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
Phase: PHASE3
Conditions: Chronic HCV Infection
Sponsor: Gilead Sciences

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The inf01mation contained in this document, pruiicularly unpublished data, is the propetiy or 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
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Gilead Sciences, Inc.
Amendment 2.0
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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............................................................................................................................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

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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 ....................................................................................................................................................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

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Amendment 2.0
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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
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: 
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Gilead Sciences, Inc.
Amendment 2.0
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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 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). 
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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 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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01 August 2014 

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Amendment 2.0
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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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Gilead Sciences, Inc.
Amendment 2.0
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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.

Sofosbuvir/Ledipasvir FDC
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Gilead Sciences, Inc.
Amendment 2.0
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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
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Gilead Sciences, Inc.
Amendment 2.0
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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 
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• 
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 
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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 
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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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lPPD 
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 
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• 
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 
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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 
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 
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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10.
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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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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.
26807
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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Protocol GS-US-337-0131
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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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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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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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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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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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Amendment 2.0
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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
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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CONFIDENTIAL
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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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CONFIDENTIAL
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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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Amendment 2.0
CONFIDENTIAL
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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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Amendment 2.0
CONFIDENTIAL
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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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CONFIDENTIAL
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01 August 2014
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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URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA 
Notes: 
Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to Dipstick 
Hematuria.
With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for the 
AE.

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

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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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SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or  
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA

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

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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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Gilead Sciences, Inc.
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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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Gilead Sciences, Inc.
Amendment 2.0
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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%