subjects:  
For treatment experienced subjects, a confidence interval approach will be used to justify the 
sample size given that our goal is to characterize the SVR rate in a population with limited 
treatment options and not to test a specific hypothesis. With 100 subjects in China, the two-sided 
95% exact confidence interval for the SVR12 rate will extend at most 20% in length. 


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2. 
TYPE OF PLANNED ANALYSIS 
2.1. 
Posttreatment Week 4 Analysis 
A posttreatment Week 4 analysis will be conducted for administrative purposes when all subjects 
in China have completed the posttreatment Week 4 visit or have prematurely discontinued from 
the study. All efficacy and safety data through the posttreatment Week 4 visit will be included 
(SVR12 data will not be evaluated at this time). The results will be restricted to a limited group 
of individuals within Gilead. There will be no changes to the study design or study conduct as a 
result of this administrative analysis (eg, the analysis would not lead to early termination of the 
study, and there would be no early stopping, no potential for sample size adjustment, and no 
changes in the design of the study). This analysis is for evaluation of safety and to facilitate 
development of the clinical study report. 
2.2. 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint analysis (for SVR12) will be conducted when all subjects enrolled 
in China have completed the 12 week post treatment visit or prematurely discontinue from study, 
and all the safety and efficacy data through the Posttreatment Week 12 visit will be finalized and 
included in the analysis. 
2.3. 
Final Analysis 
The final analysis will be conducted when all subjects enrolled in China have completed the 
24 week post treatment visit or prematurely discontinue from study. The data will be finalized 
after all data queries are resolved for study visits through completion of the 24-week 
posttreatment visit. At the conclusion of data finalization, the study statistician and statistical 
programmers will run the final version of tables, figures and listings (TFLs). 


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3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
3.1. 
Analysis Sets 
Analysis sets define which subjects are included in an analysis. A summary of the number and 
percentage of subjects in each analysis set will be provided for China and Overall (i.e., China 
plus Korea plus Taiwan) as part of the subject disposition summary. 
3.1.1. 
Enrolled Analysis Set  
The enrolled analysis set includes subjects who were enrolled into the study.  
3.1.2. 
Full Analysis Set 
The full analysis set (FAS) includes subjects who were enrolled and received at least 1 dose of 
study drug, and have chronic genotype 1 HCV infection.  
The study drug in this study is LDV/SOF. 
3.1.3. 
Safety Analysis Set 
The safety analysis set includes subjects who were enrolled and received at least 1 dose of study 
drug. 
3.1.4. 
Pharmacokinetic Analysis Set 
The PK analysis set will include all enrolled subjects who received at least 1 dose of study drug, 
and for whom at least 1 population PK parameter can be derived for LDV, SOF or its metabolites 
(as appropriate).  
The PK analysis set will be used for the analyses related to the population PK parameters.  
3.2. 
Subject Groups 
Subjects will be grouped for analyses according to prior treatment experience (treatment naïve or 
treatment experienced) for efficacy analysis using the FAS.  
3.3. 
Strata and Covariates 
Not Applicable.  


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3.4. 
Examination of Subject Subsets 
In addition to analyzing by groups according to prior treatment experience, the primary efficacy 
endpoint, SVR12, will be analyzed for the following subsets: 
• age group on date of first dose of study drug (< 65 years, ≥ 65 years) 
• sex (male, female) 
• baseline BMI (< 25 kg/m2 , ≥ 25 kg/m2) 
• cirrhosis (cirrhosis, absence of  cirrhosis) 
• response to prior HCV treatment (nonresponse, relapse/breakthrough, IFN intolerant) for 
treatment experienced subjects 
• IFN eligibility (IFN eligible, IFN ineligible, IFN unwilling) for treatment naive subjects 
• baseline HCV RNA (< 800,000 IU/mL, ≥ 800,000 IU/mL) and (< 5 log10 IU/mL, 
≥ 5 log10 IU/mL 
• baseline ALT (≤ 1.5 × ULN, > 1.5 × ULN) 
• IL28B (CC, Non-CC (CT, TT))  
• adherence to study drug (<80%, ≥ 80%) 
3.5. 
Data Handling Conventions and Transformations 
The COBAS Taqman HCV Test v2.0 for use with the High Pure System assay was used to 
determine HCV RNA results of Korea and Taiwan in this study. The lower limit of quantitation 
(LLOQ) of the assay is 25 IU/mL. Quantitative HCV RNA data for Korea and Taiwan were 
reported in the CSR dated 10 October 2014 and the synoptic CSR dated 26 February 2015. 
The COBAS® AmpliPrep/COBAS® TaqMan® HCV Test v2.0 is used to determine HCV RNA 
results of China in this study. The lower limit of quantitation (LLOQ) of the assay is 15 IU/mL. 
When the calculated HCV RNA value is within the linear range of the assay, then the result will 
be reported as the “<< numeric value>> IU/mL”. This result will be referred to in this document 
as the numeric result or as “≥ LLOQ detected” for categorical result. 
When HCV RNA is not detected, the result is reported as “No HCV RNA detected” or “target 
not detected”. This result will be referred to in this document as “< LLOQ target not detected” or 
“< LLOQ TND”. 


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When the HCV RNA IU/mL is detected but less than LLOQ of the assay, the result is reported as 
“< 15 IU/mL HCV RNA detected” for China subjects and “<25 IU/mL HCV RNA detected” for 
Korean/Taiwan subjects. These results will be referred to in this document as “< LLOQ 
detected”. 
Numerical HCV RNA data with values below LLOQ will be set to the LLOQ minus 1 
(ie, 14 IU/mL for China subjects and 24 IU/mL for Korean/Taiwan subjects). HCV RNA values 
returned as “target not detected” will also be set to 14 IU/mL or 24 IU/mL for China and 
Korean/Taiwan subjects, respectively. 
For selected analyses, HCV RNA data (IU/mL) will be transformed to the logarithmic (base 10) 
scale (log10 IU/mL). 
HCV RNA data for China will be summarized. No analysis of quantitative HCV RNA data for 
Overall (China plus Korea plus Taiwan) will be conducted. 
Categorical data (HCV RNA < LLOQ or ≥ LLOQ for China and for Korea and Taiwan) will be 
summarized for China and Overall (China plus Korea plus Taiwan) regardless of the LLOQs.  
Total bilirubin values entered as < 0.2 mg/dL will be analyzed as 0.1 mg/dL; direct bilirubin 
values entered as < 0.1 mg/dL will be analyzed as 0.05 mg/dL {Nehls 1973}. In general, other 
than the above 2 exceptions, laboratory data that are continuous in nature but are less than the 
lower limit of quantitation or above the upper limit of quantitation will be imputed to the value 
of the lower or upper limit minus or plus 1 significant digit, respectively (eg, if the result of a 
continuous laboratory test is < 20, a value of 19 will be assigned). 
Exposure parameters that are selected for statistical analysis will be natural log-transformed. 
Concentration values that are BLQ will be excluded for any ratio or natural log-transformed 
statistical analysis. 
3.6. 
Missing Data and Outliers 
3.6.1. 
Missing Data 
A missing data point for a given study visit may be due to any one of the following reasons: 
• A visit occurred but data were not collected or were unusable 
• A visit did not occur 
• A subject permanently discontinued from the study before reaching the window 
For analyses of categorical HCV RNA data, if a data point is missing and is preceded and 
followed in time by values that are “< LLOQ 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 
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preceded by “< LLOQ TND” and followed by “< LLOQ detected”, then the missing value will 
be set to “< LLOQ detected”; otherwise the data point will be termed a failure (ie, ≥ LLOQ 
detected).  
Subjects with missing data due to premature discontinuation of the study will have missing data 
imputed up to the time of their last dose (for on-treatment displays). If study days associated with 
the last dosing date is greater than or equal to the lower bound of a visit window, and the value at 
the visit is missing, then the value will be imputed. If the study days associated with the last 
dosing date is less than the lower bound of a visit window then the on-treatment value at that 
visit will remain missing.  
If no HCV RNA values are obtained after the last dose of any study drug, the subject will be 
considered a treatment failure for SVR endpoints. However, 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 {Chen 2013}. 
For the analyses of continuous HCV RNA efficacy data for China, any subject with a missing 
value in a visit window that is bracketed by prior and subsequent values of “< LLOQ TND” will 
be set to “< LLOQ TND” (ie, 14 IU/mL). Subjects with a missing data point preceded and 
followed by values that are “< LLOQ detected”, preceded by “< LLOQ detected” and followed 
by “< LLOQ TND”, or preceded by “< LLOQ TND” and followed by “< LLOQ detected” will 
be set to “< LLOQ detected” (ie, 14 IU/mL). No other imputation will be performed for 
continuous data. No Overall analysis of continuous HCV RNA data will be conducted. 
For health-related quality of life data (ie, SF-36), missing data will not be imputed.  
Except for the imputation rules described above, values for other missing data (including all 
safety data) will not be imputed. 
3.6.2. 
Outliers 
Outliers will be identified during data management and data analysis process, but no sensitivity 
analyses will be done to evaluate the impact of outliers on efficacy or safety outcomes. All data 
will be included in the data analysis. 
3.7. 
Visit Windows 
3.7.1. 
Definition of Study Day 1, First/Last Dosing Date, and Baseline 
Study Day 1 is defined as the first dose date of study drug (ie, LDV/SOF).  
The date of last dose of study drug will be the end date on study drug administration CRF for the 
record where the “subject permanently discontinued” flag is ‘Yes’.  
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If there are subjects for whom the date of last study drug is unknown due to the reason that the 
subject was lost to follow-up, the date of last dose will be estimated using the maximum of 
nonmissing study drug start or stop dates and on-treatment visit dates and laboratory collection 
dates (post-treatment visits and unscheduled visits are not included).  
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of study drug. If multiple measurements occur on the same day, the last nonmissing value prior 
to the time of first dose of study drug will be considered as the baseline value. If these multiple 
measurements occur at the same time or time is not available, the average of these measurements 
(for continuous data) or the worst among these measurements (for categorical data) will be 
considered as baseline value. If multiple ECG measurements occur on the same day prior to first 
dose of study drug, the average will be used considered as baseline value for continuous data, 
regardless of the timing of these multiple ECG measurements. 
3.7.2. 
Analysis Windows 
Subject visits might not occur on protocol-specified days. Therefore, for the purposes of analysis, 
visit windows will be utilized when a single value at a visit is required for analysis. 
Visit windows are defined for HCV RNA, vital signs and safety laboratory data. No analysis 
windows will be defined for health related quality of life data and pregnancy data. 
All available HCV RNA data will be included in efficacy analysis, unless a subject starts 
alternative HCV medication. HCV RNA data collected after starting alternative HCV medication 
will be excluded. Imputation for missing HCV RNA values are described in Section 3.6. For 
safety data, subjects who are permanently discontinued from study drug will be included in 
safety analyses to last dosing date of any study drug + 30 days unless otherwise specified.  
HCV RNA, vital signs, and safety laboratory test data collected up to the last dose date of any 
study drug + 2 days are considered to be on-treatment data and HCV RNA, vital signs and safety 
laboratory data collected after the last dose date of any study drug + 2 days are considered 
posttreatment data. On-treatment and posttreatment data will follow 2 different sets of visit 
windows.  
Visit windows will be calculated from Study Day 1 (ie, Study Day = collection date minus date 
Study Day 1; +1 if result is ≥ 0) for HCV RNA, vital signs and other safety laboratory data as 
shown in Table 3-1. 


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Table 3-1. 
On-Treatment Visit Windows for Selected Tests 
Visit ID 
On-Treatment 
Visit Windows for HCV RNA, Vital Signs and Safety Laboratory Data 
Baseline 
Study Day ≤ 1 
Week 1 
2 ≤ Study Day ≤ 11 
Week 2 
12 ≤ Study Day ≤ 21 
Week 4 
22 ≤ Study Day ≤ 35 
Week 6 
36 ≤ Study Day ≤ 49 
Week 8 
50 ≤ Study Day ≤ 63 
Week 10 
64 ≤ Study Day ≤ 77 
Week 12 
78 ≤ Study Day ≤ 98 
 
HCV RNA, vital signs, and safety laboratory data collected after the last dose date of study drug 
+ 2 days will be assigned to the posttreatment FU visit windows. Windows will be calculated 
from the last dose date of study drug (ie, FU Day = collection date minus the last dose date of 
study drug) as shown in Table 3-2. 
Table 3-2. 
Post-treatment Visit Windows for Selected Tests 
Off-Treatment FU 
Visit ID 
Post-treatment Visit Windows for HCV 
RNA a(Days from Last Dose Date) 
Vital Signs and Safety Laboratory 
Data b (Days from Last Dose Date) 
FU-4 
21 ≤ FU Day ≤ 69 
3 ≤ FU Day ≤ 30 
FU-12 
70 ≤ FU Day ≤ 146 
N/A 
FU-24 
147 ≤ FU Day ≤ 190 
N/A 
a 
SVR follow-up visit window (lower bound) must occur within 7, 14, and 21 days of target for SVR4, SVR12, and SVR24, 
respectively. 
b 
Vital signs and safety labs will only be summarized for the 4-week follow-up visit (up to 30 days post last dose). 
Qualitative assessments of whether the ECG is normal or abnormal will be assessed based on the 
following visit windows shown in Table 3-3: 
Table 3-3. 
On-Treatment Visit Windows for ECGs 
Visit ID 
On-Treatment Visit Windows for ECG Data 
Baseline 
Study Day ≤ 1 
Week 1 
2  < Study Day  ≤ 18 
End of Treatment 
18  < Study Day ≤ Study Day of Last dose date +2 
Note: ECGs are to be collected at screening, baseline, Week 1, Week 12 and End of Treatment. For purposes of analysis, 
Baseline will be the last available value prior to first dose and End of treatment is last available ECG on/prior to last dose date of 
study drug +2 day. 


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3.7.3. 
Selection of Data in the Event of Multiple Records in a Window 
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. When a single value is 
needed, the following rules will be used: 
• Select the record closest to the nominal day (ie, visit weeks x 7 days) for that visit except for 
HCV RNA post-treatment follow-up visits, for which the latest record in the analysis window 
should be selected. 
• If there are 2 visits equidistant from the nominal day within the analysis window, take the 
latest. 
• If there is more than 1 record on the selected day, take the average (for continuous data) or 
the worst (for categorical data). If there are 2 values on the same day, the second may be a 
retest because there was a problem with the first test (eg, specimen hemolyzed). In cases 
where the first test is cancelled, the retest value should be used. 
• For ECG end of treatment value, select the last value on/prior to last dose date of study drug 
+2. (if applicable) 


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4. 
SUBJECT DISPOSITION 
4.1. 
Subject Enrollment 
The number and percentage of subjects enrolled and treated by each investigator will be 
summarized by prior treatment experience (treatment naive and treatment experienced subjects) 
for China and Overall. The denominator for this calculation will be the number of subjects in the 
safety analysis set for that column.  
4.2. 
Disposition of Subjects 
A summary of subject disposition will be provided for China and Overall.  This summary will 
present the number of subjects screened, rescreened, subjects not enrolled (with reasons), 
enrolled, enrolled and treated (ie, Safety Analysis Set), FAS, PK Analysis Set, and the number 
and percentage of subjects meeting the following criteria:  
• Completed study treatment  
• Discontinued study treatment (with summary of reasons for not completing the study 
treatment period) 
• On study treatment (if applicable) 
• Completed the study 
• Did not complete the study (with summary of reasons for not completing the study) 
• On study (ongoing; if applicable) 
Among subjects who completed study treatment and who discontinued study treatment, the 
number and percentage of subjects will be summarized for: 
• Who had no HCV posttreatment Week 4 assessment (No HCV FU-4 Assessment) 
• Who had HCV posttreatment Week 4 assessment but no HCV posttreatment Week 12 
assessment (With HCV FU-4 but No FU-12 Assessment) 
If a subject did not have any HCV RNA assessment beyond 21 days after the last dose of any 
study drug (ie, lower bound of FU-4 visit for HCV), the subject is categorized as having “No 
HCV FU-4 Assessment”. If a subject had the HCV FU-4 assessment but did not have any HCV 
RNA assessment beyond 70 days after the last dose of any study drug (ie, lower bound of FU-12 
visit for HCV), the subject is categorized as having “With HCV FU-4 but No FU-12 
Assessment”. 
The denominator for the percentages of subjects in each category will be the number of subjects 
in the safety analysis set for that column.  


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No inferential statistics will be generated.  
A data listing of date of informed consent, first dose date, last dose date of study drug (study 
day), date completed study (study day), completed study treatment (yes/no), completed study 
(yes/no) and reasons for premature study treatment/study discontinuation will be provided. The 
last available observed nonmissing HCV RNA value prior to discontinuation and for up to 2 days 
after last dose of study drug will be included in this listing. 
4.3. 
Extent of Exposure 
4.3.1. 
Duration of Exposure to Study Drug 
Duration of exposure to study treatment will be defined as (Last Dose Date of Study Drug – First 
dose Date of Study Drug + 1), regardless of temporary interruptions in study drug 
administration, and will be expressed in weeks (recorded to 1 decimal place, eg, 12.1 weeks).  
Duration of exposure to the study drug will be summarized using descriptive statistics (sample 
size, mean, standard deviation [SD], median, first quartile [Q1], third quartile [Q3], minimum 
and maximum) and as the number of subjects exposed through (ie, cumulative counts): Baseline 
(Day 1); Week 1 (Day 7); Week 2 (Day 14); Week 4 (Day 28); Week 6 (Day 42); Week 8 
(Day 56); Week 10 (Day 70); Week 12 (Day 84). 
Summaries will be provided by prior treatment experience for China and Overall for the safety 
analysis set.  
4.3.2. 
Adherence to Study Drug 
Adherence will be calculated for LDV/SOF (tablets) as: 
(Number of tablets taken) ÷ (Number of tablets prescribed at Baseline for study drug) × 100% 
Note: If calculated adherence is greater than 100%, the result will be set to 100%. 
4.3.2.1. 
Calculation of Number of Tablets Prescribed for Study Drug 
For subjects who complete study drug or prematurely discontinue study drug for a reason other 
than virologic failure (ie, met virologic failure stopping criteria) the number of tablets prescribed 
is: 
• Prescribed LDV/SOF (90 mg/400 mg) would require 84 tablets (ie, 1 tablet/day x 84 days) 
for the 12-week treatment period. 
Subjects who prematurely discontinue study drug for lack of efficacy (ie, virologic failure) will 
have prescribed medications calculated for the number of study days at the first date when 
virologic stopping criteria were met (ie, substitute number of days to virologic failure [date of 
first of 2 consecutive measurements or a last available value meeting criteria] for 84 days). 


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4.3.2.2. 
Calculation of Number of Tablets Taken 
The number of tablets taken for LDV/SOF during the treatment period will be calculated as the 
sum of (number of tablets dispensed – number of tablets returned) at each distinct dispensing 
period across all bottles/blister packs dispensed. For subjects who discontinue for virologic 
failure, bottles dispensed after the subject first met virologic failure criteria will not be included 
in calculations. If a bottle is dispensed, and the bottle is returned empty, then the number of 
tablets returned will be entered as zero. If a bottle is dispensed but not returned (missing), the 
number of tablets taken from that bottle will be counted as zero.  
Descriptive statistics for adherence to LDV/SOF (sample size, mean, SD, median, Q1, Q3, 
minimum and maximum) along with the number and percentage of subjects belonging to 
adherence categories (e.g., < 80%, ≥ 80 to < 90%, ≥ 90%) will be provided by prior treatment 
experience for China and Overall for the safety analysis set.  
No inferential statistics will be provided. 
4.4. 
Protocol Deviations 
In Section 3.1.4, PK analysis set definition is slightly different from protocol amendment 3 
Section 8.2.1.3 Pharmacokinetics: The PK analysis set will include all subjects who are enrolled 
and have received at least one dose of study drug, and for whom concentration data of analytes 
[SOF, LDV, and metabolite(s), as appropriate] are available. The rationale for this change in PK 
analysis set definition in SAP from protocol is because if there is concentration record for a 
subject but is not usable for POP PK modeling, this concentration record is considered no value 
for PK interpretation.  
 A summary of important protocol violations will be provided by the Clinical Operations group 
for subjects in the safety analysis set. 


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5. 
BASELINE DATA 
5.1. 
Demographics and Baseline Characteristics 
The following subject demographic and baseline characteristics will be summarized by prior 
treatment experience (treatment naive and treatment experienced subjects) for China and Overall 
(i.e., China plus Korea plus Taiwan) using descriptive statistics (sample size, mean, standard 
deviation, median, Q1, Q3, minimum and maximum) for continuous data and by the number and 
percent of subjects for categorical data. Variables to be summarized include the following: 
• age (on date of first dose of study drug) as a continuous variable and for categories 
(< 65 years, ≥ 65 years)  
• sex (male, female) 
• race and race subcategory (Chinese, Korean, Taiwanese and Other) 
• ethnicity (Hispanic or Latino, non-Hispanic or Latino) 
• body mass index as a continuous variable and for categories (< 25 kg/m2 and ≥ 25 kg/m2) 
• HCV genotype subtype 
• cirrhosis (cirrhosis, absence of  cirrhosis) 
• IL28B (CC, Non-CC (CT, TT))  
• baseline HCV RNA as a continuous variable and for categories (<800,000 IU/mL, 
≥ 800,000 IU/mL) and (< 5 log10 IU/mL, ≥ 5 log10 IU/mL) 
• baseline ALT as a continuous variable and for categories (≤1.5 x ULN, > 1.5 x ULN) 
• response to prior HCV treatment (nonresponse, relapse/breakthrough, IFN intolerant) for 
treatment experienced subjects 
• interferon eligibility (IFN eligible, IFN ineligible, IFN unwilling) for treatment naive 
subjects 
• estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault equation 
Age is calculated as the integer of age in years at first dose of study drug. eGFR will be 
calculated by the Cockcroft-Gault method: eGFRCG (mL/min) = [(140 - age (yrs)) × weight (kg) 
× (0.85 if female)] / (serum creatinine (mg/dL) × 72), where weight is total body mass in 
kilograms. 


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The summary of demographic data and baseline characteristics will be provided for the safety 
analysis set.  
5.2. 
Medical History 
General medical history (ie, conditions not specific to the disease being studied) data will be 
listed only. General medical history data will not be coded. 


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6. 
EFFICACY ANALYSES  
6.1. 
Primary Efficacy Endpoint 
6.1.1. 
Definition of the Primary Efficacy Endpoint 
The primary efficacy endpoint is SVR 12 (HCV RNA < LLOQ 12 weeks after discontinuation of 
all study drugs) in the FAS population. The COBAS® AmpliPrep/COBAS® TaqMan® HCV Test 
v2.0 will be used to determine HCV RNA results of China in this study. The LLOQ of the assay 
is 15 IU/mL. 
The COBAS® Taqman® HCV Test v2.0 for use with the High Pure System was used to measure 
HCV RNA of Korea and Taiwan. The LLOQ of the assay was 25 IU/mL. 
6.1.2. 
Primary Analysis of the Primary Efficacy Endpoint 
The primary efficacy analysis described below will compare the observed SVR12 rate for the 
investigational regimen (i.e., LDV/SOF FDC for 12 weeks) versus the adjusted historical SVR 
null rate in treatment–naïve, Chinese subjects only. 
In addition, a point estimate with a two-sided 95% exact confidence interval using the binomial 
distribution (Clopper-Pearson method{Clopper 1934}) will be constructed for the SVR12 rate by 
prior treatment experience for China and Overall (i.e., Korea , Taiwan and China).  
Treatment Naïve Subjects 
In the primary efficacy analysis the SVR12 rate from China will be compared to the adjusted 
historical SVR null rate of 57% (as calculated in Appendix 3) using a two-sided exact 
one-sample binomial test.  
The hypothesis for superiority in China is: 
H0: SVR12 rate = 57%,  
H1: SVR12 rate ≠ 57%. 
Treatment Experienced Subjects:  
There is no treatment option available in China, Korea or Taiwan for treatment experienced 
patients with GT-1 infection. In the absence of effective antiviral therapy, spontaneous clearance 
of the HCV is rare. Consequently a nominal SVR rate of 5% is assumed for treatment-
experienced subjects. 
No statistical hypothesis testing will be performed in treatment experienced subjects. For China 
and Overall (i.e., China plus Korea plus Taiwan), a point-estimate with two-sided 95% exact 
confidence interval using the binomial distribution (Clopper-Pearson method) will be constructed 
for the SVR12 rate. 


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6.1.3. 
Subgroup Analysis of the Primary Efficacy Endpoint 
Point estimates and 95% exact confidence intervals of the SVR12 rates by prior treatment 
experience for China and Overall (i.e., China plus Korea plus Taiwan) will be displayed for each 
subgroup outlined in Section 3.4. The 2-sided 95% exact confidence intervals will be based on 
Clopper-Pearson method {Clopper 1934}. 
A Forest plot will graphically present estimates and 95% confidence intervals of SVR12 rates for 
each of the subgroups. 
6.2. 
Secondary Efficacy Endpoints 
6.2.1. 
Definition of Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following: 
• The proportion of subjects who attain SVR at 4 and 24 weeks after stopping therapy, defined 
as HCV RNA < LLOQ 4 and 24 weeks after stopping treatment (SVR 4 and SVR 24) 
• The proportion of subjects with HCV RNA below LLOQ by study visit 
• HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) through 
Week 12 for China only 
• The proportion of subjects with virologic failure as the following: 
 On-treatment virologic failure 
1) HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ, while on 
treatment, confirmed with 2 consecutive values (note: second confirmation value can 
be posttreatment), or last available on-treatment measurement with no subsequent 
follow up values (ie breakthrough) 
2) > 1 log10IU/mL increase in HCV RNA from nadir while on treatment, confirmed with 
2 consecutive values (note: second confirmation value can be posttreatment), or last 
available on-treatment measurement with no subsequent follow up values (ie 
rebound) 
3) HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (ie. nonresponse) 
 Relapse 
1) HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA 
< LLOQ at end of treatment, confirmed with 2 consecutive values or last available 
posttreatment measurement 
• Characterization of HCV drug resistance substitutions at baseline, during, and after 
therapy with LDV/SOF 


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6.2.2. 
Analysis Methods for Secondary Efficacy Endpoints 
For analyses of HCV RNA < LLOQ by visit while on treatment and during the post-treatment 
(SVR) follow-up period, subjects will be assigned a value at each visit based on the categorical 
imputation rules described in Section 3.5. The 2-sided 95% exact confidence interval based on 
Clopper-Pearson exact method will be provided for the proportion by prior treatment experience 
for China and Overall {Clopper 1934}. The “HCV RNA < LLOQ” category will be split into the 
following 2 subcategories: “< LLOQ TND” for subjects with target not detected and “< LLOQ 
detected” for subjects with < LLOQ in tabular displays.  
Graphs for the proportion of subjects with HCV RNA < LLOQ over time during treatment will 
be displayed. 
Summary statistics will be presented for absolute values and change from baseline in HCV RNA 
(log10 IU/mL) by visit and by prior treatment experience through Week 12 in China. Since 
LLOQ is 15 IU/mL of COBAS® AmpliPrep/COBAS® TaqMan® HCV Test v2.0 used to 
determine HCV RNA results of China, while LLOQ is 25 IU/mL of the COBAS® Taqman® 
HCV Test v2.0 for use with the High Pure System used in Korea and Taiwan, summary statistics 
for absolute values and change from baseline in HCV RNA for Overall (ie, China, Korea, plus 
Taiwan) will not be provided. Results for Korea and for Taiwan using the LLOQ of 25 IU/mL 
have been reported separately in the GS-US-337-0131 interim CSR dated 10 October 2014. 
Imputation rules described in Section 3.5 will be used to assign HCV RNA values for missing 
values at a visit that are bracketed by “< LLOQ TND”and/or “< LLOQ detected”. Otherwise, a 
missing = excluded analysis will be performed. Plots of the mean ± SD and median (Q1, Q3) of 
absolute values and changes from baseline in HCV RNA through Week 12 for subjects in China 
will be presented. 
For the SVR12 endpoint analysis, a summary table of the number and percentage of subjects 
with SVR12, virologic failure (VF), and Other will be created by prior treatment experience. All 
subjects who achieve SVR12 will be categorized as SVR12. Virologic failure will be 
descriptively summarized as “on-treatment virologic failure” and relapse (which will be 
summarized by study drug completed yes/no). Subjects who do not achieve SVR12 and do not 
meet criteria for VF will be categorized as “Other”. The denominator for relapse will be the 
number of subjects who had HCV RNA < LLOQ on their last observed on-treatment HCV RNA 
measurement; otherwise, the denominator will be the number of subjects in the FAS. 
Drug resistant substitutions will be analyzed as part of the Virology Study Report. 


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Exploratory Efficacy Endpoints 
6.3.1. 
PPD 
I 
I 
I 
I 
6.3.2. 
PD 
Definition of Exploratory Efficacy Endpoints 
Analysis Methods for Exploratory Efficacy Endpoints 
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6.4. 
Changes From Protocol-Specified Efficacy Analyses 
There are no changes from protocol-specified efficacy analyses. 
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7. 
SAFETY ANALYSES 
Safety data will be summarized for subjects included in the safety analysis set. Summaries of 
safety data (treatment-emergent [TE] adverse events [AEs], TE maximum toxicity grades, 
changes from baseline in laboratory and vital signs parameters) will include all data collected on 
or after the first dose date of any study drug through the last dose date of any study drug plus 
30 days for subjects who have stopped all study drugs, and all available data in the database for 
subjects still on treatment at the time of the analysis. 
All safety data (except for laboratory tests with results that were cancelled by the lab) will be 
included in data listings based on the safety analysis set. 
7.1. 
Adverse Events 
7.1.1. 
Adverse Event Dictionary 
Clinical and laboratory AEs will be coded using the current version of 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. 
7.1.2. 
Adverse Event Severity 
Adverse events are graded by the investigator according to the Gilead Sciences, Inc. (Gilead) 
Grading Scale for Severity of Adverse Events and Laboratory Abnormalities as specified in the 
clinical study protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings, and will be 
considered the least severe for the purposes of sorting for data presentation. 
7.1.3. 
Relationship of Adverse Events to Study Drug 
The relationship of AE to study drug will be assessed by investigators as “Yes” or “No”. Events 
for which the investigator did not record the relationship to study drug will be considered to be 
related to study drug for summary purposes. However, data listings will present the relationship 
as missing. 
7.1.4. 
Serious Adverse Events 
Serious adverse events will be identified and captured as SAEs if AEs met the definitions of SAE 
specified in the study protocol. Serious adverse events captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead Drug Safety and 
Public Health Department before database finalization. 


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7.1.5. 
Treatment-Emergent Adverse Events 
7.1.5.1. 
Definition of Treatment-Emergent  
Treatment-emergent AEs are 
• Any AEs with onset date of on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug or   
• Any AEs leading to premature discontinuation of study drug  
7.1.5.2. 
Incomplete Dates 
If the date of onset is incomplete, then the month and year (or year alone if month is not 
recorded) of onset determine whether the AE is treatment emergent. The event is treatment 
emergent if the month and year of onset (or year of onset) of the event meets both of the 
following criteria: 
• The same as or after the month and year (or year) of the first dose of any study drug 
• The same as or before the month and year (or year) of the 30th day after the date of the last 
dose of any study drug  
7.1.6. 
Summaries of Adverse Events and Deaths 
A brief summary of AEs will show, for China and Overall (i.e., China plus Korea plus Taiwan), 
the number and percentage of subjects who (1) had any TE AE, (2) had any Grade 3 and 4 TE 
AE, (3) had any Grade 2, 3 and 4 TE AE, (4) had any TE treatment-related AE, (5) had any 
Grade 3 and 4 TE treatment-related AE, (6) had any Grade 2, 3 and 4 TE treatment-related AE, 
(7) had any TE SAE, (8) had any TE treatment-related SAE, (9) AEs leading to permanent 
discontinuation from LDV/SOF (10) had any AE leading to interruption of LDV/SOF and (11) 
TE death during the study. 
Summaries (number and percentage of subjects) of adverse events (by SOC and PT) will be 
provided for China and Overall using the safety analysis set as follows: 
• All TE AEs 
• Combined Grade 3 or 4 TE AEs 
• Combined Grade 2, 3 or 4 TE AEs 
• TE treatment-related AEs 
• Combined Grade 3 or 4 TE treatment-related AEs 
• Combined Grade 2, 3 or 4 TE treatment-related AEs 


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• TE SAEs 
• TE treatment-related SAEs  
• Adverse Events Leading to permanent discontinuation from LDV/SOF 
• All deaths 
Multiple events will be counted once only per subject in each summary. For data presentation, 
SOC will be ordered alphabetically, with PT sorted by decreasing total frequency within an SOC. 
For summaries by severity grade, the most severe event will be selected.  
In addition to the presentation by SOC and PT, summaries will also be presented by PT only, 
ordered by decreasing total frequency for: (1) TE treatment-related AEs; (2) TE AEs that 
occurred in more than 5% of subjects within any region; (3) AEs leading to permanent 
discontinuation of LDV/SOF; (4) TE SAEs; and (5) TE grade 3 or 4 AEs. 
Data listings, with a variable indicating whether the event is treatment-emergent, will be 
provided for the following: 
• All AEs 
• SAEs 
• Deaths 
• AEs leading to permanent discontinuation from LDV/SOF 
• Grade 3 and 4 AEs 
7.2. 
Laboratory Evaluations 
Summaries of laboratory data will be provided for the safety analysis set and will include data 
collected up to last dose of any study drug plus 30 days for subjects who have stopped all study 
drugs and all available data in the database for subjects who are ongoing at the time of analysis. 
Analysis will be based on values reported in conventional units. Laboratory results cancelled by 
the central laboratory will not be included in analysis. 
No inferential statistics will be generated. 


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7.2.1. 
Summaries of Numeric Laboratory Results 
Descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum and maximum) will be 
provided for China and Overall for ALT, AST, total bilirubin, alkaline phosphatase , 
hemoglobin, reticulocytes, white blood cell (WBC) counts, neutrophils, lymphocytes, platelets, 
and INR as follows: 
• Baseline values  
• Values at each postbaseline analysis window 
• Change from baseline at each postbaseline analysis window  
The mean, median, Q1, Q3, minimum and maximum will be displayed to reported number of 
digits, standard deviation to reported number of digits +1 for visits up to Week 12 (end of 
treatment). The Week 4 safety follow-up visit will be presented as an additional separate visit. 
Median (Q1, Q3) of the absolute values for these laboratory parameters will be plotted for China 
and Overall by visit. In the case of multiple values in an analysis window, data will be selected 
for analysis as described in Section 3.7.3. 
The number of subjects with hemoglobin < 10 g/dL or < 8.5 g/dL at any postbaseline visit (up to 
30 days after the last dose of any study drug) will be summarized for China and Overall. 
7.2.2. 
Graded Laboratory Values 
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used for assignment of toxicity grades to laboratory results for purposes of analysis as Grade 0, 
Grade 1 (mild) , Grade 2 (moderate), Grade 3 (severe) or Grade 4 (potentially life threatening). 
Grade 0 includes all values that do not meet criteria for an abnormality of at least Grade 1.  
Some laboratory tests have laboratory toxicity criteria for both increased and decreased levels; 
analyses for each direction (ie, increased, decreased) will be presented separately. 
7.2.2.1. 
Treatment-Emergent Laboratory Abnormalities 
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any time postbaseline up to the last dose of any study drug plus 
30 days for subjects who have stopped all study drugs or all available data in the database for 
subjects still on treatment at the time of analysis. 
If the relevant baseline laboratory data are missing, then any abnormality of at least Grade 1 will 
be considered treatment emergent. 


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7.2.2.2. 
Summaries of Laboratory Abnormalities 
The following summaries (number and percentage of subjects) of laboratory abnormalities using 
the Gilead Grading Scale will be provided for China and Overall (subjects categorized according 
to most severe postbaseline abnormality grade): 
• TE graded laboratory abnormalities 
• TE Grade 3 and 4 laboratory abnormalities 
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values (up to 30 days after last dose of any study drug) for the 
laboratory parameter of interest. 
A listing of TE Grade 3 or Grade 4 laboratory abnormalities will be provided. This listing will 
include the complete laboratory test profile for each laboratory test with the graded result 
throughout the study. 
All valid laboratory values will be listed. Values falling outside of the relevant reference range 
and/or meeting Gilead Grading Scale will be flagged, as appropriate, in the data listings. 
7.3. 
Body Weight, Height, BMI and Vital Signs 
Absolute value and change from baseline in vital signs (systolic blood pressure [SBP], diastolic 
blood pressure [DBP] and pulse) at each visit will be summarized for the safety analysis set 
using descriptive statistics for China and Overall for each post baseline analysis window. In the 
case of multiple values in an analysis window, data will be selected for analysis as described in 
Section 3.7.3. No inferential statistics will be generated. 
A listing of height (at screening), body weight, and BMI, and a listing of SBP, DBP, pulse, 
temperature, and respiration will be provided. 
7.4. 
Concomitant Medications 
Concomitant medications (ie, medications other than study drug that are taken while receiving 
study drug) will be coded using the World Health Organization (WHO) Drug Dictionary. The 
WHO preferred name and drug code will be attached to the clinical database. Use of concomitant 
medications up to the last dose of any study drug will be summarized (number and percentage of 
subjects) for China and Overall, WHO drug class, and WHO generic name. Multiple drug use 
(by preferred name) will be counted once only per subject. The summary will be sorted 
alphabetically by drug class and then by decreasing total frequency within a class. 
For purposes of programming, any medication with a stop date that is on/prior to first dosing 
date or start date that is after the last dose of any study drug will be excluded from this summary. 
Otherwise, dates that are completely missing will be included in the summary. If a partial stop 
date is entered, then the month and year (if day is missing) or year (if day and month are 


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missing) that is prior to the study drug start date will be excluded from the summary. If a partial 
start date is entered, then the month and year (if day is missing) or year (if day and month are 
missing) that is after the study drug stop date will be excluded from the summary.  
Summaries of concomitant medications will be provided for the safety analysis set.  No 
inferential statistics will be generated. 
A listing of all concomitant medications reported during the study will be provided. 
7.5. 
Electrocardiogram Results 
A shift table of the investigator’s assessment of ECG results at baseline (normal, abnormal but 
not clinically significant, abnormal and clinically significant, or missing) versus the 
investigator’s assessment at each on-treatment visit (normal, abnormal but not clinically 
significant, abnormal and clinically significant, or missing) will be presented for China and 
Overall. The number and percent of subjects in each cross-classification group will be presented 
(subjects with a missing value at baseline or on-treatment visit will not be included in the 
denominator for percent calculation). 
A listing of ECG results including comments regarding clinically significant abnormalities will 
be provided. 
7.6. 
Other Safety Measures 
A data listing for cirrhosis determination will be provided for all subjects at screening. 
A data listing will be provided for subjects who become pregnant during the study. 


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8. 
PHARMACOKINETIC ANALYSES 
Single PK samples are collected at weeks 1, 2, 4, 6, 8, 10, and 12 (sparse PK sampling). 
Concentration of LDV and SOF (and its metabolites) in plasma will be determined using 
validated bioanalytical assays. 
Population PK models for LDV, SOF, and GS-331007, previously developed for the phase 2/3 
LDV/SOF US NDA population analyses, will be applied to the data from all PK samples 
(intensive and sparse) collected in this study. PK parameters (AUCtau, Cmax and Ctau of LDV; 
AUCtau and Cmax of SOF and GS-331007) will be estimated from the simulated LDV, SOF, and 
GS-331007 concentration data using the population PK model. The population PK model-
derived PK parameters will be listed and summarized.  
The population PK parameters of LDV, SOF and GS-331007 will be summarized by China and 
overall.  
The population PK parameters of LDV, SOF, and GS-331007 in this study will also be compared 
to the population PK parameters of LDV, SOF, and GS-331007 in the phase 2/3 LDV/SOF US 
NDA population to assess the difference in PK exposure between subjects from China and 
Overall in GS-US-337-0131 versus the phase 2/3 LDV/SOF US NDA population. The geometric 
mean ratios and corresponding 90% confidence interval will be provided.  


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9. 
REFERENCES 
Chen J, Florian J, Carter W, Fleischer RD, Hammerstrom TS, Jadhav PR, et al. Earlier Sustained 
Virologic Response End Points for Regulatory Approval and Dose Selection of 
Hepatitis C Therapies. Gastroenterology 2013;144 (7):1450-5. 
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Dec. Biometrika 1934;26 (4):pp. 404-13. 
Heo N-Y, Lim Y-S, Lee HC, Lee YS, Kim KM, Byum KS, et al. High effectiveness of 
peginterferon alfa-2a plus ribavirin therapy in Korean patients with chronic 
hepatitis C in clinical practice. Clin Mol Hepatol 2013;19 (1):60-9. 
Nehls G, Akland G. Procedures for Handling Aerometric Data. Journal of the Air Pollution 
Control Association 1973;23 (3):180-4. 
Park SY, Rim MY, Yo IK, Ha MS, Kim JS, Lee JW, et al. [Efficacy of peginterferon and 
ribavirin combination therapy of chronic hepatitis C: a pooled analysis]. The 
Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi 2012;60 
(5):306-14. 
 


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10. 
SOFTWARE 
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA. 
nQuery Advisor(R) Version 7.0. Statistical Solutions, Cork, Ireland. 


