Conditions: Hepatitis C Virus Infection
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 226
Healthy volunteers: no

Brief summary:
The primary objective of the PK Lead-in Phase of the study is to evaluate the steady state pharmacokinetics (PK) and confirm the dose of ledipasvir/sofosbuvir (LDV/SOF) fixed dose combination (FDC) in hepatitis C virus (HCV)-infected pediatric participants. The PK Lead-in Phase will also evaluate the safety, tolerability, and antiviral activity of 10 days of dosing of LDV/SOF FDC in HCV-infected pediatric participants.

The Treatment Phase will be initiated by age cohort after confirmation of age-appropriate LDV/SOF FDC dosage levels. Participants from the PK Lead-in Phase will immediately rollover into the Treatment Phase with no interruption of study drug administration. The primary objective of the Treatment Phase is to evaluate the antiviral efficacy, safety, and tolerability of LDV/SOF FDC +/- ribavirin (RBV) for 12 or 24 weeks in pediatric participants with HCV.

During screening, participants will receive placebo to match LDV/SOF FDC to assess ability to swallow tablets.

Detailed description:

Arms:
arm 1: Participants between 12 to \< 18 years of age weighing ≥ 45 kg will receive LDV/SOF FDC (90/400 mg tablet or 4 x 22.5 mg/100 mg tablets or 8 x 11.25/50 mg granules based on swallowability assessment during screening).

Treatment duration will be dependent on HCV genotype, prior treatment experience, cirrhosis status, and country of enrollment.

United Kingdom:

* HCV genotypes (GT) 1, 4, 5, or 6 treatment-naive (TN) with or without cirrhosis = LDV/SOF 12 weeks
* HCV GT 1, 4, 5, or 6 treatment-experienced (TE) without cirrhosis = LDV/SOF 12 weeks
* HCV GT 1, 4, 5, or 6 TE with cirrhosis = LDV/SOF 24 weeks
* HCV GT 3 TE with or without cirrhosis = LDV/SOF+RBV 24 weeks

United States/Australia/New Zealand:

* HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks
* HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks
* HCV GT 1 TE with cirrhosis = LDV/SOF 24 weeks
* HCV GT 4, 5, or 6 TE with cirrhosis = LDV/SOF 12 weeks arm 2: Participants between 6 to \< 12 years of age weighing ≥ 17 kg and \< 45 kg will receive LDV/SOF FDC (45/200 mg as 2 x 22.5/100 mg tablets or 4 x 11.25/50 mg granules based on swallowability assessment during screening).

Treatment duration will be dependent on HCV genotype, prior treatment experience, cirrhosis status, and country of enrollment.

United Kingdom:

* HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks
* HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks
* HCV GT 1, 4, 5, or 6 TE with cirrhosis = LDV/SOF 24 weeks
* HCV GT 3 TE with or without cirrhosis = LDV/SOF+RBV 24 weeks

United States/Australia/New Zealand:

* HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks
* HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks
* HCV GT 1 TE with cirrhosis = LDV/SOF 24 weeks
* HCV GT 4, 5, or 6 TE with cirrhosis = LDV/SOF 12 weeks arm 3: Participants between 3 to \< 6 years of age weighing ≥ 17 kg will receive LDV/SOF FDC (45/200 mg granules as 4 x 11.25/50 mg packets) and participants weighing \< 17 kg will receive LDV/SOF FDC (33.75/150 mg oral granules as 3 x 11.25/50 mg packets).

Treatment duration will be dependent on HCV genotype, prior treatment experience, cirrhosis status, and country of enrollment.

United Kingdom:

* HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks
* HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks
* HCV GT 1, 4, 5, or 6 TE with cirrhosis = LDV/SOF 24 weeks
* HCV GT 3 TE with or without cirrhosis = LDV/SOF+RBV 24 weeks

United States/Australia/New Zealand:

* HCV GT 1, 4, 5, or 6 TN with or without cirrhosis = LDV/SOF 12 weeks
* HCV GT 1, 4, 5, or 6 TE without cirrhosis = LDV/SOF 12 weeks
* HCV GT 1 TE with cirrhosis = LDV/SOF 24 weeks
* HCV GT 4, 5, or 6 TE with cirrhosis = LDV/SOF 12 weeks

Interventions: intervention 1: LDV/SOF intervention 2: RBV
Intervention descriptions: intervention 1: LDV/SOF FDC administered orally once daily intervention 2: Ribavirin (RBV) oral solution or capsules will be administered orally in a divided daily dose based on weight

Protocol document:
Prot_003.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir 
Fixed Dose Combination +/- Ribavirin in Adolescents and 
Children with Chronic HCV-Infection
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive 
Foster City, CA 94404, USA
IND No.:
EudraCT Number:
115268
2014-003578-17
Indication:
Hepatitis C Virus Infection 
Protocol ID:
GS-US-337-1116
Gilead Sciences Medical 
Monitor:
Name:
Bittoo Kanwar, MD
Telephone:
Mobile:
Fax:
E-mail:
Protocol Version/Date:
Original:
10 July 2014
Amendment 1.0:
08 October 2014
Amendment 2.0:
08 December 2014
Amendment 2.1:
09 January 2015 (United Kingdom Only)
Amendment 2.2: 
01 April 2015 (United Kingdom Only)
Amendment 3.0: 
28 May 2015
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................17
1.
INTRODUCTION ..............................................................................................................................................20
1.1.
Background ............................................................................................................................................20
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................21
1.2.1.
Summary of Additional Clinical Experience with Ledipasvir/Sofosbuvir 
Fixed-Dose Combination .....................................................................................................21
1.3.
Ribavirin (RBV).....................................................................................................................................23
1.4.
Rationale for the Current Study .............................................................................................................24
1.5.
Rationale for Dose Selection of LDV/SOF FDC ...................................................................................25
1.6.
Overall Risk/Benefit Assessment...........................................................................................................27
2.
OBJECTIVES.....................................................................................................................................................29
3.
STUDY DESIGN................................................................................................................................................30
3.1.
Treatment Plan and Regimen .................................................................................................................30
3.1.1.
PK Lead-in ...........................................................................................................................30
3.1.2.
Treatment Phase ...................................................................................................................31
3.2.
Visit Schedule ........................................................................................................................................33
3.2.1.
PK Lead-in ...........................................................................................................................33
3.2.2.
Treatment Phase ...................................................................................................................33
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................34
3.4.
Treatment Discontinuations Criteria ......................................................................................................34
3.5.
Discontinuations.....................................................................................................................................35
3.6.
Pharmacogenomic Substudy ..................................................................................................................35
3.7.
Long-Term Follow-Up...........................................................................................................................35
3.8.
Breakthrough Futility Assessment .........................................................................................................35
3.9.
Reconsent...............................................................................................................................................35
4.
SUBJECT POPULATION..................................................................................................................................36
4.1.
Number of Subjects and Subject Selection ............................................................................................36
4.2.
Inclusion Criteria....................................................................................................................................36
4.3.
Exclusion Criteria...................................................................................................................................37
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................39
5.1.
Randomization and Blinding..................................................................................................................39
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................39
5.2.1.
Description and Handling.....................................................................................................39
5.2.2.
Storage and Handling...........................................................................................................40
5.2.3.
Dosage and Administration of LDV/SOF FDC ...................................................................41
5.3.
Ribavirin (GT-3 Subjects Only).............................................................................................................42
5.3.1.
Description and Handling of RBV .......................................................................................42
5.3.2.
Dosage and Administration of RBV (GT-3 Subjects Only).................................................43
5.4.
Co-administration of LDV/SOF FDC and RBV (GT-3 Subjects Only).................................................43
5.5.
Study Drug Compliance.........................................................................................................................44
5.6.
Prior and Concomitant Medications.......................................................................................................44


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6.
STUDY PROCEDURES ....................................................................................................................................46
6.1.
Subject Enrollment.................................................................................................................................46
6.2.
Screening Assessments ..........................................................................................................................46
6.2.1.
Screening Visit (Day –28 to Day 0) .....................................................................................46
6.3.
PK Lead-in: Treatment Assessments .....................................................................................................48
6.3.1.
Day 1 ....................................................................................................................................48
6.3.2.
Day 3 ....................................................................................................................................49
6.3.3.
Day 10 – Intensive PK..........................................................................................................49
6.4.
Treatment Phase: Treatment Assessments .............................................................................................51
6.4.1.
Day 1 ....................................................................................................................................51
6.4.2.
Weeks 1 and 2 (3 days) .....................................................................................................52
6.4.3.
Weeks 4 and 8 (3 days) .....................................................................................................53
6.4.4.
Week 12 (3 days) - Subjects on 12 Week Treatment Regimen Only................................54
6.4.5.
Week 12 (3 days) - Subjects on 24 Week Treatment Regimen Only................................54
6.4.6.
Week 16 and 20 (3 days) – Subjects on 24 Week Treatment Regimen 
Only......................................................................................................................................55
6.4.7.
Week 24 (3 days) – Subjects on 24 Week Treatment Regimen Only ...............................56
6.4.8.
Unscheduled Visit/Early Termination Visit .........................................................................56
6.5.
Post-Treatment Assessments..................................................................................................................58
6.5.1.
4-Week Post-Treatment Visit (5 days)..............................................................................58
6.5.2.
12-Week Post-Treatment Visit (5 days)............................................................................58
6.5.3.
24-Week Post-Treatment Visit (5 days)............................................................................59
6.6.
Procedures and Specifications................................................................................................................60
6.6.1.
Clinical Laboratory Analytes ...............................................................................................60
6.6.2.
Medical History....................................................................................................................60
6.6.3.
Complete Physical Examination...........................................................................................61
6.6.4.
Tanner Pubertal Stage Assessment.......................................................................................61
6.6.5.
Height & Weight Measurement............................................................................................61
6.6.6.
Bone Age Assessment..........................................................................................................61
6.6.7.
Swallowability Assessment..................................................................................................61
6.6.8.
Vital Signs............................................................................................................................61
6.6.9.
Estimated Glomerular Filtration Rate (GFR) .......................................................................62
6.6.10.
Viral Sequencing (Archive)..................................................................................................62
6.6.11.
Pregnancy Testing................................................................................................................62
6.6.12.
Quality of Life Survey (PedsQL™).......................................................................................62
7.
TOXICITY MANAGEMENT............................................................................................................................63
7.1.
Modification of Dose/Schedule Due to Toxicity....................................................................................63
7.2.
Subject Stopping Rules for LDV/SOF FDC and RBV...........................................................................63
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................64
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................64
8.1.1.
Adverse Events.....................................................................................................................64
8.1.2.
Serious Adverse Events........................................................................................................64
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................65
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................65
8.2.1.
Assessment of Causality for Study Drug and Procedures ....................................................65
8.2.2.
Assessment of Severity ........................................................................................................66
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................66
8.4.
Gilead Reporting Requirements.............................................................................................................68
8.5.
Special Situations Reports......................................................................................................................68


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8.5.1.
Definitions of Special Situations..........................................................................................68
8.5.2.
Instructions for Reporting Special Situations.......................................................................69
9.
STATISTICAL CONSIDERATIONS................................................................................................................71
9.1.
Analysis Objectives and Endpoints........................................................................................................71
9.1.1.
Analysis Objectives..............................................................................................................71
9.1.2.
Primary Endpoints................................................................................................................72
9.1.3.
Secondary Endpoints............................................................................................................72
9.2.
Analysis Conventions.............................................................................................................................72
9.2.1.
Analysis Sets ........................................................................................................................72
9.2.2.
Data Handling Conventions .................................................................................................73
9.2.3.
Interim Analysis ...................................................................................................................74
9.3.
Demographic Data and Baseline Characteristics ...................................................................................74
9.4.
Pharmacokinetic Analysis......................................................................................................................74
9.5.
Safety Analysis.......................................................................................................................................76
9.5.1.
Extent of Exposure...............................................................................................................76
9.5.2.
Adverse Events.....................................................................................................................76
9.5.3.
Laboratory Evaluations ........................................................................................................77
9.5.4.
Other Safety Evaluations......................................................................................................77
9.6.
Efficacy Analysis ...................................................................................................................................77
9.6.1.
Key Efficacy Analysis..........................................................................................................78
9.6.2.
Secondary Efficacy Analysis................................................................................................78
9.6.3.
Subgroup Analysis ...............................................................................................................78
9.7.
Quality of Life Analysis.........................................................................................................................78
9.8.
Data Monitoring Committee ..................................................................................................................78
9.9.
Sample Size............................................................................................................................................79
10.
RESPONSIBILITIES..........................................................................................................................................80
10.1.
Investigator Responsibilities ..................................................................................................................80
10.1.1.
Good Clinical Practice..........................................................................................................80
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................80
10.1.3.
Informed Consent/Assent.....................................................................................................81
10.1.4.
Confidentiality......................................................................................................................81
10.1.5.
Study Files and Retention of Records ..................................................................................81
10.1.6.
Case Report Forms...............................................................................................................82
10.1.7.
Drug Accountability.............................................................................................................83
10.1.8.
Inspections............................................................................................................................83
10.1.9.
Protocol Compliance............................................................................................................83
10.2.
Sponsor Responsibilities ........................................................................................................................83
10.2.1.
Protocol Modifications.........................................................................................................83
10.2.2.
Study Report and Publications .............................................................................................84
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................84
10.3.1.
Access to Information for Monitoring..................................................................................84
10.3.2.
Access to Information for Auditing or Inspections ..............................................................84
10.3.3.
Study Discontinuation..........................................................................................................85
11.
REFERENCES ...................................................................................................................................................86
12.
APPENDICES ....................................................................................................................................................88
Appendix 1.
Investigator Signature Page....................................................................................................89
Appendix 2.
Study Procedures Table..........................................................................................................90
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............95


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Appendix 4.
Tanner Stages .......................................................................................................................119
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................120
LIST OF IN-TEXT TABLES
Table 1-1.
Steady-state PK and Statistical Comparisons of LDV, SOF and GS-331007 PK in 
Adolescent Subjects (PK Lead-in) and Adult Subjects (Phase 2/3 Population PK 
Analysis).................................................................................................................................23
Table 3-1.
Subject Enrollment by HCV Genotype, Country and Treatment Duration ............................32
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................45
Table 7-1.
RBV Dose Reduction Guidelines...........................................................................................63
Table 9-1.
GS-331007, SOF, and LDV PK Parameters after Once-Daily Administration of 
SOF/LDV FDC in HCV-Infected Adults Subjects (Population PK Analysis from 
Phase 2 and 3 Studies)............................................................................................................75
LIST OF IN-TEXT FIGURES
Figure 1-1.
Predicted LDV, SOF and GS-331007 AUCtau following administration of LDV/SOF 
45 mg/200 mg in Children (6 to < 12 years of age)................................................................26
Figure 3-1.
PK Lead-in Phase Study Schema ...........................................................................................31


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed 
Dose Combination +/- Ribavirin in Adolescents and Children with 
Chronic HCV-Infection
IND Number:
EudraCT Number:
115268
2014-003578-17
Study Centers:
Approximately 30 sites in the United States, Europe, Australia, and 
New Zealand
Number of Subjects:
Approximately 200 subjects
Target Population:
Adolescents and children (aged 3 to < 18) chronic hepatitis C virus 
(HCV) infection
Treatment Duration:
PK Lead-in – 10 days
Treatment Phase – 12 or 24 weeks
Objectives:
The primary objective of the PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm 
the dose of LDV/SOF FDC in chronic HCV-infected pediatric 
subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 
10 days of dosing of LDV/SOF FDC in chronic HCV infected 
pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV 
for 12 or 24 weeks in chronic HCV-infected pediatric subjects. 