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11. 
SAP REVISION 
Revision Date 
(dd month, yyyy) 
Section 
Summary of Revision 
Reason for Revision 
 
 
 
 
 
 
 
 
 


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12. 
APPENDICES 
Appendix 1. 
Table of Contents for Statistical Tables, Figures, and Listings 
Appendix 2. 
Schedule of Assessments 
Appendix 3. 
Calculation of Historical Control SVR12 for Treatment naïve Chinese Subjects with 
Chronic GT-1 HCV Infection 
 


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Appendix 1. 
Table of Contents for Statistical Tables, Figures, and Listings 
Table 
Number 
Title 
Analysis Set 
1 
Subjects Enrolled and Treated by Investigator  
Safety Analysis Set 
2 
Subject Disposition 
Screened Subjects 
3 
Reasons for Screen Failure 
Screened Subjects 
4 
Demographics and Baseline Characteristics 
Safety Analysis Set 
4.1 
Summary of Categories for Interferon Eligibility and Reasons 
for Interferon Ineligible 
Safety Analysis Set 
4.2 
Summary of Categories for Response to Prior HCV Treatment 
and Reasons for Interferon Intolerance 
Safety Analysis Set 
5 
Duration of Exposure to Study Drug 
Safety Analysis Set 
6 
Concomitant Medications 
Safety Analysis Set 
7 
Adherence to Study Drug 
Safety Analysis Set 
8.1 
SVR12 
Full Analysis Set 
8.2 
SVR12 by Subgroup 
Full Analysis Set 
9 
Concordance between SVR12 and SVR24 
Full Analysis Set 
10 
Virologic Outcome 
Full Analysis Set 
11 
Proportion of Subjects with HCV RNA Less than LLOQ 
While on Treatment by Visit 
Full Analysis Set 
12 
SVR by Visit During Posttreatment Follow-Up 
Full Analysis Set 
13 
HCV RNA (log10 IU/mL) and Change from Baseline by Visit 
Through Week 12  
Subjects in China in Full Analysis 
Set 
14 
Proportion of Subjects with ALT Normalization by Visit 
Full Analysis Set with ALT>ULN 
at Baseline 
15 
Adverse Events: Brief Summary 
Safety Analysis Set 
16 
All Treatment-Emergent Adverse Events 
Safety Analysis Set 
17 
Treatment-Emergent Treatment-Related Adverse Events 
Safety Analysis Set 
17.1 
Treatment-Emergent Treatment-Related Adverse Events by 
Preferred Term  
Safety Analysis Set 
18 
Grade 3 or 4 Treatment-Emergent Adverse Events  
Safety Analysis Set 
19 
Grade 3 or 4 Treatment-Emergent Treatment-Related Adverse 
Events 
Safety Analysis Set 
20 
Grade 2, 3, or 4 Treatment-Emergent Adverse Events  
Safety Analysis Set 
21 
Grade 2, 3, or 4 Treatment-Emergent Treatment-Related 
Adverse Events 
Safety Analysis Set 


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Table 
Number 
Title 
Analysis Set 
22 
Adverse Events Leading to Permanent Discontinuation from 
LDV/SOF 
Safety Analysis Set 
23 
Treatment-Emergent Serious Adverse Events 
Safety Analysis Set 
24 
Treatment-Emergent Treatment-Related Serious Adverse 
Events 
Safety Analysis Set 
25 
All Deaths 
Safety Analysis Set 
27 
Treatment-Emergent Adverse Events Occurring in At Least 
5% of Subjects by Preferred Term 
Safety Analysis Set 
28 
Adverse Events Leading to Permanent Discontinuation of 
LDV/SOF by Preferred Term 
Safety Analysis Set 
29 
Treatment-Emergent Serious Adverse Events by Preferred 
Term 
Safety Analysis Set 
30 
Treatment-Emergent Grade 3 or 4 Adverse Events by 
Preferred Term 
Safety Analysis Set 
31.1 
ALT (U/L) and Change from Baseline by Visit 
Safety Analysis Set 
31.2 
AST (U/L) and Change from Baseline by Visit 
Safety Analysis Set 
31.3 
Total Bilirubin (mg/dL) and Change from Baseline by Visit 
Safety Analysis Set 
31.4 
Alkaline Phosphatase (U/L) and Change from Baseline by 
Visit 
Safety Analysis Set 
31.5 
Hemoglobin (g/dL) and Change from Baseline by Visit 
Safety Analysis Set 
31.6 
Subjects with Postbaseline Hemoglobin < 10 g/dL or < 8.5 
g/dL 
Safety Analysis Set 
31.7 
Reticulocytes (x 103 /μL) and Change from Baseline by Visit 
Safety Analysis Set 
31.8 
WBC (x 103 /μL) and Change from Baseline by Visit 
Safety Analysis Set 
31.9 
Neutrophils (x103 /μL) and Change from Baseline by Visit 
Safety Analysis Set 
31.10 
Lymphocytes (x103 /μL) and Change from Baseline by Visit 
Safety Analysis Set 
31.11 
Platelets (x 103 /μL) and Change from Baseline by Visit 
Safety Analysis Set 
31.12 
INR and Change from Baseline by Visit 
Safety Analysis Set 
32 
Treatment-Emergent Graded Laboratory Abnormalities 
Safety Analysis Set 
33 
Treatment-Emergent Grade 3 or 4 Laboratory Abnormalities 
Safety Analysis Set 
34 
Shift Table of Baseline versus On-Treatment 12-lead ECG 
Assessment by Visit 
Safety Analysis Set 
35.1 
Systolic Blood Pressure (mmHg) and Change from Baseline 
by Visit 
Safety Analysis Set 
35.2 
Diastolic Blood Pressure (mmHg) and Change from Baseline 
by Visit 
Safety Analysis Set 


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Table 
Number 
Title 
Analysis Set 
35.3 
Pulse (bpm) and Change from Baseline by Visit 
Safety Analysis Set 
36 
Summary of SF-36 Quality of Life Questionnaire 
Full Analysis Set 
38 
Individual and Summary of Population PK Model-derived PK 
Parameters Overall and by Region 
PK Analysis Set 
40.1 
Summary of Population PK Parameters in Study GS-US-337-
0131 (Overall and by Region) Compared to the LDV/SOF US 
NDA Population Following Administration of LDV/SOF  
PK Analysis Set 
 


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Figure 
Number 
Title 
Analysis Set 
1 
Subject Disposition 
Safety Analysis Set 
2 
Forest Plot of SVR12 by Subgroup 
Full Analysis Set 
3 
Proportion of Subjects with HCV RNA < LLOQ While on 
Treatment by Visit 
Full Analysis Set 
4.1 
Mean ± SD Change from Baseline in HCV RNA (log10 
IU/mL) by Visit Through Week 12  
Subjects in China in Full Analysis 
Set 
4.2 
Median (Q1, Q3) Change from Baseline in HCV RNA (log10 
IU/mL) by Visit Through Week 12  
Subjects in China in Full Analysis 
Set 
4.3 
Mean ± SD in HCV RNA (log10 IU/mL) by Visit Through 
Week 12  
Subjects in China in Full Analysis 
Set 
4.4 
Median (Q1, Q3) in HCV RNA (log10 IU/mL) by Visit 
Through Week 12  
Subjects in China in Full Analysis 
Set 
5.1 
Median (Q1, Q3) ALT (U/L) by Visit 
Safety Analysis Set 
5.2 
Median (Q1, Q3) AST (U/L) by Visit 
Safety Analysis Set 
5.3 
Median (Q1, Q3) Total Bilirubin (mg/dL) by  Visit 
Safety Analysis Set 
5.4 
Median (Q1, Q3) Alkaline Phosphatase (U/L) by Visit 
Safety Analysis Set 
5.5 
Median (Q1, Q3) Hemoglobin (g/dL) by Visit 
Safety Analysis Set 
5.6 
Median (Q1, Q3) Reticulocytes (x 103 /μL) by Visit 
Safety Analysis Set 
5.7 
Median (Q1, Q3) WBC (x 103 /μL) by Visit 
Safety Analysis Set 
5.8 
Median (Q1, Q3) Neutrophils  (x 103 /μL) by Visit 
Safety Analysis Set 
5.9 
Median (Q1, Q3) Lymphocytes (x 103 /μL) by Visit 
Safety Analysis Set 
5.10 
Median (Q1, Q3) Platelets (x 103 /μL) by Visit 
Safety Analysis Set 
6 
Mean ± SD Change from Baseline in SF-36 Quality of Life 
Questionnaire by visit 
Full Analysis Set 
 


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Listing 
Number 
Title 
Analysis Set 
1 
Inclusion and Exclusion Criteria 
Subjects Not Treated 
2.1 
Subjects Who were Excluded from Safety and Full Analysis Sets 
All Enrolled Subjects 
2.2 
Subjects Enrolled and Treated Who Did Not Meet Eligibility 
Criteria 
Safety Analysis Set 
3 
Subject Disposition 
Safety Analysis Set 
4.1 
Subject Demographics and Baseline Characteristics 
Safety Analysis Set 
4.2 
Cirrhosis Determination 
Safety Analysis Set 
4.3 
Interferon Ineligible Reasons 
Safety Analysis Set 
4.4 
Interferon Intolerant Reasons 
Safety Analysis Set 
4.5 
Response to Prior HCV Treatment 
Safety Analysis Set 
5 
Medical History 
Safety Analysis Set 
6.1 
Study Drug Administration 
Safety Analysis Set 
6.2 
Study Drug Accountability and Adherence 
Safety Analysis Set 
7 
Prior and Concomitant Medications 
Safety Analysis Set 
8.1 
HCV RNA (log10 IU/mL) and Change from Baseline  
Safety Analysis Set 
8.2 
Subjects with Virologic Failure 
Safety Analysis Set 
8.3 
Subjects with Postbaseline Hemoglobin < 10 g/dL or < 8.5 g/dL 
Safety Analysis Set 
9 
SF-36 Quality of Life Questionnaire 
Safety Analysis Set 
10 
All Adverse Events 
Safety Analysis Set 
11 
Grade 3 or 4 Adverse Events 
Safety Analysis Set 
12 
Adverse Events Leading to Permanent Discontinuation from 
LDV/SOF 
Safety Analysis Set 
13 
Serious Adverse Events 
Safety Analysis Set 
14 
Pregnancy 
Safety Analysis Set 
15 
Deaths 
Safety Analysis Set 
16 
Central Laboratory (Covance) Reference Ranges 
Safety Analysis Set 
17 
Subjects with Treatment-Emergent Grade 3 or 4 Laboratory 
Abnormalities 
Safety Analysis Set 
18 
Screen Labs: HBsAg, Anti-HIV Ab, Anti-HCV Ab, HbA1c, and 
Serum Beta hCG 
Safety Analysis Set 
19.1 
Hematology: Hematocrit, Hemoglobin, Reticulocyte Count, 
MCV, RBC, WBC, and Platelets 
Safety Analysis Set 
19.2 
Hematology: WBC, Neutrophils, and Lymphocytes 
Safety Analysis Set 
19.3 
Hematology: Eosinophils, Basophils, and Monocytes 
Safety Analysis Set 


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Listing 
Number 
Title 
Analysis Set 
20.1 
Chemistry: Sodium, Potassium, Serum Creatinine, Estimated 
GFR (Cockcroft-Gault), and Glucose 
Safety Analysis Set 
20.2 
Chemistry: AST, ALT, Total Bilirubin, Direct Bilirubin, Alkaline 
Phosphatase, GGT, Albumin, and Lipase 
Safety Analysis Set 
20.3 
Coagulation and Other Laboratory Tests: INR, APTT, and TSH 
Safety Analysis Set 
21.1 
Urinalysis: Urine Blood, Glucose, pH, Protein, Urobilinogen, and 
Leukocyte Esterase 
Safety Analysis Set 
21.2 
Microscopic Urinalysis for Subjects with Abnormal Leukocyte 
Esterase 
Safety Analysis Set 
22 
12-Lead Electrocardiogram Results 
Safety Analysis Set 
23.1 
Vital Signs 
Safety Analysis Set 
23.2 
Height, Weight, and BMI 
Safety Analysis Set 
 


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Appendix 2. 
Schedule of Assessments 
Appendix Table 1. 
Screening and On-Treatment Study Visits 
Clinical Assessments 
Screeninga 
On Treatment Period 
Day -28 
to Day -1 
Baseline/ 
Day 1b 
Week 1 
(±3 days) 
Week 2 
(±3 days) 
Week 4 
(±3 days) 
Week 6 
(±3 days) 
Week 8 
(±3 days) 
Week 10 
(±3 days) 
Week 12 
(±3 days) 
ET 
Informed Consent 
X 
 
  
  
  
  
  
  
 
  
Determine Eligibility 
X 
X 
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
 
Physical Examination 
X 
X 
  
  
  
  
 
  
X  
X 
Liver Imaging (Cirrhotics Only) 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
  
  
  
  
  
  
  
  
  
Weight 
X 
X 
  
  
  
  
 
  
X 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGd 
X 
X 
X  
  
  
  
  
  
X  
 X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Prevention 
Counseling 
  
X 
  
  
  
  
 
  
X  
X 
Health Related Quality of Life 
  
X 
  
X 
X  
  
X 
  
X 
X 
Hematology & Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
  
  
  
  
 
  
X 
X 
Serum HCV RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Single PK Sample 
  
  
X 
X 
X 
X 
X 
X 
X 
X 


Ledipasvir/Sofosbuvir 
GS-US-337-0131 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 45 
28 July 2017 
Clinical Assessments 
Screeninga 
On Treatment Period 
Day -28 
to Day -1 
Baseline/ 
Day 1b 
Week 1 
(±3 days) 
Week 2 
(±3 days) 
Week 4 
(±3 days) 
Week 6 
(±3 days) 
Week 8 
(±3 days) 
Week 10 
(±3 days) 
Week 12 
(±3 days) 
ET 
Viral RNA Sequencing 
/Phenotyping Sample (Plasma)e 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Archive Sample j 
 
X 
 
 
 
 
 
 
X 
X 
Serum or Urine Pregnancy Testk 
X 
X 
  
  
 X 
  
X 
 
X 
X 
Urinalysis 
X 
  
  
  
  
  
  
  
  
  
IL28B Genotype, HCV 
Genotype 
X 
  
  
  
  
  
  
  
  
  
HCV Ab, HIV Ab and HBsAg 
X 
  
  
  
  
  
  
  
  
  
Hemoglobin A1c, TSH 
X 
  
  
  
  
  
  
  
  
  
PK Substudy Collectionf 
  
  
  
X 
X  
  
  
  
  
  
Single Pharmacogenomic 
Sampleg 
  
X 
  
  
  
  
  
  
  
  
Review of Study Drug 
Adherence and Drug 
Accountabilityh 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Dispensingi 
  
X 
  
  
X  
  
X 
 
 
 
a 
The screening window can be extended to 42 days for subjects requiring liver biopsy or additional HCV genotype testing.  
b 
Baseline/Day 1 assessments must be performed prior to dosing. 
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 gross abnormalities. 
e 
Serum samples will be collected and stored for potential HCV sequencing and other virology studies. 
f 
The optional PK substudy is conducted in Taiwan and Korea only. Subjects that consent to the optional PK substudy will have serial PK samples drawn at Week 2 or Week 4 
visit. 


Ledipasvir/Sofosbuvir 
GS-US-337-0131 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 46 
28 July 2017 
g 
Only for subjects who have provided consent for this sample and testing (Taiwan and Korea only). This sample can be obtained at a subsequent visit if not obtained at Day 1. 
h 
Study medication and dosing diary, will be reconciled at every post-baseline visit by the investigator or designee in order to monitor the subject’s adherence with the 
medication regimen.     
i 
Study Drug will be dispensed per IWRS directions.  Subjects must be instructed to bring back all bottles of study medication(s) in the original container at every post baseline 
study visits through the end of treatment.  
j 
Archive plasma samples will be collected at the Baseline/Day 1 visit and at the end of treatment for subjects who have not opted out of sample collection 
k 
 For female subjects of childbearing potential. In the event of a positive urine test, a serum pregnancy test will be done. 


Ledipasvir/Sofosbuvir 
GS-US-337-0131 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 47 
28 July 2017 
Appendix Table 2. 
Post Treatment Study Visits 
Clinical Assessments 
Post Treatment Perioda 
Post Treatment Week 4 
(±5 days) 
Post Treatment Week 12 
(±5 days) 
Post Treatment Week 24 
(±5 days) 
Weight 
  
X 
X 
Vital Signsb 
X 
X 
X 
Adverse Events 
X 
  
  
Concomitant Medications 
X 
  
  
Pregnancy Prevention Counseling 
X 
 
 
Health Related Quality of Life 
X 
X 
 
Hematology & Chemistry 
X 
  
  
Serum HCV RNA 
X 
X 
X 
Viral Sequencing Sample (Plasma)c 
X 
X 
X 
Serum or Urine Pregnancy Testd 
X 
 
 
a 
All subjects will complete both 4-week and 12-week Post-Treatment visits regardless of the treatment duration. Subjects with HCV RNA < LLOQ at their 12-week 
Post-Treatment visit will complete a 24-week Post-Treatment visit, unless viral relapse is determined. The end of study will occur at the 24-week Post-Treatment visit.  
b 
Vital signs include resting blood pressure, pulse, respiratory rate and temperature. 
c 
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies.  
d 
For female subjects of childbearing potential. In the event of a positive urine test, a serum pregnancy test will be done. 


Ledipasvir/Sofosbuvir 
GS-US-337-0131 China and Overall 
Statistical Analysis Plan    
Version 1.0 
CONFIDENTIAL 
Page 48  
28 July 2017 
Appendix 3. 
Calculation of Historical Control SVR12 for Treatment naïve Chinese 
Subjects with Chronic GT-1 HCV Infection 
This section details the calculation for the historical control SVR12 rate for Treatment naïve 
Chinese subjects with chronic GT-1 HCV infection.  
For China, the historical control rate has been calculated according to the reference studies in 
Appendix Table 3. SVR rates are not reported separately for elderly patients or those with 
cirrhosis in these references. Consequently, the calculated historical SVR rate of 57% has not 
been adjusted by different population. 
Appendix Table 3. 
Literature References for Historical Control Rate Calculations in 
China 
SVR Rates in China 
Population 
SVR% 
SVR n/N 
Reference 
GT-1 Treatment Naïve (Peg-IFN/RBV 48 Weeks) 
70.3 
102/145 
{Heo 2013}  
43.9 
18/41 
{Heo 2013}  
46.0 
58/126 
{Park 2012}  
Overall SVR Rate 
(102+18+58)/(145+41+126)=57% 
 

Prot_001.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Study Director: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3b, Multicenter, Open-Label Study to Investigate the Efficacy 
and Safety of Sofosbuvir/Ledipasvir Fixed-Dose Combination in 
Treatment-Naive and Treatment-Experienced Subjects with Chronic 
Genotype 1 HCV Infection 
Gilead Sciences, Inc. 
333 Lakeside Dtive 
Foster City, CA 94404, USA 
Not Applicable 
Not Applicable 
To be detennined 
Hepatitis C Vims Infection 
GS-US-337-0131 
Name: 
Telephone: 
Fax: 
E-mail: 
Kathi 
PPD 
PPD 
t-Jt-JU 
Original: 
28 May 2013 
Amendment 1.1: 12 December 2013 
Amendment 2.0: 01 August 2014 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pruiicularly unpublished data, is the propetiy 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 Boru·d or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaty to obtain infonned consent from those 
persons to whom the dm g may be administered. 


Sofosbuvir/Ledipasvir FDC
Protocol GS-US-337-0131
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 2
01 August 2014
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................12
1.
INTRODUCTION ..............................................................................................................................................16
1.1.
Background ............................................................................................................................................16
1.1.1.
HCV Infection......................................................................................................................16
1.1.2.
HCV Infection in Korea .......................................................................................................17
1.1.3.
HCV Infection in Taiwan.....................................................................................................18
1.1.4.
HCV Infection in China .......................................................................................................19
1.1.5.
Summary ..............................................................................................................................20
1.2.
Sofosbuvir (formerly GS-7977) and Ledipasvir (formerly, GS-5885) Fixed Dose Combination..........20
1.2.1.
General Information .............................................................................................................20
1.2.2.
Summary of Additional Clinical Experience with Sofosbuvir and 
Ledipasvir.............................................................................................................................21
1.3.
Rationale for This Study ........................................................................................................................24
1.4.
Rationale for Dose Selection of SOF/LDV FDC ...................................................................................25
1.5.
Overall Risk/Benefit Assessment...........................................................................................................25
1.6.
Compliance ............................................................................................................................................26
2.
OBJECTIVES.....................................................................................................................................................27
3.
STUDY DESIGN................................................................................................................................................28
3.1.
Endpoints ...............................................................................................................................................28
3.2.
Study Design..........................................................................................................................................28
3.3.
Study Treatment.....................................................................................................................................28
3.4.
Duration of Treatment............................................................................................................................28
3.5.
Discontinuation Criteria.........................................................................................................................29
3.6.
Source Data............................................................................................................................................29
4.
SUBJECT POPULATION..................................................................................................................................30
4.1.
Number of Subjects and Subject Selection ............................................................................................30
4.2.
Inclusion Criteria....................................................................................................................................30
4.3.
Exclusion Criteria...................................................................................................................................32
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................34
5.1.
Randomization and Treatment Codes ....................................................................................................34
5.2.
Description and Handling of Sofosbuvir/Ledipasvir Fixed-Dose Combination.....................................34
5.2.1.
Formulation..........................................................................................................................34
5.2.2.
Packaging and Labeling .......................................................................................................34
5.2.3.
Storage and Handling...........................................................................................................34
5.3.
Dosage and Administration of Sofosbuvir/Ledipasvir FDC ..................................................................35
5.4.
Prior and Concomitant Medications.......................................................................................................35
5.5.
Accountability for SOF/LDV FDC ........................................................................................................36
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................37
6.
STUDY PROCEDURES ....................................................................................................................................38
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................38
6.2.
Pretreatment Assessments......................................................................................................................38
6.2.1.
Screening Visit (Day -28 to Day -1).....................................................................................38


Sofosbuvir/Ledipasvir FDC
Protocol GS-US-337-0131
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 3
01 August 2014
6.3.
Randomization .......................................................................................................................................40
6.4.
Treatment Assessments..........................................................................................................................40
6.4.1.
Baseline/Day 1 Visit.............................................................................................................40
6.4.2.
Week 1 (3 days) ................................................................................................................41
6.4.3.
Week 2 (3 days) ................................................................................................................41
6.4.4.
Week 4 (3 days) ................................................................................................................42
6.4.5.
Week 6 (3 days) ................................................................................................................43
6.4.6.
Week 8 (3 days) ................................................................................................................43
6.4.7.
Week 10 (3 days) ..............................................................................................................44
6.4.8.
Week 12 (3 days) ..............................................................................................................44
6.4.9.
Early Termination (ET)/Unscheduled Visit .........................................................................45
6.5.
Post-Treatment Assessments..................................................................................................................46
6.5.1.
Post Treatment Week 4 (5 days) .......................................................................................46
6.5.2.
Post Treatment Weeks 12 and 24 (5 days)........................................................................47
6.6.
Procedures and Specifications................................................................................................................47
6.6.1.
Clinical Laboratory Analytes ...............................................................................................47
6.6.2.
Medical History....................................................................................................................48
6.6.3.
Complete Physical Examination...........................................................................................48
6.6.4.
Vital Signs............................................................................................................................48
6.6.5.
Creatinine Clearance ............................................................................................................49
6.6.6.
12-Lead ECGs......................................................................................................................49
6.6.7.
Viral RNA Sequencing / Phenotyping Sample.....................................................................49
6.6.8.
Archive Sample....................................................................................................................50
6.6.9.
Single Pharmacokinetic (PK) Sample ..................................................................................50
6.6.10.
Intensive Pharmacokinetic (PK) Substudy (Korea and Taiwan only) ..................................50
6.6.11.
Pharmacogenomic (PG) Substudy........................................................................................50
6.6.12.
Pregnancy Testing................................................................................................................51
6.6.13.
Health Related Quality of Life Survey.................................................................................51
6.7.
Assessments for Premature Discontinuation from Study.......................................................................51
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................52
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................52
7.1.1.
Adverse Events.....................................................................................................................52
7.1.2.
Serious Adverse Events........................................................................................................52
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................53
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................53
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................54
7.4.
Gilead Reporting Requirements.............................................................................................................55
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................56
7.6.
Subject Stopping Rules ..........................................................................................................................56
7.7.
Special Situations Reports......................................................................................................................57
7.7.1.
Definitions of Special Situations..........................................................................................57
7.7.2.
Instructions for Reporting Special Situations.......................................................................57
8.
STATISTICAL CONSIDERATIONS................................................................................................................59
8.1.
Analysis Objectives and Endpoints........................................................................................................59
8.1.1.
Analysis Objectives..............................................................................................................59
8.1.2.
Primary Endpoint .................................................................................................................59
8.1.3.
Secondary Endpoint .............................................................................................................60
8.1.4.
Other Endpoints of Interest ..................................................................................................60
8.2.
Analysis Conventions.............................................................................................................................60


Sofosbuvir/Ledipasvir FDC
Protocol GS-US-337-0131
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 4
01 August 2014
8.2.1.
Analysis Sets ........................................................................................................................60
8.3.
Data Handling Conventions ...................................................................................................................61
8.3.1.
Interim Analysis ...................................................................................................................62
8.4.
Demographic Data and Baseline Characteristics ...................................................................................62
8.5.
Efficacy Analysis ...................................................................................................................................62
8.5.1.
Primary Analysis..................................................................................................................62
8.5.2.
Secondary Analysis..............................................................................................................63
8.6.
Safety Analysis.......................................................................................................................................64
8.6.1.
Extent of Exposure...............................................................................................................64
8.6.2.
Adverse Events.....................................................................................................................64
8.6.3.
Laboratory Evaluations ........................................................................................................65
8.7.
Pharmacokinetic Analysis......................................................................................................................65
8.8.
Sample Size............................................................................................................................................65
9.
RESPONSIBILITIES..........................................................................................................................................67
9.1.
Investigator Responsibilities ..................................................................................................................67
9.1.1.
Good Clinical Practice..........................................................................................................67
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................67
9.1.3.
Informed Consent.................................................................................................................68
9.1.4.
Confidentiality......................................................................................................................68
9.1.5.
Study Files and Retention of Records ..................................................................................68
9.1.6.
Case Report Forms...............................................................................................................70
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................70
9.1.8.
Inspections............................................................................................................................70
9.1.9.
Protocol Compliance............................................................................................................70
9.2.
Sponsor Responsibilities ........................................................................................................................71
9.2.1.
Protocol Modifications.........................................................................................................71
9.2.2.
Study Report and Publications .............................................................................................71
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................71
9.3.1.
Access to Information for Monitoring..................................................................................71
9.3.2.
Access to Information for Auditing or Inspections ..............................................................72
9.3.3.
Study Discontinuation..........................................................................................................72
10.
REFERENCES ...................................................................................................................................................73
11.
APPENDICES ....................................................................................................................................................80
Appendix 1.
Investigator Signature Page....................................................................................................81
Appendix 2.
Study Procedures Table..........................................................................................................82
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............86
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................109
Appendix 5.
Calculation of Historical Control SVR12 for Treatment-naïve Korean Subjects and 
for Treatment-naïve Chinese Subjects with Chronic GT-1 HCV Infection..........................111
LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-334-0111 Geometric Least-Squares Mean Ratios (90% Confidence 
Intervals) for Sofosbuvir, GS-566500, GS-331007, and Ledipasvir Primary PK 
Parameters in Japanese versus Caucasian Subjects ................................................................22
Table 1-2.
GS-US-337-0113 Number (and Percentage) of Subjects with SVR12...................................24
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................36


Sofosbuvir/Ledipasvir FDC
Protocol GS-US-337-0131
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 5
01 August 2014
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 3b, Multicenter, Open-Label Study to Investigate the Efficacy 
and Safety of Sofosbuvir/Ledipasvir Fixed-Dose Combination in 
Treatment-Naïve and Treatment-Experienced Subjects with Chronic 
Genotype 1 HCV Infection
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
Not applicable
Not applicable
To be determined
Study Centers 
Planned:
Approximately 14 sites in China
Approximately 14 sites in Korea 
Approximately 10 sites in Taiwan
Objectives:
The primary objectives of this study are:

To determine the antiviral efficacy of treatment with sofosbuvir 
(SOF)/ledipasvir (LDV) fixed-dose combination (FDC) as 
measured by the proportion of subjects with sustained virologic 
response (SVR) 12 weeks after discontinuation of therapy 
(SVR12, defined as HCV RNA < lower limit of quantification 
[LLOQ] 12 weeks post treatment)

To evaluate the safety and tolerability of SOF/LDV FDC as 
assessed 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 discontinuation of therapy (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during treatment 
and after treatment discontinuation

To evaluate the emergence of viral resistance to SOF and LDV 
during treatment and after treatment discontinuation


Sofosbuvir/Ledipasvir FDC 
Protocol GS-US-337-0131 
Gilead Sciences, Inc. 
Study Design: 
Final 
Amendment 2.0 
The explorat01y objectives of this study are: 
PPO 
I 
Intemational (China, Korea and Taiwan), multicenter, open-label study 
in treatment-naive and treatment-experienced adults with chronic 
genotype 1 HCV infection. 
Approximately 180 u·eatment-naive and 180 treatment-experienced 
subjects will receive treatment with SOF 400 mg/LDV 90 mg fixed 
dose combination (FDC) tablet for 12 weeks. 
It is estimated that approximately 200 subjects will be enrolled in 
China, 80 subjects will be enrolled in Korea, and 80 subjects in 
Taiwan. Within each country approximately 50% (i.e., n~100 or 40) of 
subjects will be u·eatment-naive and 50% will be 
u·eatment-experienced (i.e., n~100 or 40). 
Treatment-naive is defined as having never received u·eatment for 
HCV with any interferon (IFN), ribavirin (RBV), or other approved or 
experimental HCV-specific direct acting antivirals. 
Treatment-experienced is defmed as: 
a) IFN intolerant 
Note: Subjects intolerant of Peg-IFNa+RBV+HCV protease 
inhibitor regimens are included in this category. 
b) Non-response 
c) Relapse/Breakthrough 
Note: For treatment-experienced subjects, prior exposure to 
HCV NS3/NS4A protease inhibitors is permitted. 
Up to 20% of subjects enrolled in the study may have compensated 
cinhosis at Screening. 
Number of 
Approximately 360 subjects 
Subjects Planned: 
Target Population: 
Treatment-naive and u·eatment-experienced, chronic genotype 1 HCV 
infected adults 
Duration of 
12 weeks 
Treatlnent: 
CONFIDENTIAL 
Page6 
01 August 2014 


Sofosbuvir/Ledipasvir FDC
Protocol GS-US-337-0131
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 7
01 August 2014
Diagnosis and 
Main Eligibility 
Criteria:
Chronic genotype 1, HCV infected, male and 
non-pregnant/non-lactating female subjects, ages 20 years and older, 
treatment-naïve or treatment-experienced, of whom approximately 
20% may have compensated cirrhosis, may be eligible for the study.
Reference Section 4.2 and 4.3 for detailed Inclusion and Exclusion 
criteria.
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the
Baseline/Day 1 visit. The screening window can be extended to 
42 days for subjects requiring liver biopsy or additional 
HCV genotyping.
Study visits will occur at Screening, Baseline/Day 1, and on-treatment 
at the end of Weeks 1, 2, 4, 6, 8, 10, and 12. Following the last dose of 
study medication, all subjects will complete 4-Week and 12-Week 
Post-Treatment Visits. Subjects with HCV RNA < LLOQ at the 
12-Week Post-Treatment Visit will also complete a 24-Week 
Post-Treatment Visit unless confirmed viral relapse occurs.
Administration of interferon or any HCV-directed treatment, other than 
the study drug, is prohibited from 12 weeks prior to Screening until 
completion of the final post-treatment follow-up visit.
Screening assessments include physical examination, height, weight, 
vital signs, 12-lead electrocardiogram (ECG), medical history, adverse 
events (AEs), concomitant medications, safety laboratory tests 
(hematology, chemistry, coagulation, urinalysis), HCV RNA, serology 
(HIV, HCV, HBV), hemoglobin A1c (HbA1c), assessment of the 
presence or absence of cirrhosis, liver imaging for HCC 
(cirrhotics only), serum β-hCG (females of child bearing 
potential only), thyroid stimulating hormone (TSH), HCV genotyping, 
IL28B genotyping.
On-treatment assessments include adverse events (AEs), concomitant 
medications, review of study drug adherence, physical examinations, 
vital signs, safety laboratory tests, HCV RNA, pharmacokinetic 
samples, and urine pregnancy tests (females of child bearing 
potential only).
Single 12-lead ECGs will be collected at Screening, Baseline/Day 1 
(prior to study drug administration) and on-treatment visits at the end 
of Weeks 1 and Week 12. 
Weight will be measured at Screening, Baseline/Day 1, on-treatment
visit at the end of Week 12, and post-treatment Weeks 12 and 24 visits 
(as applicable).


Sofosbuvir/Ledipasvir FDC 
Protocol GS-US-337-0131 
Gilead Sciences, Inc. 
Optional 
Substudies: 
CONFIDENTIAL 
Final 
Amendment 2.0 
Health Related Quality of Life (HRQoL) Survey will be conducted at 
Baseline/Day 1, on-u·eatment visits at the end of Weeks 2, 4, 8, and 12, 
and Post-Treatment Week 4 and 12 visits. 
Pregnancy prevention counseling will be addressed with the subject at 
Baseline/Day 1, on-u·eatment visit at the end of Week 12, and 
post-treatment Week 4 visits. 
Post-u·eatment assessments include AEs, concomitant medications, 
vital signs, safety laborat01y tests, HCV RNA, and urine pregnancy 
tests (females of child bearing potential only). 
Samples for viral RNA sequencing/phenotyping will be collected at 
Baseline/Day 1 and eve1y visit thereafter. Single PK samples will be 
collected during on-u·eatment visits for PK analysis of study dmg. 
Two archive plasma samples will be collected, one at Baseline/Day 1 
and the second at the end of u·eatment visit for potential future 
biomarker testing. Subjects will have the opportunity to opt out of the 
archive sample collection. For subjects who provide their additional 
and specific consent, a blood sample will be collected at the 
Baseline/Day 1 visit for human phannacogenomic testing (this sample 
may be drawn after Baseline/Day 1, if necessary). 
Page 8 
01 August 2014 


Sofosbuvir/Ledipasvir FDC 
Protocol GS-US-337-0131 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
Phrumacokinetics: 
Statistical Methods: 
CONFIDENTIAL 
PD 
Final 
Amendment 2.0 
SOFILDV is manufactured as a FDC tablet, consisting of 400 mg SOF 
and 90 mg LDV, for oral administr·ation. Subjects will take 1 tablet 
daily with or without food. 
None. 
AEs and safety laborat01y tests will be collected throughout the study 
(through the 4-Week Post-Treatment Visit). 
Efficacy will be evaluated using scheduled assessments ofHCV RNA 
perf01med using COBAS® TaqMan® HCV Test, v2.0 for use with the 
High Pure System. 
In China, Korea and Taiwan, a single PK blood srunple will be 
collected at each on-tr·eatment visit for all sub'ects. PPD 
conducted, a tru·get of ~ 10-15 subjects may be emolled from each 
country. Serial PK srunples would be collected over 24 hours 
post-dose. The PK of SOF (and its metabolites GS-566500 and 
GS-331007) and LDV will be assessed. 
The primruy efficacy endpoint is SVR12 in all emolled and tr·eated 
subjects with chronic genotype-I HCV infection. The primary endpoint 
will be perf01med on the Full Analysis Set (F AS). 
Treatment-Naive Subjects 
The primruy endpoint will be assessed by compru·ison of the observed 
SVR12 rate for tr·eatment-nai:ve subjects with HCV GT-1 infection 
from Korea and China versus the historical SVR null rate of 49% and 
57% respectively (as calculated in Appendix 5) using a two-sided exact 
one-sample binomial test. 
In addition, for each region (i.e., China, Korea or Taiwan), Korea plus 
Taiwan, and overall (i.e., China plus Korea plus Taiwan), 
a point-estimate with two-sided 95% exact confidence interval using 
the binomial distr·ibution (Clopper-Pearson method) will be constructed 
for the SVR12 rate. 
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A sample size of 40 Korean subjects in the treatment-naïve group will 
provide at least 90% power to detect a 27% improvement in SVR12 
rate from the adjusted historical control rate of 49% using 2-sided 
exact one-sample binomial test at significant level of 0.05.
A sample size of 100 Chinese subjects in the treatment-naïve group 
will provide at least 90% power to detect a 17% improvement in 
SVR12 rate from the historical control rate of 57% using 2-sided exact 
one-sample binomial test at significant level of 0.05.
In addition, with 40 subjects in Korea (or Taiwan), the 2 sided 95% 
exact confidence interval for the SVR12 rate will extend at most 32% 
in length. With 80 subjects (Korea plus Taiwan) in the treatment-naïve 
group, a two-sided 95% exact confidence interval for the SVR12 rate 
will extend at most 23% in length. With 100 subjects in China, the 
2 sided 95% exact confidence interval for the SVR12 rate will extend 
at most 20% in length.
Treatment-Experienced Subjects 
There is no treatment option available in China, Korea or Taiwan for 
treatment-experienced patients with GT-1 infection. In the absence of 
effective antiviral therapy, spontaneous clearance of the HCV is rare.
Consequently a nominal SVR rate of 5% is assumed for 
treatment-experienced subjects.
No statistical hypothesis testing will be performed in 
treatment-experienced subjects. For each region (i.e., China, Korea or 
Taiwan), Korea plus Taiwan, and overall (i.e., China plus Korea plus
Taiwan), a point-estimate with two-sided 95% exact confidence 
interval using the binomial distribution (Clopper-Pearson method) will 
be constructed for the SVR12 rate.
With 40 subjects in Korea (or Taiwan), the 2 sided 95% exact 
confidence interval for the SVR 12 rate will extend at most 32% in 
length. With 80 subjects (Korea plus Taiwan) in the 
treatment-experienced group, a two-sided 95% exact confidence 
interval for the SVR12 rate will extend at most 23% in length. With 
100 subjects in China, the 2 sided 95% exact confidence interval for 
the SVR12 rate will extend at most 20% in length.
Secondary efficacy endpoints include the proportion of subjects with 
SVR4, SVR24, breakthrough and relapse; and HCV RNA change from 
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All continuous endpoints (except safety endpoints) will be summarized 
using an 8-number summary (n, mean, standard deviation, median, 
Q1, Q3, minimum, maximum) by treatment-naïve and 
treatment-experienced subjects for each region and overall. All 
categorical endpoints will be summarized by number and percentage of 
subjects who meet the endpoint definition. 
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnormalities for categorical values or 
8-number summary (n, mean, standard deviation, median, Q1, Q3, 
minimum, maximum) for continuous data.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase  (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval 
(tau)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BT
breakthrough
BW
body weight
CFR
Code of Federal Regulations
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
Observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
DAA
Direct acting antiviral
DCV
Daclatasvir
dL
Deciliter
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
ECIRB/IEC
Ethics Committee Institutional Review Board/ Independent Ethics Committee
eCRF
Electronic case report form(s)
Emax
Maximal effect
ESA
Erythropoiesis stimulating agent
eSAE
electronic Serious Adverse Event (system)
ESLD
End Stage Liver Disease
ET
early termination
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
FDC
Fixed Dose Combination
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GMRs
geometric-least squares means ratios
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular Carcinoma
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
HRQoL
Health Related Quality of Life (Survey)
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN
interferon
IL28B
IL28B gene
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
INR
International Normalized Ratio
IRB
Institutional Review Board
IU
International Units
IUD
Intrauterine Device
IV
Intravenous
IVDA
Intravenous drug abuse
IWRS
Interactive Web Response System
kg
Kilogram
L
Liter
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
LLT
Lower-Level Term 
LTFU
Lost to follow up
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
mL
Milliliter
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
Peg-IFNα
pegylated interferon
PG
Pharmacogenomic
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
PT
Preferred Term
QA
Quality Assurance
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’ formula
RBC
Red blood cell count 
RBV
Ribavirin
RNA
ribonucleic acid
RVR
rapid virologic response 
SAE
serious adverse event
SD
Standard deviation
SF-36
Short-Form-36
SOC
Standard of Care or System Organ Class
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
TE
Treatment-Experienced
TN
Treatment-Naïve
TGV
Tegobuvir
TND
Target not detected
TPO
thrombopoietin
TSH
Thyroid stimulating hormone
t½
An estimate of the terinal elimination half-life of the drug in 
serum/plasma/PBMC, calculated by dividing the natural log of 2 by the terminal 
elimination rate contstant (λz)
ULN
upper limit of the normal range


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
US
United States
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
1.1.1.
HCV Infection
Infection with the hepatitis C virus (HCV) is a serious, progressive, and often life-threatening 
disease affecting approximately 180 million adults worldwide {21360}. The infection, if 
untreated, can result in progressive liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and 
end stage liver disease (ESLD). Transmission of HCV infection is parenteral with the majority of 
infections occurring through administration of contaminated blood products, unsafe medical 
procedures, intravenous drug use or sexual transmission {8076}. The hepatitis C virus is 
classified into six major genotypes (GT), i.e., 1-6, with further division to a subtype level 
(e.g., a, b, c) {21479}. Virologic response rates to currently available therapies vary according to 
host IL28B genotype, baseline levels of HCV RNA and HCV genotype. The distribution of HCV 
genotypes and subtypes varies according to geographic region with the most common HCV 
genotypes in the United States and Europe being GT-1, GT-2 and GT-3. In China GT-1, GT-2 
and GT-6 are generally the most common although regional differences in genotype distribution, 
such as GT-3 in the South, are apparent {24217}. In Korea and Taiwan it is estimated that 
approximately 50% of infections are associated GT-1b and 50% with GT-2a {24218}, {24242}, 
{24215}. Genotypes 4, 5 and 6 are most prevalent in the Middle East, South Africa and 
Southeast Asia respectively {22110}.
Following acute infection approximately 15-20% of patients are able to clear the virus without 
intervention, however around 80% of patients go on to establish chronic hepatitis C {8076}. 
Treatment of chronic infection is currently based upon weekly subcutaneous administration of 
pegylated interferon (Peg-IFNα) with orally administered ribavirin (RBV) for 24 to 48 weeks 
dependent upon genotype and virologic response. In Caucasians, this treatment regimen affords 
sustained virologic response rates (SVR) on the order of 42-46% in treatment-naïve patients with 
GT-1 and 76-82% in patients with GT-2/3 infection {23342}, {23351}. Observed SVR rates using 
the same interferon (IFN)-based treatment regimens are generally higher in Asian patients. This
observation has been largely attributed to a higher proportion of Asian patients (>85%) 
possessing the host IL28B-CC genotype which confers a favorable virologic outcome following 
treatment with IFN-containing regimens {22075}, {24243}, {22156}, {21337}, {22098}. Although 
relatively high SVR rates can be achieved in Asian patients with IFNα+RBV, the safety and 
tolerability of IFN-containing regimens is sub-optimal. Contraindications to IFN preclude its use 
by a significant number of patients {22156} while management of adverse effects commonly 
results in dose reductions and may lead to treatment discontinuation. Safety and tolerability are
particularly problematic in an aging population with chronic hepatitis C. Moreover, lower SVR 
rates are also observed in older patients {24406}.
Recently, first generation protease inhibitors (PI) (i.e., telaprevir (TVR) and boceprevir (BCV)) 
have been approved in certain countries for use in patients with GT-1 infection when combined 
with Peg-IFNα+RBV. The Peg-IFNα+RBV+PI regimens have incrementally improved SVR 
rates in GT-1 treatment-naïve patients to approximately 70%; however, they are associated with 


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significant safety and tolerability concerns {17996}, {17492}. Moreover, Peg-IFNα+RBV+PI 
regimens are not currently available in Korea, Taiwan or China and, consequently, patients with 
GT-1 infection who fail to respond to Peg-IFNα +RBV have no current treatment options.
1.1.2.
HCV Infection in Korea
In Korea, chronic HCV infection is one of the leading causes of chronic liver disease and 
hepatocellular carcinoma (HCC) {24211}. The age-standardized prevalence of HCV antibody 
(HCV Ab) in patients greater than 40 years of age is reported to be on the order of 1.3% which 
equates to around 193,000 people {24215}. The prevalence of HCV infection increases with age 
and peaks in those individuals aged 60 years and older {24211}. The majority of infections 
occurred via contaminated blood transfusions prior to the introduction of blood-donor HCV Ab 
screening in 1991 {24216}. Consequently the majority of patients with chronic hepatitis C in 
Korea are elderly {24215} and are more likely to have progressive liver disease. HCV infection is 
more closely associated with HCC in the elderly Korean patients than are HBV infection and 
alcoholism {24210}, {24208}. Since the decline of transfusion-related hepatitis C the majority of 
new infections are behavior-related. Of particular note is the practice of acupuncture for chronic 
illnesses including joint disease, pain, sequelae of trauma and other conditions non-responsive to 
conventional therapies. Shin et al reported results of a case study in which 34.1% of men and 
62.9% of women in rural Korea reported multiple acupuncture procedures with the associated 
risk fraction for HCV infection being 38% for men and 55% for women {24214}. Intravenous 
drug abuse (IVDA) is not thought to be a major contributor to the overall prevalence of 
HCV infection in Korea however this route of infection may contribute in young adults and those 
living in harbor cities on the southern and western coasts {24209}, {24211}. The predominant 
HCV genotypes in Korea are GT-1b and GT-2a which are roughly present in equal proportions 
and combined account for around 80-90% of infections {24216}, {24215}, {24209}. Host IL28B 
genotype has been widely reported as a predictor of virologic response to interferon (IFN)-based 
therapies for chronic HCV infection {22075}. The IL28B-CC genotype which confers a favorable 
virologic outcome to IFN-based therapy predominates in Korea with approximately 80-90% of 
patients with this genotype {24212}, {24238}. Consequently the sustained virologic response 
rates in Korean clinical trials evaluating Peg-IFNα+RBV in treatment-naïve GT-1 infection are 
on the order of 55-70% following 48 weeks of therapy {24211}, {24595}, {24387}, {24385}, 
{24237}, {24404}, {24388} . Although relatively high rates of virologic response are achievable
with Peg-IFNα+RBV in treatment-naïve Korean patients due to the high proportion of IL28B CC 
genotype, Heo et al {24236} recently reported a significant difference in SVR rate observed in a 
clinical trial cohort versus that observed in clinical practice based upon ‘Intention To Treat’ 
(ITT) analysis; 81% (21/26) versus 55% (58/106). Although no difference was observed in the 
SVR rates between the clinical trial cohort and the clinical practice cohort according to per 
protocol analysis, the ITT is important since it more likely reflects the observed SVR in clinical 
practice across the country. The authors attribute the lower ITT SVR rate in the clinical practice 
cohort to decreased adherence to assigned therapy including dose reduction for clinical and 
laboratory adverse events. As previously described, the highest prevalence rates for HCV Ab in 
Korean patients are in those individuals aged 60 years and older. These elderly patients are more 
likely to be treatment-experienced and have progressive liver disease. Comorbid conditions 
(e.g., diabetes and cardiovascular disease) are common in this population and pose significant 


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challenges to the use of Peg-IFNα+RBV therapy. As this group of patients continues to age the 
proportion of patients with chronic hepatitis C who will develop complications, including liver 
cirrhosis, HCC and ESLD is significant; {22077}. In addition, it is important to consider the 
proportion of patients who are ineligible for, intolerant of, or unwilling to receive 
Peg-IFNα+RBV who have no currently available antiviral treatment options {21256}. This also 
applies to patients who have previously failed to respond to Peg-IFNα+RBV therapy. Although 
Peg-IFNα+RBV can achieve high rates of SVR in treatment-naïve patients with chronic HCV 
infection when assigned therapy is tolerated, there is an unmet medical need for effective, safe, 
well-tolerated, all oral therapies that can be used in an aging patient population in Korea.
1.1.3.
HCV Infection in Taiwan
Taiwan has one of the highest prevalence rates of chronic hepatitis C in North-East Asia. In a 
nationwide survey conducted between 1996 and 2005 involving over 164,000 participants in 
out-reach community-based hepatitis screening programs the HCV seroprevalence was estimated 
to be 4.4% {24235}. The study reported an approximately equal seroprevalence in males (4.5%)
and females (4.3%). Importantly seroprevalence varied geographically with certain areas of 
hyperendemicity such as Miaoli and Chiayi Counties where the age-adjusted seroprevalence was 
reported to be 7.6% and 6.1% respectively. The proportion of subjects with HCV antibodies 
progressively increased after the age of 20 years. The predominant routes of transmission are 
thought to be iatrogenic in nature including history of blood transfusion, medical injections and 
acupuncture {24239}, {24396}. Historically, glucose supplements, vitamins, and treatments for 
minor medical conditions have often been administered by injection. Prior to 1980 reusable 
syringes were commonly used particularly in rural areas with poor sterilization techniques likely 
contributing to the spread of HCV infection. After 1980, the rate of HCV infection was likely
reduced following the introduction of disposable syringes. This may in part explain the higher 
prevalence of HCV infection in the elderly population in Taiwan. It has also been postulated that 
inhabitants of communities with high rates of HCV infection may have been repeatedly exposed 
to a common reservoir of infection contributing to the establishment of hyperendemic areas 
{24239}.
As previously described for Korea, the predominant HCV genotypes in Taiwan are GT-1b and 
GT-2a which are present in similar proportions and account for around 80-90% of all infections 
{24596}, {24218}, {24242}. The IL28B-CC host genotype conferring favorable virologic outcome 
to IFN-based therapy predominates with approximately 80-90% of patients with this genotype 
{22075}, {24241}. As a consequence the SVR rates in Taiwanese clinical trials evaluating 
Peg-IFNα+RBV in GT-1 infection are approximately 49-56% and 76-80% in treatment-naïve 
patients receiving 24 weeks and 48 weeks of treatment respectively {24410}, {24382}. However, 
as previously described in Taiwan the seroprevalence of HCV antibodies increases with age with 
the highest rates observed in those 60 years and older {24235}. The use of currently available 
therapy is problematic in the elderly due to contraindications to IFN and RBV and comorbidities 
such as cardiovascular disease and diabetes. In Taiwan for treatment-naïve patients with GT-1 
infection aged ≥65 years the SVR rate for Peg-IFNα+RBV administered for 48 weeks has been 
reported to be 51.9% {24390}. The elderly patient population is more likely to have progressive 
liver disease and be at higher risk for the development of HCC and ESLD. For GT-1 infection 


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the SVR rates for Taiwanese age-matched patients with HCC (post-curative management) and 
cirrhosis are reported to be 33% and 55% respectively {24240}. The safety, tolerability and 
efficacy of IFN+RBV therapy is suboptimal in this population. Finally, there are no currently 
available treatment options for those patients who are ineligible for, intolerant of, or who have 
previously failed to respond to IFN+RBV therapy.
1.1.4.
HCV Infection in China
Reports indicate that around 2% of the population in China, or approximately 27 million people,
may be infected with the hepatitis C virus {19682},{24217},{25129}. Approximately 68% of 
patients are infected with HCV GT-1b, 14% with GT-2, 4% with GT-3 and 13% with GT-6 
{19682},{24217}. GT-1 and GT-2 infection are generally more common in older patients whereas 
GT-3 and GT-6 are more frequent in younger adults. This observation may be related to the 
mode of HCV transmission, with GT-1/GT-2 commonly acquired through prior blood 
transfusion and GT-3/GT-6 associated with IVDA {25094}.
Risk factors for HCV infection are similar to those reported in other parts of the world {25095}. 
Of note, however, is the reported risk of acquiring transfusion-related HCV infection which is on 
the order of 1 in 40,000-60,000 donations {25093}. Such high rates of transfusion-related 
hepatitis C have been attributed in part to the practice of paid blood donation. Following 
introduction of mandatory HCV screening of blood/blood products in the 1990’s and the 
implementation of the blood donation law in 1998, the incidence of post-transfusion hepatitis C 
has been significantly reduced {24392, 25127}. The association of GT-1 infection with blood 
transfusion and the timing of the new requirements related to blood donation may in part explain 
the higher GT-1 infection rates in the elderly. Since the introduction of blood-bank screening, the 
predominant mode of new HCV infection is now intravenous drug use (IDU). 
The recommended treatment regimen for treatment-naïve patients with HCV GT-1 in China
according to the Chinese Society of Hepatology {24428}is subcutaneous or intramuscular 
administration of IFNα or Peg-IFNα plus orally administered RBV for 24 to 48 weeks according 
to baseline viral load and virologic response. These recommendations are aligned with those by 
the APASL Consensus Committee {24699},{22156}. SVR rates in China for GT-1have been 
reported to be on the order of 44% to 70% {24797}, {13261}, {24391}.
A significant number of patients in China are in the 3rd-4th decade of infection and have 
progressive liver disease. The use of IFNα+RBV therapy in the elderly is problematic. Comorbid 
conditions are common (eg, cardiovascular disease, diabetes, mental anomaly, decreased renal 
function) and may preclude IFNα use {24428} {22156} {24398}. Older patients generally report a 
higher frequency of adverse events and of greater severity compared to younger patients. Lower 
levels of treatment adherence are also observed. These factors contribute to overall lower SVR 
rates observed with IFN-based therapy in the elderly {24390}. As patients continue to age, the 
number developing hepatic complications including cirrhosis, HCC and ESLD will be significant 
{22077}. 


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The use of IFNα-based therapy is also problematic in the IVDA population. The risk for 
developing severe IFNα-related psychiatric events including depression, suicidal ideation, 
cognitive disturbances, psychotic symptoms, fatigue and habit relapse is high. Adherence to 
therapy may be low and effective treatment requires multidisciplinary support {25091}. 
A significant number of patients are ineligible for, or unwilling to undergo treatment with 
IFN-based therapy. For these patients, there are presently no available therapeutic options 
available.
1.1.5.
Summary
There is a need for early intervention and eradication of HCV infection to reduce the burden of 
progressive liver disease including of HCC and ESLD. While early introduction of effective 
antiviral therapy is critical in order to reduce the potential future burden of advanced liver 
disease, safe and effective antiviral therapies that can be used in elderly patients with advanced 
disease is of paramount importance today. Gilead Sciences is developing the all-oral, 
interferon- and ribavirin-free SOF/LDV FDC regimen to address this need in Chinese, Korean 
and Taiwanese patients with chronic genotype-1 HCV infection.
1.2.
Sofosbuvir (formerly GS-7977) and Ledipasvir (formerly, GS-5885) Fixed 
Dose Combination
Sofosbuvir/Ledipasvir fixed dose combination (FDC) combines two HCV specific DAA agents 
into a single tablet for the treatment of chronic HCV infection. More than 2500 subjects have 
received treatment with this combination tablet to date.
Sofosbuvir (SOF), formerly GS-7977, is a nucleotide analog that is a potent and selective 
inhibitor of NS5B-directed HCV replication. Over 4,000 subjects have received SOF containing 
regimens to date, from single doses up to repeat dosing for 24 weeks.
Ledipasvir (LDV), formerly GS-5885, is a novel HCV NS5A inhibitor that has demonstrated 
potent anti-HCV activity against genotype (1a and 1b) HCV infection. More than 1000 HCV 
infected subjects have been dosed with LDV in Phase 2 clinical studies, and over 700 subjects 
have been dosed with LDV for over 12 weeks.
1.2.1.
General Information
For further information on SOF/LDV FDC and the individual components, refer to the 
Investigator’s Brochure (IB) for sofosbuvir/ledipasvir fixed-dose combination including:

In Vitro Anti-HCV Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience


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1.2.2.
Summary of Additional Clinical Experience with Sofosbuvir and Ledipasvir
1.2.2.1.
GS-US-334-0111 Pharmacokinetic Bridging Study in Japanese Subjects
To support the conduct of clinical studies in Japan, a PK bridging study was conducted in 
accordance with ICHE5 to compare the safety, tolerability and PK profile in Japanese and 
Caucasian subjects following single-dose administration of SOF at the 200 mg, 400 mg 
(the intended therapeutic dose) and 800 mg dose levels. This study also evaluated the 
pharmacokinetic parameters of the 400 mg dose of SOF and the 90 mg dose of LDV 
administered as a single dose of the SOF/LDV FDC. This study was conducted in the 
United States.
The study enrolled Japanese and Caucasian subjects with an approximately even distribution of 
healthy males and healthy, non-pregnant, non-lactating females between 18–45 years, inclusive, 
with a body mass index (BMI) 18 ≤ BMI ≤ 30. Japanese subjects must have been born in Japan, 
not lived outside Japan for more than 10 years, could trace maternal and paternal Japanese 
ancestry of parents and grandparents, and their lifestyle, including diet, had not significantly 
changed since leaving Japan. Caucasian subjects must not have been of Japanese or Asian 
descent; those with parents or grandparents born in Japan or in any Asian country were excluded. 
Eligible subjects received one dose of study treatment on Day 1 corresponding to their assigned 
group. Each group comprised 8 Japanese and 8 Caucasian subjects and received SOF at either 
the 200 mg, 400 mg or 800 mg dose levels (Groups 1-3), or 400 mg SOF + 90 mg LDV 
administered as a single dose of the SOF/LDV FDC (Group 4). Safety was assessed by 
evaluation of vital signs, 12-lead ECGs, and adverse events. Plasma and urine samples were 
collected at selected time points to assess the PK of SOF, its metabolites GS-566500 and
GS-331007, and LDV.
SOF and SOF/LDV FDC were well tolerated in this study. 
Pharmacokinetic (plasma) results are in Table 1-1.


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Table 1-1.
GS-US-334-0111 Geometric Least-Squares Mean Ratios 
(90% Confidence Intervals) for Sofosbuvir, GS-566500, GS-331007, 
and Ledipasvir Primary PK Parameters in Japanese versus 
Caucasian Subjects
SOF 200 mg
% GLSM Ratio 
(90% CI)
SOF 400 mg
% GLSM Ratio 
(90% CI)
SOF 800 mg
% GLSM Ratio 
(90% CI)
SOF/LDV FDC 
(400 mg/90 mg)
% GLSM Ratio 
(90% CI)
SOF PK Parameter
AUClast (ng•h/mL)
97.02
(63.62, 147.96)
122.62 
(92.54, 162.47)
106.20 
(82.63, 136.49)
90.52 
(54.44, 150.50)
AUCinf (ng•h/mL)
97.30 
(64.77, 146.16)
121.98 
(92.30, 161.20)
106.27 
(82.84, 136.33)
90.77 
(54.90, 150.07)
Cmax (ng/mL)
101.56 
(62.88, 164.02)
107.05 
(76.31, 150.18)
96.37 
(62.23, 149.23)
93.82
(64.53, 136.42)
GS-566500 PK Parameter
AUClast (ng•h/mL)
158.37 
(119.80, 209.34)
149.64
(117.13, 191.17)
125.17 
(103.74, 151.03)
114.13 
(78.15, 166.67)
AUCinf (ng•h/mL)
153.51 
(117.65, 200.30)
147.47
(116.45, 186.74)
124.39 
(103.30, 149.79)
113.27 
(78.24, 163.98)
Cmax (ng/mL)
154.48 
(116.12, 205.51)
138.62 
(108.12, 177.72)
117.59 
(98.72, 140.06)
130.16 
(93.88, 180.44)
GS-331007 PK Parameter
AUClast (ng•h/mL)
80.29 
(64.62, 99.77)
94.44 
(78.30, 113.90)
82.32 
(71.98, 94.16)
85.63 
(63.56, 115.36)
AUCinf (ng•h/mL)
82.37
(67.59, 100.36)
95.93
(80.14, 114.82)
83.68
(74.25, 94.30)
85.40
(64.04, 113.89)
Cmax (ng/mL)
72.72
(57.86, 91.40)
113.48
(91.12, 141.32)
102.44
(73.52, 142.73)
94.34
(68.03, 130.82)
LDV PK Parameter
AUClast (ng•h/mL)
—
—
—
106.07
(68.95, 163.18)
AUCinf (ng•h/mL)
—
—
—
106.66 
(69.13, 164.59)
Cmax (ng/mL)
—
—
—
125.63 
(83.83, 188.26)
No clinically significant differences in the PK of SOF, its metabolites GS-566500 and 
GS-331007, or LDV were observed between Japanese and Caucasian subjects. The safety and 
pharmacokinetic profiles support the use of SOF 400 mg or SOF/LDV FDC (400 mg/90 mg) in 
Japanese and non-Japanese subjects.


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1.2.2.2.
Phase 3 International Registration Studies with SOF/LDV FDC
The SOF/LDV phase 3 international registration program consists of 3 clinical studies for which 
data are available: GS-US-337-0102 (ION-1), GS-US-337-0109 (ION-2), and GS-US-337-0108 
(ION-3). Studies GS-US-337-0102 and GS-US-337-0109 are evaluating treatment with 
SOF/LDVRBV for 12 or 24 weeks in treatment-naive and treatment-experienced subjects, 
respectively, who are infected with genotype 1 HCV. Both studies enrolled up to 20% of 
HCV-infected subjects who had documented compensated cirrhosis. ION-3 is evaluating 
SOF/LDV±RBV treatment for 8 weeks and SOF/LDV treatment for 12 weeks in noncirrhotic 
treatment-naive subjects with genotype 1 HCV infection.
Across all studies, SOF/LDV demonstrated a high degree of efficacy with point estimates for 
SVR12 > 93% in subjects with genotype 1 HCV infection. The addition of RBV to the 
SOF/LDV regimen did not impact the SVR rate.
Across the SOF/LDV Phase 3 studies, treatment with SOF/LDV was generally safe and well 
tolerated. The 3 most frequently occurring AEs were fatigue, headache, and nausea. A higher 
incidence of each event was reported in subjects receiving SOF/LDV+RBV compared with 
subjects receiving SOF/LDV: fatigue (38.0% vs. 22.2%), headache (26.1% vs. 20.6%), and 
nausea (17.4% vs. 10.4%). The most common Grade 3 or 4 chemistry laboratory abnormalities 
across all treatment groups were increased lipase (1.7%) and increased serum glucose (1.5%). 
In subjects with Grade 3 or 4 increased lipase, no case was associated with clinical signs or 
symptoms of pancreatitis. Among subjects who experienced a Grade 3 or 4 increased serum 
glucose, all subjects had a history of diabetes, were taking diabetes medication, or had glucose 
intolerance (denoted by HbA1c 6.0% at screening).
1.2.2.3.
Study GS-US-337-0113 SOF/LDV FDC Study in Japan
An open-label, randomized, phase 3b study (GS-US-337-0113) is also being conducted in Japan
to assess the efficacy and safety of 12 weeks of SOF/LDV with or without RBV in 
treatment-naive (TN) and treatment-experienced (TE) subjects with genotype 1 HCV infection. 
A total of 341 subjects (166 treatment-naïve and 175 treatment-experienced) were randomized
(1:1) to receive treatment. The majority of subjects are female (58%), and all are Japanese. The 
majority of subjects have genotype 1b HCV infection (97%), non-CC IL28B alleles (52%), high 
baseline viral load (99% had HCV RNA 5 log10 IU/mL), 22% had liver cirrhosis at baseline, 
and 33% were 65 years of age or older.
SVR12 was achieved by 100% (171/171) of subjects receiving SOF/LDV for 12 weeks and by
98% (167/170) subjects receiving SOF/LDV+RBV for 12 weeks (Table 1-2). The study met its 
primary endpoint of superiority compared to a predefined historical SVR12 rate. Factors that 
have historically been predictive of or associated with lower rates of SVR 
(including age ≥65 years, cirrhosis, and prior treatment failure) had no impact on SVR12 rates in 
this study. Three subjects who received SOF/LDV+RBV did not achieve SVR12: 1 subject 
relapsed after discontinuation of therapy, 1 patient discontinued therapy after 1 week of 
treatment due to rash and 1 patient died during the study.


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Table 1-2.
GS-US-337-0113 Number (and Percentage) of Subjects with SVR12
Treatment-Naive
Treatment-Experienced
SOF/LDV
12 Weeks
(N=83)
SOF/LDV+RBV
12 Weeks
(N=83)
SOF/LDV
12 Weeks
(N=88)
SOF/LDV+RBV
12 Weeks
(N=87)
Overall SVR12
83/83 (100%)
80/83 (96%)
88/88 (100%)
87/87 (100%)
Treatment with SOF/LDV±RBV was generally well tolerated. Most AEs were mild or moderate 
in severity. The addition of RBV to the SOF/LDV treatment regimen resulted in increased rate of 
observed AEs (64% of subjects who received SOF/LDV and 75% of those who received 
SOF/LDV+RBV). The most commonly reported AEs in the RBV-free group were 
nasopharyngitis, headache, and malaise. The most commonly reported AEs in the 
SOF/LDV+RBV group were nasopharyngitis, anemia, headache and rash. Nasopharyngitis was 
thought to be related to the winter season during which the study took place. Two subjects, both 
in the SOF/LDV+RBV group, permanently discontinued study treatment due to an AE.
Consistent with the expected toxicity profile of RBV, decreases from baseline in hemoglobin and 
lymphocytes, and increases in reticulocytes and platelets and total bilirubin were observed in the 
SOF/LDV+RBV 12 Week group.
1.3.
Rationale for This Study
This Phase 3b study is designed to evaluate the efficacy and safety of the SOF/LDV FDC tablet 
administered for 12 weeks in treatment-naïve and treatment-experienced subjects with chronic 
genotype 1 HCV infection. Up to 20% of subjects enrolled in the study may have compensated 
cirrhosis at screening.
As previously described in Sections 1.1.2 and 1.1.3 in there is a significant unmet medical need 
in China, Korea and Taiwan for simple, well-tolerated, IFN-free, all-oral antiviral regimens for 
the treatment of chronic HCV infection.  The current standard of care (Peg-IFNα+RBV) for these 
patients in China, Korea and Taiwan is associated with significant toxicity, with many patients 
unwilling to be treated with these regimens. There also exists substantial numbers of patients 
who cannot receive Peg-IFNα due to relative or absolute contraindications {20450}, {17893}, 
{17893}, {15573}, {17892}, {3291}.
Gilead has developed an FDC consisting of SOF with LDV, 2 well-tolerated, potent, once-daily 
antiviral agents in late phase clinical development. Based on Phase 2 data, the SOF/LDV FDC 
has the potential to be a simple and highly effective all-oral, once daily treatment regimen for 
chronic genotype 1 HCV infection, after 12 weeks of treatment.
In the Phase 3 ION studies, the same SOF/LDV FDC regimen proposed for this study in China, 
Korea and Taiwan was evaluated in patients with HCV GT-1 infection. SVR12 rates following 
SOF/LDV for 12 weeks greater than 93% were observed in treatment-naïve subjects with and 
without cirrhosis (Studies GS-US-337-0102, GS-US-337-0108).  In treatment-experienced 


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subjects in GS-US-337-0109, the SVR12 rate was 94% (n=102/109) overall, with 95% of 
subjects without cirrhosis achieving SVR12 and 86% of those with cirrhosis achieving SVR12. 
In Japanese subjects with chronic genotype 1 HCV infection, the SVR12 rate was 100% in both 
treatment naïve (n=83) and treatment-experienced (n=88) patients following treatment with 
SOF/LDV for 12 weeks.
Current data for the SOF/LDV FDC indicates the regimen to be safe, well-tolerated and 
associated with high degrees of antiviral efficacy, supporting the conduct of the proposed 
Phase 3 study in Chinese, Korean and Taiwanese subjects with GT-1 chronic hepatitis C.
1.4.
Rationale for Dose Selection of SOF/LDV FDC
Gilead has developed a fixed-dose combination (FDC) tablet consisting of SOF 400 mg with 
LDV 90 mg, 2 well-tolerated, potent, once-daily antiviral agents. SOF 400 mg is the marketed 
dose of SOF in the US and Europe for the treatment of HCV-infection and as such, has been 
selected for co-formulation with LDV. LDV 90 mg was selected for co-formulation with SOF 
based on safety, PK and antiviral activity data (studies GS-US-256-0102 and GS-US-248-0120). 
Study GS-US-256-0102 established the anti-HCV activity of LDV and indicated that the 
exposures achieved following administration of the 30 mg dose provides >95% of maximal 
antiviral response in GT 1a HCV infected subjects. It was also observed that 30 mg or greater of 
LDV likely provided coverage of some drug related mutations that doses less than 30 mg did not, 
based on an analysis of NS5A mutants that arose in response to exposure to LDV. Therefore, 
30 mg and 90 mg of LDV were selected for further clinical evaluation. In Study 
GS-US-248-0120, 30 mg of LDV was compared to 90 mg of LDV, on a background of 3 other 
antivirals, vedroprevir (VDV, formerly GS-9451, PI), tegobuvir (formerly GS-9190, NNI), and 
RBV. Based on a breakthrough rate in the 90 mg arms of 12% compared to a 27% breakthrough 
rate in the 30 mg arm, 90 mg LDV was selected for further clinical development.
The fixed-dose combination tablet (FDC) of sofosbuvir/ledipasvir 400 mg/90 mg with or without 
RBV has demonstrated favorable safety and efficacy profiles in over 2500 HCV-infected 
subjects across different patient populations in Phase 2 and 3 trials. These doses represent the 
proposed marketed doses of ledipasvir and sofosbuvir that are currently under regulatory review 
in the US, EU and certain other countries worldwide.
1.5.
Overall Risk/Benefit Assessment
The SOF/LDV FDC product combines a potent HCV nucleotide NS5B inhibitor and a potent 
HCV NS5A inhibitor. 
The potential benefits of SOF/LDV FDC for the treatment of chronic HCV are:

Greater antiviral efficacy (i.e., rapid and durable eradication of HCV) compared to the 
current standard of care (Peg-IFNα +RBV)

A reduction in the AEs currently associated with the use of Peg-IFNα+RBV


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
A simple, well-tolerated regimen to replace the current complex, response-guided Peg-IFNα
+RBV regimens.

The potential benefit of a shortened SOF/LDV FDC therapy of 12 weeks is a decrease in the 
burden of treatment for both patients and physicians, through a reduction in the overall 
number of patient visits.
The safety profile of SOF includes more than 3000 chronic HCV-infected subjects that have 
been administered over 12 weeks of SOF in combination with a DAA, Peg-IFNα, with or 
without RBV. No clinical safety issues related to SOF have been identified to date. The safety 
profile of LDV includes over 1000 chronic HCV-infected subjects, of whom over 700 have been 
administered more than 12 weeks of LDV, which was given in combination with other DAAs, 
Peg-IFNα, with or without RBV. No clinical safety issues related to LDV have been identified to 
date.
Furthermore, there is no expectation of significant overlapping or new, unexpected toxicities 
upon administration of SOF/LDV together as an FDC. To date, the SOF/LDV FDC ± RBV has 
been administered to over 2500 HCV infected subjects in phase 2/3 trials. No clinical safety 
issues related to the SOF/LDV FDC have been identified to date.
During the conduct of the study the Sponsor will perform ongoing safety data review.
In summary, there is no currently approved all-oral treatment available for HCV-infected 
patients. This study will support the registration of the SOF/LDV FDC in treatment-naïve and 
treatment-experienced Chinese, Korean and Taiwanese subjects with chronic genotype 1 HCV 
infection including those with compensated cirrhosis.
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2. 
OBJECTIVES 
The prima1y objectives of this study are: 
Final 
Amendment 2.0 
• 
To determine the antiviral efficacy of treatment with sofosbuvir (SOF)/ledipasvir (LDV) 
fixed-dose combination (FDC) as measured by the prop01tion of subjects with sustained 
virologic response (SVR) 12 weeks after discontinuation of therapy (SVR12, defmed as 
HCV RNA < lower limit of quantitation [LLOQ] 12 weeks post treatment) 
• 
To evaluate the safety and tolerability of SOFILDV FDC as assessed by review of the 
accumulated safety data 
The secondary objectives of this study are as follows: 
• 
To detennine the prop01tion of subjects who attain SVR at 4 and 24 weeks after 
discontinuation of therapy (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after treatment 
discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV during treatment and after 
treatment discontinuation 
The explorat01y objectives of this study are: 
PPO 
I 
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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoints of this study are:

The primary efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after discontinuation 
of therapy) in the Full Analysis Set (FAS) population.

The primary safety endpoint is any AE leading to permanent discontinuation of study drug.
Secondary endpoints of this study include:

Secondary efficacy endpoints include the proportion of subjects with: HCV RNA < LLOQ at 
4 and 24 weeks after discontinuation of therapy (SVR4 and SVR24); viral breakthrough; 
relapse; and HCV RNA change from baseline.
3.2.
Study Design
This will be an international (China, Korea and Taiwan), multicenter, open-label study in 
treatment-naïve and treatment-experienced adults with chronic genotype 1 HCV infection.
It is estimated that approximately 200 subjects will be enrolled in China, 80 subjects will be 
enrolled in Korea and 80 subjects in Taiwan for a total of 360 enrolled subjects. Within each 
country approximately 50% (i.e., n~100 or 40) of subjects will be treatment-naïve and 50% will 
be treatment-experienced (i.e., n~100 or 40).
Up to 20% of subjects enrolled in the study may have compensated cirrhosis at Screening.
3.3.
Study Treatment
Approximately 180 treatment-naïve and 180 treatment-experienced subjects will receive 
treatment with SOF 400 mg/LDV 90 mg fixed dose combination (FDC) tablet for 12 weeks.
3.4.
Duration of Treatment
All subjects will complete screening, on-treatment, and post-treatment assessments. Screening 
assessments will be completed within 28 days of the Baseline/Day 1 visit or within 42 days if a 
liver biopsy or additional HCV genotyping is required. All subjects will receive treatment for 
12 weeks. All subjects will complete a 4-week and 12-week Post-Treatment visit. Subjects with 
HCV RNA < LLOQ at the 12-Week Post-Treatment visit will also complete a 24-Week 
Post-Treatment visit unless confirmed viral relapse occurs.
The assessments performed at each visit are described in Section 6.


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3.5.
Discontinuation Criteria 
When medically feasible, the Medical Monitor must be consulted prior to the premature 
discontinuation of treatment in a given subject.
Study drug must be discontinued in the following instances:

Unacceptable toxicity, as defined in Section 7 of the protocol, or toxicity that, in the 
judgment of the investigator, compromises the ability to continue study-specific procedures 
or is considered to not be in the subject’s best interest

Pregnancy of female subject
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 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.
All subjects will complete the 4-Week and 12-Week Post-treatment visits. Subjects with 
HCV RNA < LLOQ at the 12-week Post-treatment visit will return for the 24-week 
Post-treatment visit, unless confirmed viral relapse occurs. Study drug may be discontinued in 
the following instances:

Significant protocol violation

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason

Discontinuation of the study at the request of Gilead, regulatory agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)
If a subject meets discontinuation criteria during treatment, an Early Termination (ET) visit will 
be required (Section 6.4.9). Following completion of the Early Termination visit, all subjects 
must complete the 4-week and 12-week Post-Treatment visits. All patients with 
HCV RNA < LLOQ at the 12-week Post-Treatment visit must return to the clinic for 24-week 
Post Treatment assessments, unless confirmed viral relapse occurs.
3.6.
Source Data
A Health Related Quality of Life survey, Short-Form-36 (SF-36) will be completed by subjects 
at various timepoints during the study and be used as source data. The subject should read the 
questionnaire by himself/herself and write/mark answers directly onto the questionnaire.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 360 subjects will be enrolled in this study with approximately 
180 treatment-naïve subjects and approximately 180 treatment-experienced subjects. Up to 
20% of subjects enrolled in the study may have compensated cirrhosis at screening.
In order to manage the total study enrollment, Gilead Sciences, Inc., at its sole discretion, may 
suspend screening and/or enrollment at any site or study-wide at any time.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Willing and able to provide written informed consent
2) Male or female, age 20 years
3) Body weight 40 kg
4) HCV RNA 104 IU/mL at Screening
5) HCV treatment-naïve, as defined as no prior exposure to any IFN, RBV, or other approved or 
experimental HCV-specific direct-acting antiviral agent; OR HCV treatment-experienced 
with medical records that include sufficient detail of prior treatment with IFN to allow for 
categorization of prior response as either:
a) IFN Intolerant:  Subject completed ≤ 12 weeks of treatment (ending ≥ 3 months prior to 
Screening) with IFN-containing regimen and discontinued treatment due to development 
or significant worsening of at least one of the following conditions:

Significant local or systemic adverse reaction to IFN (e.g., hypersensitivity, injection 
site reactions)

Psychiatric disease necessitating hospitalization or period of disability or psychosis, 
schizophrenia, bipolar disorder, depression, schizoaffective disorder, suicidal 
ideation, or suicide attempt

Significant cognitive impairment

Neuropathy

Disabling flu-like symptoms (arthralgias, fatigue, pyrexia, myalgia)

Gastrointestinal toxicity with nausea, vomiting or diarrhea 

Thrombocytopenia (platelets < 25,000/μL)

Neutropenia (ANC < 500/μL)

Development of colitis, non-alcoholic pancreatitis or ophthalmologic disorders


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
Autoimmune disorder including but not limited to: myositis, hepatitis, inflammatory 
bowel disease, interstitial lung disease, interstitial nephritis, immune (idiopathic) 
thrombocytopenic purpura, psoriasis, rheumatoid arthritis, sarcoidosis, systemic lupus 
erythematosus, thrombotic thrombocytopenic purpura, thyroiditis.

AE related to the IFN-containing regimen that is not listed after consultation with the 
Medical Monitor
1. Note: Subjects intolerant of Peg-IFNα+RBV+HCV protease inhibitor regimens 
are included in this category.
b) Non-Response: Subject did not achieve undetectable HCV RNA levels while on 
treatment
c) Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during treatment 
or within 4 weeks of the end of treatment but did not achieve a sustained virologic 
response (SVR).
6) Genotype 1 HCV at Screening as determined by the Central Laboratory. Any non-definitive 
results will exclude the subject from study participation
7) Confirmation of chronic HCV infection documented by either:
a) A positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping 
test at least 6 months prior to the Baseline/Day 1 visit, or
b) A liver biopsy performed prior to the Baseline/Day 1 visit with evidence of chronic HCV 
infection
8) Cirrhosis determination [up to 20% of subjects enrolled in the study may have compensated 
cirrhosis]: 
a) Cirrhosis is defined as any one of the following:
i)
Liver biopsy showing cirrhosis (e.g. Metavir score = 4 or Ishak score 5)
ii) Fibroscan indicative of cirrhosis as evidenced by a result > 12.5 kPa
b) Absence of cirrhosis is defined as any one of the following:
i)
Liver biopsy within 2 years of Screening showing absence of cirrhosis
ii) Fibroscan within 6 months of Baseline/Day 1 with a result of ≤ 12.5 kPa
c) In the absence of a definitive diagnosis of the presence or absence of cirrhosis by the 
above criteria, a liver biopsy is required; liver biopsy results will supersede any imaging 
studies or blood test results and be considered definitive.
9) Liver imaging within 6 months of Baseline/Day 1 to exclude hepatocellular carcinoma 
(HCC) is required in patients with cirrhosis
10) Screening ECG without clinically significant abnormalities


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11) Subjects must have the following laboratory parameters at screening: 
a) ALT 10 the upper limit of normal  (ULN)
b) AST 10 ULN
c) Direct bilirubin 1.5 ULN
d) Platelets  50,000/µL
e) HbA1c 8.5%
f)
Creatinine clearance (CLcr) 50 mL /min, as calculated by the Cockcroft-Gault equation 
{2202}
g) Hemoglobin  11 g/dL for female subjects; 12 g/dL for male subjects.
h) Albumin 3g/dL 
i)
INR ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR.
12) 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 Baseline/Day 1 prior to 
enrollment.
13) 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.
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.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Current or prior history of any of the following:
a) Clinically-significant illness (other than HCV) or any other major medical disorder that 
may interfere with subject treatment, assessment or compliance with the protocol; 
subjects currently under evaluation for a potentially clinically-significant illness (other 
than HCV) are also excluded.  
b) Gastrointestinal disorder or post-operative condition that could interfere with the 
absorption of the study drug. 


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c) Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy.
d) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).
e) Solid organ transplantation.
f)
Significant pulmonary disease, significant cardiac disease or porphyria.
g) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of 
their psychiatric illness within the last 5 years. Subjects with psychiatric illness
(without the prior mentioned conditions) that is well-controlled on a stable treatment 
regimen for at least 12 months prior to Baseline/Day 1 or has not required medication in 
the last 12 months may be enrolled. 
h) 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.
i)
Significant drug allergy (such as anaphylaxis or hepatotoxicity). 
2) If treatment-naïve, prior exposure to approved or experimental HCV-specific direct-acting 
antiviral agent(s). If treatment-experienced, prior exposure to approved or experimental 
HCV-specific direct-acting antiviral agent(s) other than NS3/4A protease inhibitors is
prohibited.
3) Pregnant or nursing females.
4) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency, cholangitis).
5) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
6) Donation or loss of more than 400 mL blood within 2 months prior to Baseline/Day 1.
7) Use of any prohibited concomitant medications as described in Section 5.4.
8) Administration of interferon or any HCV-directed treatment, other than the study drug, is 
prohibited from 12 weeks prior to Screening until completion of the final post-treatment 
follow-up visit.
9) Chronic use of systemically administered immunosuppressive agents 
(e.g., prednisone equivalent > 10 mg/day), azathioprine or monoclonal antibodies such as 
infliximab.
10) Known hypersensitivity to SOF, LDV, or formulation excipients. 


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Treatment Codes
This is an open-label, non-randomized study. Every subject will receive SOF/LDV FDC tablet 
for 12 weeks. An Interactive Web Response System (IWRS) will be employed to manage subject 
enrollment and study drug dispensation.
5.2.
Description and Handling of Sofosbuvir/Ledipasvir Fixed-Dose Combination 
5.2.1.
Formulation
Sofosbuvir (SOF)/ledipasvir (LDV) fixed-dose combination (FDC) tablets are orange, diamond-
shaped, film-coated tablets containing 400 mg of SOF and 90 mg of LDV. The tablets are 
debossed with “GSI” on one side and “7985” on the other side. The SOF/LDV FDC tablets
contain the following inactive ingredients: lactose monohydrate, copovidone, microcrystalline 
cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, FD&C yellow # 6 /sunset yellow 
FCF aluminum lake.
5.2.2.
Packaging and Labeling
Sofosbuvir (SOF)/ledipasvir (LDV) fixed-dose combination (FDC) tablets are packaged in 
white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets (Korea and 
Taiwan) or 28 tablets (China only) and a silica gel desiccant canister or sachet and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner.
All labels for SOF/LDV FDC bottles to be distributed to study centers in participating countries 
shall be labeled to meet all applicable requirements of the US Food and Drug Administration 
(FDA) and local regulations as applicable.
Sufficient quantities of SOF/LDV FDC tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Materials & Logistics (or its designee).
5.2.3.
Storage and Handling
Sofosbuvir (SOF)/ledipasvir (LDV) FDC bottles should be stored at controlled room temperature 
until required for administration. Controlled room temperature is defined as 25 C; excursions 
are permitted between 15 C and 30 C.
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the Investigational Medicinal Product (IMP) 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 


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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/LDV FDC.
5.3.
Dosage and Administration of Sofosbuvir/Ledipasvir FDC 
Sofosbuvir/Ledipasvir 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 IMP doses. In order to maintain compliance with the treatment regimen, SOF/LDV 
FDC should be administered at approximately the same time each day.
For missed dose(s) of study medication, subjects should be instructed to take the missed dose(s) 
of IMP as soon as possible during the same day.  Subjects should be cautioned never to double 
the next dose with a missed dose of IMP under any circumstances.
5.4.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to Screening, up to and including the date of 
the visit four weeks after discontinuation of study treatment need to be recorded in the source 
documents and electronic case report form(s) (eCRFs).
Administration of interferon or any HCV-directed treatment, other than the study drug, is 
prohibited from 12 weeks prior to Screening until completion of the final post-treatment 
follow-up visit.
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Baseline/Day 1 visit through the end of treatment:

Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO mimetics)

Chronic use of systemic immunosuppressants including, but not limited to, corticosteroids 
(prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or 
monoclonal antibodies (e.g., infliximab)

Investigational agents or devices for any indication
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters ie, P-gp) with study drug may result in pharmacokinetic interactions resulting 
in increases or decreases in exposure of study drug.  
Examples of representative medications which are prohibited from 21 days prior to 
Baseline/Day 1 through the end of treatment are listed below:


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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
Antiarrhythmics b
Quinidine
Anticonvulsantsc
Phenobarbital, phenytoin, 
carbamazepine, oxcarbazepine
Antimycobacterialsc
Rifabutin, rifapentine, rifampin
Cardiac Medicationsb
Valsartan, olmesartan, telmisartan, 
ranolazine, bosentan, digoxin
Herbal/Natural Supplementsc
St. John’s wort, Echinacea, milk 
thistle (ie, silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-
Tang)
HMG-CoA Reductase Inhibitorsd
Rosuvastatin
Atorvastatin, simvastatin, 
pravastatin, pitavastatin, fluvastatin, 
lovastatin
a
It is recommended to separate antacid and SOF/LDV administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from SOF/LDV at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with SOF/LDV or up to 2 hours after taking SOF/LDV. Proton-pump inhibitors should not be taken before 
SOF/LDV.
b
May result in an increase in the concentration of study drugs and/or concomitant medications. Coadministration of 
SOF/LDV with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration 
monitoring of digoxin is recommended when coadministered with SOF/LDV. 
c
May result in a decrease in the concentrations of study drugs.
d
Use with study drugs may result in an increase in the concentration of the HMG-CoA Reductase Inhibitors. Monitor for 
signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis.
Medications for disease conditions excluded from the protocol (eg, HIV-1 infection, 
active cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study. 
5.5.
Accountability for SOF/LDV FDC
The investigator is responsible for ensuring adequate accountability of all used and unused IMP.
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). 
All used and unused IMP dispensed to subjects must be returned to the site.
SOF/LDV FDC accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits.

Record the date, subject number, subject initials, the IMP kit number dispensed.


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
Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
Subjects must be instructed to bring back all bottles of study medication in the original container 
at every post-baseline study visit through the end of treatment.
Study medication will be reconciled using medication pill counts at every post-baseline visit by 
the investigator or designee (e.g., pharmacist, study coordinator) in order to monitor the subject’s 
adherence with the medication regimen. 
5.5.1.
Investigational Medicinal Product Return or Disposal
Please refer to Section 9.1.7 for Investigational Medicinal Product Accountability and Return.


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6.
STUDY PROCEDURES
Study visits will occur at Screening, Baseline/Day 1, and on-treatment at the end of Weeks 1, 2, 
4, 6, 8, 10, and 12. All subjects will complete 4-week and 12-week Post-Treatment visits. In 
addition, all subjects with HCV RNA < LLOQ at the 12-week Post-Treatment visit will complete 
a 24-week Post-Treatment visit unless confirmed viral relapse occurs. The end of study will 
occur at the 12-week or 24-week Post-Treatment visit according to virologic response.
Administration of interferon or any HCV-directed treatment, other than the study drug, is 
prohibited from 12 weeks prior to Screening until completion of the final post-treatment 
follow-up visit.
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. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
Information on the specific laboratory parameters to be measured and clinical assessments to be 
performed are provided below.
6.1.
Subject Enrollment and Treatment Assignment 
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit (Day -28 to Day -1)
Screening assessments will be completed within 28 days of the Baseline/Day 1 visit. The 
screening window can be extended to 42 days for subjects requiring liver biopsy or additional 
HCV genotype testing. 
Subjects will be screened to determine eligibility for participation in the study. The following 
will be performed and documented at screening:

Obtain signed informed consent
A separate informed consent will be required from subjects participating in the intensive 
pharmacokinetic and/or pharmacogenomic sub-studies.

Determine inclusion eligibility (Reference Section 4.2 and 4.3)
If the presence of cirrhosis is determined, then appropriate diagnostic imaging 
(e.g., CT or Ultrasound) should be performed to exclude the presence of hepatocellular 
carcinoma (HCC)


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
Obtain medical history (Reference Section 6.6.2)

Perform complete physical examination

Obtain body height and weight

Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature)

Perform 12-lead ECG

Assessment of AEs and concomitant medications 

Obtain blood samples for tests 
Hematology & Chemistry
Coagulation tests
HCV RNA
Serum -hCG pregnancy test for females of childbearing potential only
IL28B genotype 
Determination of genotype and subtype of HCV infection
HCV antibody, HIV 1/2 antibody, and HBV surface antigen (HBsAg)
HbA1c
TSH

Obtain urine sample for:
Urinalysis
Record any adverse events occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 28-42 days after screening for entry 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 non-serious adverse 
events related to protocol-mandated procedures on the adverse events case report form 


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(CRF/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 
CRF/eCRF.  See Section 7 Adverse Events and Toxicity Management for additional details.
6.3.
Randomization
This is a non-randomized study. An Interactive Web Response System (IWRS) will be employed 
to manage subject enrollment and study drug dispensation.
6.4.
Treatment Assessments
6.4.1.
Baseline/Day 1 Visit
The following baseline tests and procedures must be completed prior to dosing/dispensing:

Confirm eligibility

Perform complete physical examination

Obtain body weight

Obtain vital signs

Perform 12-lead ECG

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Subject completes Health Related Quality of Life Survey, SF-36

Obtain blood samples for:
Hematology & Chemistry
Coagulation tests
HCV RNA
Viral RNA Sequencing / Phenotyping Sample
Archive Sample (for subjects that have not opted out)
Pharmacogenomic testing (for subjects who have consented to participate in the 
Pharmacogenomic Substudy)


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
Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Drug Administration
Dispense study drugs 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 drugs and record the time of first dose.
6.4.2.
Week 1 (3 days)
The following procedures/assessments are to be completed at the end of Week 1.

Obtain vital signs

Perform 12-lead ECG

Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Single PK Sample
Viral RNA Sequencing / Phenotyping Sample

Complete medication pill count and review patient diary data with subject
6.4.3.
Week 2 (3 days)
The following procedures/assessments are to be completed at the end of Week 2:

Obtain vital signs

Assessment of AEs and concomitant medications

Subject completes Health Related Quality of Life Survey, SF-36


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
Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Single PK Sample
Viral RNA Sequencing / Phenotyping Sample 
If applicable at Week 2, collect serial PK substudy samples (for subjects who have 
consented to participate in the PK substudy)

Complete medication pill count and review dosing diary data with subject
6.4.4.
Week 4 (3 days)
The following procedures/assessments are to be completed at the end of Week 4:

Obtain vital signs

Assessment of AEs and concomitant medications

Subject completes Health Related Quality of Life Survey, SF-36

Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Single PK Sample
Viral RNA Sequencing / Phenotyping Sample 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only
If applicable at Week 4, collect serial PK substudy samples (for subjects who have 
consented to participate in the PK substudy)

Complete medication pill count and review patient diary data with subject

Dispense study drugs as directed by the IWRS


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6.4.5.
Week 6 (3 days)
The following procedures/assessments are to be completed at the end of Week 6.

Obtain vital signs

Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Single PK Sample
Viral RNA Sequencing / Phenotyping Sample 

Complete medication pill count and review patient diary data with subject
6.4.6.
Week 8 (3 days)
The following procedures/assessments are to be completed at the end of Week 8:

Obtain vital signs

Assessment of AEs and concomitant medications

Subject completes Health Related Quality of Life Survey, SF-36

Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Single PK Sample
Viral RNA Sequencing / Phenotyping Sample

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Complete medication pill count and review patient diary data with subject

Dispense study drugs as directed by the IWRS


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6.4.7.
Week 10 (3 days)
The following procedures/assessments are to be completed at the end of Week 10.

Obtain vital signs

Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Single PK Sample
Viral RNA Sequencing / Phenotyping Sample

Complete medication pill count and review patient diary data with subject
6.4.8.
Week 12 (3 days)
The following procedures/assessments are to be completed at the end of Week 12:

Perform complete physical examination

Obtain body weight

Obtain vital signs

Perform 12-lead ECG

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Subject completes Health Related Quality of Life Survey, SF-36

Obtain blood samples for:
Hematology & Chemistry
Coagulation tests
HCV RNA
Single PK Sample


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Viral RNA Sequencing / Phenotyping Sample
Archive Sample (for subjects that have not opted out)

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Complete medication pill count and review patient diary data with subject
6.4.9.
Early Termination (ET)/Unscheduled Visit 
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments at the unscheduled visits are at the investigator’s discretion. At all unscheduled 
visits initiated for the purpose of confirming virologic failure, a Viral RNA
Sequencing / Phenotyping Sample must be collected.
The Sponsor (e.g. Medical Monitor and Clinical Program Manager)/ CRO must be informed, as 
soon as possible, when a subject prematurely discontinues treatment. The primary reason for 
premature treatment discontinuation must be provided to the Sponsor/ CRO.
If a subject discontinues treatment early for any reason then the following assessments for the 
Early Termination (ET) Visit must be performed:

Perform complete physical examination

Obtain body weight

Obtain vital signs

Perform 12-lead ECG

Assessment of AEs and concomitant medications

Pregnancy prevention counseling

Subject completes a Health Related Quality of Life Survey, SF-36

Obtain blood samples for:
Hematology & Chemistry
Coagulation tests
HCV RNA


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Single PK Sample
Viral RNA Sequencing / Phenotyping Sample
Archive Sample (for subjects that have not opted out)

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Complete medication pill count and review dosing diary data with subject
6.5.
Post-Treatment Assessments
All subjects must complete the Post-Treatment Week 4 and Week 12 visits. For subjects who 
have completed an ET visit, the post-treatment Week 4 and Week 12 follow-up visits will be 
scheduled at 4 and 12 weeks after the last dose of study drug. All subjects with 
HCV RNA < LLOQ at the 12-week Post-Treatment visit will also complete the 24-week 
Post-Treatment visit, unless viral relapse is determined.
6.5.1.
Post Treatment Week 4 (5 days)
The following procedures/assessments are to be completed for all subjects, 4 Weeks after taking 
the last dose of study drug:

Obtain vital signs

Assessment of AEs and concomitant medications

Pregnancy prevention counseling 

Subject completes a Health Related Quality of Life Survey, SF-36

Obtain blood samples for:
Hematology & Chemistry
HCV RNA
Viral RNA Sequencing / Phenotyping Sample 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only
All subjects, including those who prematurely discontinue study drug, must return for 
Post Treatment Visit at Week 12.


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6.5.2.
Post Treatment Weeks 12 and 24 (5 days)
The following procedures/assessments are to be completed for the Post-treatment Week 12 and 
24 Visits:

Obtain body weight

Obtain vital signs

Subject completes a Health Related Quality of Life Survey, SF-36 (Post treatment Week 12 
only)

Obtain blood samples for:
HCV RNA
Viral RNA Sequencing / Phenotyping Sample 
Subjects with HCV RNA < LLOQ at the Post-Treatment Week 12 Visit will return at the 
post-treatment Week 24 Visit. 
6.6.
Procedures and Specifications
6.6.1.
Clinical Laboratory Analytes
Hematology: Hematocrit, Hemoglobin (Hb), Platelet count, Red blood cell count (RBC), 
White blood cell count (WBC) with differential (absolute and percentage) including 
Lymphocytes, Monocytes, Neutrophils, Eosinophils, Basophils, Reticulocyte count and MCV.
Coagulation: INR, Prothrombin time (PT), Activated partial thromboplastin time (APTT).
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct Bilirubin), 
Direct Bilirubin at Screening only, Glucose, Lipase, Potassium, Sodium; Gamma-glutamyl 
transferase (GGT) at Baseline only.
Urinalysis: Appearance, Blood, Color, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV, HBV and HIV. HCV RNA will be measured using the 
COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System. HCV genotype and 
subtype will be determined using the Siemens VERSANTHCV Genotype INNO-LiPA 
2.0 Assay. Gilead reserves the right to use alternate assays for HCV RNA and HCV genotype 
should the above assays become unavailable 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.