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Amendment 3.0
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The secondary objectives of the Treatment Phase of this study are:

To determine the antiviral efficacy of 12 or 24 weeks of 
LDV/SOF FDC +/- RBV treatment in chronic HCV infected
subjects (including the impact of HCV genotype, IL28B
genotype, and prior treatment experience), as assessed by the 
proportion of subjects with sustained virological response (SVR) 
12 weeks after completion of treatment (SVR12)

To determine the antiviral efficacy of 12 or 24 weeks of 
LDV/SOF FDC +/- RBV treatment in chronic HCV-infected 
subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during 
treatment and after completion of treatment

To evaluate the emergence of viral resistance to LDV and SOF 
during treatment and after completion of treatment

To evaluate the effect of growth and development on pediatric 
subjects during and after treatment
The exploratory objective of this study is:

 
 
Study Design:
Open-label, multi-cohort, two-part study evaluating the PK, safety, 
and antiviral activity of LDV/SOF FDC +/- RBV in chronic 
HCV-infected pediatric subjects.
The study will be divided into 2 parts and will commence with GT-1, 
-3, and -4 HCV-infected pediatric subjects as follows (subjects with 
GT-2, -5, and -6 will be included once adult data are available, if 
appropriate):
PK Lead-in Phase: PK Lead-in will evaluate and/or confirm age 
appropriate LDV/SOF FDC doses by analyzing PK, safety, and 
antiviral activity of LDV/SOF FDC through 10 days of dosing for 
each of the three cohorts. Children aged 3 to < 6, children aged 
6 to < 12 years, and adolescents aged 12 to < 18 years with evidence 
of chronic HCV and HCV RNA ≥1000 IU/mL at study entry will be 
evaluated.  Subjects must be treatment naïve without history of 
cirrhosis to participate in the PK Lead-in Phase.
PPD


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Three cohorts of at least 10 subjects each will be sequentially 
enrolled: 

Cohort 1: 12 to < 18 years old, weighing ≥ 45kg

Cohort 2: 6 to < 12 years old, weighing ≥ 17 kg and < 45 kg

Cohort 3: 3 to < 6 years old 
The study will start with Cohort 1. Subjects will receive LDV/SOF 
FDC (90 mg/ 400 mg fixed dose combination tablet or 
4 x 22.5 mg/ 100 mg based on LDV/SOF FDC swallowability 
assessment) for 10 days with intensive PK conducted on Day 10.
Once Cohort 1 data is analyzed and a Cohort 2 dose is determined, 
Cohort 2 will open for screening. Cohort 2 subjects will receive 
45 mg/ 200 mg LDV/SOF FDC (2 x 22.5 mg/ 100 mg tablets or 
subject enrollment will be deferred until oral granulate formulation is 
available, if determined necessary based on the LDV/SOF FDC 
swallowability assessment) for 10 days with intensive PK conducted 
on Day 10.
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 10
of the PK Lead-in Phase. They will continue dosing with LDV/SOF 
FDC with no interruption of study drug administration. Subjects 
rolling over from the PK Lead-in will not be required to perform 
Treatment Phase Screening, Day 1, or Week 1 visits in the Treatment 
Phase.  
Following completion of study treatment in the PK Lead-in of each 
Cohort, intensive PK and safety results of study treatment will be 
reviewed to confirm the appropriateness of the evaluated LDV/SOF 
FDC dose for the Treatment Phase of that Cohort as well as to 
determine the age-appropriate dose to be evaluated in the PK Lead-in 
of the next Cohort.
Treatment Phase: Treatment Phase will be initiated sequentially by 
cohort after confirmation of age-appropriate LDV/SOF FDC dosage 
levels. Subjects who participate in PK Lead-in Phase will 
immediately rollover into Treatment Phase, with no interruption of 
study drug administration, until the appropriateness of the dose is 
confirmed by PK and safety data from the PK Lead-In Phase. These 
subjects will start at the Week 2 visit of the Treatment Phase. 
Additional subjects will be enrolled in the Treatment Phase of each 
Cohort upon confirmation of the appropriateness of the dose.


LDV/SOF FDC
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Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
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Children aged 3 to < 12 years and adolescents aged 12 to < 18 years 
with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study 
entry (those who were dosed in the PK Lead-in Phase will have met 
these criteria prior to enrollment) will be evaluated. The study will 
commence with GT-1, -3, and -4 HCV infected pediatric subjects and 
will subsequently enroll subjects with GT-2, -5, and -6 once adult 
data is available, if appropriate.
Subjects enrolled in the study will receive the following regimen:

United Kingdom:
GT-1 and GT-4 treatment-naïve with or without cirrhosis: 
LDV/SOF FDC for 12 weeks
GT-1 and GT-4 treatment-experienced without cirrhosis: 
LDV/SOF FDC for 12 weeks
GT-1 and GT-4 treatment-experienced with cirrhosis (as 
determined by liver biopsy): LDV/SOF FDC for 24 weeks
GT-3 treatment-experienced with or without cirrhosis: 
LDV/SOF FDC + RBV for 24 weeks

United States/Australia/New Zealand (GT-1 only):
GT-1 treatment-naïve with or without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1 treatment-experienced without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1 treatment-experienced with cirrhosis (as determined by 
liver biopsy): LDV/SOF FDC for 24 weeks
The study will enroll both treatment-naïve and treatment experienced 
pediatric subjects, with up to 40 subjects allowed to be treatment 
experienced. Approximately 200 total subjects, including subjects 
that participated in the PK Lead-in Phase, will be enrolled in 
Treatment Phase as follows:

Group 1: Approximately 100 adolescent subjects (12 to < 18 years 
of age)

Group 2: Approximately 100 pediatric subjects (3 to < 12 years of 
age)


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Amendment 3.0
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The following definitions will be used for treatment experienced 
subjects: 

Interferon intolerant: Subject who discontinued therapy 
(≤12 weeks total) due to ≥ 1 adverse event 

Interferon non-responder: Subject who did not achieve 
undetectable HCV RNA levels while on treatment 
Relapse/breakthrough: Subject who achieved undetectable HCV RNA 
during treatment or within 4 weeks of the end of treatment but did not 
achieve a sustained virologic response (SVR)
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, and 12 (and Weeks 16, 20, and 24 for subjects 
requiring 24 weeks of treatment) during the treatment phase followed 
by post-treatment visits 4, 12 and 24 weeks after discontinuation of 
therapy.
All subjects who do not attain SVR or have viral relapse will be 
encouraged to discuss treatment with standard-of-care (SOC) therapy 
with their healthcare provider.
Substudy and Long-
Term Follow-Up 
Study:
Pharmacogenomics (PG) Substudy
 
Long-Term Follow-up
Subjects who attain SVR24 or those who do not attain SVR24 and do 
not initiate other experimental or approved anti-HCV therapy will be 
followed every 6 months for the first 2 years followed by every 
12 months for assessments of growth, quality of life, and long-term 
viral suppression (if applicable) in a separate protocol 
(GS-US-334-1113). This follow-up will continue for 5 years.
Diagnosis and Main 
Eligibility Criteria: 
Chronic HCV-infected, treatment-naïve and treatment experienced
(up to 40 subjects); male and female subjects aged 3 to < 18 as 
determined at Day 1. The study will commence with GT-1, -3, and -4
HCV-infected pediatric subjects and will subsequently enroll subjects 
with GT-2, 5 and -6 once adult data are available, if appropriate. 
Inclusion Criteria:

Chronic HCV infection documented by either:
A) positive anti-HCV antibody test or positive HCV RNA or 
positive HCV genotyping test at least 6 months prior to the 
Day 1 visit, or
PPD


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B) liver biopsy performed prior to the Day 1 visit with evidence 
of chronic HCV- infection

HCV RNA ≥ 1000 IU/mL at Screening 

PK Lead-in Only: subjects in Cohort 1 (age 12 to < 18 years of 
age) must weigh ≥ 45 kg

PK Lead-in Only: subjects in Cohort 2 (age 6 to < 12 years of 
age) must weigh ≥ 17 kg and < 45 kg

Females of childbearing potential (as defined in Appendix 5) must 
have a negative pregnancy test at Screening and Day 1.

Hematologic or biochemical parameters at screening within the 
protocol-specified requirements
Exclusion Criteria:

HIV, acute hepatitis A virus (HAV) or chronic HBV infection

History of or current decompensated liver disease

Hepatocellular carcinoma or other malignancy (with exception of 
certain resolved skin cancers)

Chronic liver disease of a non-HCV etiology 
(e.g., hemochromatosis, Wilson’s disease, alpha-1 antitrypsin 
deficiency)

Systemic corticosteroid use for > 2 weeks (pulmonary/nasal 
administration is permitted)

Active or recent history (≤ 1 year) of drug or alcohol abuse

History or current evidence of any condition, therapy, laboratory
abnormality or other circumstance that might confound the results 
of the study, or interfere with the subject’s participation for the 
full duration of  the study, such that it is not in the best interest of 
the subject to participate.

Sexually active subjects who are not willing to use 2 forms of an 
effective method of contraception , as referenced in Appendix 5
See Sections 4.2 and 4.3 of the protocol for full eligibility criteria.
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the Day 1 
visit. 
Screening assessments will include: medical history (including 
parental height, if available), complete physical examination, vital 
signs (including body height and weight), concomitant medications,
LDV/SOF FDC Swallowability Assessment (may be performed at 


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screening up to Day 1), hematology, safety laboratory tests, 
coagulation tests, HCV RNA, serum β-human chorionic gonadotropin 
(hCG - females of childbearing potential only), urinalysis, and urine 
drug screen, IL28B genotyping, serology (HIV, HAV, HCV, and 
HBV, HCV genotyping), HbA1c, thyroid stimulating hormone
(TSH), alpha fetoprotein, alpha-1 anti-trypsin.
For subjects continuing from PK Lead-in into the Treatment Phase, a 
screening visit for the Treatment Phase will not be required.
PK Lead-in Phase: 
Study Visits will occur at Day 1, Day 3, and Day 10.
On-Treatment assessments include physical examination, Tanner 
Pubertal Stage Assessment (Day 1 only), vital signs (including body 
height and weight), bone age assessment (Day 1 only), adverse events 
(AEs), concomitant medications, pregnancy prevention counseling 
(Day 1 only; all subjects ≥ 12 years of age and subjects 
< 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status), quality of life survey (Day 1 only), safety 
laboratory tests, HCV RNA, viral sequencing sampling and 
urinalysis. Coagulation testing and urine pregnancy tests (females of 
child bearing potential only) will be performed at Day 1 and Day 10 
only. LDV/SOF FDC swallowability assessment with placebo will be 
performed (if not performed at Screening) on Day 1 to assess a 
subject’s ability to swallow the 90 mg/ 400 mg or 22.5 mg/ 100 mg
FDC tablet (only subjects administered LDV/SOF FDC in tablet 
form). 
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in 
Phase will participate in an intensive PK evaluation on Day 10. 
Following completion of the Day 10 intensive PK visit, subjects will 
then return for scheduled study visits outlined in the Treatment Phase 
and will continue dosing with LDV/SOF FDC with no interruption of 
study drug administration. Subjects will be administered a dosing 
diary with instructions.
Treatment Phase: 
Study visits will occur at Day 1, and at the end of Weeks 1, 2, 4, 8, 
and 12 (and Weeks 16, 20, and 24 for subjects requiring 24 weeks of 
treatment). All Treatment Phase subjects will then return for 
follow-up visits at 4, 12 and 24 weeks after discontinuation of 
therapy. 
On-treatment assessments will include physical examination, vital 
signs (including body height and weight), AEs, concomitant 
medications, pregnancy prevention counseling (all subjects 


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≥12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status), safety laboratory
tests, coagulation tests, HCV RNA, viral sequencing, urine pregnancy 
tests (females of childbearing potential only), PK samples, a quality 
of life survey, and urinalysis. Tanner Pubertal Stage assessment will 
be performed at Day 1 and end of treatment visits; parental heights 
will be recorded at Day 1. The Bone Age Assessment will be 
performed at the Day 1 visit. LDV/SOF FDC swallowability 
assessment will be performed (if not performed at Screening) on
Day 1 to assess a subject’s ability to swallow a placebo to match the 
90 mg/ 400 mg or 22.5 mg/ 100 mg LDV/SOF FDC tablet (only 
subjects administered LDV/SOF FDC in tablet form). For subjects 
continuing from the PK Lead-in, the screening, Day 1, and Week 1 
visits of the Treatment Phase will not be required. Samples for viral 
RNA sequencing/phenotyping will be collected at Day 1 and every 
visit thereafter.
Post-treatment assessments will include vital signs (including body 
weight and height), symptom-directed physical examination, AEs 
(only SAEs will be captured at post-treatment Week 12 and 
post-treatment Week 24), concomitant medications (only 
post-treatment Week 4), safety laboratory tests, HCV RNA, Tanner 
Pubertal Stage assessment (only post-treatment Week 12 and 
post-treatment Week 24), Bone Age Assessment (only post-treatment 
Week 24) and urine pregnancy tests (as defined in Appendix 5).  
 