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Pregnancy Tests: Serum -hCG or Urine -hCG (if positive, requires immediate confirmation 
with Serum -hCG)
Additional Tests: Hemoglobin A1c (HbA1c), and TSH (reflex free T4).
6.6.2.
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. Additionally, for treatment naïve subjects, any relative or absolute contraindications to 
interferon treatment (“IFN ineligible”) should be identified. Information related to 
HCV infection will also be collected.
For treatment-experienced subjects, obtain HCV treatment history, in order to categorize the 
patient as either IFN-intolerant, non-responder or relapse/breakthrough, defined as:

IFN-intolerant:  Subjects considered to be IFN-intolerant must (according to investigator 
judgment) have sufficiently recovered from IFN-related clinical adverse events and/or 
laboratory abnormalities prior to Screening. In addition, all other protocol eligibility criteria 
must be met.

Non-Responder: Subject did not achieve undetectable HCV RNA levels 
(HCV RNA ≥LLOQ) while on treatment. For Peg-IFNα/IFN/RBV non-responders, subjects 
should be further defined as Null or Partial Responders:
Null Responders: HCV RNA < 2 Log10 reduction during the first 12 weeks of treatment.
Partial Responders: HCV RNA ≥ 2 Log10 reduction during the first 12 weeks of 
treatment.

Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels 
(HCV RNA < LLOQ) during treatment or within 4 weeks of end of treatment, but did not 
achieve a sustained virologic response (SVR).
6.6.3.
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and 
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological. 
6.6.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.


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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.
6.6.5.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} using actual body 
weight (BW). 
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)
6.6.6.
12-Lead ECGs
Subjects will be required to rest in a supine position for 5 minutes prior to making a recording.
The investigator (or qualified designee) should review the ECG traces recorded in real time for 
clinically significant abnormalities.  On-treatment ECGs should be compared to the subject’s 
Baseline as part of routine safety monitoring.
6.6.7.
Viral RNA Sequencing / Phenotyping Sample 
Plasma samples will be collected at Baseline/Day 1 and each additional visit for viral sequence 
analysis. At any unscheduled visit initiated for the purpose of confirming virologic breakthrough, 
a plasma sample for viral sequence analysis must be collected. Untested samples may be 
archived.
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual.


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6.6.8. 
Archive Sample 
Final 
Amendment 2.0 
A plasma sample will be obtained from all subjects at the Baseline/Day 1 visit and at the end of 
treatment (i.e., Week 12) or Early Termination visit for future research use. Unlike the other 
samples drawn from subjects, this protocol does not defme the type of research that may be 
conducted using this sample. This research could involve the use of the sample for HCV 
genotyping/phenotyping assays (as applicable) or their development, for retesting the amount of 
HCV in the blood, for measurement of antiviral dmg levels in the blood, for future testing to 
leam more about how the study dmg has worked against HCV or for clinicallaborat01y testing to 
provide additional clinical data. No human genetic testing will be perf01m ed. This plasma 
sample will be stored for up to 10 years after the study closure. Subjects emolled in the study 
will have the opportunity to withdraw consent from storage and use of the Archive sample for 
future research. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.6.9. 
Single Pharmacokinetic (PK) Sample 
Single PK blood samples will be collected for all subjects at each on-treatment visit after 
Baseline/Day 1 and archived for PK analysis of SOF (and its metabolites GS-566500 and 
GS-331 007) and LDV. 
Details regarding the collection, processing, and shipping of samples will be included in the lab 
manual. 
6.6.10. 
Intensive Pharmacokinetic (PK) Substudy (Korea and Taiwan only) 
PPD 
6.6.11. 
Pharmacogenomic (PG) Substudy 
PD 
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6.6.12. 
Pregnancy Testing 
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All females of childbearing potential will have urine pregnancy testing eve1y 4 weeks during the 
dosing period and for a minimum of 1 month following the last dose of study dmg. In the event 
of a positive urine pregnancy test result, subjects will be instructed to stop study dmgs 
immediately and retum to the clinic as soon as possible for a confmnat01y semm pregnancy test. 
6.6.13. 
Health Related Quality of Life Survey 
A health related quality oflife survey, SF-36 will be completed by patients at Baseline/Day 1, 
On-ti·eatinent Weeks 2, 4, 8, 12, Post-ti·eatment Weeks 4 and 12, and Early Tennination 
(if applicable). The subject should read the questionnaire by himself/herself and write/mark 
answers directly onto the questionnaire. 
6.7. 
Assessments for Premature Discontinuation from Study 
If a subject discontinues study dosing (for example, as a result of an AE), eve1y attempt should 
be made to keep the subject in the study and continue to perf01m the required study-related 
follow-up and procedures (see Section 6.4.9). If this is not possible or acceptable to the subject 
or investigator, the subject may be withdrawn from the study. 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. AEs may also include pre- or post treatment complications that 
occur as a result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse 
reports, or occupational exposure. Preexisting events that increase in severity or change in nature 
during or as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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


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7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
All SAEs, regardless of causal relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-mandated procedures performed from screening 
onwards.
All AEs, regardless of causal relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP must be reported to the CRF/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 post-treatment follow up 
period.
Investigators are not obligated to actively seek SAEs after post treatment follow-up. However, if 
the investigator learns of any SAEs that occur after study participation has concluded, i.e., after 
the 12-week or 24-week post treatment visit (as applicable) and the event is deemed relevant to 
the use of IMP, he/she should promptly document and report the event to Gilead DSPH.
Gilead DSPH contact information is as follows: Email: Safety_FC@gilead.com and 
Fax: +1 (650) 522-5477.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours as described above.
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.


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CRO and Gilead Sciences Phrumacovigilance Representative contact inf01mation is as follows: 
CRO Phannacovigilance 
Representative 
(for sites in Korea and Taiwan): 
CRO Phrumacovigilance 
Representative 
(for sites in China): 
CRO Medical Monitor 
(for sites in Korea and Taiwan): 
CRO Medical Monitor 
(for sites in China) 
Gilead Sciences Medical Monitor 
(Back-Up): 
SAE Hotline: 
Korea: 
Taiwan: 
E-mail: 
China: 
E-mail: 
Name: 
Phone: 
Fax: 
E-mail: 
TBD 
Name: 
Phone: 
Mobile: 
Fax: 
E-mail: 
+ 65 6221 8582 
+ 00308 13 2766 
+ 00801 10 4423 
medical_ singapore@parexel.com 
TBD 
TBD 
Viola Yang 
PPD 
PPD 
PPD 
TBD 
Phil Pan , MD, PhD 
PPD 
PPD 
1-'1-'U 
1-'1-'U 
I 
• 
For fatal or life-threatening events, copies of hospital case reports, autopsy rep01is, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occm without personal subject identification, 
maintaining the u·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensme the timely completion of accmate safety 
rep01is. 
Any medications necessruy for u·eahnent of the SAE must be recorded onto the concomitant 
medication section of the subject's CRF/eCRF and the event description section of the SAE 
f01m. 
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 regulat01y agencies reports of SAEs, serious adverse dmg reactions (SADRs), or 
suspected lmexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
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Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. 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.
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).
Severity should be recorded and graded according to the GSI Grading Scale for Severity of AEs 
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.
7.6.
Subject Stopping Rules
The Medical Monitor must be consulted prior to dose discontinuation of SOF/LDV 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/LDV FDC dose reduction. If SOF/LDV FDC is stopped due to toxicity, it 
must not be restarted; if SOF/LDV FDC is discontinued, the subject must complete an ET visit. 
Post-treatment 4-Week and 12-Week visits must also be scheduled, 4 and 12 weeks from the last 
dose of study drug. Subjects with HCV RNA < LLOQ at the 12-week Post-Treatment visit will 
complete the 24-week Post-Treatment visit, unless viral relapse is determined. 
Subjects who meet any of the following laboratory criteria must stop study medication:

Elevation of ALT and/or AST > 5x Baseline/Day 1 or nadir, confirmed by immediate repeat 
testing

Abnormal elevation of ALT > 3 x Baseline/Day 1 and total bilirubin > 2 x ULN, confirmed 
by immediate repeat testing


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
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 as related to SOF/LDV FDC
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, and 
pregnancy reports regardless of an associated AE.  Also includes reports of adverse reactions in 
infants following exposure from breastfeeding, and reports of adverse reactions associated with 
product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure to 
the medicinal product.
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. 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.
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the CRO Pharmacovigilance Representative using the 
pregnancy report form within 24 hours of becoming aware of the pregnancy. 
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.


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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 
the Serious Adverse Events section (Section 7.3). Furthermore, any SAE occurring as an adverse 
pregnancy outcome post study must be reported to the CRO Pharmacovigilance Representative.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to the CRO Pharmacovigilance Representative using 
the pregnancy outcome report form. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead DSPH. Gilead DSPH contact 
information is as follows: Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Pregnancies of female partners of male study subjects exposed to Gilead study drugs must also 
be reported and relevant information should be submitted to the CRO Pharmacovigilance 
Representative using the pregnancy and pregnancy outcome forms within 24 hours. Monitoring 
of the subject’s partner should continue until the conclusion of the pregnancy. If the end of the 
pregnancy occurs after the study has been completed, the outcome should be reported directly to 
Gilead DSPH, fax number +1 650 522-5477 or email Safety_FC@gilead.com.
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to the CRO Pharmacovigilance Representative within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study IMP, 
but do not apply to concomitant medications. Except for situations that result in AEs, special 
situations involving concomitant medications will not be reported. Any inappropriate use of 
medications prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y analysis objectives of this study are: 
Final 
Amendment 2.0 
• 
To detennine the antiviral efficacy of combination treatment with sofosbuvir 
(SOF)/ledipasvir (LDV) fixed-dose combination (FDC) as measmed by the prop01iion of 
subjects with sustained virologic response (SVR) 12 weeks after discontinuation of therapy 
(SVR12, defmed as HCV RNA < lower limit of quantitation [LLOQ] 12 weeks post 
treatment). 
• 
To evaluate the safety and tolerability of SOFILDV FDC as assessed by review of the 
accumulated safety data 
The secondmy objectives of this study m·e as follows: 
• 
To determine the prop01iion of subjects who attain SVR at 4 and 24 weeks after 
discontinuation of therapy (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA dming treatment and after treatment 
discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV dming treatment and after 
treatment discontinuation 
The explorat01y objectives of this study are: 
PPO 
I 
8.1.2. 
Primary Endpoint 
The prima1y efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after discontinuation of 
therapy) in the Full Analysis Set (F AS) population. 
The prima1y safety endpoint is any AE leading to pennanent discontinuation of study dmg. 
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8.1.3.
Secondary Endpoint
Secondary efficacy endpoints include the proportion of subjects with: HCV RNA < LLOQ at 
4 and 24 weeks after discontinuation of therapy (SVR4 and SVR24); viral breakthrough; relapse; 
and HCV RNA change from baseline.
8.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include ALT normalization; and the health related quality of 
life endpoints.
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).
Last dose of study drug refers to the last dose of SOF/LDV 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 post-treatment time points.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which includes 
subjects who were enrolled and received at least one dose of study drug and have chronic 
genotype (1a, 1b, or mixed 1a/1b) HCV infection. 
8.2.1.2.
Safety
The primary analysis set for safety analyses is defined as subjects who were enrolled and 
received at least one dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of 
study drug through the date of the last dose of study drug plus 30 days.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all subjects who are enrolled and have received at least one dose 
of study drug and for whom concentration data of analytes [SOF, LDV, and metabolite(s), as 
appropriate] are available. The PK analysis set will be used for analyses of general PK.


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8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. In general, values for 
missing data will not be imputed. 
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and is 
immediately preceded and followed in time by values that are deemed successes, then the 
missing data point will be termed a success; otherwise the data point will be termed a failure.
Any subject with missing data due to premature discontinuation of the study will be considered a 
failure at the time points on, or following, the date of discontinuation. If no HCV RNA values 
are obtained after the last dose of study medication, the subject will be considered a treatment 
failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of adverse 
events according to the treatment received; otherwise, if the subject is not dosed then they 
will be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a pre-dose value, then the subject will be excluded from the calculation of 
summary statistics for the pre-dose value and the change from pre-dose values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pre-treatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for 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).
PK concentration values below the lower limit of quantitation (BLQ) will be treated as zero for 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing. For the presentation of summary and order statistics, 
if at least 1 subject has a concentration value BLQ for the time point, then the minimum value 
will be displayed as “BLQ”. If more than 50% of the subjects have a concentration data value 


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BLQ for the time point, then the minimum and median values will be displayed as “BLQ”. If all 
subjects have concentration data values BLQ for the time point, then all order statistics 
(minimum, first quartile [Q1], median, third quartile [Q3], maximum) will be displayed as 
“BLQ”.
Exposure parameters that are selected for statistical analysis will be natural log-transformed. 
Concentration values that are BLQ will be excluded for any ratio or natural log-transformed 
statistical analysis.
8.3.1.
Interim Analysis
An interim analysis will be performed after all subjects enrolled from Korea and Taiwan have 
been followed through 12 weeks post-treatment or discontinued from the study to support 
regulatory submissions in these two countries.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment-naive and treatment-experienced subjects.
Demographic summaries will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include a summary of body mass index, HCV RNA level 
(log10 IU/mL), HCV genotype (1a or 1b, or mixed 1a/1b), IL28B genotype, presence/absence of 
cirrhosis, baseline ALT level, and additional endpoints as necessary.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after discontinuation of 
therapy) in the FAS population. The primary analysis will be performed after all enrolled 
subjects have been followed through 12 weeks post-treatment or discontinued from study.
The primary efficacy analysis described below will compare the observed SVR12 rate for the 
investigational regimen (i.e., SOF/LDV FDC for 12 weeks) versus the historical SVR null rate in 
treatment–naïve Korean subjects and in treatment–naïve Chinese subjects, respectively.
In addition, a point estimate with a two-sided 95% exact confidence interval using the binomial 
distribution (Clopper-Pearson method) {20839} will be constructed for the SVR12 rate by 
treatment-naïve and treatment-experienced subjects for each region (i.e., China, Korea or 
Taiwan), Korea plus Taiwan and overall (i.e., China plus Korea plus Taiwan).
Treatment-Naïve Subjects
In the primary efficacy analysis the SVR12 rate from Korea and China will be compared to the 
adjusted historical SVR null rate of 49% in Korea and historical control rate of 57% in China, 
respectively (as calculated in Appendix 5) using a two-sided exact one-sample binomial test. 


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The hypothesis for superiority in Korea is: 
• 
HO: SVRI2 rate = 49%, 
• 
HI: SVRI2 rate :;t 49%. 
The hypothesis for superiority in China is: 
• 
HO: SVRI2 rate = 57%, 
• 
HI: SVRI2 rate :;t 57%. 
Treatment-Experienced Subjects 
Final 
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There is no treatment option available in China, Korea or Taiwan for treatment-experienced 
patients with GT -I infection. In the absence of effective antiviral therapy, spontaneous clearance 
of the HCV is rare. Consequently a nominal SVR rate of 5% is assumed for 
treatment -experienced subjects. 
No statistical hypothesis testing will be perfonned in u·eatment-experienced subjects. For each 
region (i.e., China, Korea or Taiwan), Korea plus Taiwan, and overall (i.e., China plus Korea 
plus Taiwan), a point-estimate with two-sided 95% exact confidence interval using the binomial 
disu·ibution (Clopper-Pearson method) will be consti11cted for the SVRI2 rate. 
8.5.2. 
Secondary Analysis 
The proportion of subjects with HCV RNA below LLOQ over time (including SVRI2) will be 
presented by u·eatment-naive and u·eatment-experienced subjects for each region 
(i.e., China, Korea or Taiwan), Korea plus Taiwan, and overall (i.e., China plus Korea 
plus Taiwan) in tabular and graphical fonn. 
Descriptive summaries and listings will be provided for additional efficacy evaluations including 
the proportion of subjects who experience virologic fail me, AL T n01malization, semm HCV 
RNA actual values and change from baseline and health related quality of life endpoints. 
Exj)lorat01y analyses may be erfonned to assess the PPD 
Details on efficacy analyses will be described in the statistical analysis plan. 
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8.6.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements, at various time points during the study, and by the documentation of AEs.
All safety data collected on or after the first dose of study drug administration up to 30 days after 
the last dose of study drug will be summarized for each region (i.e., China, Korea or Taiwan), 
Korea plus Taiwan, and overall (i.e., China plus Korea plus Taiwan). Safety endpoints will be 
summarized as the number (proportion) of subjects with events or abnormalities for categorical
data or as an 8-number summary (n, mean, standard deviation, median, Q1, Q3, minimum, 
maximum) for continuous data.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to IMP data will be generated from the IMP 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 new or worsening adverse event that begins on or after the 
date of first dose of IMP up to the date of last dose of IMP plus 30 days.
Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC, HLT, and PT) will be provided:

All AEs,

All study drug-related AEs,

Combined Grade 2, 3 and 4 AEs,

Combined Grade 3 and 4 AEs,

Combined Grade 2, 3 and 4 study drug-related AEs,

Combined Grade 3 and 4 study drug-related AEs,

All AEs that caused permanent discontinuation from study drug,

All AEs that caused change in dose or temporary interruption of study drug,


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
All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
8.6.3.
Laboratory Evaluations
Selected laboratory data (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be 
summarized at study visits along with corresponding change from baseline. 
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
defined in Appendix 3 of this protocol. The incidence of treatment-emergent laboratory 
abnormalities, defined as values that increase by at least one toxicity grade from baseline at any 
time post-baseline up to the date of last dose of study drug plus 30 days will be summarized. If 
baseline data are missing, then any post-baseline graded abnormality (i.e., at least Grade 1) will 
be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
8.7.
Pharmacokinetic Analysis
. Intensive plasma concentrations of the study drug and metabolite(s) over time, if analyzed, will 
be summarized using descriptive statistics. Details of the analysis plan will be provided in the 
statistical analysis plan.  Population PK parameters for the study drugs and metabolite(s), as 
applicable, will be estimated and summarized using descriptive statistics
8.8.
Sample Size
Treatment-Naïve Subjects:
A sample size of 40 Korean subjects in the treatment-naïve group will provide at least 90% 
power to detect a 27% improvement in SVR12 rate from the adjusted historical control rate of 
49% using 2-sided exact one-sample binomial test at significant level of 0.05.
A sample size of 100 Chinese subjects in the treatment-naïve group will provide at least 90% 
power to detect a 17% improvement in SVR12 rate from the historical control rate of 57% using 
2-sided exact one-sample binomial test at significant level of 0.05.
In addition, with 40 subjects in Korea (or Taiwan), the 2 sided 95% exact confidence interval 
will extend at most 32% in length. With 80 subjects (Korea plus Taiwan) in the treatment-naive 
group a two-sided 95% exact confidence interval will extend at most 23% in length. With 
100 subjects in China, the 2 sided 95% exact confidence interval for the SVR12 rate will extend 
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Treatment-Experienced Subjects:
For Treatment Experienced subjects, a confidence interval approach will be used to justify the 
sample size given that our goal is to characterize the SVR rate in a population with limited 
treatment options and not to test a specific hypothesis. With 40 subjects in Korea (or Taiwan), 
the 2 sided 95% exact confidence interval will extend at most 32% in length. With 80 subjects 
(Korea plus Taiwan) in the treatment-experienced group, a two-sided 95% exact confidence 
interval will extend at most 23% in length. With 100 subjects in China, the 2 sided 95% exact 
confidence interval for the SVR12 rate will extend at most 20% in length.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the ECIRB/IEC and/or Regulatory Body has been documented and provided 
as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the ECIRB/IEC and/or Regulatory Body 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.


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9.1.3. 
Informed Consent 
Final 
Amendment 2.0 
The investigator is responsible for obtaining written infonned consent from each individual 
pati icipating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazat·ds of the study and before lmde1iaking any study-related procedures. The 
investigator must use the most cmTent IRB- or IEC-approved infonned consent f01m (ICF) for 
docmnenting written inf01m ed consent. Each infonned consent (or assent as applicable) will be 
appropriately signed and dated by the subject or the subject's legally authorized representative 
and the person conducting the consent discussion, and also b an impa1tial witness if re uired by 
IRB or IEC or local requirements. PPD 
Phatm acogenomic consent f01m will inf01m subjects about phatm acogenomic testing and sample 
retention, and their right to receive clinically relevant phatm acogenomic analysis results. 
9.1.4. 
Confidentiality 
The investigator must assure that subjects' anonymity will be strictly maintained and that their 
identities at·e protected from lmauthorized patties. Only subject initials, date of bnth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
f01m or biological sample submitted to the Sponsor, IRB [or] IEC, or laborat01y. Laborat01y 
specilnens must be labeled in such as way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laborat01y instructions. NOTE: The 
investigator must keep a screening log showing codes, naines, and addresses for all subjects 
screened and for all subjects emolled in the n·ial. Subject data will be processed in accordance 
with all applicable regulations. 
The investigator agrees that all inf01m ation received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study inf01m ation, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This infonnation is not to be disclosed to any thll·d patty (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 fmt her agxees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third pat·ty or othe1wise into the 
public domain. 
9.1.5. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully docmnented and the study data to be subsequently verified. These docmnents should 
be classified into at least the following two categories: (1) investigator's study file, and 
(2) subject clinical source docmnents. 
The investigator's study file will contain the protocol/ainendments, CRF and que1y f01m s, IRB 
[or] IEC and govemmental approval with conespondence, inf01m ed consent, dmg records, staff 
cmTiculmn vitae and authorization fonns, and other appropriate documents and con espondence. 
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The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.


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9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in the 
audit trail of the system. Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will used his/her log in credentials to confirm 
that the forms have been reviewed, and that the entries required per the protocol scheduled of 
events and procedures. System-generated or manual queries will be issued to the investigative 
site staff as data discrepancies are identified by the monitor or internal Gilead staff, who 
routinely review the data for completeness, correctness, and consistency. The site coordinator is 
responsible for responding to the queries in a timely manner, within the system, either by 
confirming the data as correct or updating the original entry, and providing the reason for the 
update (e.g. data entry error). At the conclusion of the trial, Gilead will provide the site with a 
read-only archive copy of the data entered by that site. This archive must be stored in accordance 
with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead (Quality Assurance) QA, the site may destroy used (empty or partially empty) and unused 
IMP supplies in accordance with that site’s approved SOP. A copy of the site’s approved SOP 
will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs [or] IECs, or to regulatory authority or health 
authority inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB [or] 
IEC in accordance with local requirements and receive documented 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 agencies. 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be 
prepared in certain cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead in an abstract, manuscript, or presentation form or the study has been completed at 
all study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.


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9.3.2.
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.
9.3.3.
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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rs12979860 is a critical predictor for on-treatment and sustained virologic 
response in patients with hepatitis C virus genotype-1 infection. PLoS ONE 
2011;6 (3):e18322.
24242
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prevalence of hepatitis C virus genotypes: molecular epidemiology and clinical 
implications in the hepatitis C virus hyperendemic areas and a tertiary referral 
center in Taiwan. J Med Virol 2001;65 (1):58-65.
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Yu ML, Huang CF, Huang JF, Chang NC, Yang JF, Lin ZY, et al. Role of 
interleukin-28B polymorphisms in the treatment of hepatitis C virus genotype 2 
infection in Asian patients. Hepatology 2011;53 (1):7-13.
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Liu CH, Liu CJ, Lin CL, Liang CC, Hsu SJ, Yang SS, et al. Pegylated interferon-
alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus 
genotype 1 infection: a multicenter, randomized controlled trial. Clin Infect Dis 
2008;47 (10):1260-9.
24385
Lee HJ, Eun JR, Choi JW, Kim KO, Moon HJ. [Comparison of therapeutic results 
between combination therapy of peginterferon alpha-2a plus ribavirin and 
interferon alpha-2b plus ribavirin according to treatment duration in patients with 
chronic hepatitis C]. The Korean journal of hepatology 2008;14 (1):46-57.
24387
Kim JI, Kim SH, Lee BS, Lee HY, Lee TH, Kang YW, et al. [Efficacy of initial 
treatment with peginterferon alpha-2a versus peginterferon alpha-2b in 
combination with ribavirin in naive chronic hepatitis C patients living in Daejeon 
and Chungcheong Province in Korea: a comparative study]. The Korean journal 
of hepatology 2008;14 (4):493-502.


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Gilead Sciences, Inc.
Amendment 2.0
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Jun DW, Tak WY, Bae SH, Lee YJ. Recent trends in the treatment of chronic 
hepatitis C. The Korean journal of hepatology 2012;18 (1):22-8.
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safety of pegylated interferon combined with ribavirin for the treatment of older 
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pegylated-interferon-alpha and ribavirin therapy in Chinese patients infected with
different hepatitis C virus genotype. Virology journal 2012;9:123.
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Gao X, Cui Q, Shi X, Su J, Peng Z, Chen X, et al. Prevalence and trend of 
hepatitis C virus infection among blood donors in Chinese mainland: a systematic 
review and meta-analysis. BMC Infect Dis 2011;11:88.
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Sun CA, Chen HC, Lu SN, Chen CJ, Lu CF, You SL, et al. Persistent 
hyperendemicity of hepatitis C virus infection in Taiwan: the important role of 
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Marcus EL, Tur-Kaspa R. Chronic hepatitis C virus infection in older adults. Clin 
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Cheong HR, Woo HY, Heo J, Yoon KT, Kim DU, Kim GH, et al. [Clinical 
efficacy and safety of the combination therapy of peginterferon alpha and 
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hepatology 2010;16 (1):38-48.
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Zheng YY, Fan XH, Wang LF, Tian D, Huo N, Lu HY, et al. Efficacy of 
pegylated interferon-alpha-2a plus ribavirin for patients aged at least 60 years 
with chronic hepatitis C. Chinese medical journal 2012;125 (11):1852-6.
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Yu ML, Dai CY, Lin ZY, Lee LP, Hou NJ, Hsieh MY, et al. A randomized trial 
of 24- vs. 48-week courses of PEG interferon alpha-2b plus ribavirin for 
genotype-1b-infected chronic hepatitis C patients: a pilot study in Taiwan. Liver 
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Guidelines for Hepatitis C Prevention and Treatment. Chin J Prev Med 2004;38 
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Protocol GS-US-337-0131
Final
Gilead Sciences, Inc.
Amendment 2.0
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Academiae Medicinae Sinicae 2010;32 (3):320-3.
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Zhou Y, Wang X, Mao Q, Fan Y, Zhu Y, Zhang X, et al. Changes in modes of 
hepatitis C infection acquisition and genotypes in southwest China. J Clin Virol 
2009;46 (3):230-3.
25095
Huang C, Qiu F, Guo M, Yi Y, Shen L, Wang F, et al. Prevalence and risk factors 
of hepatitis C among former blood donors in rural China. Int J Infect Dis 2012;16 
(10):e731-4.
25127
Weir MR. Renal effects of nonselective NSAIDs and coxibs. Cleve Clin J Med 
2002;69 Suppl 1:SI53-8.
25129
Yilmaz A, Price RW, Gisslen M. Antiretroviral drug treatment of CNS HIV-1 
infection. J Antimicrob Chemother 2012;67 (2):299-311.
26389
Jin YJ, Lee JW, Lee JI, Park SH, Park CK, Kim YS, et al. Multicenter comparison 
of PEG-IFN alpha2a or alpha2b plus ribavirin for treatment-naive HCV patient in
Korean population. BMC gastroenterology 2013;13:74.


Sofosbuvir/Ledipasvir FDC
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Gilead Sciences, Inc.
Amendment 2.0
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26390
Kim HI, Kim IH, Jeon BJ, Lee S, Kim SH, Kim SW, et al. Treatment Response 
and Tolerability of Pegylated Interferon-alpha Plus Ribavirin Combination 
Therapy in elderly Patients (>/= 65 years) With Chronic Hepatitis C in Korea. 
Hepat Mon 2012;12 (7):430-6.
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analysis]. The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi 
2012;60 (5):306-14.


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Protocol GS-US-337-0131
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Gilead Sciences, Inc.
Amendment 2.0
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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
Appendix 5.
Calculation of Historical Control SVR12 for Treatment-naïve Korean Subjects and 
for Treatment-naïve Chinese Subjects with Chronic GT-1 HCV Infection


Sofosbuvir/Ledipasvir FDC 
Protocol GS-lJS-337-0131 
Gilead Sciences, !nc. 
Appendix t. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER ClTY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment 2.0 
A Phase 3b, Multicenter, Open-Label Study to Investigate the Efficacy and Safety of 
Sofosbuvir/Ledipasvir Fixed-Dose Combination in Treatment-NaYve and Treatment-Experience-d 
Subjects with Chronic Genotype 1 HCV Infection 
GS-US-337-0131, Amendment 2.0, 01 August 2014 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Phil Pang, r 0, PhD (Printed 
Medical Monitor 
Date 
PPD 
-
lNVESTlGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree thaL it contains all necessary 
details for me and my staff to conduct this study as described. 1 will conduct this study as 
outlined herein and will make a reasonable etlort to complete the study within the time 
designated. 
I wi II 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 arc fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Pa~e 81 
01 August 2014 


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Amendment 2.0
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Appendix 2.
Study Procedures Table
Table 1.
Screening and On-Treatment Study Visits
Clinical Assessments
Screeninga
On Treatment Period
Day -28
to Day -1
Baseline/
Day 1b
Week 1
(3 days)
Week 2
(3 days)
Week 4
(3 days)
Week 6
(3 days)
Week 8
(3 days)
Week 10
(3 days)
Week 12
(3 days)
ET
Informed Consent
X
Determine Eligibility
X
X
Medical History
X
Physical Examination
X
X
X
X
Liver Imaging (Cirrhotics Only)
X
Height
X
Weight
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
12-lead ECGd
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention 
Counseling
X
X
X
Health Related Quality of Life
X
X
X
X
X
X
Hematology & Chemistry
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
Serum HCV RNA
X
X
X
X
X
X
X
X
X
X


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Gilead Sciences, Inc.
Amendment 2.0
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01 August 2014
Clinical Assessments
Screeninga
On Treatment Period
Day -28
to Day -1
Baseline/
Day 1b
Week 1
(3 days)
Week 2
(3 days)
Week 4
(3 days)
Week 6
(3 days)
Week 8
(3 days)
Week 10
(3 days)
Week 12
(3 days)
ET
Single PK Sample
X
X
X
X
X
X
X
X
Viral RNA Sequencing 
/Phenotyping Sample (Plasma)e
X
X
X
X
X
X
X
X
X
Archive Sample j
X
X
X
Serum or Urine Pregnancy Test
X
X
X
X
X
X
Urinalysis
X
IL28B Genotype, HCV 
Genotype
X
HCV Ab, HIV Ab and HBsAg
X
Hemoglobin A1c, TSH
X
PK Substudy Collectionf
X
X
Single Pharmacogenomic 
Sampleg
X
Review of Study Drug 
Adherence and Drug 
Accountabilityh
X
X
X
X
X
X
X
X
Study Drug Dispensingi
X
X
X
a
The screening window can be extended to 42 days for subjects requiring liver biopsy or additional HCV genotype testing. 
b
Baseline/Day 1 assessments must be performed prior to dosing.
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 gross abnormalities.
e
Serum samples will be collected and stored for potential HCV sequencing and other virology studies.


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Amendment 2.0
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f
Subjects that consent to the optional PK substudy will have serial PK samples drawn at Week 2 or Week 4 visit.  
g
Only for subjects who have provided consent for this sample and testing. This sample can be obtained at a subsequent visit if not obtained at Day 1.
h
Study medication and dosing diary, will be reconciled at every post-baseline visit by the investigator or designee in order to monitor the subject’s adherence with the 
medication regimen. 
i
Study Drug will be dispensed per IWRS directions.  Subjects must be instructed to bring back all bottles of study medication(s) in the original container at every post baseline 
study visits through the end of treatment. 
j
Archive plasma samples will be collected at the Baseline/Day 1 visit and at the end of treatment for subjects who have not opted out of sample collection


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Amendment 2.0
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Table 2.
Post Treatment Study Visits
Clinical Assessments
Post Treatment Perioda
Post Treatment Week 4
(5 days)
Post Treatment Week 12
(5 days)
Post Treatment Week 24
(5 days)
Weight
X
X
Vital Signsb
X
X
X
Adverse Events
X
Concomitant Medications
X
Pregnancy Prevention Counseling
X
Health Related Quality of Life
X
X
Hematology & Chemistry
X
Serum HCV RNA
X
X
X
Viral Sequencing Sample (Plasma)c
X
X
X
Serum or Urine Pregnancy Test
X
a
All subjects will complete both 4-week and 12-week Post-Treatment visits regardless of the treatment duration. Subjects with HCV RNA < LLOQ at their 12-week 
Post-Treatment visit will complete a 24-week Post-Treatment visit, unless viral relapse is determined. The end of study will occur at the 24-week Post-Treatment visit. 
b
Vital signs include resting blood pressure, pulse, respiratory rate and temperature.
c
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies. 


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Amendment 2.0
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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18June2012
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L


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Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
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01 August 2014
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
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
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L


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Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
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01 August 2014
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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
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% 


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Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
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01 August 2014
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 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


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Protocol GS-US-337-0131
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 90
01 August 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L


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01 August 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.14 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 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL


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Gilead Sciences, Inc.
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L
Bicarbonate
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
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
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
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


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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
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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Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 94
01 August 2014
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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01 August 2014
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


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Amendment 2.0
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


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Gilead Sciences, Inc.
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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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01 August 2014
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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01 August 2014
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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Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
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01 August 2014
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 


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


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


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


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


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


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


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


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Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Background
Non-clinical toxicity studies of sofosbuvir and ledipasvir demonstrated no adverse effect on 
embryo-fetal development. However, there are no clinical studies of sofosbuvir or ledipasvir in 
pregnant women. Please refer to the latest version of the investigator’s brochure for additional 
information.
2) Definition of Female of Childbearing Potential and Contraceptive Requirements for Female 
Subjects (and their male partners)
Women > 54 years of age with cessation for ≥ 12 months of previously occurring menses, or 
women of any age who have had a hysterectomy, or have had both ovaries removed, or have had 
medically documented ovarian failure will be considered to be of non-childbearing potential. 
Women ≤54 years of age (including those with amenorrhea of any duration) who have not had a 
hysterectomy, and have not had both ovaries removed, and have not had medically documented 
ovarian failure will be considered to be of childbearing potential. 
Women of childbearing potential must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on the Baseline/Day 1 visit prior to randomization. They must also 
agree to one of the following from 3 weeks prior to Baseline/Day 1 until 30 days after last dose 
of study drug.

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
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 last dose of study drug: 
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization
vasectomy in male partner
hormone-containing contraceptive:
implants of levonorgestrel


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injectable progesterone
oral contraceptives (either combined or progesterone only)
contraceptive vaginal ring 
transdermal contraceptive patch
3) Contraceptive Requirements for Male Subjects (and their female partners)
All male study participants must agree to consistently and correctly use a condom from the date 
of Screening until 90 days after the last dose of study drug. If their female partner is of child 
bearing potential (as defined above), their female partner must use 1 of the methods of birth 
control listed above from the date of Screening until 90 days after the last dose of study drug. 
Male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of 
study drug. 
4) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they (or their partner) become pregnant at 
any time during the study, or if they become pregnant within 30 days (90 days for partners of 
male subjects) of last study drug dose. Subjects who become pregnant or who suspect that they 
are pregnant must report the information to the investigator and discontinue study drug 
immediately. Subjects whose partner has become pregnant or suspects she is pregnant must 
report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.7.2.1.


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Appendix 5.
Calculation of Historical Control SVR12 for Treatment-naïve Korean 
Subjects and for Treatment-naïve Chinese Subjects with Chronic 
GT-1 HCV Infection
This section details the calculation for the historical control SVR12 rates for treatment-naïve
Korean subjects and for treatment-naïve Chinese subjects with chronic GT-1 HCV infection. 
The historical control calculation for Korea assumes that of the treatment-naïve subjects with 
HCV GT-1 infection to be enrolled in Korea, approximately 60% will have ‘Uncomplicated 
Infection’, ~30% will be ‘Elderly’, and ~10% will be ‘Cirrhotic’. Based on discussions with 
clinical investigators in these countries, these assumptions ensure a conservative estimation of 
the historical SVR rate following Peg-IFNα+RBV in the respective populations. The references 
used for the calculation of the historical control rates are provided in Appendix Table 2 below.
For Korea, the SVR rates among each of the three patient populations are calculated according to 
the reference studies (Appendix Table 2). The overall historical SVR rate is subsequently 
calculated as the weighted average of the population-specific rates, with the weight being the 
expected percentages of patients in each population. With these assumptions in mind and using 
the referenced literature, the adjusted historical SVR control rate for the populations in Korea are 
calculated as follows:
Appendix Table 1.
SVR rates following Peg-IFNα+RBV in Treatment-Naïve Korean 
Subjects with GT-1 HCV Infection
Country 
Uncomplicated 
Infection
Elderly
Cirrhotic
Weighted Average
Korea
62.7%
30.8%
24%
62.7% * 0.6 + 30.8% * 0.3 + 24% *0.1= 49%
Therefore, a null adjusted historical SVR rate for this study is 49% following estimation of the 
SVR rate for Korea. 
For China, the historical control rate has been calculated according to the reference studies in 
Appendix Table 3. SVR rates are not reported separately for elderly patients or those with 
cirrhosis in these references. Consequently, the calculated historical SVR rate of 57% has not 
been adjusted by different population.


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Appendix Table 2.
Literature References for Historical Control Rate Calculations in 
Korea
SVR Rates in Korea
Population
SVR%
SVR n/N
Reference
GT-1 Treatment Naïve (Peg-IFN/RBV 48 Weeks)
80.8
21/26
{24236}
54.7
58/106
{24236}
62.7
341/543
{26807}
62.2
158/254
{26389}
64.2
104/162
{26389}
66.0
31/47
{26390}
Overall SVR Rate
62.7%
SVR Rates in Korea Elderly
Population
SVR%
SVR n/N
Reference
GT-1 Treatment Naïve (Peg-IFN/RBV 48 weeks)
30.8
4/13
{26390}
Overall SVR Rate
30.8%
SVR Rates in Korea Cirrhotics
Population
SVR%
SVR n/N
Reference
GT-1 Treatment Naïve (Peg-IFN/RBV 48 weeks)
24.0
12/50
{24405}
Overall SVR Rate
24.0%
Appendix Table 3.
Literature References for Historical Control Rate Calculations in 
China
SVR Rates in China
Population
SVR
%
SVR n/N
Reference
GT-1 Treatment Naïve (Peg-IFN/RBV 48 weeks)
70.3
102/145
{24797}
43.9
18/41
{13261}
46.0
58/126
{24391}
Overall SVR Rate
(102+18+58) / (145+41+126) = 57%

Prot_000.pdf: 


Sofosbuvir/Ledipasvir FDC 
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Gilead Sciences, Inc. 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ....................................................................................................................................... 2 
LIST OF IN-TEXT TABLES ................................................................................................................................. 5 
LIST OF IN-TEXT FIGURES ............................................................................................................................... 6 
PROTOCOL SYNOPSIS ....................................................................................................................................... 7 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................ 13 
1. 
INTRODUCTION ....................................................................................................................................... 17 
1.1. 
Background ..................................................................................................................................... 17 
1.1.1. 
HCV Infection ............................................................................................................... 17 
1.1.2. 
HCV Infection in Korea ................................................................................................ 17 
1.1.3. 
HCV Infection in Taiwan .............................................................................................. 19 
1.2. 
Sofosbuvir (formerly GS-7977) and Ledipasvir (formerly, GS-5885) Fixed Dose 
Combination .................................................................................................................................... 20 
1.2.1. 
General Information ...................................................................................................... 20 
1.2.2. 
Summary of Additional Clinical Experience with Sofosbuvir ...................................... 20 
1.2.3. 
Summary of Additional Clinical Experience with Sofosbuvir and 
Ledipasvir ...................................................................................................................... 28 
1.2.4. 
Summary of Additional Clinical Experience with LDV ............................................... 40 
1.3. 
Rationale for This Study ................................................................................................................. 52 
1.4. 
Rationale for Dose Selection of SOF .............................................................................................. 53 
1.5. 
Rationale for Dose Selection of LDV ............................................................................................. 55 
1.6. 
Overall Risk/Benefit Assessment .................................................................................................... 56 
1.7. 
Compliance ..................................................................................................................................... 56 
2. 
OBJECTIVES .............................................................................................................................................. 57 
3. 
STUDY DESIGN ........................................................................................................................................ 58 
3.1. 
Endpoints ........................................................................................................................................ 58 
3.2. 
Study Design ................................................................................................................................... 58 
3.3. 
Study Treatment .............................................................................................................................. 58 
3.4. 
Duration of Treatment ..................................................................................................................... 58 
3.5. 
Discontinuation Criteria .................................................................................................................. 59 
3.6. 
Source Data ..................................................................................................................................... 60 
4. 
SUBJECT POPULATION ........................................................................................................................... 61 
4.1. 
Number of Subjects and Subject Selection ..................................................................................... 61 
4.2. 
Inclusion Criteria ............................................................................................................................ 61 
4.3. 
Exclusion Criteria ........................................................................................................................... 64 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS .................................................................................... 66 
5.1. 
Randomization and Treatment Codes ............................................................................................. 66 
5.2. 
Description and Handling of Sofosbuvir/Ledipasvir Fixed-Dose Combination ............................. 66 
5.2.1. 
Formulation ................................................................................................................... 66 
5.2.2. 
Packaging and Labeling ................................................................................................ 66 
5.2.3. 
Storage and Handling .................................................................................................... 66 
5.3. 
Dosage and Administration of Sofosbuvir/Ledipasvir FDC ........................................................... 67 
5.4. 
Prior and Concomitant Medications ................................................................................................ 67 
5.5. 
Accountability for SOF/LDV FDC ................................................................................................. 68 
5.5.1. 
Investigational Medicinal Product Return or Disposal .................................................. 69 


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6. 
STUDY PROCEDURES ............................................................................................................................. 70 
6.1. 
Subject Enrollment and Treatment Assignment .............................................................................. 70 
6.2. 
Pretreatment Assessments ............................................................................................................... 70 
6.2.1. 
Screening Visit (Day -28 to Day -1) ............................................................................. 70 
6.3. 
Randomization ................................................................................................................................ 72 
6.4. 
Treatment Assessments ................................................................................................................... 72 
6.4.1. 
Baseline/Day 1 Visit ..................................................................................................... 72 
6.4.2. 
Week 1 (± 3 days) ......................................................................................................... 73 
6.4.3. 
Week 2 (± 3 days) ......................................................................................................... 73 
6.4.4. 
Week 4 (± 3 days) ......................................................................................................... 74 
6.4.5. 
Week 6 (± 3 days) ......................................................................................................... 74 
6.4.6. 
Week 8 (± 3 days) ......................................................................................................... 75 
6.4.7. 
Week 10 (± 3 days) ....................................................................................................... 75 
6.4.8. 
Week 12 (± 3 days) ....................................................................................................... 76 
6.4.9. 
Early Termination (ET)/Unscheduled Visit .................................................................. 77 
6.5. 
Post-Treatment Assessments ........................................................................................................... 78 
6.5.1. 
Post Treatment Week 4 (± 5 days) ................................................................................ 78 
6.5.2. 
Post Treatment Weeks 12 and 24 (± 5 days) ................................................................. 78 
6.6. 
Procedures and Specifications ......................................................................................................... 79 
6.6.1. 
Clinical Laboratory Analytes ........................................................................................ 79 
6.6.2. 
Medical History ............................................................................................................. 80 
6.6.3. 
Complete Physical Examination ................................................................................... 80 
6.6.4. 
Vital Signs ..................................................................................................................... 80 
6.6.5. 
Creatinine Clearance ..................................................................................................... 81 
6.6.6. 
12-Lead ECGs ............................................................................................................... 81 
6.6.7. 
Viral RNA Sequencing / Phenotyping Sample ............................................................. 81 
6.6.8. 
Archive Sample ............................................................................................................. 81 
6.6.9. 
Single Pharmacokinetic (PK) Sample ........................................................................... 82 
6.6.10. 
Intensive Pharmacokinetic (PK) Substudy .................................................................... 82 
6.6.11. 
Pharmacogenomic (PG) Substudy ................................................................................. 82 
6.6.12. 
Pregnancy Testing ......................................................................................................... 83 
6.6.13. 
Health Related Quality of Life Survey .......................................................................... 83 
6.7. 
Assessments for Premature Discontinuation from Study ................................................................ 83 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ........................................................................ 84 
7.1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events .......................... 84 
7.1.1. 
Adverse Events ............................................................................................................. 84 
7.1.2. 
Serious Adverse Events ................................................................................................. 84 
7.2. 
Assessment of Adverse Events and Serious Adverse Events .......................................................... 85 
7.2.1. 
Assessment of Causality for Study Drugs and Procedures ............................................ 85 
7.3. 
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .................................................................................................. 86 
7.4. 
Gilead Reporting Requirements ...................................................................................................... 88 
7.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events 
or Serious Adverse Events .............................................................................................................. 88 
7.6. 
Subject Stopping Rules ................................................................................................................... 88 
7.7. 
Special Situations Reports .............................................................................................................. 89 
7.7.1. 
Definitions of Special Situations ................................................................................... 89 
7.7.2. 
Instructions for Reporting Special Situations ................................................................ 90 
8. 
STATISTICAL CONSIDERATIONS ......................................................................................................... 92 
8.1. 
Analysis Objectives and Endpoints ................................................................................................. 92 
8.1.1. 
Analysis Objectives ....................................................................................................... 92 


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8.1.2. 
Primary Endpoint .......................................................................................................... 92 
8.1.3. 
Secondary Endpoint ...................................................................................................... 93 
8.1.4. 
Other Endpoints of Interest ........................................................................................... 93 
8.2. 
Analysis Conventions ..................................................................................................................... 93 
8.2.1. 
Analysis Sets ................................................................................................................. 93 
8.3. 
Data Handling Conventions ............................................................................................................ 93 
8.3.1. 
Interim Analysis ............................................................................................................ 95 
8.4. 
Demographic Data and Baseline Characteristics ............................................................................ 95 
8.5. 
Efficacy Analysis ............................................................................................................................ 95 
8.5.1. 
Primary Analysis ........................................................................................................... 95 
8.5.2. 
Secondary Analysis ....................................................................................................... 95 
8.6. 
Safety Analysis ............................................................................................................................... 96 
8.6.1. 
Extent of Exposure ........................................................................................................ 96 
8.6.2. 
Adverse Events ............................................................................................................. 96 
8.6.3. 
Laboratory Evaluations ................................................................................................. 97 
8.7. 
Pharmacokinetic Analysis ............................................................................................................... 97 
8.8. 
Sample Size ..................................................................................................................................... 97 
9. 
RESPONSIBILITIES .................................................................................................................................. 98 
9.1. 
Investigator Responsibilities ........................................................................................................... 98 
9.1.1. 
Good Clinical Practice .................................................................................................. 98 
9.1.2. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Review and Approval .......................................................................................... 98 
9.1.3. 
Informed Consent .......................................................................................................... 99 
9.1.4. 
Confidentiality .............................................................................................................. 99 
9.1.5. 
Study Files and Retention of Records ........................................................................... 99 
9.1.6. 
Case Report Forms ...................................................................................................... 101 
9.1.7. 
Investigational Medicinal Product Accountability and Return ................................... 101 
9.1.8. 
Inspections .................................................................................................................. 102 
9.1.9. 
Compliance ................................................................................................................. 102 
9.2. 
Sponsor Responsibilities ............................................................................................................... 102 
9.2.1. 
Protocol Modifications ................................................................................................ 102 
9.2.2. 
Study Report and Publications .................................................................................... 102 
9.3. 
Joint Investigator/Sponsor Responsibilities .................................................................................. 103 
9.3.1. 
Access to Information for Monitoring ......................................................................... 103 
9.3.2. 
Access to Information for Auditing or Inspections ..................................................... 103 
9.3.3. 
Study Discontinuation ................................................................................................. 103 
10 
REFERENCES .......................................................................................................................................... 104 
11. APPENDICES ........................................................................................................................................... 109 
 
Appendix 1. 
Investigator Signature Page ......................................................................................... 110 
Appendix 2. 
Study Procedures Table ............................................................................................... 111 
Appendix 3. 
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities ........................................................................................... 115 
Appendix 4. 
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements ................................................................ 139 
 
 


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LIST OF IN-TEXT TABLES 
Table 1-1 
The Proportions of Subjects Achieving Viral Load Below the 
Lower Limit of Quantification (HCV RNA <25 IU/mL) in Study 
AI444-040 ..................................................................................................................... 22 
Table 1-2. 
Study AI444-040 HCV RNA <25 IU/mL during and 
post-treatment. ............................................................................................................... 22 
Table 1-3. 
NIAID Study 11-1-0258: Percentage of Subjects with HCV 
RNA Achieving SVR .................................................................................................... 23 
Table 1-4. 
GS-US-334-0108: Number (Percentage) of Subjects with 
SVR12 by Genotype (Full Analysis Set) ...................................................................... 27 
Table 1-5. 
Pooled Phase 3 Studies: Subjects with Post-Baseline 
Hemoglobin < 10 g/dL and < 8.5 g/dL (Safety Analysis Set) ....................................... 28 
Table 1-6. 
GS-US-334-0111 Geometric Least-Squares Mean Ratios (90% 
Confidence Intervals) for Sofosbuvir, GS-566500, GS-331007, 
and Ledipasvir Primary PK Parameters in Japanese versus 
Caucasian Subjects ........................................................................................................ 30 
Table 1-7. 
Study P7977-0523 (ELECTRON): SOF, GS-566500, 
GS-331007 and LDV PK Parameters Following Administration 
of SOF 400 mg + LDV 90 mg + RBV or SOF 400 mg/LDV 90 
mg FDC ± RBV (Preliminary Data) .............................................................................. 32 
Table 1-8. 
Study P7977-0523 (ELECTRON): Arm 12 and Arm 13: SVR 
Data ............................................................................................................................... 33 
Table 1-9. 
Study P7977-0523 (ELECTRON): Arm 21 (FDC+RBV): 
Available SVR Data ...................................................................................................... 33 
Table 1-10. 
Study P7977-0523 (ELECTRON): Subjects with Baseline 
Ledipasvir RAVs in NS5A in Arms 12 and 13 ............................................................. 34 
Table 1-11. 
Study GS-US-337-0118 (LONESTAR): SOF, GS-566500, 
GS-331007 and LDV PK Parameters Following Administration 
of SOF/LDV (400 mg/90 mg) ± RBV (Preliminary Data) ............................................ 36 
Table 1-12. 
Study GS-US-337-0118 (LONESTAR): Groups 1, 2, 3, 4 and 5 
SVR Data ...................................................................................................................... 37 
Table 1-13. 
Study GS-US-337-0118 (LONESTAR): Subjects with Baseline 
Ledipasvir RAVs ........................................................................................................... 39 
Table 1-14. 
GS-US-248-0117: LDV Steady-State Pharmacokinetic 
Parameters and Statistical Comparisons in Subjects with 
Moderate Hepatic Impairment and Matched Controls with 
Normal Hepatic Function Following Administration of 
LDV+GS-9451±TGV ................................................................................................... 41 
Table 1-15. 
Study GS-US-334-0101: Pharmacokinetic Data for SOF, 
Metabolites (GS-566500 and GS-331007) and LDV on 
Administration of Sofosbuvir (SOF) and LDV Alone or in 
Combination .................................................................................................................. 46 
Table 1-16. 
Study GS-US-337-0101: Preliminary Pharmacokinetic Data for 
SOF, Metabolites (GS-566500 and GS-331007) and LDV on 
Administration of SOF/LDV FDC and SOF+LDV as Individual 
Components .................................................................................................................. 48 
Table 1-17. 
Study GS-US-337-0101: Preliminary Pharmacokinetic Data for 
SOF, Metabolites (GS-566500 and GS-331007) and LDV on 
Administration of SOF/LDV FDC Fasted or with a Moderate-
Fat Meal or with A High-Calorie/High Fat Meal .......................................................... 49 
Table 1-18. 
Treatment-Emergent Adverse Events Experienced by 10% of 
Subjects in Any Interferon-Free Regimen ..................................................................... 52 


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Table 5-1. 
Disallowed and Concomitant Medications to be Used with 
Caution .......................................................................................................................... 68 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1-1. 
Day 3 Change from Baseline HCV RNA vs GS-331007 AUCtau 
during SOF or GS-9851 Monotherapy .......................................................................... 54 
 


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PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
 
 
Study Title:  
A Phase 3b, Multicenter, Open-Label Study to Investigate the 
Efficacy and Safety of Sofosbuvir/Ledipasvir Fixed-Dose 
Combination in Treatment-Naïve and Treatment-Experienced 
Korean and Taiwanese Subjects with Chronic Genotype 1 HCV 
Infection 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Not applicable 
Not applicable 
To be determined 
Study Centers 
Planned: 
Approximately 14 sites in Korea  
Approximately 10 sites in Taiwan 
Objectives: 
The primary objectives of this study are: 
• 
To determine the antiviral efficacy of treatment with 
sofosbuvir (SOF)/ledipasvir (LDV) fixed-dose combination 
(FDC) as measured by the proportion of subjects with 
sustained virologic response (SVR) 12 weeks after 
discontinuation of therapy (SVR12, defined as HCV RNA 
< lower limit of quantification [LLOQ] 12 weeks post 
treatment) 
• 
To evaluate the safety and tolerability of SOF/LDV FDC as 
assessed 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 discontinuation of therapy (SVR4 and 
SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during 
treatment and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV 
during treatment and after treatment discontinuation 




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Diagnosis and 
Main Eligibility 
Criteria: 
Chronic genotype 1, HCV infected, male and non-
pregnant/non-lactating female subjects, ages 20 years and older, 
treatment-naïve or treatment-experienced, of whom approximately 
20% may have compensated cirrhosis, may be eligible for the study. 
Reference Section 4.2 and 4.3 for detailed Inclusion and Exclusion 
criteria. 
Study Procedures/ 
Frequency: 
Screening assessments will be completed within 28 days of the 
Baseline/Day 1 visit. The screening window can be extended to 
42 days for subjects requiring liver biopsy or additional HCV 
genotyping. 
Study visits will occur at Screening, Baseline/Day 1, and on-
treatment at the end of Weeks 1, 2, 4, 6, 8, 10, and 12. Following the 
last dose of study medication, all subjects will complete 4-Week and 
12-Week Post-Treatment Visits. Subjects with HCV RNA < LLOQ 
at the 12-Week Post-Treatment Visit will also complete a 24-Week 
Post-Treatment Visit unless confirmed viral relapse occurs. 
Administration of interferon or any HCV-directed treatment, other 
than the study drug, is prohibited from 12 weeks prior to Screening 
until completion of the final post-treatment follow-up visit. 
Screening assessments include physical examination, height, weight, 
vital signs, 12-lead electrocardiogram (ECG), medical history, 
adverse events (AEs), concomitant medications, safety laboratory 
tests (hematology, chemistry, coagulation, urinalysis), HCV RNA, 
serology (HIV, HCV, HBV), hemoglobin A1c (HbA1c), assessment 
of the presence or absence of cirrhosis, liver imaging for HCC 
(cirrhotics only), serum ȕ-hCG (females of child bearing potential 
only), thyroid stimulating hormone (TSH), HCV genotyping, IL28B 
genotyping. 
On-treatment assessments include adverse events (AEs), 
concomitant medications, review of study drug adherence, physical 
examinations, vital signs, safety laboratory tests, HCV RNA, 
pharmacokinetic samples, and urine pregnancy tests (females of 
child bearing potential only). 
Single 12-lead ECGs will be collected at Screening, Baseline/Day 1 
(prior to study drug administration) and on-treatment visits at the 
end of Weeks 1 and Week 12.  
Weight will be measured at Screening, Baseline/Day 1, on-treatment 
visit at the end of Week 12, and post-treatment Weeks 12 and 24 
visits (as applicable). 






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change from baseline. 
All continuous endpoints (except safety endpoints) will be 
summarized using an 8-number summary (n, mean, standard 
deviation, median, Q1, Q3, minimum, maximum) by 
treatment-naïve and treatment-experienced subjects for each region 
and overall. All categorical endpoints will be summarized by 
number and percentage of subjects who meet the endpoint 
definition.  
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnormalities for categorical values or 
8-number summary (n, mean, standard deviation, median, Q1, Q3, 
minimum, maximum) for continuous data. 
 
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents. 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
° C  
degrees Celsius 
° F 
degrees Fahrenheit 
ȕ-hCG 
ȕ-human chorionic gonadotropin 
AE 
adverse event 
ALT 
alanine aminotransferase (also SGPT) 
ANC 
absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase  (also SGOT) 
AUC 
area under the curve 
AUCtau 
area under the plasma concentration versus time curve over the dosing 
interval (tau) 
BID 
twice a day  
BLQ 
below the lower limit of quantification 
BMI 
body mass index 
BT 
breakthrough 
BW 
body weight 
CFR 
Code of Federal Regulations 
CLcr 
creatinine clearance 
Cmax 
the maximum observed serum/plasma/peripheral blood mononuclear 
(PBMC) concentration of drug 
Ctau 
Observed drug concentration at the end of the dosing interval (tau) 
CRF 
case report form(s) 
CRO 
Contract (or clinical) research organization  
DAA 
Direct acting antiviral 
DCV 
Daclatasvir 
dL 
Deciliter 
DNA 
deoxyribonucleic acid 
DSPH 
Drug Safety and Public Health 
ECG 
Electrocardiogram 
ECIRB/IEC 
Ethics Committee Institutional Review Board/ Independent Ethics 
Committee 
eCRF 
Electronic case report form(s) 
Emax 
Maximal effect 
ESA 
Erythropoiesis stimulating agent 
eSAE 
electronic Serious Adverse Event (system) 
ESLD 
End Stage Liver Disease 
ET 
early termination 
EU 
European Union 
FAS 
full analysis set 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
FDA 
(United States) Food and Drug Administration 
FDC 
Fixed Dose Combination 
FEV1 
forced expiratory volume in one second 
GCP 
Good Clinical Practice (Guidelines) 
GCSF 
Granulocyte colony stimulating factor 
GGT 
gamma glutamyl transferase 
GMRs 
geometric-least squares means ratios 
GSI 
Gilead Sciences, Inc. 
GT 
Genotype (viral) 
Hb 
Hemoglobin 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C virus 
HCV Ab 
Hepatitis C virus antibody 
HDPE 
high-density polyethylene 
HIV 
Human Immunodeficiency Virus 
HLGT 
High-Level Group Term 
HLT 
High-Level Term 
HRQoL 
Health Related Quality of Life (Survey) 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IL28B 
IL28B gene 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IU 
International Units 
IUD 
Intrauterine Device 
IV 
Intravenous 
IVDA 
Intravenous drug abuse 
IWRS 
Interactive Web Response System 
kg 
Kilogram 
L 
Liter 
LDV 
Ledipasvir 
LLN 
lower limit of the normal range 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
LLOQ 
Lower limit of quantification 
LLT 
Lower-Level Term  
LTFU 
Lost to follow up 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
mL 
Milliliter 
mmHg 
millimeters mercury 
NS (3/4A/5A/5B) 
Non-structural Protein 
PBMC 
peripheral blood mononuclear cell(s) 
Peg-IFNĮ 
pegylated interferon 
PG 
Pharmacogenomic 
P-gp 
P-glycoprotein 
PI 
Protease inhibitor 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QA 
Quality Assurance 
QD 
once daily (use only in tables) 
QTcF 
QT interval corrected using Fridericia’ formula 
RBC 
Red blood cell count  
RBV 
Ribavirin 
RNA 
ribonucleic acid 
RVR 
rapid virologic response  
SAE 
serious adverse event 
SD 
Standard deviation 
SF-36 
Short-Form-36 
SOC 
Standard of Care or System Organ Class 
SOF 
Sofosbuvir 
SOP 
Standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SVR 
Sustained Virologic Response 
TE 
Treatment-Experienced 
TN 
Treatment-Naïve 
TGV 
Tegobuvir 
TND 
Target not detected 
TPO 
thrombopoietin 
TSH 
Thyroid stimulating hormone 
t½ 
An estimate of the terinal elimination half-life of the drug in 
serum/plasma/PBMC, calculated by dividing the natural log of 2 by the 
terminal elimination rate contstant (Ȝz) 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
ULN 
upper limit of the normal range 
US 
United States 
WBC 
white blood cell count 


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1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. 
HCV Infection 
Infection with the hepatitis C virus (HCV) is a serious, progressive, and often life-threatening 
disease affecting approximately 180 million adults worldwide {21360}. The infection, if 
untreated, can result in progressive liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC) 
and end stage liver disease (ESLD). Transmission of HCV infection is parenteral with the 
majority of infections occurring through administration of contaminated blood products, 
unsafe medical procedures, intravenous drug use or sexual transmission {8076}. The hepatitis 
C virus is classified into six major genotypes (GT), i.e., 1-6, with further division to a 
subtype level (e.g., a, b, c) {21479}. Virologic response rates to currently available therapies 
vary according to host IL28B genotype, baseline levels of HCV RNA and HCV genotype. 
The distribution of HCV genotypes and subtypes varies according to geographic region with 
the most common HCV genotypes in the United States and Europe being GT-1, GT-2 and 
GT-3. In Korea and Taiwan it is estimated that approximately 50% of infections are 
associated GT-1b and 50% with GT-2a {24218}, {24242}, {24215}. Genotypes 4, 5 and 6 are 
most prevalent in the Middle East, South Africa and Southeast Asia respectively {22110}. 
Following acute infection approximately 15-20% of patients are able to clear the virus 
without intervention, however around 80% of patients go on to establish chronic hepatitis C 
{8076}. Treatment of chronic infection is currently based upon weekly subcutaneous 
administration of pegylated interferon (Peg-IFNĮ) with orally administered ribavirin (RBV) 
for 24 to 48 weeks dependent upon genotype and virologic response. This treatment regimen 
affords sustained virologic response rates (SVR) on the order of 42-46% in treatment-naïve 
patients with GT-1 and 76-82% in patients with GT-2/3 infection {23342}, {23351}. Recently, 
first generation protease inhibitors (PI) (i.e., telaprevir (TVR) and boceprevir (BCV)) have 
been approved in certain countries for use in patients with GT-1 infection when combined 
with Peg-IFNĮ+RBV. The Peg-IFNĮ+RBV+PI regimens have incrementally improved SVR 
rates in GT-1 treatment-naïve patients to approximately 70% however they are not approved 
for use in GT-2 infection and are associated with significant safety and tolerability concerns 
{17996}, {17492}. Peg-IFNĮ+RBV+PI regimens are not currently available in Korea or 
Taiwan and consequently patients with GT-1 infection failing to respond to Peg-IFNĮ +RBV 
have no current treatment options with spontaneous clearance of HCV negligible in these 
patients. 
1.1.2. 
HCV Infection in Korea 
In Korea, chronic HCV infection is one of the leading causes of chronic liver disease and 
hepatocellular carcinoma (HCC) {24211}. The age-standardized prevalence of HCV antibody 
(HCV Ab) in patients greater than 40 years of age is reported to be on the order of 1.3% 
which equates to around 193,000 people {24215}. The prevalence of HCV infection increases 


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with age and peaks in those individuals aged 60 years and older {24211}. The majority of 
infections occurred via contaminated blood transfusions prior to the introduction of 
blood-donor HCV Ab screening in 1991 {24216}. Consequently the majority of patients with 
chronic hepatitis C in Korea are elderly {24215} and are more likely to have progressive liver 
disease. HCV infection is more closely associated with HCC in the elderly Korean patients 
than are HBV infection and alcoholism {24210}, {24208}. Since the decline of transfusion-
related hepatitis C the majority of new infections are behavior-related. Of particular note is 
the practice of acupuncture for chronic illnesses including joint disease, pain, sequelae of 
trauma and other conditions non-responsive to conventional therapies. Shin et al reported 
results of a case study in which 34.1% of men and 62.9% of women in rural Korea reported 
multiple acupuncture procedures with the associated risk fraction for HCV infection being 
38% for men and 55% for women {24214}. Intravenous drug abuse (IVDA) is not thought to 
be a major contributor to the overall prevalence of HCV infection in Korea however this 
route of infection may contribute in young adults and those living in harbor cities on the 
southern and western coasts {24209}, {24211}. The predominant HCV genotypes in Korea 
are GT-1b and GT-2a which are roughly present in equal proportions and combined account 
for around 80-90% of infections {24216}, {24215}, {24209}. Host IL28B genotype has been 
widely reported as a predictor of virologic response to interferon (IFN)-based therapies for 
chronic HCV infection {22075}. The IL28B-CC genotype which confers a favorable 
virologic outcome to IFN-based therapy predominates in Korea with approximately 80-90% 
of patients with this genotype {24212}, {24238}. Consequently the sustained virologic 
response rates in Korean clinical trials evaluating Peg-IFNĮ+RBV in treatment-naïve GT-1 
infection are on the order of 55-70% following 48 weeks of therapy {24211}, {24595},  
{24387}, {24385}, {24237}, {24404}, {24388} . Although relatively high rates of virologic 
response are achievable with Peg-IFNĮ+RBV in treatment-naïve Korean patients due to the 
high proportion of IL28B CC genotype, Heo et al {24236} recently reported a significant 
difference in SVR rate observed in a clinical trial cohort versus that observed in clinical 
practice based upon ‘Intention To Treat’ (ITT) analysis; 81% (21/26) versus 55% (58/106). 
Although no difference was observed in the SVR rates between the clinical trial cohort and 
the clinical practice cohort according to per protocol analysis, the ITT is important since it 
more likely reflects the observed SVR in clinical practice across the country. The authors 
attribute the lower ITT SVR rate in the clinical practice cohort to decreased adherence to 
assigned therapy including dose reduction for clinical and laboratory adverse events. As 
previously described, the highest prevalence rates for HCV Ab in Korean patients are in 
those individuals aged 60 years and older. These elderly patients are more likely to be 
treatment-experienced and have progressive liver disease. Comorbid conditions 
(e.g., diabetes and cardiovascular disease) are common in this population and pose 
significant challenges to the use of Peg-IFNĮ+RBV therapy. As this group of patients 
continues to age the proportion of patients with chronic hepatitis C who will develop 
complications, including liver cirrhosis, HCC and ESLD is significant; {22077}. In addition, 
it is important to consider the proportion of patients who are ineligible for, intolerant of, or 
unwilling to receive Peg-IFNĮ+RBV who have no currently available antiviral treatment 
options {21256}. This also applies to patients who have previously failed to respond to 
Peg-IFNĮ+RBV therapy. Although Peg-IFNĮ+RBV can achieve high rates of SVR in 
treatment-naïve patients with chronic HCV infection when assigned therapy is tolerated, 


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there is an unmet medical need for effective, safe, well-tolerated, all oral therapies that can be 
used in an aging patient population in Korea. 
1.1.3. 
HCV Infection in Taiwan 
Taiwan has one of the highest prevalence rates of chronic hepatitis C in North-East Asia. In a 
nationwide survey conducted between 1996 and 2005 involving over 164,000 participants in 
out-reach community-based hepatitis screening programs the HCV seroprevalence was 
estimated to be 4.4% {24235}. The study reported an approximately equal seroprevalence in 
males (4.5%) and females (4.3%). Importantly seroprevalence varied geographically with 
certain areas of hyperendemicity such as Miaoli and Chiayi Counties where the age-adjusted 
seroprevalence was reported to be 7.6% and 6.1% respectively. The proportion of subjects 
with HCV antibodies progressively increased after the age of 20 years. The predominant 
routes of transmission are thought to be iatrogenic in nature including history of blood 
transfusion, medical injections and acupuncture {24239}, {24396}. Historically, glucose 
supplements, vitamins, and treatments for minor medical conditions have often been 
administered by injection. Prior to 1980 reusable syringes were commonly used particularly 
in rural areas with poor sterilization techniques likely contributing to the spread of HCV 
infection. After 1980, the rate of HCV infection was likely reduced following the 
introduction of disposable syringes. This may in part explain the higher prevalence of HCV 
infection in the elderly population in Taiwan. It has also been postulated that inhabitants of 
communities with high rates of HCV infection may have been repeatedly exposed to a 
common reservoir of infection contributing to the establishment of hyperendemic areas 
{24239}. 
As previously described for Korea, the predominant HCV genotypes in Taiwan are GT-1b 
and GT-2a which are present in similar proportions and account for around 80-90% of all 
infections {24596}, {24218}, {24242}. The IL28B-CC host genotype conferring favorable 
virologic outcome to IFN-based therapy predominates with approximately 80-90% of 
patients with this genotype {22075}, {24241}. As a consequence the SVR rates in Taiwanese 
clinical trials evaluating Peg-IFNĮ+RBV in GT-1 infection are approximately 49-56% and 
76-80% in treatment-naïve patients receiving 24 weeks and 48 weeks of treatment 
respectively {24410}, {24382}. However, as previously described in Taiwan the 
seroprevalence of HCV antibodies increases with age with the highest rates observed in those 
60 years and older {24235}. The use of currently available therapy is problematic in the 
elderly due to contraindications to IFN and RBV and comorbidities such as cardiovascular 
disease and diabetes. In Taiwan for treatment-naïve patients with GT-1 infection aged 65 
years the SVR rate for Peg-IFNĮ+RBV administered for 48 weeks has been reported to be 
51.9% {24390}. The elderly patient population is more likely to have progressive liver 
disease and be at higher risk for the development of HCC and ESLD. For GT-1 infection the 
SVR rates for Taiwanese age-matched patients with HCC (post-curative management) and 
cirrhosis are reported to be 33% and 55% respectively {24240}. The safety, tolerability and 
efficacy of IFN+RBV therapy is suboptimal in this population. Finally, there are no currently 
available treatment options for those patients who are ineligible for, intolerant of, or who 
have previously failed to respond to IFN+RBV therapy. 


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There is a need for early intervention and eradication of HCV infection to reduce the burden 
of progressive liver disease including of HCC and ESLD. While early introduction of 
effective antiviral therapy is critical in order to reduce the potential future burden of 
advanced liver disease, safe and effective antiviral therapies that can be used in elderly 
patients with advanced disease is of paramount importance today. Gilead Sciences is 
developing the all-oral, interferon- and ribavirin-free SOF/LDV FDC regimen to address this 
need in Korean and Taiwanese patients with chronic genotype-1 HCV infection. 
1.2. 
Sofosbuvir (formerly GS-7977) and Ledipasvir (formerly, GS-5885) Fixed 
Dose Combination 
Sofosbuvir/ Ledipasvir Fixed Dose Combination (FDC) combines two HCV specific DAA 
agents into a single tablet for the treatment of chronic HCV infection. More than 1200 
subjects have received treatment with this combination tablet to date. 
Sofosbuvir (SOF), formerly GS-7977, is a nucleotide analog that is a potent and selective 
inhibitor of NS5B-directed HCV replication. Over 2,000 subjects have received SOF 
containing regimens to date, from single doses up to repeat dosing for 24 weeks. 
Ledipasvir (LDV), formerly GS-5885, is a novel HCV NS5A inhibitor that has demonstrated 
potent anti-HCV activity against genotype (1a and 1b) HCV infection. More than 1000 HCV 
infected subjects have been dosed with LDV in ongoing Phase 2 clinical studies, and over 
700 subjects have been dosed with LDV for over 12 weeks. 
1.2.1. 
General Information 
For further information on SOF/LDV FDC, refer to the Investigator’s Brochure (IB) for 
Sofosbuvir/GS-5885 Fixed Dose Combination including: 
• In Vitro Anti-HCV Activity 
• Nonclinical Pharmacokinetics and In Vitro Metabolism 
• Nonclinical Pharmacology and Toxicology 
• Clinical Experience 
1.2.2. 
Summary of Additional Clinical Experience with Sofosbuvir 
1.2.2.1. 
Clinical Pharmacology Studies with Sofosbuvir 
A number of Phase 1 studies have been conducted with SOF and are summarized in the 
investigator brochure including: a relative bioavailability study (P7977-0111) to compare 
human exposure after administration of PSI-7851 (diastereomeric mixture of SOF and GS-
491241; Investigator Brochure) to SOF, a human mass balance study (P7977-0312) to 
evaluate routes of elimination for SOF and metabolites, a methadone interaction study 
(P7977-0814) which demonstrated no interaction between SOF and methadone; and a 


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thorough QTc study (P7977-0613) demonstrating no effect of SOF upon the QT interval in 
humans.  
A Phase I ethnic bridging study has also been conducted to compare the pharmacokinetics of 
single dose administration of SOF and SOF/LDV FDC in healthy Japanese and Caucasian 
subjects. This study which supports the global development program is described in 
Section 1.2.3.1.1 below. 
1.2.2.2. 
Phase 2 Studies with Sofosbuvir 
1.2.2.2.1. 
Study AI444-040 (Bristol-Myers Squibb IND 79,599) 
AI444-040 {20485} was designed to evaluate the potential to achieve SVR with an oral, 
pan-genotypic, once-daily treatment regimen combining  the investigational agents SOF and 
a NS5A inhibitor, daclatasvir (DCV), with or without RBV, in treatment naïve subjects 
chronically infected with genotypes 1, 2, or 3 HCV {24592}. In the initial phase of this study, 
subjects were randomized into six groups, evaluating three different dosing schedules in 
subjects with either genotype 1 HCV (n=44) or genotype 2/3 HCV (n=44). The groups were: 
• SOF 400 mg QD for 7 days then DCV 60 mg QD + SOF 400 mg QD for 23 weeks 
• SOF 400 mg QD + DCV 60 mg QD for 24 weeks  
• SOF 400 mg QD + DCV 60 mg QD + RBV for 24 weeks  
The primary endpoint of the study was SVR12. An interim analysis for safety and antiviral 
activity was conducted at 12 weeks on-treatment. 
The study was subsequently expanded to evaluate SOF + DCV ± RBV for 24 weeks in 
genotype 1 HCV infected subjects who have previously failed telaprevir or boceprevir 
treatment and for 12 weeks in treatment-naïve genotype 1 HCV subjects. Preliminary data on 
the 12 and 24 week arms are available. 
1.2.2.2.1.1. 
Study AI444-040 Preliminary Safety 
Preliminary safety data have been reported. The most frequent (greater than or equal to 
15% overall) adverse events (AEs) on treatment were fatigue, headache and nausea. Adverse 
events were generally mild to moderate intensity and did not lead to treatment 
discontinuation. Grade 3-4 laboratory abnormalities included anemia in subjects receiving 
RBV. Two subjects discontinued treatment for non-drug related AEs and both achieved 
SVR4. No subjects discontinued therapy due to treatment-related AEs. 
1.2.2.2.1.2. 
Study AI444-040 Preliminary Efficacy 
Preliminary efficacy data are tabulated in Table 1-1 below. 


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Table 1-1 
The Proportions of Subjects Achieving Viral Load Below the 
Lower Limit of Quantification (HCV RNA <25 IU/mL) in Study 
AI444-040 
Time 
(Week) 
Genotype 1 
Genotype 2 or 3 
SOF(LI) 
+DCV b 
24 weeks 
(Group A) 
(N = 15) 
n (%) 
SOF 
+DCV  
24 
weeks 
(Group 
C) 
(N = 14) 
n (%) 
SOF+ 
DCV+ 
RBV 
24 weeks
(Group E) 
(N = 15) 
n (%) 
SOF 
+DCV 
12 
weeks 
(Group 
G) 
(N = 41)
n (%) 
SOF 
+DCV 
+RBV 
12 
weeks 
(Group 
H) 
(N = 41)
n (%) 
SOF(LI)+ 
DCV 
24 weeks
(Group B) 
(N = 16) 
n (%) 
SOF+ 
DCV 
24 weeks 
(Group D) 
(N = 14)  
n (%) 
SOF 
+DCV 
+RBV 
24 weeks
(Group F) 
(N = 14) 
n (%) 
4 
15 (100) 
14 (100) 
15 (100) 
39 (95) 
41 (100) 
16 (100) 
14 (100) 
14 (100) 
EOT a 
15 (100) 
14 (100) 
15 (100) 
41 (100) 
41 (100) 
15 (94) 
14 (100) 
14 (100) 
SVR4 
15 (100) 
14 (100) 
15 (100) 
40 (98) 
39 (95) 
14 (88) 
14 (100) 
12 (86) 
SVR12 
15 (100) 
14 (100) 
15 (100) 
Pendingc 
Pendingc 
14 (88) 
14 (100) 
12 (86) 
a 
EOT, End of Treatment 
a 
LI, lead in; DCV, daclatasvir 
b 
Pending, data collection ongoing 
 
Preliminary HCV RNA data is also available on the SOF+DCV±RBV regimen administered 
for 24 weeks in GT-1 non-cirrhotics who had previously failed telaprevir or boceprevir 
containing regimens {24592}. Most of the subjects enrolled were HCV GT-1a (83%), IL28B 
non-CC (98%) and had estimated METAVIR stage F2. The mean baseline HCV RNA was 
6 log IU/mL. All subjects receiving SOF+DCV either with or without concomitant RBV, 
achieved rapid virologic suppression with HCV RNA <25 IU/mL by the on-treatment 
Week 4 visit. Early virologic suppression was maintained through the end of treatment 
(Week 24) with 100% (41/41) of subjects going on to achieve SVR4. 
Table 1-2. 
Study AI444-040 HCV RNA <25 IU/mL during and 
post-treatment. 
HCV RNA <25 IU/mL 
GT1a/1b, prior Telaprevir or Boceprevir failure 
DCV+SOF, 24 Weeks 
(n=21) 
DCV+SOF+RBV, 24 Weeks 
(n=20) 
On treatment Week 4 
21 (100) 
19 (95)a 
End of Treatment (Week 24) 
21 (100) 
20 (100) 
SVR4 
21 (100) 
20 (100) 
Notes: a1 missing 
 


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1.2.2.2.2. 
NIAID Study 11-I-0258 (IND 112,681) 
Study 11-I-0258 is a randomized controlled open-label study to assess safety, tolerability and 
efficacy of SOF 400 mg QD in combination with RBV in a total of 60 treatment-naïve HCV 
genotype 1 mono-infected individuals. The NIAID is the sponsor of the study under 
IND 112,681. Subjects were enrolled into 2 phases to evaluate both treatment duration as 
well as RBV dose. Phase 1 enrolled 10 subjects who were dosed with SOF 400 mg QD in 
combination with weight based RBV (1000 mg for participants weighing < 75 kg and 
1200 mg for participants weighing  75kg) for 24 weeks; all subjects had ≤ stage 2 fibrosis. 
Upon completion of an interim safety review of these subjects at Week 12 of treatment, 
Phase 2 was initiated in 50 subjects with any stage of fibrosis. Phase 2 subjects were 
randomized in a 1:1 ratio to receive 24 weeks of SOF QD in combination with weight-based 
RBV (1000 mg or 1200 mg daily) or 24 weeks of SOF 400 mg QD with low dose RBV 
(600mg). All subjects have completed therapy in both phases of the study. 
1.2.2.2.2.1. 
NIAID Study 11-I-0258 (IND 112,681) Preliminary Safety Data 
The population was predominantly African American, genotype 1a, with a median baseline 
HCV RNA log10  ≥ 6.05. All subjects in Phase 1 were < Stage 2 fibrosis while, in Phase 2, 
24% of those receiving full-dose RBV and 28% of those receiving low-dose RBV had 
advanced fibrosis. The interim safety analysis is completed and SOF was assessed as being 
safe and well-tolerated. There were no SAEs and the safety profile was consistent with that 
expected for RBV. 
1.2.2.2.2.2. 
NIAID Study 11-I-0258 (IND 112,681) Preliminary Efficacy Data 
Preliminary HCV RNA data for both study phases are presented in Table 1-3. 
Table 1-3. 
NIAID Study 11-1-0258: Percentage of Subjects with HCV RNA 
Achieving SVR 
Time 
(Week) 
Part 1 
Part 2 
SOF+Weight-based RBV 
24 Weeks 
N=10 
n (%) 
SOF+Weight-based RBV 
24 Weeks 
N=25 
n (%) 
SOF+600 mg RBV 
24 weeks 
(N = 25)  
n (%) 
4 
9/10 (90%) b 
24/25 (96%) b 
24/25 (100%) 
EOT a 
9/10 (90%) 
24/25 (96%) b 
22/25 (88%) c 
SVR4 
9/10 (90%) 
18/25 (72%) b 
14/25 (56%) 
SVR12 
9/10 (90%) 
17/25 (68%) 
12/25 (48%) 
a 
EOT, End of Treatment 
b 
One subject discontinued therapy at Week 3 
c 
3 subjects dropped out before Week 8  
 


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1.2.2.3. 
Phase 3 Studies with Sofosbuvir 
The SOF Phase 3 program includes 4 clinical studies: P7977-1231 (FISSION), 
GS-US-334-0107 (POSITRON), GS-US-334-0108 (FUSION), and GS-US-334-0110 
(NEUTRINO). 
Studies P7977-1231, GS-US-334-0107, and GS-US-334-0108 evaluated the efficacy and 
safety of SOF+RBV in different genotype 2 and 3 HCV patient populations. Study 
GS-US-334-0110 evaluated the efficacy and safety of SOF+Peg-IFNĮ+RBV for 12 weeks 
for treatment-naive subjects with genotype 1, 4, 5, and 6 HCV infection.  Preliminary safety 
and efficacy data for each study are summarized below. 
1.2.2.3.1. 
P7977-1231 (FISSION) 
This Phase 3, randomized, multicenter, open-label, active-controlled study evaluated SVR12 
rates of treatment-naïve, genotype 2 or 3 HCV-infected subjects randomized 1:1 to receive 
either 12 weeks of treatment with SOF (400 mg once daily) +RBV (1000 or 1200 mg per day 
in divided [BID] doses, as determined by subject’s weight) or 24 weeks of treatment with 
Peg-IFNĮ (180 μg/week) +RBV (800 mg/day). 
1.2.2.3.1.1. 
P7977-1231 (FISSION) Preliminary Safety Data 
Treatment with SOF+RBV was well tolerated in this study, and the overall safety profile of 
SOF+RBV was favorable to that of Peg-IFNĮ +RBV. Specifically, the SOF+RBV group had 
lower rates of AEs (SOF+RBV 86%; Peg-IFNĮ+RBV 96%); Grade 3 or higher AEs 
(SOF+RBV 7%; Peg-IFNĮ +RBV 19%); Grade 2 or higher AEs (SOF+RBV 40%;  
Peg-IFNĮ +RBV 69%); treatment-related AEs (SOF+RBV 72%;  Peg-IFNĮ +RBV 94%); 
AEs leading to permanent discontinuation of any of the study drugs (SOF+RBV 1%; 
Peg-IFNĮ +RBV 12%); and AEs leading to study drug interruption or dose modification 
(SOF+RBV 10%; Peg-IFNĮ+RBV 27%). The safety profile of SOF+RBV treatment was 
similar to the expected safety profile of RBV treatment. 
Fatigue occurred with the highest AE incidence in both treatment groups, reported in 
92 subjects (36%) in the SOF+RBV group and 134 subjects (55%) in the Peg-IFNĮ+RBV 
group. All of the other most common AEs (ie, those in  10% of subjects in either treatment 
group) were also reported in a lower percentage of subjects in the SOF+RBV group than the  
Peg-IFNĮ +RBV group. These AEs included events commonly associated with  Peg-IFNĮ 
+RBV treatment, such as anemia, headache, nausea, insomnia, diarrhea, irritability, rash, 
myalgia, decreased appetite, pruritus, dizziness, influenza-like illness, arthralgia, chills, 
depression, pyrexia, pain, and neutropenia). 
Serious AEs were infrequent in both treatment groups (SOF+RBV 3%, 7 subjects/8 events;  
Peg-IFNĮ+RBV 1%, 3 subjects/6 events). All individual SAE preferred terms were reported 
for only 1 subject, and no pattern was apparent in the types of events. 
Most lab abnormalities in both groups were Grade 1 or 2 in severity. 


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1.2.2.3.1.2. 
P7977-1231 (FISSION) Preliminary Efficacy Data 
Overall SVR12 rates were 67% (170/253) in the SOF+RBV group and 67% (162/243) in the  
Peg-IFNĮ+ RBV group. Since the lower bound of the 2-sided 95% confidence interval (CI) 
of the difference in the response rate (SOF+RBV í  Peg-IFNĮ+ RBV) was greater than the 
prespecified 15% noninferiority margin, treatment with SOF+RBV for 12 weeks was 
determined to be noninferior to treatment with  Peg-IFNĮ+ RBV for 24 weeks. The SVR12 
rates for genotype 2 subjects were 97% versus 78% for those receiving SOF+RBV versus  
Peg-IFNĮ+ RBV, respectively, and for genotype 3 subjects were 56% versus 63% for those 
receiving SOF+RBV versus  Peg-IFNĮ+ RBV, respectively. Among subjects with cirrhosis 
at baseline who received SOF+RBV, 47% achieved SVR12 compared with 38% of those 
who received  Peg-IFNĮ+ RBV. 
With the exception of one subject who was non-compliant (drug levels were undetectable), 
all subjects in the SOF+RBV arm became HCV negative on treatment and relapse accounted 
for the virologic failures. 
1.2.2.3.2. 
GS-US-334-0107 (POSITRON) 
Subjects (n=278) with genotype 2 and 3 HCV infection who were interferon intolerant or 
interferon ineligible or unwilling to take interferon were randomized (3:1) to receive 
12 weeks of SOF (400 mg/day) plus RBV (1000 or 1200 mg/day) or matching placebo.  
1.2.2.3.2.1. 
GS-US-334-0107 (POSITRON) Preliminary Safety Data 
Treatment for 12 weeks with SOF+RBV was well tolerated in this study. The safety profile 
of SOF+RBV treatment was similar to the expected safety profile of RBV treatment.  
The majority of subjects in both groups experienced at least 1 AE. The most frequently 
reported overall AEs and treatment-related AEs in both groups were fatigue, headache, and 
nausea. Most AEs were either Grade 1 (mild) or Grade 2 (moderate) in severity. Eight AEs 
leading to discontinuation of any study drug were reported in 5 (2%) SOF+RBV subjects and 
4 AEs leading to discontinuation of any study drug were reported in 3 (4%) placebo subjects. 
No individual AE that led to discontinuation was experienced by more than 1 subject.  No 
trends in SAE type or onset time were observed. Most laboratory abnormalities were Grade 1 
or 2 in severity. 
1.2.2.3.2.2. 
GS-US-334-0107 (POSITRON) Preliminary Efficacy Data 
SVR12 was achieved by 78% (161/207) subjects receiving SOF+RBV compared with 0% 
(0/71) subjects receiving placebo (p < 0.001). Relapse accounted for all virologic failures in 
the SOF+RBV arm.  
Subjects with genotype 2 HCV infection had a higher SVR12 rate than subjects with 
genotype 3 HCV infection (93% vs 61%).  Overall 15% of subjects had cirrhosis at baseline; 
61% of those receiving SOF+RBV achieved SVR12. 


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1.2.2.3.3. 
Study GS-US-334-0108 (FUSION) 
This ongoing Phase 3, randomized, double-blind, multicenter study assessed the efficacy and 
safety of 12 or 16 weeks of SOF+RBV treatment in subjects with chronic genotype 2 or 3 
HCV infection who had failed prior treatment with an interferon-based regimen. Eligible 
subjects were randomized in a 1:1 ratio to 12 or 16 weeks of treatment with SOF 
(400 mg/day) plus RBV (1000 to 1200 mg/day). 
1.2.2.3.3.1. 
Study GS-US-334-0108 (FUSION) Preliminary Safety Data  
Treatment with SOF+RBV for 12 or 16 weeks was generally well tolerated in this study, 
with no deaths, no discontinuations during SOF+RBV treatment, and few SAEs or Grade 3 
or 4 AEs or laboratory abnormalities. Extending treatment duration to 16 weeks did not alter 
the safety profile of the regimen in terms of overall frequency or severity of AEs or 
laboratory abnormalities. The safety profile of SOF+RBV treatment was similar to the 
expected safety profile of RBV treatment. 
The most frequently reported overall AEs in both treatment groups were fatigue, headache, 
nausea, and insomnia. Most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. 
Most laboratory abnormalities were Grade 1 or Grade 2 in severity. 
1.2.2.3.3.2. 
Study GS-US-334-0108 (FUSION) Preliminary Efficacy Data 
A total of 50% of subjects (50/100) in the SOF+RBV 12-week group and 73% of subjects 
(69/95) in the SOF+RBV 16-week group achieved SVR12. The study met its primary 
endpoint of superiority over an historical control rate of 25% (p < 0.001). Treatment with 
SOF+RBV for 16 weeks resulted in higher SVR12 rates compared with the shorter treatment 
duration of 12 weeks. This difference was primarily a result of a lower response rate in 
subjects with genotype 3 HCV infection receiving 12 weeks of treatment. Among the 34% of 
FUSION participants who had compensated cirrhosis at baseline, 31% achieved SVR12 in 
the 12-week arm, and 66% achieved SVR12 in the 16-week arm. 
Subjects with genotype 2 HCV infection had higher SVR12 rates than subjects with genotype 
3 HCV infection in both the SOF+RBV 12-week group and the SOF+RBV 16-week group.  
Table 1-4 presents SVR12 by HCV genotype. In both treatment groups, relapse accounted 
for all virologic failures. 