 
Test Product, Dose, 
and Mode of 
Administration:
PK Lead-in: 
(Cohort 1) LDV/SOF FDC is manufactured as a tablet, consisting of 
400 mg SOF and 90 mg LDV, for oral administration.  LDV/SOF 
FDC tablets will be administered once daily. Subjects unable to 
swallow the LDV/SOF FDC 90 mg/ 400 mg adult tablets (as 
determined by LDV/SOF FDC Swallowability Assessment at 
Screening or at any time during the study) will be re-assigned to 
4 x 22.5 mg/ 100 mg LDV/SOF FDC tablets daily.
(Cohort 2) LDV/SOF FDC 45 mg/ 200 mg (2 x 22.5 mg/ 100 mg) 
will be administered once daily. Subjects unable to swallow the 
LDV/SOF FDC 22.5 mg/ 100 mg tablets (as determined by 
LDV/SOF FDC Swallowability Assessment) will be deferred until 
oral granulate formulation is available.
PPD


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Intensive PK and safety results from the PK Lead-in of each Cohort 
will be reviewed to confirm the appropriateness of the evaluated 
LDV/SOF FDC dose for the Treatment Phase of that Cohort as well 
as to determine the age-appropriate dose to be evaluated in the PK 
Lead-in of the next Cohort.
Treatment Phase: 
Subjects who participated in PK Lead-in of each Cohort will continue 
in the Treatment Phase with no interruption of study drug 
administration until the appropriateness of the dose is confirmed by 
PK and safety data from the PK-Lead-in. Additional subjects will be 
enrolled in the Treatment Phase of each Cohort upon confirmation of 
the appropriateness of the dose.
RBV Weight-Based Dosing (GT-3 Subjects only):
The RBV dose is:
Body Weight kg
(lbs.)
RBV Daily 
Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution.  Divided dose in the 
morning and evening.
47-49 (103-108)
600 mg/day
1 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
50-65 (110 – 143)
800 mg/day
2 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
66-80 (145 – 176)
1000 mg/day
2 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
81-105 (178-231)
1200 mg/day
3 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
>105 (>231)
1400 mg/day
3 x 200-mg capsules A.M.
4 x 200-mg capsules P.M.
*
Note:  Subjects with a body weight greater than or equal to 47 kg may utilize the RBV 
oral solution if necessary.
The morning dose of RBV will be taken with food with an 
age-appropriate dose of LDV/SOF FDC. The evening dose of RBV 
will be taken with food.
Reference Therapy:
None
Evaluation Criteria:
Safety:
AEs, laboratory tests, physical examinations, and vital sign 
measurements will be collected throughout the study. 


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Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using COBAS® AmpliPrep/COBAS® TaqMan®
HCV Test.
PK:
For subjects in the PK Lead-in, the steady-state PK of LDV, SOF,
and its major metabolites (GS-331007 and GS-566500) will be 
assessed at Day 10. For Cohorts 1 and 2, plasma samples will be 
collected for PK analyses following dosing of study drug on Day 10
at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, and 
12 hours postdose (with predose also serving as t= 24). For Cohort 3, 
plasma samples for PK analyses will be collected at the following 
time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours postdose (with 
predose also serving as t = 24).
Plasma PK parameters such as Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, and 
t1/2 will be estimated. 
For all subjects in the Treatment Phase, a single PK blood sample will 
be collected at all visits while on treatment. The PK of GS-331007,
SOF and LDV will be assessed.
The effect of age and LDV/SOF FDC dose on PK (GS-331007, SOF, 
and LDV) will be explored.
Statistical Methods:
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, Ctau, 
AUCtau, AUClast, and t1/2 will be estimated. The PK parameters will be 
summarized by cohort. The effect of age and LDV/SOF FDC dose on 
PK (GS-331007, SOF, and LDV) will be explored.
For the Treatment Phase, the primary safety endpoint is any AE 
leading to permanent discontinuation of study drug and will be 
summarized by the 4 regimens based on treatment-experience,
cirrhosis status and genotype, by age group, by regimen and age 
group, and overall. The key efficacy endpoint is SVR12 in all 
enrolled and treated subjects and will be summarized the 4 regimens 
based on by treatment-experience, cirrhosis status and genotype, by 
age group, by regimen and age group, and overall. Point estimate and 
its 95% confidence interval will be provided. 
Subgroup analysis on SVR12 will be performed by 
treatment-experience and cirrhosis status, by IL28B genotype, and by 
GT. Other clinically relevant subgroup analyses may be conducted as 
appropriate (i.e., assuming that adequate numbers of patients in these 
subsets are available for analysis). 


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All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation, median, Q1, Q3, minimum, 
and maximum). 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 by the 4 regimens based on 
treatment-experience, cirrhosis status and GT, by age group, by 
regimen and age group, and overall.
With approximately 100 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 
SVR12 rate will extend at most 5.9% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 90%.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
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)
BLQ
below the lower limit of quantification
BMI
body mass index
CK
creatine kinase
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
dL
Deciliter
DNA
deoxyribonucleic acid
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
ESA
Erythropoiesis stimulating agent
ESPGHAN
European Society for Paediatric Gastroenterology
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed-Dose Combination
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
HAV
Hepatitis A Virus


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
peginterferon alfa-2a
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
QD
once daily (use only in tables)
RBC
Red blood cell count
RBV
ribavirin
RNA
ribonucleic acid
SADR
Serious adverse drug reaction


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
SAE
serious adverse event
SD
Standard deviation
SOC
Standard-of-Care
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TSH
Thyroid stimulating hormone
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant 
(λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease worldwide 
and accounts for 70% of cases of chronic hepatitis in industrialized countries. The global 
prevalence of chronic hepatitis C is estimated to average 3% {19705}. 
The natural history of chronic HCV-infection in children differs from that in adults since 
HCV-infection in children is relatively benign. Most children chronically infected with HCV are 
asymptomatic or have mild nonspecific symptoms. Clinical symptoms are present in 
approximately 20% of children in the first 4 years of life, with hepatomegaly being the most 
frequent sign (10%). Many, but not all, perinatally infected children will have intermittently or 
persistently abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
levels, particularly in the first 2 years of life. In children with vertical HCV-infection who have
undergone liver biopsy, the histological spectrum is usually mild, although severe liver disease is 
encountered {19801}. Despite the overall more favorable prognosis compared to adults, 
approximately 4% to 6% of children with chronic HCV-infection have evidence of advanced 
fibrosis or cirrhosis and some children eventually require liver transplantation for end-stage liver 
disease as a consequence of HCV-infection {19799}.
The goal of HCV treatment in both pediatric and adult populations is eradication of the virus, 
thereby preventing hepatic inflammation, hepatic fibrosis, cirrhosis, and liver failure resulting in 
either death or need for liver transplantation. This goal, however, is limited by the nature of the 
disease and the fact that not all patients are suitable candidates for currently approved treatments. 
In addition, pediatric treatment is controversial as the current treatment options are limited and 
severe side effects and tolerability can significantly limit or preclude their use. Despite 
well-established guidelines for the treatment of HCV in adults, there is no universal consensus 
on when or if to treat chronic HCV-infection in children. In 2010, the European Society for 
Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) issued guidance for clinical 
trial development for chronic HCV-infection in children {20286}. In the guideline, the 
ESPGHAN suggested that the primary goal of treatment in children is to eradicate the infection 
to prevent late complications. Hence, the goal is not the treatment of an ongoing liver disease, 
but rather the prevention of a future one.
PEG and weight-based RBV are currently considered the SOC for the treatment of 
HCV-infection in children. Current recommendations are that patients with GT-2 or GT-3 be 
treated with PEG+RBV for 24 weeks and those with GT-1 or GT-4 should receive 48 weeks of 
therapy. Successful treatment of GT-1, however, has proved very difficult to achieve in spite of 
additional therapy or increased duration of treatment. A number of pediatric studies have 
reported that despite 48 weeks of treatment, sustained virologic response (SVR24) was observed 
in only 36% to 53% of subjects with GT-1, while response rates were > 80% in subjects with 
GT-2 or GT-3 {20285}.


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Most children treated with PEG+RBV experience at least 1 adverse event due to treatment 
{20285}. Although most of these events are mild to moderate in severity, many of them result in 
dose reductions of 1 or both of the drugs. The most common adverse events have consisted of 
influenza-like illness (91%), headache (62%), and injection site reactions (45%), often leading to 
poor compliance and/or discontinuation from treatment.
Additionally, the concern for growth and development in this age group and the role that both 
PEG and RBV potentially play in reducing growth rates has initiated significant debate among 
pediatric hepatologists as to whether these treatments should even be considered in the pediatric 
population {20282}. Many pediatricians currently advocate delay of treatment past adolescence 
or even into adulthood when options with DAAs are possible {20282}. Unfortunately, in the 
25% of pediatric patients who do meet the criteria for treatment (elevated transaminases and viral 
loads), the option of PEG+RBV therapy remains inadequate in regard to both efficacy in GT-1 
and safety due to the many risks associated with this treatment.
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
Ledipasvir/Sofosbuvir fixed-dose combination (LDV/SOF FDC) combines two HCV specific 
direct acting antiviral (DAA) agents into a single tablet for the treatment of chronic 
HCV-infection. SOF is a nucleotide analog that is a potent and selective inhibitor of 
NS5B-directed HCV replication with demonstrated activity against GT 1-6 HCV-infection. 
Ledipasvir (LDV) is a novel HCV NS5A inhibitor that has demonstrated potent anti-HCV 
activity, with the highest activity against GT1 HCV-infection. Harvoni® (LDV/SOF FDC) has 
been approved in the United States by the Food and Drug Administration (FDA) for treatment of 
HCV infection GT-1 adult patients. Harvoni® is indicated for both treatment-naïve and 
treatment-experienced subjects with or without cirrhosis with a 12 week treatment duration. For 
treatment-experienced subjects with cirrhosis a 24 week treatment duration is recommended. 
Harvoni® is also approved in the EU for treatment of HCV infection GT-1 and GT-4 adult 
patients as outlined above and for GT-3 treatment-experienced adults with cirrhosis and/or prior 
treatment failure subjects for 24 weeks treatment duration with ribavirin (RBV).
1.2.1.
Summary of Additional Clinical Experience with Ledipasvir/Sofosbuvir 
Fixed-Dose Combination
The LDV/SOF FDC phase 3 program consisted of 3 clinical studies: GS-US-337-0102 {28583}, 
GS-US-337-0109 {28585}, and GS-US-337-0108 {28587}. Studies GS-US-337-0102 and 
GS-US-337-0109 evaluated treatment with LDV/SOF FDC RBV for 12 or 24 weeks in 
treatment-naïve and treatment experienced subjects, respectively, infected with GT-1 HCV. Both 
studies enrolled up to 20% of HCV-infected subjects who had documented compensated 
cirrhosis. GS-US-337-0108 evaluated LDV/SOF FDC ± RBV treatment for 8 weeks and 
LDV/SOF FDC treatment for 12 weeks in non-cirrhotic treatment-naïve subjects with GT-1 
HCV-infection. Across these 3 clinical studies, LDV/SOF FDC demonstrated a high degree of 
efficacy (> 93%) for treatment-naïve and treatment experienced subjects with GT-1 
HCV-infection in subjects with and without cirrhosis and achieved their primary efficacy 
endpoints {28583}; {28585}; {28587}. Additionally, treatment with LDV/SOF FDC ± RBV was 
safe and well tolerated in the Phase 3 studies {28583}; {28585}; {28587}.  The inclusion of RBV 
to the treatment regimen was associated with an increase in the total incidence of adverse events 
and in graded laboratory abnormalities of anemia and increased bilirubin. 


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LDV/SOF FDC indication in GT-3 HCV infection is supported by the Phase 2 Study 
GS-US-337-0122 (ELECTRON-2). In this Phase 2 open-label study, the safety and efficacy of 
LDV/SOF FDC were evaluated with or without RBV in 51 treatment-naïve patients with GT-3 
HCV infection, with or without cirrhosis. Subjects were treated with LDV/SOF FDC (n = 25) or 
LDV/SOF FDC + RBV (n = 26) for 12 weeks. SVR12 rates were 64% (16/25) and 100% (26/26) 
in the LDV/SOF FDC and LDV/SOF FDC + RBV treatment groups, respectively. The relative 
efficacy of a 12-week regimen consisting of ledipasvir/sofosbuvir + ribavirin, compared to a 
24-week regimen of sofosbuvir + ribavirin has not been investigated. Therefore, 24 weeks of 
therapy is advised in all treatment-experienced GT3 patients and those treatment-naïve GT3 
patients with cirrhosis to maximize therapeutic benefit to achieve SVR.
Both nonclinical and clinical data support the inclusion of GT-4 HCV-infected subjects in the 
Study GS-US-337-1116.
LDV displays potent antiviral activity against GT-4. In the replicon system the EC50 value of 
LDV for GT-4d HCV was 0.60 nM and 0.39 nM for GT-4a HCV (final report in preparation). 
For reference, the EC50 values of LDV for GT-1a and GT-1b is 0.031 nM and 0.004 nM, 
respectively.
In the Phase 3 Study GS-US-337-0102 (ION-1), 2 subjects with GT-4d HCV infection were 
inadvertently randomized in violation of the protocol inclusion/exclusion criteria. Both subjects 
achieved SVR12. Subject 
 was treated for 12 weeks with LDV/SOF FDC and 
Subject 
 was treated for 24 weeks with LDV/SOF FDC + RBV.
In Study GS-US-337-1119, a European study investigating the efficacy and safety of LDV/SOF
FDC in treatment-naive and treatment-experienced subjects with chronic GT-4 or GT-5 HCV 
infection, a total of 44 subjects with GT-4 HCV infection, of whom 10 (23%) have cirrhosis and 
22 (50%) are treatment experienced, have been enrolled to receive LDV/SOF FDC for 12 weeks. 
SVR12 has been achieved by 41/44 (93%) subjects, with 21/22 treatment naïve subjects and 
20/22 treatment-experienced subjects having achieved SVR12. 
In addition, preliminary data are available from Group E of the NIAID/NIH collaborative Study 
CO-US-337-0117. In this group, 21 subjects with GT-4 HCV infection are receiving 12 weeks of 
LDV/SOF FDC treatment. In total, 6 subjects have cirrhosis. Post-treatment week 12 data is 
available for 20 subjects. 20 of 21 subjects have achieved SVR12.
Preliminary data are also available for Cohort 1 adolescent subjects (N=10) who enrolled in the 
PK lead-in and received adult clinical doses of LDV/SOF 90 mg/400 mg. Mean exposures of 
LDV, SOF and GS-331007 in these subjects were comparable to observed exposures in the adult 
subjects in the Phase 2/3 LDV/SOF clinical program; thereby confirming the appropriateness of 
adult dose in the adolescent population (12 to < 18 years of age) Table 1-1.
Safety data available for Cohort 1 adolescent subjects (N=10) who enrolled in the PK lead-in and 
received adult clinical dose of LDV/SOF FDC 90 mg/ 400 mg resulted in no significant safety 
concerns.
PPD
PPD