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Table 1-4. 
GS-US-334-0108: Number (Percentage) of Subjects with SVR12 
by Genotype (Full Analysis Set) 
 
SOF+RBV 12 
Weeks + Placebo 4 
Weeks Genotype 2 
(N = 36) 
SOF+RBV 16 
Weeks Genotype 2 
(N = 32) 
SOF+RBV 12 
Weeks + Placebo 4 
Weeks Genotype 3 
(N = 64) 
SOF+RBV 16 
Weeks Genotype 3 
(N = 63) 
SVR12 
31/36 (86%)  
30/32 (94%)  
19/64 (30%)  
39/63 (62%)  
 
1.2.2.3.4. 
Study GS-US-334-0110 (NEUTRINO) 
Treatment-naïve subjects with genotype 1, 4, 5, or 6 HCV infection (n= 327) were treated for 
12 weeks with sofosbuvir (400 mg/day) plus RBV (1000 or 1200 mg/day) and 
Peg-IFNĮ (180 μg/week) in this Phase 3, open-label study. 
1.2.2.3.4.1. 
Study GS-US-334-0110 (NEUTRINO) Preliminary Safety Results 
Sofosbuvir was generally well tolerated in this study. The safety profile of SOF+Peg-
IFNĮ+RBV treatment was similar to the expected safety profile of Peg-IFNĮ+RBV 
treatment. Five subjects (1.5%) had AEs that led to treatment discontinuation. Anemia was 
the only AE that led to discontinuation or all study treatment for more than 1 subject 
(2 subjects, 0.6%). 
The most frequently reported AEs and treatment-related AEs were fatigue, headache and 
nausea.  Most AEs were either Grade 1 or Grade 2 in severity. Approximately 15% of 
subjects experienced a Grade 3 AE; the most frequent Grade 3 AEs that occurred in 
 5 subjects were neutropenia, anemia, fatigue, and headache. No Grade 4 AEs were 
reported. SAEs were infrequently reported (1%) and no deaths occurred. 
1.2.2.3.4.2. 
Study GS-US-334-0110 (NEUTRINO) Preliminary Efficacy Results 
Twelve weeks of treatment with SOF+Peg-IFNĮ+RBV resulted in a high SVR12 rate of 90% 
in treatment-naive subjects with chronic genotype 1, 4, 5, or 6 HCV infections. Among 
genotype 1 subjects, 89% achieved SVR12.  Of the 35 subjects with genotypes 4, 5, or 6, 
97% achieved SVR12.  Seventeen percent of subjects had compensated cirrhosis; 80% of 
these subjects achieved SVR12. The study met its primary endpoint of superiority over an 
historical SVR rate of 60% (p < 0.001). Relapse accounted for all virologic failures.  
1.2.2.4. 
Safety Evaluation of SOF in Combination with RBV or Peg-IFNĮ and RBV 
SOF 400 mg QD administered for up to 24 weeks has been well tolerated in studies to date 
with the observed AEs similar to those expected for the drugs with which it is coadministered 
- RBV or Peg-IFNĮ+RBV. As such, decreased hemoglobin is the most frequent laboratory 
abnormality when coadministered with RBV and with Peg-IFNĮ+RBV. Rates of decreased 
hemoglobin across the Phase 3 studies are described in Table 1-5.  


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Table 1-5. 
Pooled Phase 3 Studies: Subjects with Post-Baseline 
Hemoglobin < 10 g/dL and < 8.5 g/dL (Safety Analysis Set) 
 
Genotype 2, 3 
Genotype 1, 4, 5, 6 
Placebo 
SOF+RBV 
12 weeks 
SOF+RBV 
16 weeks 
Peg-
IFNĮ+RBV 
24 weeks 
SOF+Peg-
IFNĮ+RBV 
12 weeks 
US-GS-334-0107 
(N=71) 
P7977-1231 
US-GS-334-0107
US-334-0108 
(N=566) 
US-GS-334-0108
(N=98) 
P7977-1231 
(N=243) 
US-GS-334-0110 
(N=327) 
Number of 
subjects with 
any post-
baseline Hb 
value 
71 
563 
98 
242 
327 
Number (%) of 
subjects with 
any post-
baseline Hb 
value < 10 g/dL 
0 
48 (9%) 
5 (5%) 
35 (15%) 
74 (23%) 
Number (%) of 
subjects with 
any post-
baseline Hb 
value < 8.5 g/dL 
0 
5 (1%) 
0 
4 (2%) 
8 (2%) 
 
1.2.3. 
Summary of Additional Clinical Experience with Sofosbuvir and 
Ledipasvir 
1.2.3.1. 
Clinical Pharmacology Studies 
1.2.3.1.1. 
GS-US-334-0111 Pharmacokinetic Bridging Study in Japanese Subjects 
To support the conduct of clinical studies in Japan a PK bridging study was conducted in 
accordance with ICHE5 to compare the safety, tolerability and PK profile in Japanese and 
Caucasian subjects following single-dose administration of SOF at the 200 mg, 400 mg (the 
intended therapeutic dose) and 800 mg dose levels. This study also evaluated the 
pharmacokinetic parameters of the 400 mg dose of SOF and the 90 mg dose of LDV 
administered as a single dose of the SOF/LDV FDC. This study was conducted in the United 
States. 
1.2.3.1.1.1. 
GS-US-334-0111 Study Design 
The study enrolled Japanese and Caucasian subjects with an approximately even distribution 
of healthy males and healthy, non-pregnant, non-lactating females between 18–45 years, 
inclusive, with a body mass index (BMI) 18  BMI  30, who had either a normal 12-lead 
electrocardiogram (ECG) or one with abnormalities that were considered clinically 


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insignificant by the Investigator, normal renal function, no significant medical history, and 
were in good general health as determined by the investigator at screening. Japanese subjects 
had to be of first generation. Subjects must have been born in Japan, not lived outside Japan 
> 10 years, and could trace maternal and paternal Japanese ancestry of parents and 
grandparents. Lifestyle, including diet, has not significantly changed since leaving Japan. To 
be enrolled in the study Caucasian subjects must not have been of Japanese or Asian descent; 
those with parents or grandparents born in Japan or in any Asian country were excluded. 
Following completion of screening and baseline procedures, eligible subjects received one 
dose of study treatment on Day 1 corresponding to their assigned group. Each group 
comprised of 8 Japanese and 8 Caucasian subjects and received SOF at either the 200 mg, 
400 mg or 800 mg dose levels (Groups 1-3), or 400 mg SOF + 90 mg LDV administered as a 
single dose of the SOF/LDV FDC (Group 4). Vital signs (heart rate, blood pressure) and a 
12-lead ECG were performed at Screening, Day 0, Day 1 to 5 (Groups 1-3) or Day 7 
(Group 4), or Early Termination visit (if applicable). Vital signs were also performed at the 
follow up visit. Assessment of adverse events and concomitant medications occurred at 
screening and daily throughout the study. Plasma and urine samples were collected at 
selected time points to assess the PK of SOF, GS-566500, GS-331007, and LDV. 
1.2.3.1.1.2. 
GS-US-334-0111 Study Results 
Preliminary pharmacokinetic (plasma and urine) results are available for all subjects in 
Table 1-6. As seen below, the geometric-least squares means ratios (GMRs) and associated 
90% confidence intervals (CIs) for SOF, GS-566500, GS-331007, and LDV exposure 
parameters (AUCinf, AUClast, and Cmax) are similar in the Caucasian and Japanese subjects. 


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Table 1-6. 
GS-US-334-0111 Geometric Least-Squares Mean Ratios (90% 
Confidence Intervals) for Sofosbuvir, GS-566500, GS-331007, and 
Ledipasvir Primary PK Parameters in Japanese versus Caucasian 
Subjects 
 
SOF 200 mg 
% GLSM Ratio 
(90% CI) 
SOF 400 mg 
% GLSM Ratio 
(90% CI) 
SOF 800 mg 
% GLSM Ratio 
(90% CI) 
SOF/LDV FDC  
(400 mg/90 mg) 
% GLSM Ratio 
(90% CI) 
SOF PK Parameter 
AUClast 
(ng•h/mL) 
97.02 
 (63.62, 147.96) 
122.62  
(92.54, 162.47) 
106.20  
(82.63, 136.49) 
90.52  
(54.44, 150.50) 
AUCinf 
(ng•h/mL) 
97.30  
(64.77, 146.16) 
121.98  
(92.30, 161.20) 
106.27  
(82.84, 136.33) 
90.77  
(54.90, 150.07) 
Cmax (ng/mL) 
101.56  
(62.88, 164.02) 
107.05  
(76.31, 150.18) 
96.37  
(62.23, 149.23) 
93.82 
 (64.53, 136.42) 
GS-566500 PK Parameter 
AUClast 
(ng•h/mL) 
158.37  
(119.80, 209.34) 
149.64 
(117.13, 191.17) 
125.17  
(103.74, 151.03) 
114.13  
(78.15, 166.67) 
AUCinf 
(ng•h/mL) 
153.51  
(117.65, 200.30) 
147.47 
 (116.45, 186.74) 
124.39  
(103.30, 149.79) 
113.27  
(78.24, 163.98) 
Cmax (ng/mL) 
154.48  
(116.12, 205.51) 
138.62  
(108.12, 177.72) 
117.59  
(98.72, 140.06) 
130.16  
(93.88, 180.44) 
GS-331007 PK Parameter 
AUClast 
(ng•h/mL) 
80.29  
(64.62, 99.77) 
94.44  
(78.30, 113.90) 
82.32  
(71.98, 94.16) 
85.63  
(63.56, 115.36) 
AUCinf 
(ng•h/mL) 
82.37 
 (67.59, 100.36) 
95.93 
 (80.14, 114.82) 
83.68 
 (74.25, 94.30) 
85.40 
 (64.04, 113.89) 
Cmax (ng/mL) 
72.72 
 (57.86, 91.40) 
113.48 
 (91.12, 141.32) 
102.44 
 (73.52, 142.73) 
94.34 
 (68.03, 130.82) 
LDV PK Parameter 
AUClast 
(ng•h/mL) 
— 
— 
— 
106.07 
 (68.95, 163.18) 
AUCinf 
(ng•h/mL) 
— 
— 
— 
106.66  
(69.13, 164.59) 
Cmax (ng/mL) 
— 
— 
— 
125.63  
(83.83, 188.26) 
 


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1.2.3.1.1.3. 
GS-US-334-0111 Study Conclusions 
SOF and SOF/LDV FDC were well tolerated in this study. No clinically significant 
differences in the PK of SOF, its metabolites GS-566500 and GS-331007, or LDV were 
observed between Japanese and Caucasian subjects, supporting the use of SOF 400 mg or 
SOF/LDV FDC (400 mg/90 mg) in Japanese and non-Japanese subjects. 
1.2.3.2. 
Phase 2 Studies with SOF+LDV and SOF/LDV FDC 
1.2.3.2.1. 
Study P7977-0523 ELECTRON 
ELECTRON is an ongoing 6-part, Phase 2 study comprising 22 treatment arms. Of particular 
importance to the efficacy and/or safety of the SOF/LDV FDC regimen the proposed for use 
in GS-US-337-0131 in Korea and Taiwan are treatment Arms 12-13 (Part 4) exploring 
SOF+LDV+RBV and Arms 16-21 (Part 6), exploring SOF/LDV±RBV in various patient 
populations: 
• Arm 12: GT1, prior null responder, non-cirrhotics (12 weeks SOF+LDV+RBV; n=9) 
• Arm 13: GT1, treatment-naïve, non-cirrhotics (12 weeks SOF+LDV+RBV; n=25) 
• Arm 16: GT1, prior null responder, F4 cirrhotics (12 weeks SOF/LDV FDC; n=10) 
• Arm 17: GT1, prior null responder, F4 cirrhotics (12 weeks SOF/LDV FDC+RBV; n=10) 
• Arm 18: GT2/3: treatment-naïve, non-cirrhotics (12 weeks SOF/LDV FDC; n=10) 
• Arm 20: GT1: Hemophiliacs (12 weeks SOF/LDV FDC+RBV =13) 
• Arm 21: GT1, treatment-naïve, non-cirrhotic (6 weeks SOF/LDV FDC+RBV; n=25) 
1.2.3.2.1.1. 
P7977-0523 (ELECTRON) Preliminary Safety 
SOF+LDV+RBV and SOF/LDV ± RBV are generally well tolerated. One subject in the 
SOF+LDV+RBV groups discontinued treatment early due to a serious adverse event (colonic 
fistula) considered by the investigator not to be related to study drugs. No other serious 
adverse events have been reported. To date, no subjects receiving SOF/LDV ± RBV have 
discontinued treatment early. The most common adverse events were headache (44%), 
fatigue (23%), and nausea (22%), when safety data from Arms 12, 13, and 16-21 were 
pooled. No safety signal associated with treatment with SOF or LDV either separately or as a 
FDC has been identified. 
1.2.3.2.1.2. 
P7977-0523 (ELECTRON) Preliminary Pharmacokinetic Data 
An intensive PK substudy was conducted at Week 2 to examine the PK of SOF, GS-566500, 
GS-331007 and LDV in subjects receiving SOF+LDV+RBV (all subjects in Arms 12 and 


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13), and SOF/LDV FDC ± RBV who do not have hemophilia (target: up to 10 subjects in 
Arms 16-19, each, and up to 15 subjects in Arms 21-22). 
Preliminary PK data are available for all subjects in Arms 12 (N = 9) and 13 (N = 25), and 21 
(N = 15), and for the majority of subjects in Arms 16-17 (SOF: N = 11 out of 14, 
LDV: N = 12 out of 14). Preliminary PK data are shown in Table 1-7. 
Similar plasma exposures of SOF, GS-566500, GS-331007 and LDV were achieved in all 
treatment groups, irrespective of presence or absence of cirrhosis. 
Table 1-7. 
Study P7977-0523 (ELECTRON): SOF, GS-566500, GS-331007 
and LDV PK Parameters Following Administration of SOF 400 
mg + LDV 90 mg + RBV or SOF 400 mg/LDV 90 mg FDC ± RBV 
(Preliminary Data) 
PK Parameter  
Mean (%CV) 
Arm 12  GT1 
SOF+LDV+RBV 
Prior Nulls 
Arm 13 GT1 TN 
SOF+LDV+RBV
Arms 16-17  
GT 1 FDC± RBV F4 
cirrhotic (pooled) 
Arm 21 
GT 1 TN FDC 
SOF 
N=9 
N=25 
N = 11 
N = 15 
AUCtau (hr·ng/mL) 
1990 (66.0) 
2220 (55.3) 
2300 (28.8)* 
1860 (48.5)** 
Cmax (ng/mL) 
1040 (108) 
1100 (70.7) 
1120 (64.5) 
1190 (53.0) 
Ctau (ng/mL) 
BLQ 
BLQ 
BLQ 
BLQ 
GS-566500 
N=9 
N=25 
N = 11 
N = 15 
AUCtau (hr·ng/mL) 
2400 (22.2) 
2690 (28.0) 
3370 (23.7) 
2530 (37.3) 
Cmax (ng/mL) 
488 (25.0) 
569 (29.1) 
680 (21.5) 
519 (42.8) 
Ctau (ng/mL) 
BLQ 
BLQ 
BLQ 
BLQ 
GS-331007 
N=9 
N=25 
N = 11 
N = 15 
AUCtau (hr·ng/mL) 
8110 (16.1) 
11200 (28.3) 
11200 (36.0) 
10500 (17.2) 
Cmax (ng/mL) 
630 (17.9) 
757 (21.9) 
805 (31.1) 
768 (19.0) 
Ctau (ng/mL) 
201 (16.6) 
306 (34.4) 
284 (44.6) 
286 (26.2) 
LDV 
N=9 
N=25 
N=12 
N = 15 
AUCtau (hr·ng/mL) 
6420 (44.1) 
7030 (41.6) 
8190 (58.7) 
7910 (45.4) 
Cmax (ng/mL) 
367 (37.3) 
386 (38.1) 
437 (54.7) 
434 (42.0) 
Ctau (ng/mL) 
188 (54.7) 
216 (46.4) 
261 (59.0) 
252 (51.7) 
Preliminary data reported to 3 significant figures; * N = 10; **N=14; BLQ: below the limit of quantitation 
 


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1.2.3.2.1.3. 
P7977-0523 (ELECTRON) Preliminary Efficacy 
Virologic response data for all genotype 1 HCV-infected subjects from ELECTRON Arm 12 
(SOF+LDV+RBV for 12 weeks in null responders; n=9) and Arm 13 (SOF+LDV+RBV for 
12 weeks in GT1 treatment-naive subjects; n = 25) are presented in Table 1-8. 
All subjects (100%) in Arms 12 and 13, irrespective of HCV genotype (1A or 1B) and IL28B 
allele (CC, CT, or TT) had HCV RNA < LLOQ at post treatment Weeks 2, 4, 8, and 12; no 
relapses were reported. 
This contrasts with ELECTRON Arm 7 (SOF+RBV for 12 weeks in genotype 1 
HCV-infected null responders) and Arm 8 (SOF+RBV for 12 weeks in genotype 1 
treatment-naive subjects), where 10% and 88% of subjects, respectively, achieved SVR12. 
The addition of LDV increased the SVR12 rate in these populations to 100%, demonstrating 
the contribution of LDV to a SOF-containing regimen. 
Table 1-8. 
Study P7977-0523 (ELECTRON): Arm 12 and Arm 13: SVR Data 
Arm No. 
Duration 
N  
(GT-1) 
RVR  
% (n) 
SVR4 
% (n) 
SVR8 
% (n) 
SVR12
% (n) 
Relapse  
% (n) 
BT 
% 
(n) 
LTFU
% (n) 
Arm 12 
Nulls 
12 wks 
9 
(9/9) 
88.9 
(8/9) 
100 
(9/9) 
100 
(9/9) 
100 
(9/9) 
0 (0/9) 
0 (0) 
0 (0) 
Arm 13 
TN 
12 wks 
25 
(25/25) 
100 
(25/25) 
100 
(25/25) 
100 
(25/25) 
100 
(25/25) 
0 (0/25) 
0 (0) 
0 (0) 
BT: breakthrough; LTFU: lost to follow up; TN = treatment-naïve 
 
Available SVR data for all subjects enrolled in ELECTRON Arm 21 [SOF/LDV FDC tablet 
once daily + weight-based RBV for 6 weeks in treatment-naive genotype 1 HCV-infected 
subjects; n = 25] are tabulated below (Table 1-9). Twenty of 25 subjects achieved SVR8, 
while 5 subjects relapsed. 
Table 1-9. 
Study P7977-0523 (ELECTRON): Arm 21 (FDC+RBV): Available 
SVR Data 
Arm No. 
Duration 
N  
(GT1) 
RVR  
% (n) 
SVR4 
% (n) 
SVR8 
% (n) 
SVR12
% (n) 
Relapse  
% (n) 
BT 
% (n) 
LTFU
% (n) 
Arm 21 
GT1 TN 
6 wks 
25 (25/25) 
100 
(25/25) 
88 
(22/25) 
76 
(19/25) 
67 
(16/24)*
32 
(8/25) 
0 
(0) 
0 
(0) 
BT: breakthrough; LTFU: lost to follow up 
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The full-length NS5A region was analyzed at baseline for all 34 subjects enrolled in Arms 12 
and 13 (27 genotype 1a and 7 genotype 1b) by standard population sequencing. Overall, 
4/34 (11%) subjects had LDV RAVs present at baseline (Table 1-10). 3/4 subjects with 
baseline NS5A RAVs were genotype 1a with M28T, Q30H, or L31M variants detected. A 
single genotype 1b subject had a detectable LDV RAV (L31M) at baseline. Previous in vitro 
data demonstrates that these NS5A variants individually confer moderate to high level 
reductions in susceptibility to LDV in vitro (25- to 140-fold). No virologic breakthrough or 
relapse was observed in these subjects or any other subjects in these treatment arms, as all 
achieved SVR12. This indicates that the presence of observed NS5A RAVs does not 
preclude the ability of subjects to achieve SVR12 on SOF+ LDV+RBV treatment. Resistance 
analysis of other arms containing SOF and LDV is pending. 
Table 1-10. 
Study P7977-0523 (ELECTRON): Subjects with Baseline 
Ledipasvir RAVs in NS5A in Arms 12 and 13 
Subject 
ID 
Genotype 
Treatment Group 
NS5A 
RAV 
NS5A Single 
Mutant Fold-
change in LDV 
EC50 
SVR 4 
Result 
SVR 8 
Result 
SVR 12 
Result 
 
1b 
Arm 13: 12 W 
SOF+LDV+RBV 
(GT1 TN) 
L31M 
L31M: 140 
SVR 
SVR 
SVR 
 
1a 
Arm 13: 12 W 
SOF+LDV+RBV 
(GT1 TN) 
Q30H 
Q30H: 73 
SVR 
SVR 
SVR 
 
1a 
Arm 13: 12 W 
SOF+LDV+RBV 
(GT1 TN) 
M28T 
M28T: 25 
SVR 
SVR 
SVR 
 
1a 
Arm 12: 12 W 
SOF+LDV+RBV 
(GT1 Nulls) 
L31L/M 
L31M: 140 
SVR 
SVR 
SVR 
 
1.2.3.2.2. 
Study GS-US-337-0118 LONESTAR 
LONESTAR is a single center Phase 2 study evaluating SOF/LDV±RBV in treatment-naive 
and treatment-experienced genotype 1 HCV-infected subjects. In summary, subjects were 
enrolled into 2 cohorts as follows: 
• Cohort 1: Treatment-naive, non-cirrhotic subjects received SOF/LDV±RBV for 8 weeks 
or SOF/LDV for 12 weeks (Groups 1, 2 and 3; n ~ 20/group) 
— Group 1 (n=20): SOF/LDV FDC once daily for 8 weeks 
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Table 1-11. 
Study GS-US-337-0118 (LONESTAR): SOF, GS-566500, 
GS-331007 and LDV PK Parameters Following Administration of 
SOF/LDV (400 mg/90 mg) ± RBV (Preliminary Data) 
PK Parameter  
Mean (%CV) 
Groups 1-3 
GT1 TN FDC± RBV (pooled) 
Groups 4-5  
GT1 PI Failure FDC± 
RBV without 
Cirrhosis 
(pooled) 
Groups 4-5  
GT1 PI Failures FDC± 
RBV with Cirrhosis 
(pooled) 
SOF 
N=48 
N=14 
N=21 
AUCtau (hr·ng/mL) 
2260 (47.8)† 
2460 (42.6)* 
2440 (39.3) 
Cmax (ng/mL) 
1280 (60.1) 
1310 (48.5) 
1520 (46.4) 
Ctau (ng/mL) 
BLQ 
BLQ 
BLQ 
GS-566500 
N=47 
N=14 
N=21 
AUCtau (hr·ng/mL) 
3420 (27.5) 
4110 (37.4) 
4240 (31.8) 
Cmax (ng/mL) 
689 (34.2) 
734 (37.1) 
846 (33.2) 
Ctau (ng/mL) 
15.1 (30.5) †† 
13.5 (29.5)** 
13.3 (25.5)** 
GS-331007 
N=47 
N=14 
N=14 
AUCtau (hr·ng/mL) 
12600 (34.6) 
11600 (39.3) 
11900 (36.6) 
Cmax (ng/mL) 
937 (34.8) 
801 (36.2) 
885 (35.0) 
Ctau (ng/mL) 
336 (46.7) 
327 (48.3) 
301 (45.2) 
LDV 
N=47 
N= 14 
N= 21 
AUCtau (hr·ng/mL) 
9470 (51.8) 
6210 (44.9) 
6510 (65.1) 
Cmax (ng/mL) 
504 (43.9) 
356 (37.4) 
364 (52.7) 
Ctau (ng/mL) 
344 (63.1) 
202 (57.8) 
220 (72.8) 
Preliminary data reported to 3 significant figures; † N =45; †† N=4; *N=13; ** N=3; BLQ: below the limit of quantitation  
 
1.2.3.2.2.3. 
Study GS-US-337-0118 (LONESTAR): Preliminary Efficacy 
Virologic response data for all subjects enrolled in LONESTAR is presented in Table 1-12.  
All subjects in Groups 1-3 were treatment-naive and non-cirrhotic. In Group 1 (SOF/LDV 
FDC for 8 weeks), 95% of subjects, irrespective of HCV genotype (1A or 1B) and IL28B 
allele (CC, CT, or TT), had HCV RNA < LLOQ at post-treatment Week 12. A single subject 
relapsed at the post-treatment Week 8 assessment. In Group 2, all subjects (100%) had HCV 
RNA < LLOQ at post-treatment Weeks 4, 8, and 12. In Group 2, SVR4 and SVR8, were 
initially reported as 95%, due to Subject 
 then being unavailable for these visits. 
Subsequently, this subject was found to be < LLOQ, target not detected (TND) at 
post-treatment week 12 (SVR12), and therefore SVR4 and SVR8 data has been imputed. In 
Group 3, all subjects (100%) had HCV RNA < LLOQ at post-treatment Week 8. Of note, 
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2 subjects with missing data at post-treatment Week 4, had HCV RNA < LLOQ at 
post-treatment week 8, and thus SVR4 data was imputed for these subjects.  
All subjects in Groups 4 and 5 previously failed treatment with a PI+ Peg-IFNĮ+RBV 
regimen; in each group, approximately 50% of subjects have cirrhosis. In Group 4, 95% were 
HCV RNA < LLOQ at post-treatment Week 4. In Group 5, 95% were HCV RNA < LLOQ at 
post-treatment Week 4 (one subject in Group 5 experienced SAEs of anemia and suicidal 
ideation and has not yet returned during the post-treatment period). 
Of the 22 cirrhotic subjects in Groups 4 and 5, one subject (Group 4) experienced virologic 
failure, and one subject (Group 5) has not yet returned for any post-treatment follow up 
visits. 
Table 1-12. 
Study GS-US-337-0118 (LONESTAR): Groups 1, 2, 3, 4 and 5 
SVR Data 
Grp. No./ 
Population/ 
Regimen 
Duration 
N  
(GT1) 
RVR  
% (n) 
SVR4  
% (n) 
SVR8 
% (n) 
SVR12
% (n) 
Relapse  
% (n) 
BT
% 
(n) 
LTFU
% (n) 
1 
GT1 TN 
SOF/LDV 
8 wks 20 (20) 
100 
(20/20) 
100 (20/20) 95 (19/20)
95  
919/20)
5 (1/20) 
0 (0) 
0 (0) 
2 
GT1 TN 
SOF/LDV+RBV 
8 wks 21 (21) 
100 
(21/21) 
100 
(21/21)* 
100 
(21/21) 
100 
(21/21)
0 (0/21) 
0 (0) 
0 (0) 
3 
GT1 TN 
SOF/LDV 
12 wks 19 (19) 
100 
(19/19) 
100 (19/19)
100 
(19/19) 
100 
(16/16)**
0 (0/19) 
0 (0) 
0 (0) 
4 
GT1 PI Failures 
SOF/LDV 
12 wks 19 (19) 
100 
(19/19) 
95 (18/19)
TBD 
TBD 
5 (1/19) 
0 (0) 
0 (0) 
5 
GT1 TE 
SOF/LDV+RBV 
12 wks 21 (21) 
100 
(21/21) 
95 
(20/21)***
TBD 
TBD 
0 (0/21) 
0 (0) 
0 (0) 
BT = breakthrough; LTFU = lost to follow up; GT = genotype; TN = treatment-naive; TE = treatment-experienced 
* 
Previously reported as 95%, due to Subject 
 being unavailable for these visits. Subsequently, this subject was 
found to be < LLOQ, TND at post-treatment week 12 (SVR12), and therefore SVR4 and SVR8 data has been imputed.   
** Three subjects are pending at this time point. Data are presented as observed 
*** Subject number 
 experienced SAEs of Anemia and Suicidal Ideation and has not yet returned during the post-
treatment period. 
 
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1.2.3.2.2.4. 
Study GS-US-337-0118 (LONESTAR): Preliminary Resistance Analysis 
The full-length NS5A region was analyzed at baseline for all 100 subjects (76 genotype 1a 
and 24 genotype 1b by LiPA) by deep sequencing. Baseline NS5A resistance associated 
variants (RAVs) were detected in a total of 9/100 (9%) subjects. Eight genotype 1a subjects 
and 1 genotype 1b subject had at least one LDV RAVs present at baseline, at levels ranging 
from 1.3% to 99.9%. Eight genotype 1a subjects with baseline NS5A RAVs had M28T, 
Q30L, Q30H, Q30R, L31M, Y93C, or Y93H variants detected while one genotype 1b subject 
had Y93H RAV. All these mutants, except Q30L, have been shown to confer significant 
reductions in susceptibility to LDV in vitro (Table 1-13). Of these 9 subjects, 2/9 subjects 
experienced virologic relapse. One subject (subject 
 had L31M present at 21.45% prior 
to treatment and experienced virologic relapse following 8 weeks of FDC treatment. Another 
subject (subject 
 had >99% Q30H and >99% of Y93H (double mutants Q30H+Y93H 
likely) at baseline and experienced virologic relapse following 12 weeks of FDC treatment. 
In contrast, the remaining 7 out of 9 subjects achieved SVR4, or SVR12 (n = 5 on FDC and 
n=2 on FDC+RBV) despite the presence of baseline RAVs that confer a high level of 
reduced susceptibility to LDV. These data indicate that the presence of NS5A RAVs at 
baseline do not preclude the ability of subjects treated with SOF+LDV or SOF+LDV+RBV 
regimens from achieving a sustained virologic response. 
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Table 1-13. 
Study GS-US-337-0118 (LONESTAR): Subjects with Baseline 
Ledipasvir RAVs 
Subject 
ID 
Genotype 
Treatment 
Group 
NS5A 
Mutant 
(%) 
NS5A Single 
Mutant Fold-
change in LDV 
EC50 
SVR 4 
Result 
SVR 8 
Result 
SVR 12 
Result 
 
1a 
Group 1 
L31M 
(21.45%) 
L31M: 140 
Relapse 
 
 
 
1a 
Group 1 
L31M 
(91.54%), 
Q30H 
(3.28%) 
L31M: 140 
Q30H:73 
SVR 
SVR 
SVR 
 
1b 
Group 2 
Y93H 
(43.51%) 
Y93H: 3310 
SVR 
SVR 
SVR 
 
1a 
Group 3 
Y93C 
(14.05%) 
Y93C: 2531 
SVR 
SVR 
N/A 
 
1a 
Group 3 
Q30R 
(1.34%) 
Q30R: 170 
SVR 
SVR 
N/A 
 
1a 
Group 3 
Q30H 
(95.00%) 
Q30H: 73 
SVR 
SVR 
N/A 
 
1a 
Group 4 
Q30H 
(99.42%), 
Y93H 
(99.89%) 
Q30H: 73 
Y93H: 3029 
Relapse 
 
 
 
1a 
Group 5 
M28T 
(53.84%), 
Q30R 
(96.65%) 
M28T: 25  
Q30R: 170 
SVR 
N/A 
N/A 
 
1a 
Group 5 
Q30L 
(98.83%), 
Y93H 
(99.56%) 
Q30L: 4 
Y93H: 3029 
SVR 
N/A 
N/A 
 
1.2.3.3. 
Phase 3 Studies with SOF/LDV FDC 
1.2.3.3.1. 
GS-US-337-0102 (ION-1) 
Study GS-US-337-0102 is a Phase 3, multicenter, randomized, open-label study investigating 
efficacy and safety of SOF/LDV ± RBV for 12 and 24 weeks in treatment-naïve subjects 
with chronic genotype 1 HCV infection.  207 subjects were enrolled in Part A. The study is 
ongoing. 
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1.2.3.3.2. 
GS-US-337-0109 (ION-2) 
Study GS-US-337-0109 is a Phase 3, multicenter, randomized, open-label study to 
investigate the efficacy and safety of SOF/LDV FDC ± RBV for 12 and 24 weeks in 
treatment-experienced subjects with chronic genotype 1 HCV infection. Enrollment is 
complete. 
1.2.3.3.3. 
GS-US-337-0108 (ION-3) 
Study GS-US-337-0108 is a Phase 3, multicenter, randomized, open-label study to 
investigate the efficacy and safety of SOF/LDV FDC±RBV for 8 weeks and SOF/LDV FDC 
for 12 weeks in treatment-naive subjects with chronic genotype 1 HCV infection. Enrollment 
is ongoing. 
1.2.4. 
Summary of Additional Clinical Experience with LDV 
The adult safety database for LDV includes data for over 500 healthy volunteers and over 
1000 chronic HCV infected subjects exposed to at least one dose of LDV in the 6 ongoing 
Phase 2 studies. Over 700 chronic HCV infected subjects have been exposed to ≥ 12 weeks 
of LDV containing regimens. 
1.2.4.1. 
Ongoing Clinical Pharmacology Studies 
1.2.4.1.1. 
Study GS-US-248-0117 
GS-US-248-0117 was an open-label, Phase 1, multiple-dose, 2-cohort, pharmacokinetic (PK) 
study in subjects with Child-Pugh-Turcotte (CPT) B (moderate) hepatic impairment and 
matched healthy subjects. The PK safety and tolerability of dual or triple combination 
treatments of LDV 30 mg once daily plus GS-9451 (Gilead HCV NS3/4A protease inhibitor) 
200 mg once daily (Cohort 1) and LDV 30 mg once daily plus GS-9451 200 mg once daily 
plus tegobuvir (TGV) 30 mg twice daily (Cohort 2), administered for 12 days each, were 
evaluated. Fifty subjects (n = 20 in Cohort 1; n = 30 Cohort 2) were enrolled and received 
study drugs. 
Table 1-14 presents the steady state PK parameters and statistical comparisons of LDV 
following administration of LDV+GS-9451± TGV in subjects with moderate hepatic 
impairment and in subjects with normal hepatic function. Ledipasvir plasma PK parameters 
(AUCtau, Cmax and Ctau) were comparable in subjects with moderate hepatic impairment and 
matched controls who received a combination of LDV + GS-9451. Ledipasvir plasma 
exposure was modestly lower (~34-36%) in subjects with moderate hepatic impairment, as 
compared to matched controls upon administration of LDV + GS-9451 +TGV. These data 
indicate lack of an increase in LDV plasma exposure in subjects with moderate hepatic 
impairment relative to subjects with normal hepatic function. 


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The mean % free fraction for LDV, assessed at the time of maximum concentration (Tmax) 
and at the end of the dosing interval (Tlast), was similar in subjects with moderate hepatic 
impairment and those with normal hepatic function, demonstrating lack of an effect of 
hepatic impairment on protein binding (analysis done on Cohort 2). 
Table 1-14. 
GS-US-248-0117: LDV Steady-State Pharmacokinetic Parameters 
and Statistical Comparisons in Subjects with Moderate Hepatic 
Impairment and Matched Controls with Normal Hepatic Function 
Following Administration of LDV+GS-9451±TGV 
LDV PK Parameters  
Mean (%CV) 
Reference Treatment: 
Normal Matched 
Control Group  
Test Treatment: 
Moderate Hepatic 
Impairment Group 
GLSM Ratio (%) (90% 
CI) Test/Reference 
Cohort 1 (N = 9) 
 
 
 
AUCtau (ng*hr/ml) 
3405.0 (50.0) 
3601.1 (52.9) 
100.22 (63.42, 158.40) 
Cmax (ng/ml) 
208.6 (46.1) 
197.9 (47.3) 
90.80 (59.30, 139.04) 
Ctau (ng/ml) 
120.6 (56.4) 
138.4 (59.5) 
105.39 (62.21, 178.53) 
Cohort  2 (N = 14) 
 
 
 
AUCtau (ng*hr/ml) 
4756.0 (41.8) 
2994.8 (42.4) 
63.86 (47.36, 86.11) 
Cmax (ng/ml) 
271.7 (41.8) 
169.7 (39.9) 
63.80 (47.09, 86.45) 
Ctau (ng/ml) 
177.7 (46.0) 
113.5 (41.5) 
66.10 (48.96, 89.26) 
 
A review of the safety data showed LDV was generally well tolerated when co-administered 
with GS-9451 and with or without TGV to CPT B (moderate) hepatic impaired subjects and 
matched healthy subjects. No SAEs, Grade 3 or 4 AEs, deaths, or withdrawal due to AEs 
were reported in the study. The frequency of treatment-emergent AEs reported in the CPT B 
(moderate) hepatic impaired subjects were similar to those reported in matched healthy 
subjects. The most frequently reported AEs (in >2 subjects) overall were diarrhea, abdominal 
distension, fatigue, muscle tightness, headache, and eczema. Treatment-emergent AEs were 
mostly mild in severity except for a moderate AE of muscle tightness reported in 2 healthy 
subjects during LDV+GS-9451+TGV administration. A Grade 3 hyperbilirubinemia was 
noted in 2 moderately hepatic impaired subjects co-administered LDV and GS-9451, a result 
consistent with the known inhibition of bilirubin transporters by GS-9451. No other Grade 3 
or 4 laboratory abnormality was reported in >1 subject. 
Based on these data, dose adjustment of LDV in moderate or mild hepatic impairment is not 
warranted. 
1.2.4.1.2. 
Study GS-US-248-0125 
GS-US-248-0125 was an open-label, Phase 1, cross-over, multiple-dose, multi-cohort study 
that evaluated the effect and drug interaction potential of a triple combination of DAAs, LDV 


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90 mg QD +GS-9451 200 mg QD+TGV 30 mg BID, on OATP, BCRP, and Pgp substrates 
using phenotypic probes in healthy volunteers. In addition, the drug interaction potential of 
DAAs with Pgp inducers, Pgp inhibitors and mixed OATP/MRP2/Pgp inhibitors was 
assessed. 
Effect of LDV+GS-9451+TGV on OATP, BCRP, Sodium-Taurocholate Cotransporting 
Polypeptide (NTCP), or Pgp Substrates Using Phenotypic Probes 
Administration of LDV+GS-9451+TGV with an OATP substrate pravastatin resulted in a 
modest increase of ~ 2.7 to 2.8-fold in AUC and Cmax of the probe drug, as compared to 
pravastatin administration alone. Pravastatin t1/2 remained similar in both treatments; 
suggestive of the effect of DAAs on the relative bioavailability and not the systemic 
clearance of the probe drug. The magnitude of this interaction is comparable to that observed 
with clarithromycin and is likely caused by the first-pass inhibition of hepatic drug 
transporters OATP by GS-9451, a moderate/potent inhibitor of OATP1B1/1B3 
(AD-169-2275). In accordance with the prescribing information on the use of pravastatin 
with clarithromycin {18314}, pravastatin dose should be limited to 40 mg once daily with 
LDV+GS-9451+TGV. Monitoring for signs and symptoms of muscle weakness or 
myopathy, including rhabdomyolysis during co-administration of these agents is 
recommended. 
Coadministration of rosuvastatin and LDV+GS-9451+TGV resulted in increases of ~8- to 
9-fold in rosuvastatin AUC and ~18-fold increase in rosuvastatin Cmax. Considering a 
substantial increase in rosuvastatin exposure relative to a more modest increase in 
pravastatin; this interaction is likely mediated by the inhibition of several drug transporters 
that mediate uptake or efflux of rosuvastatin (i.e. OATP, BCRP and NTCP). These results are 
also consistent with GS-9451 being is a moderate/potent inhibitor of OATP, a moderate 
inhibitor of NTCP (AD-169-2275) and BCRP drug transporters (AD-169-2249), and of LDV 
being a weak to moderate inhibitor of BCRP (AD-256-2109). There were no statistically 
significant differences in rosuvastatin t1/2 in the two treatments, indicative of the lack of 
effect of LDV+GS-9451+TGV on the systemic clearance of the probe drug. The magnitude 
of an increase in rosuvastatin exposure by DAAs in this study is also modestly higher than 
that observed upon co-administration of rosuvastatin with cyclosporine {21139}. Concurrent 
administration of rosuvastatin and cyclosporine resulted in ~ 7-fold increase in rosuvastatin 
AUC and ~11-fold increase in rosuvastatin Cmax. As such, rosuvastatin should not be 
co-administered with LDV+GS-9451+TGV. 
Modestly higher digoxin (AUC: ~1.3- to 1.6-fold higher; Cmax: 1.2-fold higher) exposures 
were observed with DAAs, indicative of intestinal inhibition of Pgp transporters by GS-9451 
and/or LDV, consistent with in vitro data that show that both GS-9451 and LDV are weak 
Pgp inhibitors. These results from this study do not preclude administration of triple DAA 
combination with Pgp substrates. However, owing to digoxin narrow therapeutic index, an 
increase in digoxin exposure is considered clinically relevant (exposure increase > 1.25-fold 
{15555}) and monitoring of subjects for the signs and symptoms of digoxin toxicity is 
warranted if administered with LDV+GS-9451+TGV. 


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Effect of Pgp Inducers, Pgp Inhibitors and Mixed OATP/MRP2/Pgp Inhibitors on 
LDV+GS-9451+TGV and the Effect of LDV+GS-9451+TGV on Cyclosporine 
Substantial reductions in the exposure parameters of GS-9451, LDV and TGV were observed 
upon administration with a Pgp inducer rifampin. GS-9451 AUC and Cmax were ~ 83% and 
67% lower, respectively, with rifampin, as compared to DAAs administration alone. 
Similarly, LDV AUC was ~ 56% to 59% lower and Cmax was ~ 35% lower, respectively, 
whereas TGV AUC was ~ 60% lower and Cmax was ~25% lower. As such, these DAAs 
should not be administered with Pgp inducers. 
Coadministration of LDV+GS-9451+TGV with verapamil resulted in ~ 2-fold higher AUC 
and ~ 1.6-fold higher Cmax of GS-9451, ~ 1.5- 1.7-fold higher AUC of LDV, and 1.3- to 
1.4-fold higher AUC of TGV. Ledipasvir and TGV Cmax remained comparable in both 
treatments. These increases in DAAs exposure are likely mediated by inhibition of Pgp drug 
transporters by verapamil. Dose adjustment of GS-9451 when given with Pgp inhibitors is 
dependent on target clinical exposures. Considering only modest increase in LDV and TGV 
exposure upon administration with verapamil, these agents may be co-administered with Pgp 
inhibitors. 
Coadministration of DAAs with cyclosporine resulted in ~ 2-fold higher AUCtau and Ctau, and 
~1.8-fold higher Cmax of GS-9451. Dose adjustment of GS-9451 when given with 
cyclosporine is dependent on target clinical exposures. Ledipasvir and TGV primary 
exposure parameters AUCtau, Cmax, and Ctau and cyclosporine exposure parameters AUCinf, 
AUClast and Cmax were comparable in both treatments. The geometric least-squares means 
ratios for the test versus reference treatments and their associated 90% confidence intervals 
remained within the predefined lack of interaction bounds of 70% to 143%. As such, LDV or 
TGV may be coadministered with a mixed OATP/MRP2/Pgp inhibitor cyclosporine. 
The combination of LDV+GS-9451+TGV when administered alone or with probe drugs was 
generally well tolerated. A total of 70 treatment-emergent AEs were reported in 45 subjects. 
Of those 24, AEs were considered related to any study drug, which includes those considered 
related to probe drugs alone. The majority of treatment-emergent AEs reported were mild in 
severity with 12 moderate and 1 severe AE reported. The severe AE of interstitial 
pneumonitis was reported in a subject in Cohort 2 after completing 10 days of 
GS-9451+LDV+TGV treatment and 3 days after the subject was co-administered 
GS-9451+LDV+TGV + digoxin. The event was reported 2 days later as an SAE, when the 
subject was hospitalized for several days of fever, nausea, vomiting, and weakness. The 
subject’s symptoms and CT scan findings were suggestive of atypical pneumonia. Upon 
admission to the hospital, the subject was administered broad spectrum antibiotics. The 
subject’s symptoms improved and the subject was discharged from the hospital 12 days later. 
Due to the inability to identify a community acquired pathogen, the severe AE and SAE were 
reported as interstitial pneumonitis and considered by the investigator as possibly related to 
GS-9451, LDV, TGV, and digoxin. 






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Table 1-15. 
Study GS-US-334-0101: Pharmacokinetic Data for SOF, 
Metabolites (GS-566500 and GS-331007) and LDV on 
Administration of Sofosbuvir (SOF) and LDV Alone or in 
Combination 
SOF (n=17) 
Mean (%CV) 
SOF alone 
SOF + LDV 
%GMR (90%CI) 
AUCinf (ng.hr/mL) 
794 (36.3) 
1750 (27.8) 
229  (191, 276) 
AUClast (ng hr/mL) 
787 (36.6) 
1740 (27.8) 
230 (191, 277) 
Cmax (ng/mL) 
929 (52.3) 
1870 (27.9) 
221 (176, 278) 
GS-566500 (n=17) 
Mean (%CV) 
SOF alone 
SOF + LDV 
%GMR (90%CI) 
AUCinf (ng.hr/mL) 
1110 (31.6) 
1950 (22.8) 
179 (155, 207) 
AUClast (ng hr/mL) 
1060 (32.7) 
1890 (22.8) 
182 (157, 210) 
Cmax (ng/mL) 
312 (38.7) 
553 (26.6) 
182 (154, 216) 
GS-331007 (n=17) 
Mean (%CV) 
SOF alone 
SOF + LDV 
%GMR (90%CI) 
AUCinf (ng.hr/mL) 
10900 (17.5) 
13000 (16.7) 
119 (113, 126) 
AUClast (ng hr/mL) 
10200 (17.9) 
12100 (15.5) 
119 (113, 125) 
Cmax (ng/mL) 
1060 (17.3) 
864 (20.1) 
81.2 (76.9, 85.8) 
LDV (n=17) 
Mean (%CV) 
LDV alone 
SOF + LDV 
%GMR (90%CI) 
AUCtau (ng.hr/mL) 
11900 (26.2) 
11400 (27.1) 
95.8 (92.1, 99.5) 
Cmax (ng/mL) 
756 (24.7) 
735 (27.0) 
96.5 (89.9, 104) 
Ctau (ng/mL) 
375 (28.8) 
360 (31.2) 
95.5 (91.9, 99.1) 
Data presented as 3 significant figures. 
 
Sofosbuvir plasma exposure was increased by ~ 2.3-fold by LDV. The effect of LDV on 
SOF is likely due to inhibition of intestinal P-gp and/or BCRP, of which SOF is a known 
substrate. GS-331007 (predominant, circulating metabolite of SOF) exposure was unaffected 
by LDV. The increase in SOF (SOF, top panel) is not considered clinically significant due to 
its very low and transient exposure relative to total drug related material (DRM) exposure 
(DRM, calculated as the sum of the AUCs for each of the analytes, corrected for molecular 
weight). Based on this calculation, the AUC of SOF with LDV is only ~ 5.7% of DRM AUC.  
A drug interaction study (P7977-1819) of SOF with cyclosporine (potent multi-drug 
transporter inhibitor) demonstrated a 4-fold increase in systemic SOF exposure on 
administration with cyclosporine; the AUC of SOF increased from ~3 % (SOF alone) to 


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~11% (SOF with cyclosporine) of DRM AUC. Safety margins for all analytes of SOF on 
administration with cyclosporine continue to remain adequate (AUC safety margin ranges 
from 1.9 to 16.0) compared to exposures obtained in toxicology studies and dose 
modification of SOF is not warranted. 
Ledipasvir PK was not altered on co-administration with SOF. Accordingly, SOF and LDV 
may be co-administered without dose adjustment.  
No treatment-emergent AEs were reported in Cohort 1, based on a review of preliminary 
data. Two Grade 3 laboratory abnormalities were observed: an unconfirmed neutrophil count 
of 700 L in an African-American subject with an otherwise normal white blood cell count; 
and an unconfirmed 3+ blood in urine in an adult menstruating female. No Grade 4 
laboratory abnormalities were observed. 
1.2.4.1.6. 
Study GS-US-337-0101 
Study GS-US-337-0101 is an ongoing, single-center, Phase 1, single-dose, cross-over study 
evaluating the relative bioavailability and the effect of food on the PK of SOF 400 mg/LDV 
90 mg FDC in healthy volunteers.  
In Cohort 1, the PK of SOF 400 mg/LDV 90 mg FDC was evaluated relative to that of SOF 
400 mg + LDV 90 mg, coadministered as individual components. The effect of food 
(moderate-fat or high calorie/high-fat meals) on the PK of SOF/LDV FDC was evaluated in 
Cohort 2. 
Preliminary PK data from Cohorts 1 and 2 are presented in Table 1-16 and Table 1-17, 
respectively. 


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Table 1-16. 
Study GS-US-337-0101: Preliminary Pharmacokinetic Data for 
SOF, Metabolites (GS-566500 and GS-331007) and LDV on 
Administration of SOF/LDV FDC and SOF+LDV as Individual 
Components 
SOF (n=28) 
Mean (%CV) 
SOF/LDV FDC 
SOF + LDV 
%GMR (90%CI) 
AUCinf (ng.hr/mL) 
1350 (37.7) 
1560 (39.4) 
87.2 (77.8, 97.6) 
AUClast (ng hr/mL) 
1340 (37.9) 
1560 (39.6) 
87.2 (77.7, 97.7) 
Cmax (ng/mL) 
1320 (68.3) 
1550 (46.1) 
82.3 (71.2, 95.2) 
GS-566500 (n=28) 
Mean (%CV) 
SOF/LDV FDC 
SOF + LDV 
%GMR (90%CI) 
AUCinf (ng.hr/mL) 
1690 (30.0) 
2000 (27.8) 
85.4 (76.2, 95.8) 
AUClast (ng hr/mL) 
1650 (30.8) 
1950 (28.5) 
85.4 (75.6, 96.4) 
Cmax (ng/mL) 
429 (33.2) 
509 (28.7) 
86.0 (74.8, 98.9) 
GS-331007 (n=28) 
Mean (%CV) 
SOF/LDV FDC 
SOF + LDV 
%GMR (90%CI) 
AUCinf (ng.hr/mL) 
11900 (23.5) 
12500 (23.1) 
95.4 (89.9, 101) 
AUClast (ng hr/mL) 
11200 (24.4) 
11800 (23.6) 
95.3 (89.5, 101) 
Cmax (ng/mL) 
784 (36.2) 
764 (27.3) 
100 (91.2, 110) 
LDV (n=28) 
Mean (%CV) 
SOF/LDV FDC 
SOF + LDV 
%GMR (90%CI) 
AUCinf (ng.hr/mL) 
9570 (46.6) 
9620 (45.6) 
95.7 (79.1, 116) 
AUClast (ng hr/mL) 
7950 (41.6) 
8040 (40.0) 
95.3 (79.0, 115) 
Cmax (ng/mL) 
314 (45.2) 
314 (40.5) 
98.2 (82.1, 118) 
Data presented as 3 significant figures. 
 
Similar plasma exposures of SOF, its metabolites GS-566500 and GS-331007, and LDV 
were achieved upon administration of SOF/LDV FDC and SOF+LDV, co-administered as 
individual components. The lower bounds of the 90% confidence intervals (CIs) for the 
primary PK parameters (AUC and Cmax) of SOF, GS-566500 and LDV were greater than 
70%. The GMR% and 90% CIs for GS-331007 primary PK parameters were contained 
within bioequivalence bounds of 80-125%. Based on these data, this SOF/LDV FDC tablet 
formulation has been selected for Phase 3 clinical development. 


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Table 1-17. 
Study GS-US-337-0101: Preliminary Pharmacokinetic Data for 
SOF, Metabolites (GS-566500 and GS-331007) and LDV on 
Administration of SOF/LDV FDC Fasted or with a Moderate-Fat 
Meal or with A High-Calorie/High Fat Meal 
SOF (n=29) 
Mean (%CV) 
SOF/LDV FDC 
Fasted 
SOF/LDV FDC 
Moderate-Fat Meal 
% GMR (90% CI) 
[Moderate-Fat/Fasted] 
AUCinf (ng.hr/mL) 
1530 (39.2) 
2880 (33.6) 
194 (176, 214) 
AUClast (ng hr/mL) 
1520 (39.6) 
2870 (33.8) 
195 (1767, 215) 
Cmax (ng/mL) 
1240 (49.6) 
1540 (39.4) 
126 (109, 147) 
 
SOF/LDV FDC 
Fasted 
SOF/LDV FDC High-
Calorie/High-Fat Meal 
GMR (90% CI) 
[High-Fat/Fasted] 
AUCinf (ng.hr/mL) 
1530 (39.2) 
2590 (34.1) 
178 (161, 197) 
AUClast (ng hr/mL) 
1520 (39.6) 
2580 (34.4) 
178 (161, 197) 
Cmax (ng/mL) 
1240 (49.6) 
1380 (40.6) 
115 (99.0, 134) 
GS-566500 (n=29) 
Mean (%CV) 
SOF/LDV FDC 
Fasted 
SOF/LDV FDC 
Moderate-Fat Meal 
% GMR (90% CI) 
[Moderate-Fat/Fasted] 
AUCinf (ng.hr/mL) 
1520 (41.3) 
2490 (21.1) 
175 (161, 189) 
AUClast (ng hr/mL) 
1470 (43.3) 
2440 (21.5) 
180 (164, 196) 
Cmax (ng/mL) 
352 (42.7) 
489 (21.8) 
151 (136, 167) 
 
SOF/LDV FDC 
Fasted 
SOF/LDV FDC High-
Calorie/High-Fat Meal 
GMR (90% CI) 
[High-Fat/Fasted] 
AUCinf (ng.hr/mL) 
1520 (41.3) 
2550 (22.6) 
179 (165, 194) 
AUClast (ng hr/mL) 
1470 (43.3) 
2500 (23.0) 
184 (168, 201) 
Cmax (ng/mL) 
352 (42.7) 
507 (26.1) 
154 (139, 171) 
GS-331007 (n=29) 
Mean (%CV) 
SOF/LDV FDC 
Fasted 
SOF/LDV FDC 
Moderate-Fat Meal 
% GMR (90% CI) 
[Moderate-Fat/Fasted] 
AUCinf (ng.hr/mL) 
11800 (23.0) 
13800 (17.9) 
117 (112, 123) 
AUClast (ng hr/mL) 
11300 (23.4) 
12800 (18.3) 
114 (108, 121) 
Cmax (ng/mL) 
865 (26.6) 
696 (19.7) 
82.0 (76.0, 88.0) 
 
SOF/LDV FDC 
Fasted 
SOF/LDV FDC High-
Calorie/High-Fat Meal 
GMR (90% CI) 
[High-Fat/Fasted] 
AUCinf (ng.hr/mL) 
11800 (23.0) 
12900 (19.0) 
112 (107, 118) 
AUClast (ng hr/mL) 
11300 (23.4) 
12200 (19.4) 
110 (103, 116) 
Cmax (ng/mL) 
865 (26.6) 
597 (23.3) 
70.0 (65.0, 76.0) 


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LDV (n=27) 
Mean (%CV) 
SOF/LDV FDC 
Fasted 
SOF/LDV FDC 
Moderate-Fat Meal 
% GMR (90% CI) 
[Moderate-Fat/Fasted] 
AUCinf (ng.hr/mL) 
9610 (52.3) 
10100 (33.8) 
120 (103, 141) 
AUClast (ng hr/mL) 
7940 (51.0) 
8220 (30.0) 
118 (101, 139) 
Cmax (ng/mL) 
310 (45.4) 
313 (26.0) 
112 (96.0, 131) 
 
SOF/LDV FDC 
Fasted 
SOF/LDV FDC High-
Calorie/High-Fat Meal 
GMR (90% CI) 
[High-Fat/Fasted] 
AUCinf (ng.hr/mL) 
9610 (52.3) 
8740 (34.0) 
107 (92.0, 126) 
AUClast (ng hr/mL) 
7940 (51.0) 
7350 (31.3) 
107 (91.0, 126) 
Cmax (ng/mL) 
310 (45.4) 
254 (27.5) 
92.0 (79.0, 108) 
Data presented as 3 significant figures. 
 
Food slowed the rate of absorption of SOF (median Tmax: 1.00 versus 2.00 hours) with only 
modest alteration in the bioavailability, as evidenced by increases of 2-fold or less in SOF 
and GS-566500 plasma exposure. For GS-331007, an approximately 20-30% lower Cmax was 
observed upon SOF administration with food with no change in AUC. The %GMR and 
associated 90% CI (fed/fasted treatments) for AUC of GS-331007 were within the 
equivalence bounds of 70% to 143%. Since the decrease in GS-331007 Cmax was modest and 
the AUC parameters met the equivalence criteria, the effect of food on GS-331007 PK was 
not considered clinically significant. These results are consistent with the data from previous 
Phase 1 studies (P7977-1318 and P7977-0111), which demonstrated that SOF could be 
administered without regard to food. 
Similar LDV plasma exposures (AUC and Cmax) are achieved upon administration of LDV as 
the FDC under fasted or fed conditions. The %GMR and associated 90% CIs (fed/fasted 
treatments) were within the equivalence bounds of 70-143%.  While a “negative” food effect 
was previously observed on LDV (single agent administered as conventional formulation), 
the PK of LDV (spray dried formulation) administered within the SOF/LDV FDC does not 
appear to be altered by food. 
As such, SOF/LDV FDC may be administered without regard to food. 
Based on a preliminary safety data review of Cohorts 1 and 2, SOF/LDV FDC was generally 
well tolerated. Fifty-eight subjects were enrolled and 56 completed the study as planned. 
Two subjects withdrew consent in Cohort 2 for reasons not associated with an AE. The most 
frequently reported AEs in >1 subject were vessel puncture site pain (n=5), headache (n=5), 
abdominal pain (n=3), menstrual cramps (n=3), and constipation (n=3). AEs were transient 
and mostly mild in severity. A pregnancy was reported during the end of study follow-up 
visit in a 36 year old, 
 female, that later resulted in a SAE of spontaneous 
abortion (first trimester). No other SAEs,  Grade 2 AEs, or clinically significant laboratory 
abnormalities were reported. 
PPD


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1.2.4.2. 
Other Ongoing Phase 2 Studies 
Study GS-US-248-0120 is an ongoing all oral Phase 2 study that will examine the safety, 
tolerability and antiviral efficacy of LDV administered with GS-9451, TGV and RBV in 
treatment naïve, genotype 1 HCV infected subjects. Dosing is complete. 
Study GS-US-248-0121 is an ongoing Phase 2 study that will examine the efficacy, safety, 
and tolerability of response guided therapy of combinations LDV + GS-9451 + Peg-
IFNĮ/RBV for 6 or 12 weeks, compared to Peg-IFNĮ/RBV for 24 weeks in genotype 1 HCV 
infected, IL28B CC subjects. Dosing is complete. 
Study GS-US-248-0131 is an ongoing all oral Phase 2 study that will examine the safety, 
tolerability and antiviral efficacy of LDV, GS-9451, TGV and RBV compared with LDV, 
GS-9451 with TGV or RBV in treatment-experienced subjects with chronic genotype (1a or 
1b) HCV infection. Dosing is complete. 
Study GS-US-248-0132 is an ongoing all oral Phase 2 study that will examine the safety, 
tolerability and antiviral efficacy of LDV, GS-9451, TGV and RBV; LDV, GS-9451 and 
TGV; LDV, GS-9451 and RBV in IFN ineligible or intolerant subjects with chronic 
genotype (1a or 1b) HCV infection. Dosing is complete. 
Study GS-US-256-0148 is an ongoing Phase 2b study that will examine the efficacy, safety, 
and tolerability of response guided therapy with LDV, Peg-IFNĮ and RBV with or without 
GS-9451 in genotype 1 HCV infected, treatment-naïve subjects. Dosing is complete. 
Study GS-US-256-0124 is an ongoing Phase 2b study that will examine the efficacy, safety, 
and tolerability of response guided therapy of combinations of oral antivirals (LDV, TGV, 
and/or GS-9451) with Peg-IFNĮ and RBV in treatment experienced subjects with chronic 
genotype 1 HCV infection. Dosing is complete.  
1.2.4.2.1. 
Adverse Events in Ongoing Phase 2 Studies 
The treatment-emergent AEs reported through September 2012 for all subjects enrolled in the 
GS-US-248-0120, GS-US-248-0131, GS-US-248-0132, GS-US-248-0121 (Arm 1), 
GS-US-256-0124, GS-US-256-0148, aggregated by treatment regimen, is shown in 
Table 1-18. 


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Table 1-18. 
Treatment-Emergent Adverse Events Experienced by 10% of 
Subjects in Any Interferon-Free Regimen 
Preferred 
Terms 
LDV 
IFN-free 
regimens 
(N=469) 
LDV + GS-
9451 + 
TGV 
(N=109) 
LDV + GS-
9451 + 
TGV + 
RBV 
(N=251) 
LDV + 
GS-9451 
+ RBV 
(N=109) 
LDV IFN-
containing 
regimens 
(N=622) 
LDV + 
GS-9451 
+ Peg-
IFNĮ+ 
RBV 
(N=506) 
LDV + 
Peg-
IFNĮ+ 
RBV 
(N=116) 
Subjects 
experiencing 
any AE with 
10% 
incidence 
85% 
81% 
88% 
83% 
96% 
96% 
98% 
Fatigue 
29% 
27% 
30% 
27% 
45% 
45% 
46% 
Headache 
28% 
31% 
26% 
28% 
37% 
38% 
35% 
Nausea 
17% 
18% 
16% 
18% 
28% 
27% 
34% 
Rash 
10% 
6% 
13% 
9% 
24% 
24% 
22% 
Insomnia 
12% 
11% 
12% 
13% 
22% 
22% 
22% 
Pruritus 
13% 
10% 
14% 
12% 
19% 
18% 
22% 
Cough 
9% 
6% 
10% 
11% 
18% 
18% 
17% 
Diarrhea 
9% 
6% 
11% 
6% 
16% 
16% 
15% 
Anaemia 
6% 
0 
6% 
11% 
16% 
16% 
16% 
Dizziness 
7% 
12% 
7% 
3% 
12% 
12% 
10% 
 
1.3. 
Rationale for This Study 
This Phase 3b study is designed to evaluate the efficacy and safety of the SOF/LDV FDC 
tablet administered for 12 weeks in treatment-naïve and treatment-experienced subjects with 
chronic genotype 1 HCV infection. Up to 20% of subjects enrolled in the study may have 
compensated cirrhosis at screening.  
As previously described in Sections 1.1.2 and 1.1.3 in there is a significant unmet medical 
need in Korea and Taiwan for simple, well-tolerated, IFN-free, all-oral antiviral regimens for 
the treatment of chronic HCV infection.  The current standard of care (Peg-IFNĮ+RBV) for 
these patients in Korea and Taiwan is associated with significant toxicity, with many patients 
unwilling to be treated with these regimens. There also exists substantial numbers of patients 
who cannot receive Peg-IFNĮ due to relative or absolute contraindications {20450}, {17893}, 
{17893}, {15573}, {17892}, {3291}. 
Gilead has developed an FDC consisting of SOF with LDV, 2 well-tolerated, potent, once-
daily antiviral agents in late phase clinical development. Based on Phase 2 data, the 


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SOF/LDV FDC has the potential to be a simple and highly effective all-oral, once daily 
treatment regimen for chronic genotype 1 HCV infection, after 12 weeks of treatment. 
Initial proof of concept for the efficacy of SOF administered in combination with a HCV 
NS5A inhibitor came from the AI444-040 study (Section 1.2.2.2.1). In this study 12 weeks of 
SOF+DCV resulted in SVR4 rates of 95% and 98% when administered with RBV and 
without RBV respectively. In addition 100% (41/41) SVR4 was achieved when 
SOF+DCV±RBV was administered for 24 weeks in subjects who had failed to respond to 
Peg-IFNĮ+RBV+PI therapy. 
Subsequently, proof of concept for the efficacy of the SOF+LDV combination came from 
ELECTRON Arm 13 (n=25), in which 100% of the treatment-naïve patients who received 
SOF+LDV+RBV for 12 weeks achieved SVR12 (Section 1.2.3.2.1). Proof of concept for the 
efficacy of this same regimen in the most difficult-to-treat treatment-experienced patients 
(null responders) also came from ELECTRON Arm 12 (n=9), in which 100% of these 
patients achieved SVR12 after 12 weeks of therapy (Section 1.2.3.2.1). 
Finally demonstration that concurrent administration of RBV was not required with the 
SOF+LDV regimen to attain high rates of viral cure comes from the GS-US-337-0118 
(LONESTAR) study. Recent data from this ongoing study reports SVR8 rates of 95% 
(19/20) and 100% (21/21) in GT-1 treatment-naïve subjects for SOF/LDV FDC administered 
for 8 weeks, both with and without concomitant RBV respectively (Section 1.2.3.2.2). 
Following administration of SOF/LDV FDC for 12 weeks in GT-1 treatment-naïve subjects, 
100% (19/19) achieved SVR4. In GT-1 protease-inhibitor failures SOF/LDV FDC 
administered for 12 weeks achieved an SVR4 rate of 95% (18/19). Finally SOF/LDV FDC 
+RBV administered for 12 weeks in GT-1 treatment-experienced subjects achieved an SVR4 
rate of 95% (20/21); the final subject in this cohort is yet to return to the clinic in the post-
treatment period (Section 1.2.3.2.2). 
The ongoing, blinded GS-US-337-0102 (ION-1) Phase 3 study (Section 1.2.3.3.1) is 
evaluating the same SOF/LDV FDC regimen proposed for the study in Korea and Taiwan. 
The Data Monitoring Committee met on 25 March 2013 to evaluate the safety and predefined 
interim futility criteria, and indicated the study was safe to proceed unchanged. Neither 
Group 3 (SOF/LDV FDC, 12 weeks) nor Group 4 (SOF/LDV FDC + RBV, 12 weeks) met 
protocol defined futility criteria. 
Current data for the SOF/LDV FDC indicates the regimen to be safe, well-tolerated and 
associated high degrees of antiviral efficacy supporting the conduct of the proposed Phase 3 
study in Korean and Taiwanese subjects with GT-1 chronic hepatitis C. 
1.4. 
Rationale for Dose Selection of SOF 
The SOF dose selected for further development in Phase 3 studies is 400 mg once daily. 
Selection of the 400 mg dose is based on Emax modeling with early virologic and human 
exposure data and on efficacy and safety results from phase 2 trials. 




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In a study evaluating the efficacy of 200 mg and 400 mg doses of SOF in combination with 
Peg-IFNĮ+RBV for 12 weeks followed by Peg-IFNĮ+RBV for 12 weeks (Study P7977-0422 
[PROTON]), the 400 mg dose level was associated with higher SVR rates and lower 
occurrence of viral breakthroughs during the Peg-IFNĮ+RBV dosing phase, after completion 
of SOF+PEG-IFNĮ+RBV, in treatment-naïve subjects with genotype 1 HCV infection. 
Progression of the 400 mg SOF dose is further supported by preliminary efficacy results in 
other phase 2 studies. 
The safety profile of SOF also supports selection of 400 mg for continued development. SOF 
400 mg whether given as monotherapy, +RBV, or +Peg-IFNĮ+RBV has been well tolerated 
in studies to date. The safety and tolerability profile of the SOF 400 mg dose level was 
similar to that of the 200 mg dose level in Study P7977-0422. The AE profile observed in 
studies evaluating the combination SOF+RBV was similar to the AE profile of that expected 
following treatment with RBV alone. 
1.5. 
Rationale for Dose Selection of LDV 
Ledipasvir dose of 90 mg has been selected for co-formulation with SOF and evaluation in 
this study based on the multiple-dose safety and antiviral activity data (studies 
GS-US-256-0102 and GS-US-248-0120) and PK data (studies GS-US-256-0101 and 
GS-US-256-0110 formulation study). The Phase 1 multiple-ascending dose study 
GS-US-256-0102 established the anti-HCV activity of LDV. In this study, the maximum 
median HCV RNA log10 reduction was 3 or greater for all cohorts dosed with ≥ 3 mg of 
LDV. An Emax PK/PD model indicates that the exposures achieved following administration 
of the 30 mg dose provides > 95% of maximal antiviral response in genotype 1a HCV 
infected subjects. It was also observed that 30 mg or greater of LDV likely provided 
coverage of some drug related mutations that doses less than 30 mg did not, based on an 
analysis of NS5A mutants that arose in response to exposure to LDV. Therefore, 30 mg and 
90 mg of LDV were selected for further clinical evaluation.  
In IFN-free Study GS-US-248-0120, 30 mg of LDV (Arm 1) is being compared to 90 mg of 
LDV (Arm 2), administered with a background of 3 other antiviral agents, GS-9451, TGV, 
and RBV. When comparing these 2 arms, it is notable that the breakthrough (BT) rate 
(number of subjects with HCV RNA > lower limit of quantification (LLOQ) after having 
achieved vRVR/total number of subjects who achieved vRVR), is higher in 
Arm 1 (BT = 33%, 11/33; 30 mg LDV), than Arm 2 (BT = 12%, 9/74; 90 mg LDV). 
Therefore, the 90 mg dose of LDV may confer a greater antiviral coverage that prevents viral 
breakthrough. For this reason, a 90 mg dose has been selected as for further clinical testing in 
Phase 3 studies. More than 400 subjects have been dosed with 90 mg of LDV for over 
12 weeks. 
In study GS-US-256-0110, an optimized spray-dried formulation of LDV showed an ~25% 
increase in LDV exposure, as assessed by AUC and Cmax and a modestly lower variability in 
exposure compared to the original formulation; as such an spray dried formulation has been 
selected for clinical development and co-formulation with SOF into the FDC tablet. 


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1.6. 
Overall Risk/Benefit Assessment 
The SOF/LDV FDC product combines a potent HCV nucleotide NS5B inhibitor and a potent 
HCV NS5A inhibitor.  
The potential benefits of SOF/LDV FDC for the treatment of chronic HCV are: 
• Greater antiviral efficacy (i.e., rapid and durable eradication of HCV) compared to the 
current standard of care (Peg-IFNĮ +RBV) 
• A reduction in the AEs currently associated with the use of Peg-IFNĮ+RBV 
• A simple, well-tolerated regimen to replace the current complex, response-guided Peg-
IFNĮ +RBV regimens. 
• The potential benefit of a shortened SOF/LDV FDC therapy of 12 weeks is a decrease in 
the burden of treatment for both patients and physicians, through a reduction in the 
overall number of patient visits. 
The safety profile of SOF includes approximately 1600 chronic HCV-infected subjects that 
have been administered over 12 weeks of SOF in combination with a DAA, Peg-IFNĮ, with 
or without RBV. No clinical safety issues related to SOF have been identified to date. The 
safety profile of LDV includes over 1000 chronic HCV-infected subjects, of whom over 
700 have been administered more than 12 weeks of LDV, which was given in combination 
with other DAAs, Peg-IFNĮ, with or without RBV. No clinical safety issues related to LDV 
have been identified to date. 
Furthermore, there is no expectation of significant overlapping or new, unexpected toxicities 
upon administration of SOF/LDV together as an FDC. To date, the SOF/LDV FDC ± RBV 
has been administered to over 1200 HCV infected subjects in ongoing phase 2/3 trials. No 
clinical safety issues related to the SOF/LDV FDC have been identified to date. 
During the conduct of the study the Sponsor will perform ongoing safety data review. 
In summary, there is no currently approved all-oral treatment available for HCV-infected 
patients. This study will support the registration of the SOF/LDV FDC in treatment-naïve 
and treatment-experienced Korean and Taiwanese subjects with chronic genotype 1 HCV 
infection including those with compensated cirrhosis. 
1.7. 
Compliance 
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements. 




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3. 
STUDY DESIGN 
3.1. 
Endpoints 
The primary endpoints of this study are: 
• The primary efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after 
discontinuation of therapy) in the Full Analysis Set (FAS) population. 
• The primary safety endpoint is any AE leading to permanent discontinuation of study 
drug. 
Secondary endpoints of this study include: 
• Secondary efficacy endpoints include the proportion of subjects with: HCV 
RNA < LLOQ at 4 and 24 weeks after discontinuation of therapy (SVR4 and SVR24); 
viral breakthrough; relapse; and HCV RNA change from baseline. 
3.2. 
Study Design 
This will be an international (Korea and Taiwan), multicenter, open-label study in treatment-
naïve and treatment-experienced adults with chronic genotype 1 HCV infection. 
It is estimated that approximately 80 subjects will be enrolled in Korea and 80 subjects in 
Taiwan for a total of 160 enrolled subjects. Within each country approximately 50% 
(i.e., n~40) of subjects will be treatment-naïve and 50% will be treatment-experienced 
(i.e., n~40). 
Up to 20% of subjects enrolled in the study may have compensated cirrhosis at Screening. 
3.3. 
Study Treatment 
Approximately 80 treatment-naïve and 80 treatment-experienced subjects will receive 
treatment with SOF 400 mg/LDV 90 mg fixed dose combination (FDC) tablet for 12 weeks. 
3.4. 
Duration of Treatment 
All subjects will complete screening, on-treatment, and post-treatment assessments. 
Screening assessments will be completed within 28 days of the Baseline/Day 1 visit or within 
42 days if a liver biopsy or additional HCV genotyping is required. All subjects will receive 
treatment for 12 weeks. All subjects will complete a 4-week and 12-week Post-Treatment 
visit. Subjects with HCV RNA < LLOQ at the 12-Week Post-Treatment visit will also 
complete a 24-Week Post-Treatment visit unless confirmed viral relapse occurs.  
The assessments performed at each visit are described in Section 6. 


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3.5. 
Discontinuation Criteria  
When medically feasible, the Medical Monitor must be consulted prior to the premature 
discontinuation of treatment in a given subject. 
Study drug must be discontinued in the following instances: 
• Unacceptable toxicity, as defined in Section 7 of the protocol, or toxicity that, in the 
judgment of the investigator, compromises the ability to continue study-specific 
procedures or is considered to not be in the subject’s best interest 
• Pregnancy of female subject 
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 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. 
All subjects will complete the 4-Week and 12-Week Post-treatment visits. Subjects with 
HCV RNA < LLOQ at the 12-week Post-treatment visit will return for the 24-week Post-
treatment visit, unless confirmed viral relapse occurs. Study drug may be discontinued in the 
following instances: 
• Significant protocol violation 
• Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason 
• Discontinuation of the study at the request of Gilead, regulatory agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) 
If a subject meets discontinuation criteria during treatment, an Early Termination (ET) visit 
will be required (Section 6.4.9). Following completion of the Early Termination visit, all 
subjects must complete the 4-week and 12-week Post-Treatment visits. All patients with 
HCV RNA < LLOQ at the 12-week Post-Treatment visit must return to the clinic for 24-
week Post Treatment assessments, unless confirmed viral relapse occurs. 


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3.6. 
Source Data 
A Health Related Quality of Life survey, Short-Form-36 (SF-36) will be completed by 
subjects at various timepoints during the study and be used as source data. The subject should 
read the questionnaire by himself/herself and write/mark answers directly onto the 
questionnaire. 


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4. 
SUBJECT POPULATION 
4.1. 
Number of Subjects and Subject Selection 
Approximately 160 subjects will be enrolled in this study with approximately 
80 treatment-naïve subjects and approximately 80 treatment-experienced subjects.  Up to 
20% of subjects enrolled in the study may have compensated cirrhosis at screening. 
In order to manage the total study enrollment, Gilead Sciences, Inc., at its sole discretion, 
may suspend screening and/or enrollment at any site or study-wide at any time. 
4.2. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study. 
1) Willing and able to provide written informed consent 
2) Male or female, age ≥ 20 years 
3) Body weight ≥ 40 kg 
4) HCV RNA ≥ 104 IU/mL at Screening 
5) HCV treatment-naïve, as defined as no prior exposure to any IFN, RBV, or other 
approved or experimental HCV-specific direct-acting antiviral agent; OR HCV 
treatment-experienced with medical records that include sufficient detail of prior 
treatment with IFN to allow for categorization of prior response as either: 
a) IFN Intolerant:  Subject completed  12 weeks of treatment (ending  3 months prior 
to Screening) with IFN and discontinued treatment due to development or significant 
worsening of at least one of the following conditions: 
• Significant local or systemic adverse reaction to IFN (e.g., hypersensitivity, 
injection site reactions) 
• Psychiatric disease necessitating hospitalization or period of disability or 
psychosis, schizophrenia, bipolar disorder, depression, schizoaffective disorder, 
suicidal ideation, or suicide attempt 
• Significant cognitive impairment 
• Neuropathy 
• Disabling flu-like symptoms (arthralgias, fatigue, pyrexia, myalgia) 


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• Gastrointestinal toxicity with nausea, vomiting or diarrhea  
• Thrombocytopenia (platelets < 25,000/μL) 
• Neutropenia (ANC < 500/μL) 
• Development of colitis, non-alcoholic pancreatitis or ophthalmologic disorders 
• Autoimmune disorder including but not limited to: myositis, hepatitis, 
inflammatory bowel disease, interstitial lung disease, interstitial nephritis, 
immune (idiopathic) thrombocytopenic purpura, psoriasis, rheumatoid arthritis, 
sarcoidosis, systemic lupus erythematosus, thrombotic thrombocytopenic purpura, 
thyroiditis. 
• AE related to IFN that is not listed after consultation with the Medical Monitor 
b) Non-Response: Subject did not achieve undetectable HCV RNA levels while on 
treatment 
c) Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during 
treatment or within 4 weeks of the end of treatment but did not achieve a sustained 
virologic response (SVR). 
6) Genotype 1 HCV at Screening as determined by the Central Laboratory. Any 
non-definitive results will exclude the subject from study participation 
7) Confirmation of chronic HCV infection documented by either: 
a) A positive anti-HCV antibody test or positive HCV RNA or positive HCV 
genotyping test at least 6 months prior to the Baseline/Day 1 visit, or 
b) A liver biopsy performed prior to the Baseline/Day 1 visit with evidence of chronic 
HCV infection 
8) Cirrhosis determination [up to 20% of subjects enrolled in the study may have 
compensated cirrhosis]:  
a) Cirrhosis is defined as any one of the following: 
i) Liver biopsy showing cirrhosis (e.g. Metavir score = 4 or Ishak score ≥ 5) 
ii) Fibroscan indicative of cirrhosis as evidenced by a result > 12.5 kPa 
b) Absence of cirrhosis is defined as any one of the following: 
i) Liver biopsy within 2 years of Screening showing absence of cirrhosis 
ii) Fibroscan within 6 months of Baseline/Day 1 with a result of  12.5 kPa 


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c) In the absence of a definitive diagnosis of the presence or absence of cirrhosis by the 
above criteria, a liver biopsy is required; liver biopsy results will supersede any 
imaging studies or blood test results and be considered definitive. 
9) Liver imaging within 6 months of Baseline/Day 1 to exclude hepatocellular carcinoma 
(HCC) is required in patients with cirrhosis 
10) Screening ECG without clinically significant abnormalities 
11) Subjects must have the following laboratory parameters at screening:  
a) ALT ≤ 10 × the upper limit of normal  (ULN) 
b) AST ≤ 10 × ULN 
c) Direct bilirubin ≤ 1.5 × ULN 
d) Platelets  ≥  50,000/L 
e) HbA1c ≤ 8.5% 
f) Creatinine clearance (CLcr) ≥ 50 mL /min, as calculated by the Cockcroft-Gault 
equation {2202} 
g) Hemoglobin  ≥  11 g/dL for female subjects; ≥  12 g/dL for male subjects. 
h) Albumin ≥ 3g/dL  
i) INR  1.5 x ULN unless subject has known hemophilia or is stable on an 
anticoagulant regimen affecting INR. 
12) 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 Baseline/Day 1 prior 
to randomization. 
13) 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. 
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. 


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4.3. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. 
1) Current or prior history of any of the following: 
a) Clinically-significant illness (other than HCV) or any other major medical disorder 
that may interfere with subject treatment, assessment or compliance with the protocol; 
subjects currently under evaluation for a potentially clinically-significant illness 
(other than HCV) are also excluded.   
b) Gastrointestinal disorder or post operative condition that could interfere with the 
absorption of the study drug.  
c) Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy. 
d) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal 
hemorrhage). 
e) Solid organ transplantation. 
f) Significant pulmonary disease, significant cardiac disease or porphyria. 
g) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of 
their psychiatric illness within the last 5 years. Subjects with psychiatric illness 
(without the prior mentioned conditions) that is well-controlled on a stable treatment 
regimen for at least 12 months prior to Baseline/Day 1 or has not required medication 
in the last 12 months may be enrolled.  
h) 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. 
i) Significant drug allergy (such as anaphylaxis or hepatotoxicity).  
2) If treatment-naïve, prior exposure to approved or experimental HCV-specific direct-
acting antiviral agent(s). If treatment-experienced, prior exposure to approved or 
experimental HCV-specific direct-acting antiviral agent(s) other than NS3/4A protease 
inhibitors is prohibited. 
3) Pregnant or nursing females. 
4) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency, cholangitis). 
5) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV). 


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6) Donation or loss of more than 400 mL blood within 2 months prior to Baseline/Day 1 
7) Use of any prohibited concomitant medications as described in Section 5.4. 
8) Administration of interferon or any HCV-directed treatment, other than the study drug, is 
prohibited from 12 weeks prior to Screening until completion of the final post-treatment 
follow-up visit. 
9) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone 
equivalent > 10 mg/day), azathioprine or monoclonal antibodies such as infliximab. 
10) Known hypersensitivity to SOF, LDV, or formulation excipients.  


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5. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
5.1. 
Randomization and Treatment Codes 
This is an open-label, non-randomized study. Every subject will receive SOF/LDV FDC 
tablet for 12 weeks. An Interactive Web Response System (IWRS) will be employed to 
manage subject enrollment and study drug dispensation. 
5.2. 
Description and Handling of Sofosbuvir/Ledipasvir Fixed-Dose 
Combination  
5.2.1. 
Formulation 
Sofosbuvir (SOF)/ledipasvir (LDV) fixed-dose combination (FDC) tablets are orange, 
diamond-shaped, film-coated tablets containing 400 mg of SOF and 90 mg of LDV. The 
tablets are debossed with “GSI” on one side and “7985” on the other side. The SOF/LDV 
FDC tablets contain the following inactive ingredients: lactose monohydrate, copovidone, 
microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium 
stearate, polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, FD&C yellow # 6 
/sunset yellow FCF aluminum lake. 
5.2.2. 
Packaging and Labeling 
Sofosbuvir (SOF)/ledipasvir (LDV) fixed-dose combination (FDC) tablets are packaged in 
white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets and a silica 
gel desiccant canister or sachet and polyester packing material. Each bottle is enclosed with a 
white, continuous thread, child-resistant screw cap with an induction-sealed, aluminum-faced 
liner. 
All labels for SOF/LDV FDC bottles to be distributed to study centers in participating 
countries shall be labeled to meet all applicable requirements of the US Food and Drug 
Administration (FDA) and local regulations as applicable. 
Sufficient quantities of SOF/LDV FDC tablets to complete the entire study will be shipped to 
the investigator or qualified designee from Gilead Sciences Materials & Logistics (or its 
designee). 
5.2.3. 
Storage and Handling 
Sofosbuvir (SOF)/ledipasvir (LDV) FDC bottles should be stored at controlled room 
temperature until required for administration. Controlled room temperature is defined as 
25 °C; excursions are permitted between 15 °C and 30 °C. 
All drug products should be stored in a securely locked area, accessible only to authorized 
site personnel. To ensure the stability of the Investigational Medicinal Product (IMP) and to 


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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/LDV FDC. 
5.3. 
Dosage and Administration of Sofosbuvir/Ledipasvir FDC  
Sofosbuvir/Ledipasvir 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 IMP doses. In order to maintain compliance with the treatment regimen, 
SOF/LDV FDC should be administered at approximately the same time each day. 
For missed dose(s) of study medication, subjects should be instructed to take the missed 
dose(s) of IMP as soon as possible during the same day.  Subjects should be cautioned never 
to double the next dose with a missed dose of IMP under any circumstances. 
5.4. 
Prior and Concomitant Medications 
Concomitant medications taken within 30 days prior to Screening, up to and including the 
date of the visit four weeks after discontinuation of study treatment need to be recorded in the 
source documents and electronic case report form(s) (eCRFs). 
Administration of interferon or any HCV-directed treatment, other than the study drug, is 
prohibited from 12 weeks prior to Screening until completion of the final post-treatment 
follow-up visit. 
The following medications are prohibited during the screening period and for a minimum of 
30 days prior to the Baseline/Day 1 visit through the end of treatment: 
• Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents (ESAs); 
granulocyte colony stimulating factor (GCSF); thrombopoietin (TPO mimetics) 
• Chronic use of systemic immunosuppressants including, but not limited to,  
corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or 
monoclonal antibodies (e.g., infliximab) 
• Investigational agents or devices for any indication 
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers 
of drug transporters ie, P-gp) with study drug may result in pharmacokinetic interactions 
resulting in increases or decreases in exposure of study drug.   
Examples of representative medications which are prohibited from 30 days prior to 
Baseline/Day 1 through the end of treatment are listed below: 


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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 
Antiarrhythmics b 
 
Quinidine  
Anticonvulsantsc 
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine 
 
Antimycobacterialsc 
Rifabutin, Rifapentine, Rifampin 
 
Cardiac Medications b 
Digoxin 
Valsartan, Olmesartan, Telmisartan, 
Ranolazine, Bosentan 
Herbal/Natural 
Supplementsc 
St. John’s Wort, Echinaccea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-
to (or Xiao-Shai-Hu-Tang) 
 
HMG-CoA Reductase 
Inhibitorsd 
Rosuvastatin 
Atorvastatin (< 10 mg per day), 
Simvastatin, Pravastatin, Pitavastatin, 
Fluvastatin, Lovastatin 
Other 
Modafinilc 
 
a 
The 30 day washout period does not apply to PPIs, which can be taken up to 7 days before baseline Day 1. H2-receptor 
antagonists must not exceed a daily dose of 20 mg of famotidine or equivalent. Antacids that directly neutralize 
stomach pH (i.e. Tums, Maalox) may not be taken within 4 hours (before or after) of SOF/LDV FDC administration. 
b 
May result in an increase in the concentration of study drugs and/or concomitant medications 
c 
May result in a decrease in the concentrations of study drugs. 
d 
Use with study drugs may result in an increase in the concentration of the HMG-CoA Reductase Inhibitors. Monitor for 
signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis. 
 
Medications for disease conditions excluded from the protocol (eg, HIV-1 infection, active 
cancer, transplantation) are not listed under this Concomitant Medication section and are 
disallowed in the study.  
5.5. 
Accountability for SOF/LDV FDC  
The investigator is responsible for ensuring adequate accountability of all used and unused 
IMP. This includes acknowledgement of receipt of each shipment of IMP (quantity and 
condition). All used and unused IMP dispensed to subjects must be returned to the site. 
SOF/LDV FDC accountability records will be provided to each study site to: 
• Record the date received and quantity of IMP kits. 
• Record the date, subject number, subject initials, the IMP kit number dispensed. 
• Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information. 


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Subjects must be instructed to bring back all bottles of study medication in the original 
container at every post-baseline study visit through the end of treatment. 
Study medication will be reconciled using medication pill counts at every post-baseline visit 
by the investigator or designee (e.g., pharmacist, study coordinator) in order to monitor the 
subject’s adherence with the medication regimen.  
5.5.1. 
Investigational Medicinal Product Return or Disposal 
Please refer to Section 9.1.7 for Investigational Medicinal Product Accountability and 
Return. 


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6. 
STUDY PROCEDURES 
Study visits will occur at Screening, Baseline/Day 1, and on-treatment at the end of Weeks 1, 
2, 4, 6, 8, 10, and 12.  All subjects will complete 4-week and 12-week Post-Treatment visits. 
In addition, all subjects with HCV RNA < LLOQ at the 12-week Post-Treatment visit will 
complete a 24-week Post-Treatment visit unless confirmed viral relapse occurs. The end of 
study will occur at the 12-week or 24-week Post-Treatment visit according to virologic 
response. 
Administration of interferon or any HCV-directed treatment, other than the study drug, is 
prohibited from 12 weeks prior to Screening until completion of the final post-treatment 
follow-up visit. 
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. Additional information is 
provided in the study procedures manual. 
The investigator must document any deviation from protocol procedures and notify the 
sponsor or contract research organization (CRO). 
Information on the specific laboratory parameters to be measured and clinical assessments to 
be performed are provided below. 
6.1. 
Subject Enrollment and Treatment Assignment  
6.2. 
Pretreatment Assessments 
6.2.1. 
Screening Visit (Day -28 to Day -1) 
Screening assessments will be completed within 28 days of the Baseline/Day 1 visit. The 
screening window can be extended to 42 days for subjects requiring liver biopsy or additional 
HCV genotype testing.  
Subjects will be screened to determine eligibility for participation in the study. The following 
will be performed and documented at screening: 
• Obtain signed informed consent 
— A separate informed consent will be required from subjects participating in the 
intensive pharmacokinetic and/or pharmacogenomic sub-studies. 
• Determine inclusion eligibility (Reference Section 4.2 and 4.3) 


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— If the presence of cirrhosis is determined, then appropriate diagnostic imaging (e.g., 
CT or Ultrasound) should be performed to exclude the presence of hepatocellular 
carcinoma (HCC) 
• Obtain medical history (Reference Section 6.6.2.) 
• Perform complete physical examination  
• Obtain body height and weight 
• Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature) 
• Perform 12-lead ECG 
• Assessment of AEs and concomitant medications  
• Obtain blood samples for tests  
— Hematology & Chemistry 
— Coagulation tests 
— HCV RNA 
— Serum β-hCG pregnancy test for females of childbearing potential only 
— IL28B genotype  
— Determination of genotype and subtype of HCV infection 
— HCV antibody, HIV 1/2 antibody, and HBV surface antigen (HBsAg) 
— HbA1c 
— TSH 
• Obtain urine sample for: 
— Urinalysis 
Record any adverse events occurring after signing of the consent form. 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to 
the clinic within 28-42 days after screening for entry 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 


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non-serious adverse events related to protocol-mandated procedures on the adverse events 
case report form (CRF/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 CRF/eCRF.  See Section 7 Adverse Events and Toxicity Management for 
additional details. 
6.3. 
Randomization 
This is a non-randomized study. An Interactive Web Response System (IWRS) will be 
employed to manage subject enrollment and study drug dispensation. 
6.4. 
Treatment Assessments 
6.4.1. 
Baseline/Day 1 Visit 
The following baseline tests and procedures must be completed prior to dosing/dispensing: 
• Confirm eligibility 
• Perform complete physical examination 
• Obtain body weight 
• Obtain vital signs 
• Perform 12-lead ECG 
• Assessment of AEs and concomitant medications 
• Pregnancy prevention counseling 
• Subject completes Health Related Quality of Life Survey, SF-36 
• Obtain blood samples for: 
— Hematology & Chemistry 
— Coagulation tests 
— HCV RNA 
— Viral RNA Sequencing / Phenotyping Sample 
— Archive Sample (for subjects that have not opted out) 
— Pharmacogenomic testing (for subjects who have consented to participate in the 
Pharmacogenomic Substudy) 


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• Obtain urine sample for: 
— β-hCG pregnancy test for females of childbearing potential only 
• Drug Administration 
— Dispense study drugs 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 drugs and record the time of first 
dose. 
6.4.2. 
Week 1 (± 3 days) 
The following procedures/assessments are to be completed at the end of Week 1. 
• Obtain vital signs 
• Perform 12-lead ECG 
• Assessment of AEs and concomitant medications 
• Obtain blood samples for: 
— Hematology & Chemistry 
— HCV RNA 
— Single PK Sample 
— Viral RNA Sequencing / Phenotyping Sample  
• Complete medication pill count and review patient diary data with subject 
6.4.3. 
Week 2 (± 3 days) 
The following procedures/assessments are to be completed at the end of Week 2: 
• Obtain vital signs 
• Assessment of AEs and concomitant medications 
• Subject completes Health Related Quality of Life Survey, SF-36 


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• Obtain blood samples for: 
— Hematology & Chemistry 
— HCV RNA 
— Single PK Sample 
— Viral RNA Sequencing / Phenotyping Sample  
— If applicable at Week 2, collect serial PK substudy samples (for subjects who have 
consented to participate in the PK substudy) 
• Complete medication pill count and review dosing diary data with subject 
6.4.4. 
Week 4 (± 3 days) 
The following procedures/assessments are to be completed at the end of Week 4: 
• Obtain vital signs 
• Assessment of AEs and concomitant medications 
• Subject completes Health Related Quality of Life Survey, SF-36 
• Obtain blood samples for: 
— Hematology & Chemistry 
— HCV RNA 
— Single PK Sample 
— Viral RNA Sequencing / Phenotyping Sample  
• Obtain urine sample for: 
— β-hCG pregnancy test for females of childbearing potential only 
— If applicable at Week 4, collect serial PK substudy samples (for subjects who have 
consented to participate in the PK substudy) 
• Complete medication pill count and review patient diary data with subject 
• Dispense study drugs as directed by the IWRS 
6.4.5. 
Week 6 (± 3 days) 
The following procedures/assessments are to be completed at the end of Week 6. 