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Table 1-1.
Steady-state PK and Statistical Comparisons of LDV, SOF and 
GS-331007 PK in Adolescent Subjects (PK Lead-in) and Adult 
Subjects (Phase 2/3 Population PK Analysis)
Mean (%CV)
Adolescents (N=10)
Phase 2/3 (N=2113)
GMR% (90% CI)
LDV
AUCtau (ng*hr/ml)
10200 (50.9)
8530 (60.8)
127 (94.9, 170)
Cmax (ng/ml)
564 (41.2)
364 (51.4)
162 (125, 209)
Ctau (ng/ml)
319 (71.5)
247 (59.2)
128 (95.2, 172)
SOF*
AUCtau (ng*hr/ml)
2180 (26.6)
1380 (34.0)
160 (138, 185)
Cmax (ng/ml)
1140 (57.2)
659 (34.0)
156 (127, 190)
GS-331007
AUCtau (ng*hr/ml)
12700 (13.7)
12500 (29.2)
105 (90.6, 122)
Cmax (ng/ml)
1010 (21.5)
736 (28.2)
139 (120, 161)
Data reported to 3 significant figures; *N=1542
Please refer to the Investigator’s Brochure (IB) for additional information on the LDV/SOF FDC 
including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA 
and DNA viruses {15572}, {15668}. Ribavirin monotherapy has little or no effect on the 
replication of HCV but can result in normalization of serum ALT activity and improvement in 
liver histology. When combined with interferon or PEG therapy, RBV decreases substantially the 
relapse rate seen after cessation of interferon therapy {12557}, {12558}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to accumulate 
intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, extreme care 
must be taken to avoid pregnancy during RBV therapy and for up to 7 months following 
completion of treatment.  A comprehensive review of RBV is contained in the package 
insert/SmPC.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 24
28 May 2015
1.4.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with LDV/SOF 
FDC +/- RBV for adolescents and children with chronic HCV-infection. 
Currently PEG and weight-based RBV are considered the SOC for the treatment of 
HCV-infection in children. Therefore, there is a need for new treatments for HCV in the 
pediatric population that combine potent and sustained efficacy with improved tolerability and 
safety. The primary aim for new treatments of pediatric patients with HCV is to eliminate the 
need to use PEG. In this way, pediatric patients would be able to avoid the necessity of weekly 
injections which can be traumatic and burdensome, and significantly reduce the serious adverse 
events seen with PEG administration. The secondary aim is to eliminate RBV and the adverse 
events seen with its administration within GT-1 and GT-4 HCV infected subjects.
Harvoni® (LDV/SOF FDC) is approved in the US and EU for the treatment of adults with 
chronic HCV infection. LDV/SOF FDC +/- RBV would provide an all-oral, IFN-free regimen 
with a shorter treatment duration (12 or 24 weeks of LDV/SOF FDC +/- RBV treatment versus 
standard-of-care 24 to 48 weeks of treatment) for GT-1, -3, and -4 HCV infection subjects and 
would offer another important option in the treatment of HCV infection in the pediatric 
population.
In vitro viral replicon assay has data demonstrating LDV has potent, picomolar antiviral activity 
against GT-1a and GT-1b HCV-infection. In the LDV/SOF FDC phase 3 program, LDV/SOF 
FDC without RBV has been shown to have good efficacy and safety in adults infected with GT-1 
HCV-infection.  In the GS-US-337-0102 (ION-1), GS-US-337-1119, and CO-US-337-0117, 
LDV/SOF FDC without RBV has been shown to have good efficacy and safety in adults infected 
with GT-4 HCV-infection. In study GS-US-337-0122, a phase 2 open-label study of GT-3 
treatment-naïve adult subjects with and without cirrhosis, LDV/SOF FDC for 12 weeks resulted 
in an SVR12 of 64% whereas LDV/SOF + RBV for 12 weeks resulted in an SVR of 100% 
{29292}. The clinical data to support the use of Harvoni in patients infected with HCV GT3 are 
limited. As a result, the current study will include a 24-week RBV treatment regimen for only 
treatment experienced pediatric subjects who enroll with GT-3 HCV-infection.
Considering that SOF has pan-genotypic activity and LDV has in vitro, picomolar to nanomolar 
antiviral activity against certain subtypes within GT 4-6 and sub-micromolar antiviral activity 
against certain subtypes within GT-2, studies have been planned and/or initiated with LDV/SOF 
FDC in adult subjects with GT-2, -5, and -6.  If emerging LDV/SOF FDC data in these 
additional GTs support treatment in these genotypes in adults, pediatric subjects with GT-2, -5 
and -6 will be enrolled in the current study.  Of note, there is an ongoing study enrolling GT-2 
and -3 pediatric patients, GS-US-334-1112, for treatment with SOF + RBV for 12 and 24 weeks, 
respectively.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 25
28 May 2015
1.5.
Rationale for Dose Selection of LDV/SOF FDC
Ledipasvir /Sofosbuvir (90 mg/400 mg) fixed-dose combination tablet +/- RBV has 
demonstrated favorable safety and efficacy profiles in over 3000 HCV-infected subjects across 
different patient populations in phase 2 and 3 clinical trials. These doses represent the marketed 
dose of a ledipasvir/sofosbuvir fixed-dose combination tablet for the treatment of HCV-infection
in adults.
Selection of doses of LDV/SOF FDC +/- RBV for adolescents and younger age groups will 
target systemic exposures similar to those observed in adults at the proposed marketed dose. 
LDV and SOF are substrates for efflux drug transporters P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP). LDV is also a subject to slow oxidative metabolism via an unknown 
mechanism. SOF is extensively metabolized to the pharmacologically active nucleoside analog 
phosphate. The activation pathway involves hydrolysis by intestinal and hepatically expressed 
carboxylesterase (CES1) and Cathepsin A (CatA) enzymes {20287}, {20288}.  SOF is also 
converted to GS-331007, an inactive circulating metabolite, which is eliminated renally by active 
tubular secretion and glomerular filtration.  Available data suggest comparable hepatic 
expression of CES1 in adolescents and adults with modestly decreased expression in children.  
However, little is known about the developmental regulation of Pgp, CES, and CatA.  When 
adjusted for BSA, the processes of active secretion and glomerular filtration approximate adult 
activity by 6 to 12 months of age {5914}. 
The adult clinical dose of LDV/SOF FDC (90 mg/ 400 mg) is being evaluated in adolescent 
subjects (12 to <18 years old, weighing ≥ 45 kg).  The appropriateness of adult dose for this age 
range is supported by data from the Cohort 1 PK Lead-in subjects which demonstrated 
comparable LDV, SOF and GS-331007 exposures in adolescent subjects and in adult subjects in 
Phase 2/3 population PK analyses.
LDV/SOF FDC (45 mg/ 200 mg) dose is proposed for an evaluation in children (6 to < 12 years 
of age, weighing ≥ 17 kg and < 45 kg). This proposed dose was supported by scaling of adult 
exposures based on correlations between body weight and clearance capacity (liver volume/size 
for LDV and SOF, and renal capacity for GS-331007) for the expected body weight range in 
childen (6 to < 12 years of age) as demonstrated in Figure 1-1 {34882}, {5914}. Additionally, the 
dose of LDV/SOF FDC 45 mg/ 200 mg provides comparable dosing to the clinical adult dose on 
mg/kg basis (LDV range: 0.5 to 2.1 mg/kg; SOF range: 2.3 to 9.5 mg/kg) in Phase 2/3 program. 
Based on these scaling approaches, the dose of LDV/SOF FDC 45 mg/ 200 mg is expected to 
achieve mean systemic exposures of LDV, SOF and GS-331007 that as observed in the 
Phase 2/3 population. Safety and PK data in children (6 to < 12 years of age) who enroll in the 
PK-lead will be evaluated to confirm the appropriatness of the dose for this age group and inform 
dose selection for children < 6 years old.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 26
28 May 2015
Figure 1-1.
Predicted LDV, SOF and GS-331007 AUCtau following administration 
of LDV/SOF FDC 45 mg/ 200 mg in Children (6 to < 12 years of age)
'C 
Cll 
(ii 
(,)
-
~E 
=-.:: 
I~ ..c 
u 
• 
:::> 
C) 
<{ c 
u.. 
100000 
LDV/SOF 45 mg/200 mg 
·················································································· 
max 
~············ ···· ···· 
r o, 
95th percentile !5 :::; 
10000 ~·················'<. 
,A 
.AA 
vv 
Q3 
Q2 
cne: 
o.,. 
,"' 
1000 
~ 
············ 
.oA 
• 
• • 
• • . • • • • • • • • • . • •. • • • • • • •••• ~ • •••• ! Y.'lV.V 
~······· ········ 
, ••• , •••, •• ., •• :~.... 
.AAA 
......... "':'::': ...... . 
Q1 
-w 
~, 
3 0 
CQ_"U 
5th percentll e 
~ ~ 
0 
- · 
3 g 
!9. 
···············•······························ ········· ·· · ························ 
min 
I 
I 
I 
17 
19 
21 
23 
25 
27 
29 
31 
33 
35 
37 
39 
41 
43 
45 
10000 
weight (kg) 
o 
5th percentile 
0 
Q1 
6 
Q2 
9 
03 
o 
95th percentile 
LDV/SOF 45 mgt 200 mg 
......................................................... ......................... 
max 
r 
~-u 
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(J)I» 
01/) 
.,~ 
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-w 
95th percentile ~ -u 
3 0 
Q3 
CQ. -g 
g 
1000 
Q2 
~a 
Q1 
0 -· 
3 g 
17 
19 
21 
23 
25 
27 
29 
31 
33 
35 
37 
39 
41 
43 
45 
weight (kg) 
5th percentile !8. 
min 
o 
5th percentile 
0 
Q1 
A
Q2 
'V'Q3 
o 
95th percentile 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 27
28 May 2015
Age-appropriate formulations of LDV/SOF FDC (a smaller, 22.5 mg/ 100 mg strength tablet and 
a non-tablet formulation currently under development) that offer an important option in the 
treatment of HCV-infection in the pediatric population are planned for evaluation in children 
below 12 years of age or children who are unable to swallow the adult dose tablet formulation.
1.6.
Overall Risk/Benefit Assessment
Although the majority of pediatric patients infected with HCV exhibit minimal hepatic sequelae 
despite active viral replication and inflammation, a subset of children and adolescents will 
require treatment. Studies suggest that 3 major categories of disease can occur within 10 years 
after putative HCV exposure: (1) undetectable viremia and normal ALT, (2) persistent yet 
uncomplicated mild liver disease, and (3) progression to end-stage liver disease {20273}. It is the 
last two groups of children in whom therapy may be indicated to prevent end-stage disease, 
either during childhood/adolescence or in early adulthood.
Given that the current SOC for the treatment of children infected with HCV is PEG and RBV 
and these regimens are long in duration, relatively toxic, and not well tolerated, there continues 
to be a need for new treatments for HCV that combine potent and sustained efficacy with 
improved tolerability and safety. 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 28
28 May 2015
The combination of LDV plus SOF is anticipated to offer greater antiviral efficacy which could 
result in a shorter treatment duration and/or lead to a regimen without RBV or interferon. These 
in turn could result in reduction in adverse events.  LDV/SOF FDC could also potentially be of 
benefit in patients who have failed prior treatment with SOF+/-RBV+/- PEG.
If high rates of SVR can be obtained with short, well-tolerated regimens, the anticipated 
improvements in safety and tolerability would offer a favorable risk-benefit determination for 
individuals with chronic HCV-infection.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 29
28 May 2015
2.
OBJECTIVES
The primary objective of the PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm the dose of LDV/SOF FDC
in chronic HCV-infected pediatric subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing of LDV/SOF 
FDC in chronic HCV-infected pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV for 12 or 24 weeks in 
chronic HCV-infected pediatric subjects
The secondary objectives of the Treatment Phase of this study are:

To determine the antiviral efficacy of 12 or 24 weeks of LDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects (including the impact of HCV genotype, IL28B genotype, 
and prior treatment experience), as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12)

To determine the antiviral efficacy of 12 or 24 weeks of LDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment

To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment

To evaluate the effect of growth and development on pediatric subjects during and after 
treatment
The exploratory objective of this study is:

 
 
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 30
28 May 2015
3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and antiviral 
activity of LDV/SOF FDC +/- RBV in chronic HCV-infected pediatric subjects.
3.1.1.
PK Lead-in
The PK Lead-in Phase will evaluate and/or confirm the age appropriate LDV/SOF FDC dose by 
analyzing PK, safety, and antiviral activity of LDV/SOF FDC through 10 days of dosing for each 
cohort. Children aged 3 to < 6 years, children aged 6 to < 12 years, and adolescents 
aged 12 to < 18 years with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry 
will be evaluated. Subjects must be treatment naïve without history of cirrhosis to participate in 
the PK Lead-in Phase. Three cohorts of at least 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old, weighing ≥45kg

Cohort 2:  6 to < 12 years old, weighing ≥ 17 kg and < 45 kg

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive LDV/SOF FDC (90 mg/ 400 mg 
adult tablet or 4 x 22.5 mg/100 mg tablets if determined necessary based on LDV/SOF FDC
swallowability assessment) for 10 days with intensive PK conducted on Day 10. 
Cohort 2: Subjects will receive LDV/SOF FDC 45 mg/ 200 mg (2 x 22.5 mg/ 100 mg tablets or 
subject will be deferred until oral granulates formulation is available, if determined necessary 
based on LDV/SOF FDC swallowability assessment).
Following completion of study treatment in the PK Lead-in of Cohort 2 and pending PK and 
safety results, the PK Lead-in of Cohort 3 will initiate and receive study treatment 
(age-appropriate dose and formulation). 
Subjects enrolled in the PK Lead-in of each cohort (Cohorts 1, 2 and 3) will immediately enroll 
in the Treatment Phase as they complete Day 10 of PK Lead-in.  They will continue dosing with 
LDV/SOF FDC with no interruption of study drug administration.  Subjects rolling over from the 
PK Lead-in Phase will not be required to perform the screening, Day 1, or Week 1 visit of the 
Treatment Phase.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 31
28 May 2015
Figure 3-1.
PK Lead-in Phase Study Schema
3.1.2.
Treatment Phase
The Treatment Phase will be initiated sequentially by age group as defined in Cohort 1, 2, and 3 
of the PK Lead-in. Subjects who participated in PK Lead-in will immediately rollover into 
Treatment Phase with no interruption of study drug administration until the appropriateness of 
the dose has been confirmed by PK and safety results from the PK Lead-in.  The first visit in the 
Treatment Phase for these subjects will be the Week 2 visit.  Additional subjects will be enrolled 
in the Treatment Phase of each Cohort upon confirmation of the appropriateness of the dose from 
the PK Lead-in.
Children aged 3 to < 12 years (Group 2) and adolescents aged 12 to < 18 years (Group 1) with 
chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry (those who were dosed in 
the PK Lead-in will have met this criteria prior to enrollment) will be evaluated.
Subjects enrolled in the Treatment Phase will receive the following regimen:
a) United Kingdom:
GT-1 & GT-4 treatment-naïve subjects with or without cirrhosis: LDV/SOF FDC for 
12 weeks
GT-1 & GT-4 treatment-experienced subjects without cirrhosis: LDV/SOF FDC for 
12 weeks
GT-1 & GT-4 treatment-experienced subjects with cirrhosis: LDV/SOF FDC for 
24 weeks
GT-3 treatment-experienced subjects with or without cirrhosis: LDV/SOF FDC + RBV 
for 24 weeks


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 32
28 May 2015
b) United States/Australia/New Zealand:
GT-1 treatment-naïve subjects with or without cirrhosis: LDV/SOF FDC for 12 weeks
GT-1 treatment-experienced subjects without cirrhosis: LDV/SOF FDC for 12 weeks
GT-1 treatment-experienced subjects with cirrhosis: LDV/SOF FDC for 24 weeks
Table 3-1.
Subject Enrollment by HCV Genotype, Country and Treatment 
Duration
GT-1
GT-4
GT-3
Cirrhotic 
or 
Non-
cirrhotic 
Subjects 
(TN)
Non-
cirrhotic 
Subjects 
(TE)
Cirrhotic 
Subjects 
(TE)
Cirrhotic 
or 
Non-
cirrhotic 
Subjects 
(TN)
Non-
cirrhotic 
Subjects 
(TE)
Cirrhotic 
Subjects 
(TE)
Non-
cirrhotic or 
Cirrhotic 
Subjects 
(TE)
United States
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
N/A
N/A
N/A
N/A
Australia
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
N/A
N/A
N/A
N/A
New Zealand
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
N/A
N/A
N/A
N/A
United Kingdom
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks of 
treatment 
with 
LDV/SOF 
FDC + RBV
TN = Treatment Naïve, TE = Treatment Experienced, N/A = Not Applicable
Subjects with GT -1, -3, and -4 will be enrolled first.  If emerging LDV/SOF FDC data in GT-2,
-5, and -6 support treatment in these GTs in adults, pediatric subjects with GT-2, -5, and -6 will 
be subsequently enrolled.  


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 33
28 May 2015
The study will enroll both treatment naïve and treatment experienced pediatric subjects with up 
to 40 subjects allowed to be treatment experienced. Approximately 200 total subjects, including 
subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as follows:

Group 1: Approximately 100 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 100 pediatric subjects (3 to < 12 years of age)
The following definitions will be used for treatment experienced subjects:

Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to ≥1 adverse 
event

Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels while 
on treatment

Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment or 
within 4 weeks of the end of treatment but did not achieve a sustained virologic response 
(SVR)
All subjects who do not attain SVR or have viral relapse will be encouraged to discuss treatment 
with SOC therapy with their healthcare provider.
3.2.
Visit Schedule
3.2.1.
PK Lead-in
Screening assessments will be completed within 28 days of the Day 1 visit. 
Study Visits will occur at Screening, Day 1, Day 3, and Day 10.
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in Phase will participate in an 
intensive PK evaluation on Day 10. Subjects will be administered a dosing diary with 
instructions.  
Following completion of the Day 10 intensive PK visit, subjects will then return for scheduled 
study visits outlined in the Treatment Phase and continue dosing with LDV/SOF FDC with no 
interruption of study drug administration.  Subjects rolling over from the PK Lead-in Phase will 
not be required to perform the screening, Day 1, or Week 1 visits of the Treatment Phase.
3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. Subjects continuing 
from the PK Lead-in Phase will not be required to complete Screening, Day 1, and Week 1 visits 
of the Treatment Phase.

Subjects requiring 12 weeks of treatment: Study visits will occur at Screening, Day 1, and 
the end of weeks 1, 2, 4, 8, and 12.

Subjects requiring 24 weeks of treatment: Study visits will occur at Screening, Day 1, and 
the end of weeks 1, 2, 4, 8, 12, 16, 20, and 24.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 34
28 May 2015
All subjects will then return for follow-up visits at 4, 12, and 24 weeks after discontinuation of
therapy.
The total time to complete all study visits is approximately 40 or 52 weeks including:

28 day (4 week) screening period

12 or 24 week treatment period

24 week post-treatment period
The assessments performed at each visit are described in Section 6.
3.3.
Virologic Response-Based Stopping Criteria
HCV RNA will be unblinded to the Investigator and Sponsor.
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 from nadir 

HCV RNA ≥LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination of 
initial observation.  Subjects that meet the virologic response-based stopping criteria above will 
be notified of their eligibility to participate in the Long-Term Follow-Up Study 
(GS-US-334-1113).
3.4.
Treatment Discontinuations Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances:

Unacceptable toxicity (as defined in Section 7) 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 or female partner of male subject.

Efficacy failure as defined in Section 3.3.

Significant protocol violation including non-compliance with study assessments.

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).


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 35
28 May 2015
3.5.
Discontinuations
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Termination visit as described in the Section 6.4.8.
Subjects who permanently discontinue the study drug for any reason including safety and/or 
tolerability concerns prior to completion of the assigned dosing period will be followed 
according to the post-treatment study assessments described in Section 6.5.
3.6.
Pharmacogenomic Substudy
 
 
 
3.7.
Long-Term Follow-Up
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed every 6 months for the first 
2 years followed by every 12 months for assessments of growth, quality of life, and long-term 
viral suppression (if applicable) in a separate protocol (GS-US-334-1113). This follow-up study 
will continue for 5 years.
3.8.
Breakthrough Futility Assessment
A futility assessment will be performed after the first 10 subjects complete Week 8 on study or 
have viral breakthrough at or prior to Week 8. If 3 or more of the first 10 subjects enrolled have 
viral breakthrough at or prior to Week 8 or are non-responders (HCV RNA > LLOQ through 
8 weeks of treatment) then further enrollment of subjects will be suspended. Virologic 
breakthrough is defined as confirmed HCV RNA > LLOQ while on treatment after 
two consecutive visits with HCV RNA < LLOQ.
If a holding rule has been met and following an internal safety review it is deemed appropriate to
restart enrollment, a request to restart enrollment with pertinent data will be submitted to the 
appropriate regulatory agencies.  Enrollment will only resume after review by the appropriate 
regulatory agencies.  Any subject on treatment when a holding rule has been met will be allowed 
to continue to treatment.
Subjects with known or suspected study drug non-adherence will not be considered to meet the 
definition of virologic breakthrough, relapse, or non-responder. 
3.9.
Reconsent
When a subject reaches the age of consent in their country/region, they will be invited to consent 
as adults to allow them to continue participating in the clinical trial.
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 3.0
CONFIDENTIAL
Page 36
28 May 2015
4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 200 subjects will be enrolled in this study.
In order to manage the total study enrollment, Gilead Sciences, Inc. at its sole discretion, may 
suspend screening and/or discontinue the enrollment at any site at any time (upon written notice 
to the site). Discontinuation of the enrollment phase may result in the immediate ineligibility of 
all subjects screened but not yet enrolled, regardless of the progress or outcome of the screening 
assessments performed.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1. Parent or legal guardian able to provide written informed consent prior to any screening 
evaluations and willing to comply with study requirements.  Subjects will provide assent if 
possible.
2. 3 years to < 18 years of age as determined at Day 1 (consent of parent or legal guardian 
required)
3. PK Lead-in only: subjects in Cohort 1 (age 12 to <18 years of age) must weigh 45 kg
4. PK Lead-in only: subjects in Cohort 2 (age 6 to <12 years of age) must weigh 17 kg and 
< 45 kg
5. PK Lead-in only: all subjects must be treatment naïve: no prior exposure to any IFN, RBV, 
or other approved or experimental HCV-specific DAA agent
6. Treatment experienced subjects:  prior treatment failure to a regimen including interferon 
either with or without RBV that was completed at least 8 weeks prior to Day 1.
i.
Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to 
≥1 adverse event
ii.
Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels 
while on treatment
iii.
Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment 
or within 4 weeks of the end of treatment but did not achieve a sustained virologic 
response (SVR)
7. 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 Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV-infection


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8. Infection with HCV as determined at Screening:
a) United Kingdom Only: The study will commence with GT-1, -3, and -4 HCV-infected 
pediatric subjects and will subsequently enroll subjects with GT-2, -5, and -6 once adult 
data is available, if appropriate.
b) United States/ Australia/ New Zealand Only: The study will commence with GT-1, 
HCV-infected pediatric subjects and will subsequently enroll subjects with 
GT-2, -3, -4, -5, and -6 once adult data is available, if appropriate.
9. HCV RNA ≥1000 IU/mL at Screening
10. Adequate hematologic function (absolute neutrophil count 1,500/mm3; 
hemoglobin 11 g/dL or 12 g/dL for GT-3 males only).
11. Negative serum -HCG pregnancy test (for females of childbearing potential only, as defined 
in Appendix 5)
12. Subject able to provide written assent, if they have the ability to read and write, as 
determined by IRB/IEC/local requirements and Investigator’s discretion
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Pregnant or lactating subjects
2. Sexually-active males or females of childbearing potential who are not willing to use an 
effective method of contraception during the study (see Appendix 5 for further details)
3. Treatment-naïve subjects with GT-3 HCV infection as determined at Screening. Treatment 
naïve is define by no prior exposure to any IFN, RBV, or other approved or experimental 
HCV-specific DAA agent
4. Decompensated liver disease defined as INR 1.2 ULN, platelets 50,000/mm3, serum 
albumin 3.5 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, 
jaundice, encephalopathy, variceal hemorrhage)
5. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
6. -fetoprotein 50 ng/mL
7. Serum creatinine > 1.5 mg/dL
8. Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula


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9. Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of 
certain resolved skin cancers)
10. Co-infection with HIV, acute HAV, or HBV
11. Significant cardiovascular, pulmonary, or neurological disease
12. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications
13. History of solid organ or bone marrow transplantation
14. Chronic daily non-steroidal anti-inflammatory drug therapy
15. Systemic corticosteroid use for > 2 weeks (pulmonary/nasal administration is permitted)
16. Investigational agents taken within the past 28 days (except with the expressed approval of 
the Sponsor)
17. Clinically-relevant alcohol or drug abuse within 12 months of screening.  A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator
18. Known hypersensitivity to the study drug, the metabolites, or formulation excipients
19. Any other condition (including alcohol or substance abuse) or prior therapy that, in the 
opinion of the Investigator, would make the subject unsuitable for the study or unable to 
comply with dosing requirements
20. Use of any prohibited concomitant medications as described in Section 5.6
21. PK Lead-in only: subjects with history of cirrhosis (as determined by liver biopsy)
22. 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 enrollment or has not required medication in the last 12 months may be 
included.


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Amendment 3.0
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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
5.2.1.
Description and Handling 
5.2.1.1.
Formulation
LDV/ SOF FDC tablets are orange, diamond-shaped, film-coated tablets containing 90 mg of 
LDV and 400 mg of SOF. The tablets are debossed with “GSI” on one side and “7985” on the 
other side. The LDV/SOF 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.
Placebo to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment are 
orange, diamond-shaped, film-coated tablets debossed with “GSI” on one side and “7985” on the 
other side. The tablets contain lactose monohydrate, copovidone, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, 
polyethylene glycol, FD&C yellow # 6 /sunset yellow FCF aluminum lake.
Age-appropriate formulations of LDV/SOF FDC have been developed for subjects who are 
unable to swallow the LDV/SOF FDC 90 mg/ 400 mg tablets which include a lower dose 
strength tablet (LDV/SOF FDC 22.5 mg/ 100 mg) formulation. LDV/ SOF FDC lower dose 
strength tablets are round, plain-faced, white film-coated tablets containing 22.5 mg of LDV and 
100 mg of SOF. The LDV/SOF FDC lower dose strength tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc 
and polyethylene glycol.
Placebos to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment are 
round, plain-faced, white film-coated tablets. The placebo tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc and polyethylene glycol.
The non-tablet LDV/SOF FDC formulation will be based on the PK results obtained from 
cohorts 1 and/or 2 of this study. The formulation, composition, acceptability (including 
palatability) will be available and reflected in a protocol amendment which will be submitted for 
approval prior to dosing subjects who are unable to swallow tablets.


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Amendment 3.0
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5.2.1.2.
Packaging and Labeling
LDV/ SOF FDC 90 mg/ 400 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 or 30 tablets, a silica gel desiccant, and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child resistant screw 
cap with an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
a silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant screw cap with an induction-sealed, aluminum faced liner.
LDV/SOF FDC 22.5 mg/ 100 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets, a silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child resistant screw cap with 
an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
a silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant screw cap with an induction-sealed, aluminum faced liner.
The packaging and labeling of the non-tablet LDV/SOF FDC formulation will be based on the 
chosen formulation. The packaging and labeling will be available and reflected in a protocol 
amendment which will be submitted for approval prior to dosing subjects who are unable to 
swallow tablets.
All LDV/SOF FDC and placebo to match LDV/SOF FDC bottles to be distributed in the US, 
EU, and the rest of the countries shall be labeled to meet all applicable requirements of the 
US Food and Drug Administration (FDA), Annex 13 of Good Manufacturing Practices: 
Manufacture of investigational medicinal products (February 2010), and/or other local 
regulations as applicable.
5.2.2.
Storage and Handling
LDV/ SOF FDC tablets, 90 mg/ 400 mg, should be stored at controlled room temperature until 
required for administration. Controlled room temperature is defined as 25 °C (77 °F); excursions 
are permitted between 15 °C and 30 °C (59 °F to 86 °F).
Placebo to match LDV/ SOF FDC tablets, 90 mg/ 400 mg, for Swallowability Assessment 
should be stored at controlled room temperature until required for administration. Controlled 
room temperature is defined as 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C 
(59 °F to 86 °F).  
LDV/SOF FDC tablets, 22.5 mg/ 100 mg, should be stored at controlled room temperature until 
required for administration. Controlled room temperature is defined as 25 °C (77 °F); excursions 
are permitted between 15 °C and 30 °C (59 °F to 86 °F).


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Amendment 3.0
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Placebo to match LDV/ SOF FDC tablets, 22.5 mg/ 100 mg, for Swallowability Assessment 
should be stored at controlled room temperature until required for administration. Controlled 
room temperature is defined as 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C 
(59 °F to 86 °F).
The storage and handling of the non-tablet LDV/SOF FDC formulation will be based on the 
chosen formulation. The storage and handling will be available and reflected in a protocol 
amendment implemented prior to dosing subjects who are unable to swallow tablets.
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 
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 
LDV/SOF FDC.
Sufficient quantities of LDV/SOF FDC tablets, non-tablet LDV/SOF FDC formulation, and 
placebo tablets will be shipped to the investigator or qualified designee from Gilead Sciences 
(or its designee).
5.2.3.
Dosage and Administration of LDV/SOF FDC
PK Lead-in: 
Cohort 1: LDV/SOF FDC 90 mg/ 400 mg tablets will be administered once daily with or without 
food. Subjects determined unable to swallow the placebo to match the 90 mg/ 400 mg LDV/SOF 
FDC tablet (by LDV/SOF FDC Placebo Swallowability Assessment at Screening up to Day 1) 
will be re-assigned to 4 x 22.5 mg/ 100 mg tablets daily.  Subjects who weigh < 45 kg will be 
excluded.
Cohort 2: LDV/SOF FDC 2 x 22.5 mg/ 100 mg tablets will be administered once daily with or 
without food. Subjects determined unable to swallow the placebo to match the 22.5 mg/ 100 mg 
LDV/SOF FDC tablet (by LDV/SOF FDC Placebo Swallowability Assessment) will be deffered 
until oral granulate formulation is available. Subjects must weigh ≥ 17 kg and < 45 kg.
Intensive PK and safety results from the PK Lead-in of each Cohort will be reviewed to confirm 
the appropriateness of the evaluated LDV/SOF FDC dose for the Treatment Phase of that Cohort 
as well as to determine the age-appropriate dose to be evaluated in the PK Lead-in of the 
next Cohort.
Treatment Phase: Subjects who participated in the PK Lead-in of each Cohort will continue in 
the Treatment Phase with no interruption of study drug administration until the appropriateness 
of the dose is confirmed by PK and safety data from the PK-Lead-in.  Additional subjects will be 
enrolled in the Treatment Phase of each Cohort upon confirmation of the appropriateness of the 
dose.  