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• Obtain vital signs 
• Assessment of AEs and concomitant medications 
• Obtain blood samples for: 
— Hematology & Chemistry 
— HCV RNA 
— Single PK Sample 
— Viral RNA Sequencing / Phenotyping Sample  
• Complete medication pill count and review patient diary data with subject 
6.4.6. 
Week 8 (± 3 days) 
The following procedures/assessments are to be completed at the end of Week 8: 
• Obtain vital signs 
• Assessment of AEs and concomitant medications 
• Subject completes Health Related Quality of Life Survey, SF-36 
• Obtain blood samples for: 
— Hematology & Chemistry 
— HCV RNA 
— Single PK Sample 
— Viral RNA Sequencing / Phenotyping Sample 
• Obtain urine sample for: 
— β-hCG pregnancy test for females of childbearing potential only 
• Complete medication pill count and review patient diary data with subject 
• Dispense study drugs as directed by the IWRS 
6.4.7. 
Week 10 (± 3 days) 
The following procedures/assessments are to be completed at the end of Week 10. 


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• Obtain vital signs 
• Assessment of AEs and concomitant medications 
• Obtain blood samples for: 
— Hematology & Chemistry 
— HCV RNA 
— Single PK Sample 
— Viral RNA Sequencing / Phenotyping Sample 
Complete medication pill count and review patient diary data with subject 
6.4.8. 
Week 12 (± 3 days) 
The following procedures/assessments are to be completed at the end of Week 12: 
• Perform complete physical examination 
• Obtain body weight 
• Obtain vital signs 
• Perform 12-lead ECG 
• Assessment of AEs and concomitant medications 
• Pregnancy prevention counseling 
• Subject completes Health Related Quality of Life Survey, SF-36 
• Obtain blood samples for: 
— Hematology & Chemistry 
— Coagulation tests 
— HCV RNA 
— Single PK Sample 
— Viral RNA Sequencing / Phenotyping Sample 
— Archive Sample (for subjects that have not opted out) 
• Obtain urine sample for: 


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— β-hCG pregnancy test for females of childbearing potential only 
• Complete medication pill count and review patient diary data with subject 
6.4.9. 
Early Termination (ET)/Unscheduled Visit  
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. 
The assessments at the unscheduled visits are at the investigator’s discretion. At all 
unscheduled visits initiated for the purpose of confirming virologic failure, a Viral RNA 
Sequencing / Phenotyping Sample must be collected.  
The Sponsor (e.g. Medical Monitor and Clinical Program Manager)/ PAREXEL must be 
informed, as soon as possible, when a subject prematurely discontinues treatment.  The 
primary reason for premature treatment discontinuation must be provided to the Sponsor/ 
PAREXEL.   
If a subject discontinues treatment early for any reason then the following assessments for the 
Early Termination (ET) Visit must be performed:  
• Perform complete physical examination 
• Obtain body weight 
• Obtain vital signs 
• Perform 12-lead ECG 
• Assessment of AEs and concomitant medications 
• Pregnancy prevention counseling 
• Subject completes a Health Related Quality of Life Survey, SF-36 
• Obtain blood samples for: 
— Hematology & Chemistry 
— Coagulation tests 
— HCV RNA 
— Single PK Sample 
— Viral RNA Sequencing / Phenotyping Sample 
— Archive Sample (for subjects that have not opted out) 


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• Obtain urine sample for: 
— β-hCG pregnancy test for females of childbearing potential only 
• Complete medication pill count and review dosing diary data with subject 
6.5. 
Post-Treatment Assessments 
All subjects must complete the Post-Treatment Week 4 and Week 12 visits. For subjects who 
have completed an ET visit, the post-treatment Week 4 and Week 12 follow-up visits will be 
scheduled at 4 and 12 weeks after the last dose of study drug. All subjects with HCV RNA 
< LLOQ at the 12-week Post-Treatment visit will also complete the 24-week Post-Treatment 
visit, unless viral relapse is determined. 
6.5.1. 
Post Treatment Week 4 (± 5 days) 
The following procedures/assessments are to be completed for all subjects, 4 Weeks after 
taking the last dose of study drug: 
• Obtain vital signs 
• Assessment of AEs and concomitant medications 
• Pregnancy prevention counseling  
• Subject completes a Health Related Quality of Life Survey, SF-36 
• Obtain blood samples for: 
— Hematology & Chemistry 
— HCV RNA 
— Viral RNA Sequencing / Phenotyping Sample  
• Obtain urine sample for: 
— β-hCG pregnancy test for females of childbearing potential only 
All subjects, including those who prematurely discontinue study drug, must return for Post 
Treatment Visit at Week 12. 
6.5.2. 
Post Treatment Weeks 12 and 24 (± 5 days) 
The following procedures/assessments are to be completed for the Post-treatment Week 12 
and 24 Visits: 


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• Obtain body weight 
• Obtain vital signs 
• Subject completes a Health Related Quality of Life Survey, SF-36 (Post treatment 
Week 12 only) 
• Obtain blood samples for: 
— HCV RNA 
— Viral RNA Sequencing / Phenotyping Sample  
Subjects with HCV RNA < LLOQ at the Post-Treatment Week 12 Visit will return at the 
post-treatment Week 24 Visit.  
6.6. 
Procedures and Specifications 
6.6.1. 
Clinical Laboratory Analytes 
Hematology: Hematocrit, Hemoglobin (Hb), Platelet count, Red blood cell count (RBC), 
White blood cell count (WBC) with differential (absolute and percentage) including 
Lymphocytes, Monocytes, Neutrophils, Eosinophils, Basophils, Reticulocyte count and 
MCV. 
Coagulation: INR, Prothrombin time (PT), Activated partial thromboplastin time (APTT). 
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase 
(AST/SGOT), Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct 
Bilirubin), Direct Bilirubin at Screening only, Glucose, Lipase, Potassium, Sodium; 
Gamma-glutamyl transferase (GGT) at Baseline only. 
Urinalysis: Appearance, Blood, Color, Glucose, Leukocyte esterase, pH, Protein, 
Urobilinogen. Reflex to microscopic urinalysis if dipstick result is abnormal. 
Virological Tests: Serologies for HCV, HBV and HIV. HCV RNA will be measured using 
the COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System. HCV genotype 
and subtype will be determined using the Siemens VERSANT® HCV Genotype INNO-LiPA 
2.0 Assay. Gilead reserves the right to use alternate assays for HCV RNA and HCV genotype 
should the above assays become unavailable 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. 


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Pregnancy Tests: Serum β-hCG or Urine β-hCG (if positive, requires immediate 
confirmation with Serum β-hCG) 
Additional Tests: Hemoglobin A1c (HbA1c), and TSH (reflex free T4). 
6.6.2. 
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. Additionally, for treatment naïve subjects, any relative or absolute 
contraindications to interferon treatment (“IFN ineligible”) should be identified. Information 
related to HCV infection will also be collected. 
For treatment-experienced subjects, obtain HCV treatment history, in order to categorize the 
patient as either IFN-intolerant, non-responder or relapse/breakthrough, defined as: 
• IFN-intolerant:  Subjects considered to be IFN-intolerant must (according to investigator 
judgment) have sufficiently recovered from IFN-related clinical adverse events and/or 
laboratory abnormalities prior to Screening. In addition, all other protocol eligibility 
criteria must be met. 
• Non-Responder: Subject did not achieve undetectable HCV RNA levels (HCV RNA  
LLOQ) while on treatment. For Peg-IFNĮ/IFN/RBV non-responders, subjects should be 
further defined as Null or Partial Responders: 
— Null Responders: HCV RNA < 2 Log10 reduction during the first 12 weeks of 
treatment. 
— Partial Responders: HCV RNA  2 Log10 reduction during the first 12 weeks of 
treatment. 
• Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels (HCV RNA 
< LLOQ) during treatment or within 4 weeks of end of treatment, but did not achieve a 
sustained virologic response (SVR). 
6.6.3. 
Complete Physical Examination 
A complete physical examination must include source documentation of general appearance, 
and the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and 
tongue; chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, 
hair, nails; musculoskeletal; neurological.  
6.6.4. 
Vital Signs 
Assessment of vital signs will include measurement of resting blood pressure, pulse, 
respiratory rate, and temperature. 


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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. 
6.6.5. 
Creatinine Clearance 
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} using actual body 
weight (BW).  
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) 
6.6.6. 
12-Lead ECGs 
Subjects will be required to rest in a supine position for ≥ 5 minutes prior to making a 
recording.  
The investigator (or qualified designee) should review the ECG traces recorded in real time 
for clinically significant abnormalities.  On-treatment ECGs should be compared to the 
subject’s Baseline as part of routine safety monitoring.   
6.6.7. 
Viral RNA Sequencing / Phenotyping Sample  
Plasma samples will be collected at Baseline/Day 1 and each visit for viral sequence analysis. 
At any unscheduled visit initiated for the purpose of confirming virologic breakthrough, a 
plasma sample for viral sequence analysis must be collected. Untested samples may be 
archived. 
Details regarding the collection, processing, and shipping of samples will be included in the 
lab manual. 
6.6.8. 
Archive Sample 
A plasma sample will be obtained from all subjects at the Baseline/Day 1 visit and at the end 
of treatment (i.e., Week 12) or Early Termination visit for future research use. Unlike the 






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7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT 
7.1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events 
7.1.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and/or unintended sign, 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. AEs may also include pre- or post treatment 
complications that occur as a result of protocol specified procedures, lack of efficacy, 
overdose, drug abuse/misuse reports, or occupational exposure. Preexisting events that 
increase in severity or change in nature during or as a consequence of participation in the 
clinical study will also be considered AEs. 
An AE does not include the following: 
• Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and 
transfusion. The condition that led to the procedure may be an adverse event and must be 
reported. 
• Pre-existing diseases, conditions, or laboratory abnormalities present or detected before 
the screening visit that do not worsen 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions) 
• Overdose without clinical sequelae (see Section 7.7.1) 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not 
an AE. It is considered to be pre-existing and should be documented on the medical 
history CRF. 
7.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an event that, at any dose, results in the 
following: 
• Death 
• Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more severe.) 


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


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7.3. 
Investigator Requirements and Instructions for Reporting Adverse 
Events and Serious Adverse Events to Gilead or CRO 
All SAEs, regardless of causal relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to 
the CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. 
This also includes any SAEs resulting from protocol-mandated procedures performed from 
screening onwards. 
All AEs, regardless of causal relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP must be reported to the CRF/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 post-treatment follow 
up period.  
Investigators are not obligated to actively seek SAEs after post treatment follow-up. 
However, if the investigator learns of any SAEs that occur after study participation has 
concluded, i.e., after the 12-week or 24-week post treatment visit (as applicable) and the 
event is deemed relevant to the use of IMP, he/she should promptly document and report the 
event to Gilead DSPH. Gilead DSPH contact information is as follows: Email: 
Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
• All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines 
outlined in the CRF/eCRF completion guideline. 
• At the time of study start, SAEs may be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE 
(eSAE) system. Gilead will notify sites in writing and provide training and account 
information prior to implementing an eSAE system. 
Serious Adverse Event Paper Reporting Process 
• All SAEs will be recorded on the serious adverse event report form and submitted by 
emailing or faxing the report form within 24 hours of the investigator’s knowledge of the 
event to the attention of the designated PAREXEL Pharmacovigilance Representative. 
Electronic Serious Adverse Event (eSAE) Reporting Process  
• Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the 
event. Detailed instructions can be found in the eCRF completion guidelines. 




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7.4. 
Gilead Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to 
expedite to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions 
(SADRs), or suspected unexpected serious adverse reactions (SUSARs). In accordance with 
the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify 
worldwide regulatory agencies and the relevant IEC in concerned Member States of 
applicable SUSARs as outlined in current regulations. 
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable.  
All investigators will receive a safety letter notifying them of relevant SUSAR reports. 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. 
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). 
Severity should be recorded and graded according to the GSI Grading Scale for Severity of 
AEs 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. 
7.6. 
Subject Stopping Rules 
The Medical Monitor must be consulted prior to dose discontinuation of SOF/LDV 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/LDV FDC dose reduction. If SOF/LDV FDC is stopped due to 


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toxicity, it must not be restarted; if SOF/LDV FDC is discontinued, the subject must 
complete an ET visit. Post-treatment 4-Week and 12-Week visits must also be scheduled, 4 
and 12 weeks from the last dose of study drug. Subjects with HCV RNA < LLOQ at the 
12-week Post-Treatment visit will complete the 24-week Post-Treatment visit, unless viral 
relapse is determined.  
Subjects who meet any of the following laboratory criteria must stop study medication: 
• Elevation of ALT and/or AST > 5x Baseline/Day 1 or nadir, confirmed by immediate 
repeat testing 
• Abnormal elevation of ALT > 3 x Baseline/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 as related to SOF/LDV 
FDC 
7.7. 
Special Situations Reports 
7.7.1. 
Definitions of Special Situations 
Special situation reports include all reports of medication error, abuse, misuse, overdose, and 
pregnancy reports regardless of an associated AE.  Also includes reports of adverse reactions 
in infants following exposure from breastfeeding, and reports of adverse reactions associated 
with product complaints and reports arising from occupational exposure. 
A pregnancy report is used to report any pregnancy following maternal or paternal exposure 
to the medicinal product. 
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. In cases of a discrepancy in drug accountability, 
overdose will be established only when it is clear that the subject has taken the excess 


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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.   
7.7.2. 
Instructions for Reporting Special Situations 
7.7.2.1. 
Instructions for Reporting Pregnancies 
The investigator should report all pregnancies that are identified after the subject first 
consents to participate in the study (ie, signs the informed consent) and throughout the study, 
including the post study drug follow-up period, to the PAREXEL Pharmacovigilance 
Representative/ PAREXEL Safety Department using the pregnancy report form within 24 
hours of becoming aware of the pregnancy.  
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 the Serious Adverse Events section (Section 7.3). Furthermore, any SAE occurring as an 
adverse pregnancy outcome post study must be reported to the PAREXEL 
Pharmacovigilance Representative. 
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to the PAREXEL Pharmacovigilance 
Representative using the pregnancy outcome report form. If the end of the pregnancy occurs 
after the study has been completed, the outcome should be reported directly to Gilead DSPH. 
Gilead DSPH contact information is as follows: Email: Safety_FC@gilead.com and 
Fax: +1 (650) 522-5477.  
Pregnancies of female partners of male study subjects exposed to Gilead study drugs must 
also be reported and relevant information should be submitted to the PAREXEL 
Representative using the pregnancy and pregnancy outcome forms within 24 hours. 
Monitoring of the subject’s partner should continue until the conclusion of the pregnancy. If 
the end of the pregnancy occurs after the study has been completed, the outcome should be 
reported directly to Gilead DSPH, fax number +1 650 522-5477 or email 
Safety_FC@gilead.com. 


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Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements. 
7.7.2.2. 
Reporting Other Special Situations 
All other special situation reports must be reported on the special situations report form and 
forwarded to the PAREXEL Pharmacovigilance Representative within 24 hours of the 
investigator becoming aware of the situation. These reports must consist of situations that 
involve study IMP, but do not apply to concomitant medications. Except for situations that 
result in AEs, special situations involving concomitant medications will not be reported. Any 
inappropriate use of medications prohibited by this protocol should not be reported as 
“misuse,” but may be more appropriately documented as a protocol deviation. 
All clinical sequelae in relation to these special situation reports will be reported as AEs or 
SAEs at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the 
symptoms and signs, clinical management, and outcome will be reported, when available. 




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8.1.3. 
Secondary Endpoint 
Secondary efficacy endpoints include the proportion of subjects with: HCV RNA < LLOQ at 
4 and 24 weeks after discontinuation of therapy (SVR4 and SVR24); viral breakthrough; 
relapse; and HCV RNA change from baseline. 
8.1.4. 
Other Endpoints of Interest 
Additional efficacy evaluations may include ALT normalization; and the health related 
quality of life endpoints. 
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). 
Last dose of study drug refers to the last dose of SOF/LDV 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 post-treatment time points. 
8.2.1. 
Analysis Sets 
8.2.1.1. 
Efficacy 
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which 
includes subjects who were enrolled and received at least one dose of study drug and have 
chronic genotype (1a, 1b, or mixed 1a/1b) HCV infection.  
8.2.1.2. 
Safety 
The primary analysis set for safety analyses is defined as subjects who were enrolled and 
received at least one dose of study drug. 
Treatment-emergent data will be analyzed and defined as data collected from the first dose of 
study drug through the date of the last dose of study drug plus 30 days.  
8.2.1.3. 
Pharmacokinetics 
The PK analysis set will include all subjects who are enrolled and have received at least one 
dose of study drug and for whom concentration data of analytes [SOF, LDV, and 
metabolite(s), as appropriate] are available. The PK analysis set will be used for analyses of 
general PK. 
8.3. 
Data Handling Conventions 
Missing data can have an impact upon the interpretation of the trial data. In general, values 
for missing data will not be imputed.  


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For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and 
is immediately preceded and followed in time by values that are deemed successes, then the 
missing data point will be termed a success; otherwise the data point will be termed a failure. 
Any subject with missing data due to premature discontinuation of the study will be 
considered a failure at the time points on, or following, the date of discontinuation. If no 
HCV RNA values are obtained after the last dose of study medication, the subject will be 
considered a treatment failure for the SVR endpoints.  
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example, 
• If a subject received study medication, the subject will be included in a summary of 
adverse events according to the treatment received; otherwise, if the subject is not dosed 
then they will be excluded from the summary. 
• If safety laboratory results for a subject are missing for any reason at a time point, the 
subject will be excluded from the calculation of summary statistics for that time point. If 
the subject is missing a pre-dose value, then the subject will be excluded from the 
calculation of summary statistics for the pre-dose value and the change from pre-dose 
values. 
Values for missing safety laboratory data will not be imputed; however, a missing baseline 
result will be replaced with a screening result, if available. If no pre-treatment laboratory 
value is available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) 
for 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). 
PK concentration values below the lower limit of quantitation (BLQ) will be treated as zero 
for determination of summary and order statistics. Individual values that are BLQ will be 
presented as “BLQ” in the concentration data listing. For the presentation of summary and 
order statistics, if at least 1 subject has a concentration value BLQ for the time point, then the 
minimum value will be displayed as “BLQ”. If more than 50% of the subjects have a 
concentration data value BLQ for the time point, then the minimum and median values will 
be displayed as “BLQ”. If all subjects have concentration data values BLQ for the time point, 
then all order statistics (minimum, first quartile [Q1], median, third quartile [Q3], maximum) 
will be displayed as “BLQ”. 






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• Combined Grade 3 and 4 study drug-related AEs, 
• All AEs that caused permanent discontinuation from study drug, 
• All AEs that caused change in dose or temporary interruption of study drug, 
• All SAEs (including death), and 
• All study drug-related SAEs 
All AEs collected during the course of the study will be presented in data listings. 
8.6.3. 
Laboratory Evaluations 
Selected laboratory data (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be 
summarized at study visits along with corresponding change from baseline.  
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
defined in Appendix 3 of this protocol. The incidence of treatment-emergent laboratory 
abnormalities, defined as values that increase by at least one toxicity grade from baseline at 
any time post-baseline up to the date of last dose of study drug plus 30 days will be 
summarized. If baseline data are missing, then any post-baseline graded abnormality (i.e., at 
least Grade 1) will be considered treatment emergent. 
All laboratory abnormalities will be included in the listings of laboratory data. 
8.7. 
Pharmacokinetic Analysis 
Plasma concentrations of the study drug and metabolite(s) over time, if analyzed, will be 
summarized using descriptive statistics. Details of the analysis plan will be provided in the 
pharmacokinetic reporting and analysis plan. 
8.8. 
Sample Size 
With a sample size of 80 subjects in the treatment-naïve and in the treatment-experienced 
group, a two-sided 95% exact confidence interval will extend at most 23% in length. 


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9. 
RESPONSIBILITIES 
9.1. 
Investigator Responsibilities 
9.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of 
the Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. These standards are consistent with the European 
Union Clinical Trials Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC. 
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998. 
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or 
proprietary interests in the investigational drug under study. This documentation must be 
provided prior to the investigator’s (and any subinvestigator’s) participation in the study. The 
investigator and subinvestigator agree to notify Gilead of any change in reportable interests 
during the study and for 1 year following completion of the study. Study completion is 
defined as the date when the last subject completes the protocol-defined activities. 
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 
1993, “Retention of Bioavailability and Bioequivalence Testing Samples.” 
9.1.2. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval 
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the 
subject (such as advertisements, subject information sheets, or descriptions of the study used 
to obtain informed consent) to an IRB/IEC. The investigator will not begin any study subject 
activities until approval from the ECIRB/IEC and/or Regulatory Body has been documented 
and provided as a letter to the investigator. 
Before implementation, the investigator will submit to and receive documented approval 
from the ECIRB/IEC and/or Regulatory Body 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. 




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records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
The required source data should include sequential notes containing at least the following 
information for each subject: 
• Subject identification (name, date of birth, gender); 
• Documentation that subject meets eligibility criteria, ie, history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria); 
• Documentation of the reason(s) a consented subject is not enrolled 
• Participation in study (including study number); 
• Study discussed and date of informed consent; 
• Dates of all visits; 
• Documentation that protocol specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
• Start and end date (including dose regimen) of IMP, including dates of dispensing and 
return; 
• Record of all adverse events and other safety parameters (start and end date, and 
including causality and severity); 
• Concomitant medication (including start and end date, dose if relevant; dose changes); 
• Date of study completion and reason for early discontinuation, if it occurs. 
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing 
application in an ICH region (ie, United States, Europe, or Japan) and until there are no 
pending or planned marketing applications in an ICH region; or, if no application is filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and regulatory authorities have been notified. Investigators may be required to 
retain documents longer if specified by regulatory requirements, by local regulations, or by 
an agreement with Gilead. The investigator must notify Gilead before destroying any clinical 
study records. 
Should the investigator wish to assign the study records to another party or move them to 
another location, Gilead must be notified in advance. 


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If the investigator cannot provide for this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the investigator and Gilead to 
store these records securely away from the site so that they can be returned sealed to the 
investigator in case of an inspection. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage away from the site. 
9.1.6. 
Case Report Forms 
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should 
be completed on the day of the subject visit to enable the sponsor to perform central 
monitoring of safety data. Subsequent to data entry, a study monitor will perform source data 
verification within the EDC system. Original entries as well as any changes to data fields will 
be stored in the audit trail of the system. Prior to database lock (or any interim time points as 
described in the clinical data management plan), the investigator will used his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries required per the 
protocol scheduled of events and procedures. System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or 
internal Gilead staff, who routinely review the data for completeness, correctness, and 
consistency. The site coordinator is responsible for responding to the queries in a timely 
manner, within the system, either by confirming the data as correct or updating the original 
entry, and providing the reason for the update (e.g. data entry error). At the conclusion of the 
trial, Gilead will provide the site with a read-only archive copy of the data entered by that 
site. This archive must be stored in accordance with the records retention requirements 
outlined in Section 9.1.5. 
9.1.7. 
Investigational Medicinal Product Accountability and Return 
Gilead recommends that used and unused IMP supplies be returned to the shipping facility 
from which it came for eventual destruction. The study monitor will provide instructions for 
return. If return is not possible, the study monitor will evaluate each study center’s IMP 
disposal procedures and provide appropriate instruction for destruction of unused IMP 
supplies. If the site has an appropriate standard operating procedure (SOP) for drug 
destruction as determined by Gilead (Quality Assurance) QA, the site may destroy used 
(empty or partially empty) and unused IMP supplies in accordance with that site’s approved 
SOP. A copy of the site’s approved SOP will be obtained for central files.  
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the IMP. Upon study completion, 
copies of the IMP accountability records must be filed at the site. Another copy will be 
returned to Gilead. 
The study monitor will review IMP supplies and associated records at periodic intervals. 


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9.1.8. 
Inspections 
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs [or] IECs, or to regulatory authority or health 
authority inspectors. 
9.1.9. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
9.2. 
Sponsor Responsibilities 
9.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Gilead. The investigator must submit all protocol modifications to the 
IRB [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 agencies. 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report 
may be prepared in certain cases.  
Investigators in this study may communicate, orally present, or publish in scientific journals 
or other scholarly media only after the following conditions have been met: 
• the results of the study in their entirety have been publicly disclosed by or with the 
consent of Gilead in an abstract, manuscript, or presentation form or the study has been 
completed at all study sites for at least 2 years 
• The investigator will submit to Gilead any proposed publication or presentation along 
with the respective scientific journal or presentation forum at least 30 days before 
submission of the publication or presentation.  
• No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4). 
• The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to 
withhold publication or presentation for an additional 60 days in order to obtain patent 
protection if deemed necessary. 


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9.3. 
Joint Investigator/Sponsor Responsibilities 
9.3.1. 
Access to Information for Monitoring 
In accordance with regulations and guidelines, the study monitor must have direct access to 
the investigator’s source documentation in order to verify the accuracy of the data recorded 
in the CRF/eCRF. 
The monitor is responsible for routine review of the CRF/eCRF at regular intervals 
throughout the study to verify adherence to the protocol and the completeness, consistency, 
and accuracy of the data being entered on them. The monitor should have access to any 
subject records needed to verify the entries on the CRF/eCRF. The investigator agrees to 
cooperate with the monitor to ensure that any problems detected through any type of 
monitoring (central, on site) are resolved. 
9.3.2. 
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. 
9.3.3. 
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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Inhibitor) and GS-7977 (Nucleotide NS5B Inhibitor), +/- Ribavirin, in Treatment-
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the Case of the Binomial. Biometrika 1934 Dec;26 (4):pp. 404-13. 
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progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-
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ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 
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Korean patients with hepatocellular carcinoma. J Korean Med Sci 1998;13 
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with hepatocellular carcinoma compared with hepatitis B virus in elderly patients 
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of hepatology 2009;15 Suppl 6:S25-8. 
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the IL28B gene in Korean hepatitis C virus-infected patients treated with peg-
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hyperendemicity of hepatitis C virus infection in Taiwan: the important role of 
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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 




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Appendix 2. 
Study Procedures Table 
Appendix Table 1. 
Screening and On-Treatment Study Visits 
Clinical Assessments 
Screeninga 
On Treatment Period 
Day -28 
to Day -1 
Baseline/
Day 1b 
Week 1 
(±3 days) 
Week 2 
(±3 days) 
Week 4 
(±3 days) 
Week 6 
(±3 days) 
Week 8 
(±3 days) 
Week 10
(±3 days) 
Week 12
(±3 days) 
ET 
Informed Consent 
X 
 
  
  
  
  
  
  
 
  
Determine Eligibility 
X 
X 
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
 
Physical Examination 
X 
X 
  
  
  
  
 
  
X  
X 
Liver Imaging (Cirrhotics Only) 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
  
  
  
  
  
  
  
  
  
Weight 
X 
X 
  
  
  
  
 
  
X 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGd 
X 
X 
X  
  
  
  
  
  
X  
 X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Prevention 
Counseling 
  
X 
  
  
  
  
 
  
X  
X 
Health Related Quality of Life 
  
X 
  
X 
X  
  
X 
  
X 
X 
Hematology & Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
  
  
  
  
 
  
X 
X 
Serum HCV RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Clinical Assessments 
Screeninga 
On Treatment Period 
Day -28 
to Day -1 
Baseline/
Day 1b 
Week 1 
(±3 days) 
Week 2 
(±3 days) 
Week 4 
(±3 days) 
Week 6 
(±3 days) 
Week 8 
(±3 days) 
Week 10
(±3 days) 
Week 12
(±3 days) 
ET 
Single PK Sample 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
Viral RNA Sequencing 
/Phenotyping Sample (Plasma)e 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Archive Sample j 
 
X 
 
 
 
 
 
 
X 
X 
Serum or Urine Pregnancy Test 
X 
X 
  
  
 X 
  
X 
 
X 
X 
Urinalysis 
X 
  
  
  
  
  
  
  
  
  
IL28B Genotype, HCV 
Genotype 
X 
  
  
  
  
  
  
  
  
  
HCV Ab, HIV Ab and HBsAg 
X 
  
  
  
  
  
  
  
  
  
Hemoglobin A1c, TSH 
X 
  
  
  
  
  
  
  
  
  
PK Substudy Collectionf 
  
  
  
X 
X  
  
  
  
  
  
Single Pharmacogenomic 
Sampleg 
  
X 
  
  
  
  
  
  
  
  
Review of Study Drug 
Adherence and Drug 
Accountabilityh 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Dispensingi 
  
X 
  
  
X  
  
X 
 
 
 
a 
The screening window can be extended to 42 days for subjects requiring liver biopsy or additional HCV genotype testing.  
b 
Baseline/Day 1 assessments must be performed prior to dosing. 
c 
Vital signs include resting blood pressure, pulse, respiratory rate and temperature. 


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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 gross abnormalities. 
e 
Serum samples will be collected and stored for potential HCV sequencing and other virology studies. 
f 
Subjects that consent to the optional PK substudy will have serial PK samples drawn at Week 2 or Week 4 visit.   
g 
Only for subjects who have provided consent for this sample and testing. This sample can be obtained at a subsequent visit if not obtained at Day 1. 
h 
Study medication and dosing diary, will be reconciled at every post-baseline visit by the investigator or designee in order to monitor the subject’s adherence with the 
medication regimen.     
i 
Study Drug will be dispensed per IWRS directions.  Subjects must be instructed to bring back all bottles of study medication(s) in the original container at every post baseline 
study visits through the end of treatment.  
j 
Archive plasma samples will be collected at the Baseline/Day 1 visit and at the end of treatment for subjects who have not opted out of sample collection 
 


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Appendix Table 2. 
Post Treatment Study Visits 
Clinical Assessments 
Post Treatment Perioda 
Post Treatment Week 4 
(±5 days) 
Post Treatment Week 12 
(±5 days) 
Post Treatment Week 24 
(±5 days) 
Weight 
  
X 
X 
Vital Signsb 
X 
X 
X 
Adverse Events 
X 
  
  
Concomitant Medications 
X 
  
  
Pregnancy Prevention Counseling 
X 
 
 
Health Related Quality of Life 
X 
X 
 
Hematology & Chemistry 
X 
  
  
Serum HCV RNA 
X 
X 
X 
Viral Sequencing Sample (Plasma)c 
X 
X 
X 
Serum or Urine Pregnancy Test 
X 
 
 
a 
All subjects will complete both 4-week and 12-week Post-Treatment visits regardless of the treatment duration. Subjects with HCV RNA < LLOQ at their 12-week 
Post-Treatment visit will complete a 24-week Post-Treatment visit, unless viral relapse is determined. The end of study will occur at the 24-week Post-Treatment visit.  
b 
Vital signs include resting blood pressure, pulse, respiratory rate and temperature. 
c 
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies.  
 


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Appendix 3. 
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
Version: 18June2012 
HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
HIV POSITIVE 
 
Adult and Pediatric ≥ 57 Days 
 
8.5 to 10.0 g/dL  
 
85 to 100 g/L 
 
7.5 to < 8.5 g/dL  
 
75 to < 85 g/L 
 
6.5 to < 7.5 g/dL  
 
65 to < 75 g/L 
 
< 6.5 g/dL 
 
< 65 g/L 
HIV NEGATIVE 
 
Adult and Pediatric ≥ 57 Days  
10.0 to 10.9 g/dL 
 
100 to 109 g/L 
 
OR 
 
Any decrease from Baseline
 
2.5 to < 3.5 g/dL 
 
25 to < 35 g/L 
9.0 to < 10.0 g/dL 
 
90 to < 100 g/L 
 
OR 
 
Any decrease from Baseline 
 
3.5 to < 4.5 g/dL 
 
35 to < 45 g/L 
7.0 to < 9.0 g/dL 
 
70 to < 90 g/L 
 
OR 
 
Any decrease from Baseline 
 
≥ 4.5 g/dL 
 
≥ 45 g/L 
< 7.0 g/dL 
 
< 70 g/L 
Infant, 36–56 Days 
(HIV POSITIVE OR 
NEGATIVE) 
8.5 to 9.4 g/dL 
 
85 to 94 g/L 
7.0 to < 8.5 g/dL 
 
70 to < 85 g/L 
6.0 to < 7.0 g/dL 
 
60 to < 70 g/L 
< 6.0 g/dL 
 
< 60 g/L 
Infant, 22–35 Days 
(HIV POSITIVE OR 
NEGATIVE) 
9.5 to 10.5 g/dL 
 
95 to 105 g/L 
8.0 to < 9.5 g/dL 
 
80 to < 95 g/L 
7.0 to < 8.0 g/dL 
 
70 to < 80 g/L 
< 7.0 g/dL 
 
< 70 g/L 
Infant, 1–21 Days 
(HIV POSITIVE OR 
NEGATIVE) 
12.0 to 13.0 g/dL 
 
120 to 130 g/L 
10.0 to < 12.0 g/dL 
 
100 to < 120 g/L 
9.0 to < 10.0 g/dL 
 
90 to < 100 g/L 
< 9.0 g/dL 
 
< 90 g/L 


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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Absolute Neutrophil Count  
(ANC) 
 
Adult and Pediatric, > 7 Days 
 
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 
Infant, 2 – ≤ 7 Days 
1250 to 1500/mm3 
 
1.25 to 1.50 GI/L 
1000 to < 1250/mm3 
 
1.00 to < 1.25 GI/L 
750 to < 1000/mm3 
 
0.75 to < 1.00 GI/L 
< 750/mm3 
 
< 0.75 GI/L 
Infant, 1 Day 
4000 to 5000/mm3 
 
4.00 to 5.00 GI/L 
3000 to < 4000/mm3 
 
3.00 to < 4.00 GI/L 
1500 to < 3000/mm3 
 
1.50 to < 3.00 GI/L 
< 1500/mm3 
 
< 1.50 GI/L 
Absolute CD4+ Count 
 
HIV NEGATIVE ONLY 
 
Adult and Pediatric 
> 13 Years 
 
 
 
 
300 to 400/mm3 
 
300 to 400/μL 
 
 
 
 
200 to < 300/mm3 
 
200 to < 300/μL 
 
 
 
 
100 to < 200/mm3 
 
100 to < 200/μL 
 
 
 
 
< 100/mm3 
 
< 100/μL 
Absolute Lymphocyte Count 
 
HIV NEGATIVE ONLY 
 
Adult and Pediatric 
> 13 Years 
 
 
 
 
600 to 650/mm3 
 
0.60 to 0.65 GI/L 
 
 
 
 
500 to < 600/mm3 
 
0.50 to < 0.60 GI/L 
 
 
 
 
350 to < 500/mm3 
 
0.35 to < 0.50 GI/L 
 
 
 
 
< 350/mm3 
 
< 0.35 GI/L 


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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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 
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%  
 


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CHEMISTRY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia  
130 to <LLN mEq/L 
125 to < 130 mEq/L 
121 to < 125 mEq/L 
< 121 mEq/L 
130 to <LLN mmol/L 
125 to < 130 mmol/L 
121 to < 125 mmol/L 
< 121 mmol/L 
Hypernatremia  
146  to 150 mEq/L 
> 150 to 154 mEq/L 
> 154 to 159 mEq/L 
> 159 mEq/L 
146  to 150 mmol/L 
> 150 to 154 mmol/L 
> 154 to 159 mmol/L 
> 159 mmol/L 
Hypokalemia  
3.0 to 3.4 mEq/L 
2.5 to < 3.0 mEq/L 
2.0 to < 2.5 mEq/L 
< 2.0 mEq/L 
3.0 to 3.4 mmol/L 
2.5 to < 3.0 mmol/L 
2.0 to < 2.5 mmol/L 
< 2.0 mmol/L 
Hyperkalemia  
5.6 to 6.0 mEq/L 
> 6.0 to 6.5 mEq/L 
> 6.5 to 7.0 mEq/L 
> 7.0 mEq/L 
5.6 to 6.0 mmol/L 
> 6.0 to 6.5 mmol/L 
> 6.5 to 7.0 mmol/L 
> 7.0 mmol/L 
Hypoglycemia 
 
Adult and Pediatric 
 
≥ 1 Month 
 
 
55 to 64 mg/dL 
 
 
40 to < 55 mg/dL 
 
 
30 to < 40 mg/dL 
 
 
< 30 mg/dL 
3.03 to 3.58 mmol/L 
2.20 to < 3.03 mmol/L 
1.64 to < 2.20 mmol/L 
< 1.64 mmol/L 
Infant, < 1 Month 
50 to 54 mg/dL 
 
2.8 to 3.0 mmol/L 
40 to < 50 mg/dL 
 
2.2 to < 2.8 mmol/L 
30 to < 40 mg/dL 
 
1.7 to < 2.2 mmol/L 
< 30 mg/dL 
 
< 1.7 mmol/L 
Hyperglycemia, Nonfasting  
116 to 160 mg/dL 
> 160 to 250 mg/dL 
> 250 to 500 mg/dL 
> 500 mg/dL 
6.42 to 8.91 mmol/L 
> 8.91 to 13.90 mmol/L 
> 13.90 to 27.79 mmol/L 
> 27.79 mmol/L 
Hyperglycemia, Fasting 
110 to 125 mg/dL 
 
6.08 to 6.96 mmol/L 
>125 to 250 mg/dL 
 
>6.96 to 13.90 mmol/L 
>250 to 500 mg/dL 
 
>13.90 to 27.79 mmol/L 
>500 mg/dL 
 
>27.79 mmol/L 


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CHEMISTRY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hypocalcemia  
 
(corrected for albumin if 
appropriate*) 
 
Adult and Pediatric 
 
≥ 7 Days 
 
 
7.8 to 8.4  mg/dL 
 
 
7.0 to < 7.8 mg/dL 
 
 
6.1 to < 7.0 mg/dL 
 
 
< 6.1 mg/dL 
1.94 to 2.10 mmol/L 
1.74 to < 1.94 mmol/L 
1.51 to < 1.74 mmol/L 
< 1.51 mmol/L 
Infant, < 7 Days 
6.5 to 7.5 mg/dL 
 
1.61 to 1.88  mmol/L 
6.0 to < 6.5 mg/dL 
 
1.49 to < 1.61 mmol/L 
5.5 to < 6.0 mg/dL 
 
1.36 to < 1.49 mmol/L  
< 5.5 mg/dL 
 
< 1.36 mmol/L 
Hypercalcemia (corrected 
for albumin if appropriate*) 
Adult and Pediatric ≥ 
7 Days 
 
 
>ULN to 11.5 mg/dL 
 
 
> 11.5 to 12.5 mg/dL 
 
 
> 12.5 to 13.5 mg/dL 
 
 
> 13.5 mg/dL 
>ULN to 2.88 mmol/L 
> 2.88 to 3.13 mmol/L 
> 3.13 to 3.38 mmol/L 
> 3.38 mmol/L 
Infant, < 7 Days 
11.5 to 12.4 mg/dL 
 
2.86 to 3.10  mmol/L 
> 12.4 to 12.9 mg/dL 
 
> 3.10 to 3.23  mmol/L 
> 12.9 to 13.5 mg/dL 
 
> 3.23 to 3.38  mmol/L 
> 13.5 mg/dL 
 
> 3.38 mmol/L 
Hypocalcemia (ionized) 
3.0 mg/dL to < LLN 
2.5 to < 3.0 mg/dL 
2.0 to < 2.5 mg/dL 
< 2.0 mg/dL 
0.74 mmol/L to < LLN 
0.62 to < 0.74 mmol/L 
0.49 to < 0.62 mmol/L 
< 0.49 mmol/L 
Hypercalcemia (ionized) 
> ULN to 6.0 mg/dL 
> 6.0 to 6.5 mg/dL 
> 6.5 to 7.0 mg/dL 
> 7.0 mg/dL 
> ULN to 1.50 mmol/L 
> 1.50 to 1.63 mmol/L 
> 1.63 to 1.75 mmol/L 
> 1.75 mmol/L 


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Protocol GS-US-337-0131 
Final 
Gilead Sciences, Inc. 
Original 
 
 
 
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CHEMISTRY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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 
 
 
1.5 to < 2.0 mg/dL 
 
 
1.0 to < 1.5 mg/dL 
 
 
< 1.0 mg/dL 
0.63  to < LLN mmol/L 
0.47 to < 0.63 mmol/L 
0.31 to < 0.47 mmol/L 
< 0.31 mmol/L 
Pediatric 1 Year–14 Years  
3.0 to 3.5 mg/dL 
 
0.96 to 1.14 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 4.5 mg/dL 
 
1.12 to 1.46 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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Protocol GS-US-337-0131 
Final 
Gilead Sciences, Inc. 
Original 
 
 
 
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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 
1.5 mg/dL to < LLN 
1.0 to < 1.5 mg/dL 
0.5 to < 1.0 mg/dL 
< 0.5 mg/dL 
87 μmol/L to < LLN 
57 to < 87 μmol/L 
27 to < 57 μmol/L 
< 27 μmol/L 
Creatinine  
> 1.50 to 2.00 mg/dL 
> 2.00 to 3.00 mg/dL 
> 3.00 to 6.00 mg/dL  
> 6.00 mg/dL 
> 133 to 177 μmol/L 
> 177 to 265 μmol/L 
> 265 to 530 μmol/L 
> 530 μmol/L 
Bicarbonate 
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 
Triglycerides 
 
(Fasting) 
NA 
500 to 750 mg/dL 
> 750 to 1200 mg/dL 
> 1200 mg/dL 
 
5.64–8.47 mmol/L 
> 8.47–13.55 mmol/L 
> 13.55 mmol/L 
LDL 
 
(Fasting) 
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 
 
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 
 


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Protocol GS-US-337-0131 
Final 
Gilead Sciences, Inc. 
Original 
 
 
 
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CHEMISTRY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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 
 


Sofosbuvir/Ledipasvir FDC 
Protocol GS-US-337-0131 
Final 
Gilead Sciences, Inc. 
Original 
 
 
 
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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 
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 
 


Sofosbuvir/Ledipasvir FDC 
Protocol GS-US-337-0131 
Final 
Gilead Sciences, Inc. 
Original 
 
 
 
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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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Protocol GS-US-337-0131 
Final 
Gilead Sciences, Inc. 
Original 
 
 
 
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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 


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


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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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Original 
 
 
 
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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 


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


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


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


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


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Original 
 
 
 
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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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Original 
 
 
 
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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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Final 
Gilead Sciences, Inc. 
Original 
 
 
 
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28 May 2013 
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 
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Original 
 
 
 
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GENITOURINARY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Intermenstrual Bleeding 
(IMB) 
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam 
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle 
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle 
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated 
Urinary Tract 
obstruction (eg, stone) 
NA 
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction 
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction 
Obstruction causing life-
threatening consequences 
 
INFECTION 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Infection (any other 
than HIV infection) 
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities 
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities 
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated 
Life-threatening 
consequences (eg, septic 
shock) 
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc 
 


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Appendix 4. 
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements 
1. 
Background 
Non-clinical toxicity studies of sofosbuvir and ledipasvir demonstrated no adverse effect on 
embryo-fetal development. However, there are no clinical studies of sofosbuvir or ledipasvir 
in pregnant women. Please refer to the latest version of the investigator’s brochure for 
additional information. 
2. 
Definition of Female of Childbearing Potential and Contraceptive Requirements for 
Female Subjects (and their male partners) 
Women > 54 years of age with cessation for  12 months of previously occurring 
menses, or women of any age who have had a hysterectomy, or have had both ovaries 
removed, or have had medically documented ovarian failure will be considered to be of 
non-childbearing potential.  
Women  54 years of age (including those with amenorrhea of any duration) who have 
not had a hysterectomy, and have not had both ovaries removed, and have not had 
medically documented ovarian failure will be considered to be of childbearing potential.  
Women of childbearing potential must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test on the Baseline/Day 1 visit prior to 
randomization. They must also agree to one of the following from 3 weeks prior to 
Baseline/Day 1 until 30 days after last dose of study drug. 
• Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted. 
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 last dose of study drug:  
— intrauterine device (IUD) with a failure rate of < 1% per year 
— female barrier method: cervical cap or diaphragm with spermicidal agent 
— tubal sterilization 
— vasectomy in male partner 
— hormone-containing contraceptive: 
— implants of levonorgestrel 


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— injectable progesterone 
— oral contraceptives (either combined or progesterone only) 
— contraceptive vaginal ring  
— transdermal contraceptive patch 
3. 
Contraceptive Requirements for Male Subjects (and their female partners) 
All male study participants must agree to consistently and correctly use a condom from the 
date of Screening until 90 days after the last dose of study drug. If their female partner is of 
child bearing potential (as defined above), their female partner must use 1 of the methods of 
birth control listed above from the date of Screening until 90 days after the last dose of study 
drug.  
Male subjects must agree to refrain from sperm donation for at least 90 days after the last 
dose of study drug.  
4. 
Procedures to be Followed in the Event of Pregnancy 
Subjects will be instructed to notify the investigator if they (or their partner) become 
pregnant at any time during the study, or if they become pregnant within 30 days (90 days for 
partners of male subjects) of last study drug dose. Subjects who become pregnant or who 
suspect that they are pregnant must report the information to the investigator and discontinue 
study drug immediately. Subjects whose partner has become pregnant or suspects she is 
pregnant must report the information to the investigator. Instructions for reporting pregnancy, 
partner pregnancy, and pregnancy outcome are outlined in Section 7.7.2.1.