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An additional age-appropriate formulation for LDV/SOF FDC Oral Granulates is currently under 
development. The dose for this formulation will be dependent on the PK results obtained from 
Cohorts 1 and/or 2 of this study. The strength, composition, and dosing administration will be 
available and reflected in a protocol amendment which will be submitted for approval prior to 
dosing subjects who are unable to swallow tablets.
Subjects should be instructed that if vomiting occurs within 5 hours of dosing an additional tablet 
should be taken.  If vomiting occurs more than 5 hours after dosing, no further dose is needed.
If a dose is missed and it is within 18 hours of the normal time, subjects should be instructed to 
take the tablet as soon as possible and then subjects should take the next dose at the usual time.  
If it is after 18 hours then subjects should be instructed to wait and take the next dose at the usual 
time.  Subjects should be instructed not to take a double dose.
5.3.
Ribavirin (GT-3 Subjects Only)
5.3.1.
Description and Handling of RBV
5.3.1.1.
Formulation
REBETOL capsules consist of a white powder in a white, opaque, gelatin capsule. Each capsule 
contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose, lactose 
monohydrate (40 mg), croscarmellose sodium, and magnesium stearate. The capsule shell 
contains gelatin, titanium dioxide. The capsule shell imprint contains shellac, propylene glycol, 
ammonium hydroxide, coloring agent (E 132).The hard capsule is imprinted with blue ink.
REBETOL RBV Oral Solution 40 mg per mL is a clear, colorless to pale or light yellow bubble 
gum-flavored liquid. In addition to the active ingredient, RBV oral solution contains the 
following inactive ingredients: sucrose, glycerin, sorbitol, propylene glycol, sodium citrate, citric 
acid, sodium benzoate, natural and artificial flavor for bubble gum #15864, and water.
5.3.1.2.
Packaging and Labeling
The RBV capsules are packaged in blisters. Each blister card contains 20 capsules and seven 
cards (140 capsules) per carton.
The RBV oral solution is packaged in 4-oz amber glass bottles (100 mL/bottle) with 
child-resistant closures.
RBV capsules and oral solution to be distributed to centers in the US, EU and the rest of the 
countries shall be labeled to meet all applicable requirements of the US Food and Drug 
Administration (FDA) and Annex 13 of Good Manufacturing Practices: Manufacture of 
investigational medicinal products (February 2010) and/or other local regulations as applicable.
5.3.1.3.
Storage and Handling
RBV capsules should not be stored above 30C (86 F).
RBV oral solution should not be stored above 30°C (86°F).


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Amendment 3.0
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5.3.2.
Dosage and Administration of RBV (GT-3 Subjects Only)
RBV dose will be administered by weight as follows:
Body Weight kg (lbs.)
RBV Daily Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution.  Divided dose in the morning and 
evening.
47-49 (103-108)
600 mg/day
1 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
50-65 (110 – 143)
800 mg/day
2 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
66-80 (145 – 176)
1000 mg/day
2 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
81-105 (178-231)
1200 mg/day
3 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
>105 (>231)
1400 mg/day
3 x 200-mg capsules A.M.
4 x 200-mg capsules P.M.
*
Note:  Subjects with a body weight greater than or equal to 47 kg may utilize the RBV oral solution if necessary.
The morning dose of RBV will be taken with food and LDV/SOF FDC. The evening dose of 
RBV will be taken with food.
RBV will be supplied by Gilead Sciences for all subjects.
5.4.
Co-administration of LDV/SOF FDC and RBV (GT-3 Subjects Only)
In the Treatment Phase of the study, each subject will be given instructions to maintain 
approximately the same daily dosing interval between study drug doses.
For morning doses, subjects will be instructed to take study drugs as follows:

LDV/SOF FDC

Weight-based RBV (as per Section 5.3.2).
For evening doses, subjects will be instructed to take study drug as follows:

Weight-based RBV (as per Section 5.3.2).
If a subject forgets to take the study medication at the correct time, it may be taken later in the 
day; however, no more than 90 mg/ 400 mg dose of LDV/SOF FDC should be taken on any 
calendar day.  The subject should resume the standing dosing schedule on the next day. Study 
medications should not be cut or split.  


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Amendment 3.0
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5.5.
Study Drug Compliance
Subjects will be instructed to return any unused LDV/SOF FDC and/or RBV in the original 
container on Day 3 (PK Lead-in), Day 10 (PK Lead-in), and/or at study treatment visits every 
4 weeks (Treatment Phase).  
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.6.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 30 days 
after the last dose of study drug, need to be recorded in the source documents and electronic case 
report form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment:

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

Drugs disallowed per prescribing information of REBETOL® for GT-3 subjects only
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters i.e., P-gp) with study drug(s) may result in PK interactions resulting in 
increases or decreases in exposure of study drug(s). Examples of representative medications 
which are prohibited from 21 days prior to Day 1 through the end of treatment are listed 
below. In addition, the use of amiodarone is prohibited from 60 days prior to 
Baseline/Day 1 through the end of treatment.


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Amendment 3.0
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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
Anticonvulsantsc
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Cardiac Medications
Amiodaronee
Digoxinb, Dabigatranb
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinaccea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsd
Rosuvastatin
Atorvastatin, Simvastatin, Pravastatin, 
Pitavastatin, Fluvastatin, Lovastatin
a.
It is recommended to separate antacid and LDV/SOF FDC administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF FDC at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with LDV/SOF FDC or up to 2 hours after taking LDV/SOF FDC. Proton-pump inhibitors should not be 
taken before LDV/SOF FDC. 
b.
May result in an increase in the concentration of study drug and/or concomitant medications. Co-administration of 
LDV/SOF FDC with digoxin or dabigatran may increase the concentration of digoxin or dabigatran. Caution is warranted 
and therapeutic concentration monitoring of digoxin or clinical monitoring of dabigatran is recommended when 
co-administered with LDV/SOF FDC. 
c.
May result in a decrease in the concentrations of study drug.
d.
Use with study drug 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.
e.
May result in symptomatic bradycardia. Mechanism is not currently known. The use of amiodarone is prohibited from 
60 days prior to Baseline/Day 1 through the end of treatment.
Medications for disease conditions excluded from the protocol (e.g., active cancer, 
transplantation) are not listed under this Concomitant Medication section and are disallowed in 
the study.


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Amendment 3.0
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6.
STUDY PROCEDURES
All subjects will complete screening, on-treatment, and post-treatment assessments. Screening 
assessments will be completed within 28 days of the Day 1 visit. The end of study will occur at 
the 24-week Post-Treatment visit. The schedule of assessments is described below. 
Information on the specific laboratory parameters to be measured and clinical assessments to be 
performed are provided in Section 6.6.
6.1.
Subject Enrollment 
Each candidate’s parent or legal guardian must sign an Informed Consent Form prior to the
conduct of any screening procedures. Each study candidate who has the ability to read and write
must sign an Assent Form, as required by IRB/IEC/local requirements, prior to the conduct of 
any study procedures. Screening evaluations will be used to determine the eligibility of each 
candidate for study enrollment. Candidates who fail to meet eligibility criteria by screening 
evaluations may be re-screened once ≥ 30 days after the initial screen if there is a reasonable 
expectation that the candidate will be eligible after repeat screening.
6.2.
Screening Assessments
6.2.1.
Screening Visit (Day –28 to Day 0)
Subjects will complete all screening assessments within 28 days of the Day 1 visit. The screening 
window can be extended to 42 days for subjects requiring additional HCV GT testing or for 
extenuating circumstances.
The following procedures will be performed and documented:

Written informed consent from parent or legal guardian and assent from subject, if applicable 
(see above)

Medical history, including:
Hepatitis C history
Hepatitis C treatment history
Family history (including height of parents, if known)
Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate) and body weight and height


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
Obtain blood samples for tests as listed in Section 6.6.1:
Hematology
Chemistry
Coagulation tests
HCV RNA
Determination of HCV viral GT and subtype
HCV antibody, HIV 1/2 antibody, and HBs antigen, HAV antibody
HbA1c
TSH
IL28B
Serum -hCG pregnancy test for females of childbearing potential only
Alpha fetoprotein (AFP)
Alpha-1 anti-trypsin (ATT)

Obtain urine sample for:
Urinalysis
Urine Drug Screen

Review of concomitant medications

Ask subject and/or parent/legal guardian if the subject is able to swallow and tolerate taking 
pills.

Review of all inclusion and exclusion criteria

Perform LDV/SOF FDC swallowability assessment 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the Day 1 visit assessments.


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6.3.
PK Lead-in: Treatment Assessments 
6.3.1.
Day 1
After confirmation of eligibility has been evaluated, the following tests and procedures must be 
completed prior to enrollment and dosing/dispensing on Day 1:

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)

 

Obtain urine samples for the following procedures:
Urinalysis
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.
PPD


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6.3.1.1.
Drug Administration

Dispense study drug(s) as directed by the IWRS

Instruct the subject on the packaging, storage and administration of study drug

Perform LDV/SOF FDC swallowability assessment (for subjects administered LDV/SOF 
FDC in tablet form only if not previously completed at screening).  Observe the subject 
taking the first dose of study drug (with or without food) and record the time of first dose

Subjects will be administered a dosing diary with instructions.
6.3.2.
Day 3
The following procedures/assessments are to be completed on Day 3:

Perform a symptom-directed physical examination as needed

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Review medication compliance with subject and/or subject’s parent/guardian

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 10 – Intensive PK 
The Day 10 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 10 Intensive PK visit may 
be performed within +3 days of the protocol-specified visit date (subjects will continue 
daily dosing through the Intensive PK Visit).
Subjects should come in a fasted state for the Day 10 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 10 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 10 dose of LDV/SOF FDC must not be taken 
until the evaluations listed below are completed. 


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If the subject has already dosed prior to the Day 10 clinic visit or is not in a fasted state, the 
Day 10 intensive PK assessments must not be completed. The subject and/or parents/guardians 
should be instructed to return in a fasted state within 3 days (Days 11, 12, or 13) for the intensive 
PK visit. 
If dosing non-compliance is identified as per subject dosing diary and pill count on or prior to the 
Day 10 visit, the Day 10 intensive PK assessments must not be completed. The subject and/or 
parents/guardians should be counseled regarding proper dosing and be scheduled to return for the 
Day 10 intensive PK visit no sooner than 3 days following compliant dosing and no later than 
Day 14 (i.e., return on Day 13 or Day 14).  If dosing non-compliance is due to an AE, 
consultation with the Gilead Medical Monitor is required regarding the potential of rescheduling 
the Day 10 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded not 
to take the LDV/SOF FDC prior to arriving at the clinic on the day of the re-scheduled intensive 
PK visit. All Day 10 intensive PK assessments listed below should be completed when the 
subject returns.
The following evaluations are to be completed at the Day 10 Intensive PK visit:

Perform a symptom-directed physical examination 

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Perform study drug accountability 

Review Subject Dosing Diary

Review medication compliance with subject and/or parent/guardian.

Obtain urine samples for the following procedures:
Urinalysis
Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test 
is positive, the Intensive PK sampling will not be completed. The positive result will be 
confirmed with a serum pregnancy test. 

Obtain blood samples for the following laboratory analyses:
Hematology 
Chemistry 


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Coagulation tests
HCV RNA
Viral sequencing (archive)

Perform intensive PK sampling: 
Blood samples will be collected at 0 (predose, ≤30 minutes prior to dosing). After 
collection of the predose sample, subjects will be provided a standardized meal. Within 
5 minutes after consuming the standardized meal, subjects will be dosed with 
LDV/SOF FDC per dosing requirements.
Post-dose blood samples will be collected as follows: 
■
For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 5, 8, and 12 hours post-dose (with predose also 
serving as t= 24).
■
For Cohort 3 only: 0.5, 2, 4, 8, and 12 hours post-dose (with predose also serving as 
t = 24).
Subjects will be restricted from food intake until after collection of the 4-hour post dose 
blood sample, except for subjects in Cohort 3. Please also refer to the PK manual for 
details about standardized meals and PK sample processing instructions.
After completing the Day 10 intensive PK visit subjects will then continue to the Week 2 visit in 
Treatment Phase (described in Section 6.4.2) with no interruption in dosing.
6.4.
Treatment Phase: Treatment Assessments 
6.4.1.
Day 1
After confirmation of eligibility has been evaluated, the following tests and procedures must be 
completed prior to enrollment and dosing/dispensing on Day 1:

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements 

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Review of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status). 


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
Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)

 

Obtain urine sample for:
Urinalysis
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire

Perform LDV/SOF FDC swallowability assessment (for subjects administered 
LDV/SOF FDC in tablet form only if not previously completed at screening) 
6.4.1.1.
Drug Administration

Dispense study drug as directed by the IWRS

GT-3 subjects only: Instruct the subject on the appropriate RBV dose after weight-based 
dosage is calculated using Day 1 weight

Instruct the subject on the packaging, storage, and administration of study drug

Observe the subject taking the first dose of study drug (with or without food) and record the 
time of first dose
6.4.2.
Weeks 1 and 2 (3 days)
Subjects who participated in the PK Lead-in will start study visits in the Treatment Phase at 
Week 2.  The following procedures/assessments are to be completed at these visits:

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination
PPD


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
Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 
6.4.3.
Weeks 4 and 8 (3 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS


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6.4.4.
Week 12 (3 days) - Subjects on 12 Week Treatment Regimen Only

Perform complete physical examination

Tanner Pubertal Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles of study drug at the Week 12 Visit
6.4.5.
Week 12 (3 days) - Subjects on 24 Week Treatment Regimen Only

Perform symptom-directed physical examination

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications


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
Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS  
6.4.6.
Week 16 and 20 (3 days) – Subjects on 24 Week Treatment Regimen Only

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS


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6.4.7.
Week 24 (3 days) – Subjects on 24 Week Treatment Regimen Only

Perform complete physical examination

Tanner Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles and blister cards (if applicable) of study drug at the 
Week 24 Visit
6.4.8.
Unscheduled Visit/Early Termination Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments are at the investigator’s discretion.


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The Sponsor/CRO should be informed when a subject comes off treatment due to an adverse 
event. If a subject discontinues treatment then the assessments outlined below should be 
performed.

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles and/or blister cards (if applicable) of study drug at the Early 
Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as described in 
Section 6.5.


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6.5.
Post-Treatment Assessments
6.5.1.
4-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for: 
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status) 
Female subjects of childbearing potential on treatment with LDV/SOF FDC + RBV should be 
provided with Urine Pregnancy Test-Kits, instructed on their use and requested to continue to 
self-monitor for pregnancy for 6-months after their last dose of RBV. If required by local 
regulations, additional pregnancy tests beyond 6 months may be added.  The subject should be 
contacted every 4 weeks and asked to report results of the urine pregnancy tests. If a positive 
urine pregnancy test is reported, the subject should return to the clinic for a serum pregnancy 
test.
6.5.2.
12-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements

Perform symptom-directed physical examination

Assessment of SAEs

Perform Tanner Pubertal Stage assessment


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
Obtain blood samples for 
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire
6.5.3.
24-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of SAEs

Tanner Pubertal Stage Assessment

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Obtain blood samples for 
HCV RNA
Viral sequencing (archive)

GT-3 subjects only: Obtain urine sample for -hCG pregnancy test for females of 
childbearing potential only

GT-3 subjects only: Pregnancy prevention counseling including partner pregnancy 
prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age 
at the discretion of the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire.


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All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed every 6 months for the first 
2 years followed by every 12 months for assessments of growth, quality of life, and long-term 
viral suppression (if applicable) in a separate protocol (GS-US-334-1113). This follow-up will 
continue for 5 years.
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), Glucose, 
Lipase, Potassium, Sodium, Gamma-glutamyl transferase (GGT), alpha fetoprotein (AFP), 
alpha-1 anti-trypsin, creatine kinase (CK) and amylase.
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® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System. 
HCV GT 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 GT should the above assays become unavailable.
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 alternate assays 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum -hCG, Urine -hCG (if positive, requires immediate confirmation with 
Serum -hCG)
Additional Tests: Urine Drug Screen (for amphetimines, cocaine, methadone, opiates), 
Hemoglobin A1c (HbA1c), TSH (reflex Free T4), Alfa fetoprotein (AFP), Alpha-1 anti-trypsin
(AAT).
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. Parental heights will be recorded at Screening.


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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.
Tanner Pubertal Stage Assessment
The Tanner Stage scale is available in Appendix 4.  All subjects will receive a baseline Tanner 
Pubertal Stage Assessment. If the assessment determines that the subject is at a Tanner 5 at 
Day 1, no further Tanner Pubertal Stage Assessments are to be completed. Date of first menses 
will be documented. 
6.6.5.
Height & Weight Measurement
Height and weight measurement will be collected at each study visit. The difference in body 
weight and height measurements between Day 1 and End of Treatment, post-treatment Week 12, 
and post-treatment Week 24 will be calculated.  
6.6.6.
Bone Age Assessment
A single X-ray of the left wrist, hand, and fingers will be performed at Day 1 Visit and 
post-treatment Week 24.  Local radiologist will determine bone age from x-ray.
6.6.7.
Swallowability Assessment
A LDV/SOF FDC swallowability assessment will be performed at screening up to Day 1. 
Subjects who have indicated that they can take pills will be observed taking a placebo to match 
the 90 mg/ 400 mg LDV/SOF FDC tablet. This will confirm the swallowability of the 
90 mg/ 400 mg tablet size. If a subject is unable to swallow the 90 mg/ 400 mg LDV/SOF FDC 
tablet size, he/she will repeat the assessment with a placebo for the 22.5 mg/ 100 mg 
LDV/SOF FDC tablet. If unable to swallow the 22.5 mg/ 100 mg LDV/SOF FDC tablet, 
enrollment of the subject will be deferred until the granule formulation is available.
6.6.8.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.


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6.6.9.
Estimated Glomerular Filtration Rate (GFR)
Estimated Glomerular Filtration Rate (GFR) using Schwartz Formula (mL/min/1.73m2) = 
k L/Scr [(k is a proportionality constant, for adolescent females ≥12 years old is 0.55; and for 
adolescent males ≥12 years old is 0.70); L is height in centimeters (cm); and Scr is serum 
creatinine (mg/dL)]
6.6.10.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
Unused samples may be archived.
6.6.11.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every 4 weeks during the 
dosing period and for a minimum of 6 months following the last dose of RBV or for a minimum 
of 30 days following the last dose of LDV/SOF FDC if not taking RBV. If required by local 
regulations, additional pregnancy tests beyond 6 months for RBV or 30 days for subjects not 
taking RBV may be added. In the event of a positive urine pregnancy result, subjects will be 
instructed to stop study drug immediately (if applicable) and return to the clinic as soon as 
possible for a serum pregnancy test.
GT-3 subjects only: Pregnancy test kits will be dispensed to female subjects of child bearing 
potential at the 4 Week Post-Treatment visit. The subject will be contacted by telephone monthly 
to confirm that urine pregnancy testing has been performed post-treatment and to record the 
outcome. Alternatively, if required by local regulations or preferred by the investigator or 
subject, the subject may return to the clinic for urine pregnancy tests.
6.6.12.
Quality of Life Survey (PedsQL™)
The PedsQL ™Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be completed at 
Day 1, End of Treatment, Early Termination (if applicable), 12-Week Post-Treatment, and 
24-Week Post-Treatment visits.  
The PedsQL ™  has separate survey instruments administered by age group, including the
Teen Report (ages 13-18), Child Report (ages 8-12), Young Child Report (ages 5-7), and 
Toddlers (ages 2-4).  Each survey accompanied by the respective parent proxy survey will be 
administered to the subject and their parent/legal guardian (with the exception of the Toddlers 
Report which will only be completed by the parent/legal guardian) for the current age group at 
the time of survey administration.  


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7.
TOXICITY MANAGEMENT
7.1.
Modification of Dose/Schedule Due to Toxicity
Dose reduction of RBV (GT-3 subjects only) due to toxicity should be performed according to 
the product label. Information is provided in Table 7-1.
Table 7-1.
RBV Dose Reduction Guidelines
Laboratory Values
Reduce RBV Dose by 200 mg/daya if:
Discontinue RBV if:
Hemoglobin in subjects with no 
cardiac disease
<10 g/dL
<8.5 g/dL
Hemoglobin in subjects with 
history of stable cardiac disease
2 g/dL decrease in hemoglobin during any 
4 week period treatment
<12 g/dL despite 4 weeks at 
reduced dose
a.
Dose reduction in pediatric patients taking the oral solution is accomplished by modifying the recommended RBV dose from 
original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed.
7.2.
Subject Stopping Rules for LDV/SOF FDC and RBV
The Gilead Medical Monitor should be consulted prior to dose discontinuation of LDV/SOF 
FDC unless the investigator believes that immediate action is warranted to ensure the continued 
safety of the subject.
Administration of LDV/SOF FDC may be discontinued due to a clinical or laboratory event. 
There is no option for LDV/SOF FDC dose reduction. If LDV/SOF FDC is stopped for toxicity, 
it should not be restarted, RBV should be stopped (GT-3 subjects only), and the subject should 
complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria must stop treatment with LDV/SOF 
FDC:

Elevation of ALT and/or AST >5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT >3x Day 1 and total bilirubin >2 x ULN, confirmed by 
immediate repeat testing

Confirmed elevation of ALT >15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with LDV/SOF FDC


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8.
ADVERSE EVENTS MANAGEMENT
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
8.1.1.
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-mandated procedures, 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 8.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history CRF
8.1.2.
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.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., 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 (e.g., 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 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
8.2.
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.
8.2.1.
Assessment of Causality for Study Drug and Procedures
The investigator or qualified sub-investigator 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 investigational 
medicinal product. For SAEs, an alternative causality must be provided (e.g., pre-existing 
condition, underlying disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures (e.g.., venipuncture)
8.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4 weeks after last administration of study drug 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 protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of causal relationship, that occurs after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required 24-week 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
after informed consent is signed 


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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. Investigators are not 
obligated to actively seek SAEs after the 24 week post-treatment follow-up period.  However, if 
the investigator learns of any SAEs that occur after study participation has concluded and the 
event is deemed relevant to the use of IMP, he/she should promptly document and report the 
event directly to Gilead DSPH.  
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, i.e., the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours to:
Gilead Sciences, Drug Safety and 
Public Health:
Fax:
E-mail:
+1 650 522-5477
Safety_FC@gilead.com
Gilead Sciences, Medical 
Monitor:
Name:
Phone:
Mobile:
Fax:
E-mail:
Bittoo Kanwar, MD

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.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
report form.
PPD
PPD
PPD
PPD


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8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
8.5.
Special Situations Reports
8.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging or distribution of the medicinal product.  


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8.5.2.
Instructions for Reporting Special Situations
8.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (i.e., signs the informed consent) and throughout the study, including the 
post-treatment follow-up period, to Gilead DSPH using the pregnancy report form within 
24 hours of becoming aware of the pregnancy.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., 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 
Sections 8.1 and 8.3. Furthermore, any SAE occurring as an adverse pregnancy outcome 
post study must be reported directly to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 or Fax: +1 (650) 522-5477.
Pregnancies of female partners of male study subjects exposed to Gilead or other study drug
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy report form and pregnancy outcome report forms within 24 hours. Monitoring of the 
partner pregnancy 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. 
Clinical staff should also report any pregnancies to the Ribavirin Pregnancy Registry at 
1 800-593-2214 (see also http://www.ribavirinpregnancyregistry.com ).
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
8.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 


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Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management and outcome will be reported, when available.


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9.
STATISTICAL CONSIDERATIONS
9.1.
Analysis Objectives and Endpoints
9.1.1.
Analysis Objectives
The primary objective of PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm the dose of LDV/SOF FDC
in chronic HCV-infected pediatric subjects
The secondary objective of PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing of 
LDV/SOF FDC in chronic HCV-infected pediatric subjects
The primary objective of Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV for 12 or 24 weeks in 
chronic HCV-infected pediatric subjects
The secondary objectives of Treatment Phase of this study are:

To determine the antiviral efficacy of 12 and 24 weeks of LDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects (including the impact of HCV genotype, IL28B genotype, 
and prior treatment experience), as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12)

To determine the antiviral efficacy of 12 and 24 weeks of LDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment

To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment

To evaluate the effect of growth and development on pediatric subjects during and after 
treatment
The exploratory objective of this study is:

 
 
PPD


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9.1.2.
Primary Endpoints
For the PK Lead-in Phase, the appropriateness of the LDV/SOF FDC dose will be assessed by 
evaluating the steady-state PK of the LDV/SOF FDC. The primary endpoint for determining 
steady state PK is AUCtau of GS-331007, SOF, and LDV. Additional steady-state PK parameters 
of GS-331007, SOF, and LDV (e.g., AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½)
will be estimated and summarized as described in Section 9.4.
For the Treatment Phase, the primary safety endpoint is any AE leading to permanent 
discontinuation of study drug (s). 
9.1.3.
Secondary Endpoints
For the PK Lead-in Phase, the secondary endpoint will include antiviral activity measurements, 
including assessment of HCV RNA. AEs leading to permanent discontinuation of study drug will 
be evaluated as a secondary safety endpoint.
For the Treatment Phase, the key efficacy endpoint is SVR12 and secondary efficacy endpoints 
include SVR4, SVR24, breakthrough and relapse. Additional efficacy evaluations may include 
HCV RNA change from Day 1; ALT normalization; and viral kinetic parameters. Secondary 
safety endpoints of growth and development measurements will be assessed (e.g. height, weight, 
and Tanner Stage Assessment).
9.2.
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).
9.2.1.
Analysis Sets 
9.2.1.1.
Pharmacokinetics (PK) Analysis Sets
Intensive PK Analysis Set 
The intensive PK analysis set will include all PK Lead-in subjects who received at least one dose 
of study drug and for whom at least one non-missing PK concentration data, during the intensive 
sampling period, reported by PK lab. The PK analysis set will be used for detailed 
pharmacokinetic analysis of LDV, SOF, and metabolites.  
Sparse PK Analysis Set 
The PK analysis set will include all enrolled subjects who received at least one dose of study 
drug and for whom at least one observed concentration data of LDV, SOF, or GS-331007 are 
available. The PK analysis set will be used for analysis of general PK and single sample plasma
concentrations.


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9.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses will include subjects who were enrolled and have 
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 last dose of study drug plus 30 days.
9.2.1.3.
Efficacy Analysis Set
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which includes 
HCV-infected subjects who were enrolled and have received at least one dose of study drug.
9.2.2.
Data Handling Conventions
Natural logarithm transformation for key PK parameters, such as Cmax and AUCtau, will be 
applied for pharmacokinetic analysis.
The PK concentration values below the limit of quantitation (BLQ) will be treated as zero for the 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing and will be excluded in any calculation of geometric 
means or ratios. For the presentation of summary and order statistics, if at least 1 subject has a 
concentration value BLQ for the time point, then the minimum value will be displayed as 
“BLQ”. If more than 50% of the subjects have a concentration data value BLQ for the time 
point, then the minimum and median values will be displayed as “BLQ”. If all subjects have 
concentration data values BLQ for the time point, then all order statistics (minimum, first 
quartile [Q1], median, third quartile [Q3], maximum) will be displayed as “BLQ”.
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, 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 
preceded and followed in time by values that are deem 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 medication will be 
considered a failure at the time points subsequent to 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.


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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).
9.2.3.
Interim Analysis
No formal interim analyses are planned for this study.
9.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by age group and overall for PK Lead-in and by the 4 regimens based on 
treatment-experience, cirrhosis status and genotype, by age group, by regimen and age group, 
and overall for Treatment Phase respectively. 
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight, height, body mass index, HCV RNA level 
(log10 IU/mL), HCV GT, prior treatment experience, and additional endpoints as necessary.
9.4.
Pharmacokinetic Analysis
PK analysis will be performed for PK Lead-in using the intensive PK analysis set. The 
concentration data of LDV, SOF, and metabolites (GS-331007 and GS-566500) over sampling 
time will be listed and summarized by nominal time and cohort. Pharmacokinetic parameters 
(e.g., AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½) will be listed and 
summarized for LDV, SOF,  and metabolites (as applicable) using descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean and its 95% confidence interval, coefficient 
of variation %, standard deviation, median, Q1, Q3, minimum, and maximum) by cohort and 
overall. Plasma concentrations over time will be plotted in semilogarithmic and linear formats as 
mean ± standard deviation and median (Q1, Q3).
To evaluate if the steady-state PK of GS-331007, SOF, and LDV achieved in pediatric subjects 
of this study are similar to the exposures observed in adult subjects (Table 9-1), the GS-331007, 
SOF, and LDV exposure data from this study will be compared to the integrated adult data. The 
primary endpoint of this analysis will be evaluated by carrying out an analysis of variance 


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(ANOVA) for log-transformed GS-331007, SOF, and LDV AUCtau. The 90% confidence 
intervals will be constructed for the ratio of geometric means of each PK parameters. The 
equivalence boundary is set as 50% to 200%.  
Given that dose ranging studies for SOF established that a dose of 200 mg results in suboptimal 
exposure compared to the 400 mg dose, and the lack of clinically significant exposure-safety 
relationships observed across a broad range of GS-331007 and SOF exposure, bounds of 50% to 
200% for GS-331007 and SOF AUCtau will allow identification of a clinically relevant difference 
in exposure in the pediatric population.
A phase 2 study evaluating LDV doses of 30 or 90 mg LDV in combination with DAAs 
VDV+TGV+RBV suggested LDV exposure may be suboptimal at the 30 mg dose based on the 
incidence of virologic breakthrough being approximately half in the 90 mg arm; as such the 
90 mg dose was selected for further development.  In the 90 mg LDV arm of this study, the LDV 
AUCtau at the 25 percentile was 3230 hr*ng/mL.  While this value is 62% lower than the mean 
LDV AUCtau (8530 hr*ng/mL) observed in adult HCV-infected subjects in the LDV/SOF FDC 
Phase 2/3 population, it provides ~99.8% of maximal viral load reduction (exposure-response 
model established in the monotherapy proof of concept study).  In the Phase 2/3 population when 
administered the LDV/SOF FDC, there was a lack of clinically significant exposure-efficacy or 
safety relationships observed across the broad range of LDV exposure.  Taken together these 
data support the utility of bounds of 50% to 200% for LDV AUCtau to identify a clinically 
relevant difference in LDV exposure in the pediatric population.
In all pediatric age groups, the targeted exposures for GS-331007, SOF, and LDV are the adult 
equivalent for which safety and efficacy has been established.  In the absence of any pediatric 
PK information (i.e., variability and exposure of GS-331007, SOF, or LDV is unknown) 
assuming a 2-fold higher variability, or a 30 % difference in GS-331007, SOF, or LDV AUCtau
in the pediatric population compared to adults, the predicted 90% CIs of the geometric mean 
ratio (GMR) will be contained within the bounds of 50% to 200%.
Individual patient management will be performed by maintaining exposures comparable to 
adults.  In the event more than one subject in each cohort exhibits GS-331007, SOF, or LDV 
exposures (AUCtau) less than the 2.5th percentile of adult values, a dose assessment may be 
require for the cohort as appropriate.
The effect of age and LDV/SOF FDC dose on PK (LDV, SOF and GS-331007) will be assessed.
Table 9-1.
GS-331007, SOF, and LDV PK Parameters after Once-Daily 
Administration of SOF/LDV FDC in HCV-Infected Adults Subjects 
(Population PK Analysis from Phase 2 and 3 Studies)
Mean (%CV) PK Parametera
GS-331007 (N=2113)
SOF (N=1542)
LDV (N=2113)
AUCtau (ng•h/mL)
12,500 (29.2)
1380 (34.0)
8530 (60.8)
Cmax (ng/mL)
736 (28.2)
659 (34.0)
364 (51.4)
Ctau (ng/mL)
N/A
N/A
247 (59.2)
a.
Pharmacokinetic parameters are presented as mean (%CV) and are shown to 3 significant digits.


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9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in and overall study Treatment Phase 
respectively. Safety data will be summarized by age group and overall for PK Lead-in Phase and 
by the 4 regimens based on treatment-experience, cirrhosis status and genotype, by age group, by 
regimen and age group, and overall for the Treatment Phase respectively.
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements, and by the documentation of AEs.
All safety data collected while on or after the first dose of study drug administration up to 
30 days after the last dose of study drug will be summarized by cohort according to the study 
drug received.
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.
9.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the CRF. Exposure data will be summarized.
9.5.2.
Adverse Events
Clinical and laboratory AEs 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 study drug up to the date of last dose of study drug plus 30 days. 
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC 
and preferred term) will be provided by cohort:

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,


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
Combined Grade 3 and 4 study drug-related AEs,

All AEs that caused permanent discontinuation from study drug,

All AEs that caused change in dose or temporary interruption of study drug,

All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
9.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled visits will be summarized. Graded laboratory 
abnormalities will be defined using the grading scheme in Grading of Laboratory Abnormalities 
provided in Appendix 3. 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 
and including the date of last dose of study drug plus 30 days, will be summarized by age group 
and overall. If baseline data are missing, then any graded abnormality (i.e., at least a Grade 1) 
will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
9.5.4.
Other Safety Evaluations
9.5.4.1.
Tanner Pubertal Stage Assessment
Tanner Stages (Appendix 4) will be summarized by baseline Tanner Stage using frequency and 
percentage. Age of first menses will be summarized descriptively.
9.5.4.2.
Vital Signs (including Body Weight and Height)
Vital signs including body weight and height and change from baseline will be summarized at 
each visit.
9.6.
Efficacy Analysis
Efficacy will be evaluated using scheduled assessments of HCV RNA performed using COBAS®
TaqMan® HCV Test, v2.0 for use with the High Pure System.
Efficacy analysis will be performed by the 4 regimens based on treatment-experience, cirrhosis 
status and genotype, by age group, by regimen and age group, and overall for Treatment Phase.
All continuous endpoints will be summarized using an 8-number summary (n, mean, standard 
deviation, median, Q1, Q3, minimum, maximum). All categorical endpoints will be summarized 
by number and percentage of subjects who meet the endpoint definition.


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9.6.1.
Key Efficacy Analysis
The key efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
treatment) in the FAS population. Point estimate and its 95% confidence interval will be 
provided.  
9.6.2.
Secondary Efficacy Analysis
For the PK Lead-in Phase, serum HCV RNA actual values and change from baseline will be 
summarized at each visit.
For the Treatment Phase, the proportion of subjects with HCV RNA below LLOQ over time 
(including SVR endpoints SVR4 and SVR24) will be presented in tabular and graphical form. In 
addition, descriptive summaries and listings will be provided for additional efficacy evaluations 
including serum HCV RNA actual values and change from baseline, proportion of subjects with
virologic failures, and other endpoints of interest including ALT normalization.
 
 
 
 
9.6.3.
Subgroup Analysis
Subgroup analysis on SVR12 will be performed by treatment experience and cirrhosis status, by 
IL28B genotype, and by GT. Other clinically relevant subgroup analyses may be conducted as 
appropriate (i.e., assuming that adequate numbers of subjects in these subsets are available for 
analysis).
Details on efficacy analyses will be described in the statistical analysis plan.
9.7.
Quality of Life Analysis
The data from PedsQL ™ Pediatric Quality of Life survey will be summarized by visit and 
age group and overall.
9.8.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety and provide recommendation to Gilead about 
whether the nature, frequency, and severity of adverse effects associated with study treatment 
warrant the early termination of the study in the best interests of the participants, whether the 
study should continue as planned, or the study should continue with modifications. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
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While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
9.9.
Sample Size
With approximately 100 subjects enrolled into each age group of Treatment Phase, a two-sided 
95.0% confidence interval of the SVR12 rate will extend at most 5.9% in both directions from 
the observed SVR12 rate, assuming the expected SVR12 rate is 90%.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
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 Harmonization (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. For studies conducted under a United States IND, the investigator 
will ensure that 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, are adhered to.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Gilead Sciences, or proprietary interests in the drug being studied. 
This documentation must be provided before participation of the investigator and any 
sub-investigator. The investigator and sub-investigator agree to notify Gilead Sciences of any 
change to reportable interests during the study and for one year following completion of the 
study. Study completion is defined as the date that the last subject has completed 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.”
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
This protocol 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/assent) will be submitted by the investigator to an IRB (for studies conducted in the
United States) or IEC (for studies conducted outside of the United States). Approval from the 
IRB or IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. Additionally, modifications 
should be submitted to competent authorities, as necessary.


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10.1.3.
Informed Consent/Assent
The investigator is responsible for obtaining written informed consent from the parent/legal 
guardian of the subject participating in this study after adequate explanation to the parent/legal 
guardian and subject of the aims, methods, objectives, and potential hazards of the study and 
before undertaking any study-related procedures. Written assent should be obtained from the 
subject as required by IRB/IEC/local requirements for this age population.  The investigator must 
utilize an IRB- or IEC-approved consent/assent form for documenting written informed 
consent/assent. Each informed consent/assent will be appropriately signed and dated by the 
subject or the subject’s parent/legally authorized representative and the person obtaining 
consent/assent.
10.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, and an 
identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the Sponsor, IRB or IEC, or laboratory. The investigator must keep a screening log 
showing codes, names, and addresses for all subjects screened and for all subjects enrolled in the 
trial.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational new drug, and any 
other study information, remain the sole and exclusive property of Gilead Sciences during the 
conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Gilead Sciences. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data are listed in the Source Data verification Plan, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Participation in trial (including trial number);


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
Trial 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 trial medication (preferably drug dispensing 
and return should be documented as well);

Record of all AEs and other safety parameters (start and end date, and preferably including 
causality and intensity);

Concomitant medication (including start and end date, dose if relevant; dose changes should 
be motivated);

Date of trial completion and reason for early discontinuation, if applicable.
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) 
and until there are no pending or contemplated 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 required by applicable regulatory requirements, by local 
regulations, or by an agreement with Gilead Sciences. The investigator must notify 
Gilead Sciences 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 Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences 
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period up to 15 years for purposes of this study.
10.1.6.
Case Report Forms
For each subject enrolled, a CRF (or eCRF) must be completed and signed by the principal 
investigator or sub-investigator (as appropriate) within a reasonable time period after data 
collection. This also applies to records for those subjects who fail to complete the study 
(even during a pre-randomization screening period if a CRF was initiated). If a subject 


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withdraws from the study, the reason must be noted on the CRF. If a subject is withdrawn from 
the study because of a treatment-limiting adverse event, thorough efforts should be made to 
clearly document the outcome.
10.1.7.
Drug Accountability
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product, and comparators. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), subject 
dispensing records, and returned or destroyed study product. Dispensing records will document 
quantities received from Gilead Sciences and quantities dispensed to subjects, including lot 
number, date dispensed, subject identifier number, subject initials, and the initials of the person 
dispensing the medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRBs or IECs, 
or to regulatory authority or health authority inspectors.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB, IEC, or 
competent authorities in accordance with local requirements. Approval must be obtained before 
changes can be implemented.


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10.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies). 
Gilead Sciences 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.
After conclusion of the study and without prior written approval from Gilead Sciences, 
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 Sciences in an abstract, manuscript, or presentation form; or

the study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).
The investigator will submit 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. The investigator will comply with Gilead Sciences’ 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.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the CRFs for consistency.
The monitor is responsible for routine review of the CRFs 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 CRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences 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 Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.


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10.3.3.
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 Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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11.
REFERENCES
5914
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman 
RE. Developmental pharmacology--drug disposition, action, and therapy in 
infants and children. N Engl J Med 2003;349 (12):1157-67.
12557
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. 
Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 
weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of 
chronic infection with hepatitis C virus. International Hepatitis Interventional 
Therapy Group (IHIT). Lancet 1998;352 (9138):1426-32.
12558
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et 
al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for 
chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 
1998;339 (21):1485-92.
15572
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: January 2010.
15668
Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Roche Products Limited, Welwyn Garden City, United Kingdom. 
Revised: March 2010.
19705
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48 (1):148-62.
19799
Hu J, Doucette K, Hartling L, Tjosvold L, Robinson J. Treatment of hepatitis C in 
children: a systematic review. PLoS ONE 2010;5 (7):e11542.
19801
Mohan N, Gonzalez-Peralta RP, Fujisawa T, Chang MH, Heller S, Jara P, et al. 
Chronic hepatitis C virus infection in children. J Pediatr Gastroenterol Nutr 
2010;50 (2):123-31.
20273
Bortolotti F, Verucchi G, Camma C, Cabibbo G, Zancan L, Indolfi G, et al. Long-
term course of chronic hepatitis C in children: from viral clearance to end-stage 
liver disease. Gastroenterology 2008;134 (7):1900-7.
20282
Serranti D, Buonsenso D, Ceccarelli M, Gargiullo L, Ranno O, Valentini P. 
Pediatric hepatitis C infection: to treat or not to treat...what's the best for the 
child? European review for medical and pharmacological sciences 2011;15 
(9):1057-67.
20285
Wirth S. Current treatment options and response rates in children with chronic 
hepatitis C. World J Gastroenterol 2012;18 (2):99-104.


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20286
Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti F, Zancan L, Jara P, et al. 
High sustained virologic response rates in children with chronic hepatitis C 
receiving peginterferon alfa-2b plus ribavirin. J Hepatol 2010;52 (4):501-7.
20287
Yang D, Pearce RE, Wang X, Gaedigk R, Wan YJ, Yan B. Human 
carboxylesterases HCE1 and HCE2: ontogenic expression, inter-individual 
variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and 
permethrin. Biochem Pharmacol 2009;77 (2):238-47.
20288
Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and sex-related expression and 
activity of carboxylesterase 1 and 2 in mouse and human liver. Drug Metab 
Dispos 2009;37 (9):1819-25.
28583
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and 
sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370 
(20):1889-98.
28585
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. 
Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N 
Engl J Med 2014;370 (16):1483-93.
28587
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. 
Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N 
Engl J Med 2014;370 (20):1879-88.
29292
Gane E, Hyland RH, An D, Pang PS, Symonds WT, McHutchison JG, et al. 
Ledipasvir/Sofosbuvir Fixed-Dose Combination Is Safe and Effective in Difficult-
to-Treat Populations Including GT 3 Patients, Decompensated GT 1 Patients, and 
GT 1 Patients With Prior Sofosbuvir Experience [Oral Presentation 6]. 49th 
Annual Meeting of The European Association for the Study of the Liver (EASL); 
2014 April 9-13; London, UK. 
34663
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. 
Archives of disease in childhood 1970;45 (239):13-23.
34664
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. 
Archives of disease in childhood 1969;44 (235):291-303.
34882
Fanta S, Jonsson S, Backman JT, Karlsson MO, Hoppu K. Developmental 
pharmacokinetics of ciclosporin--a population pharmacokinetic study in 
paediatric renal transplant candidates. Br J Clin Pharmacol 2007;64 (6):772-84.


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12.
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.
Tanner Stages*
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety and 
Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination+/- Ribavirin in Adolescents 
and Children with Chronic HCV -infection 
GS-US-337-1116, Protocol Amendment 3.0, 28 May 2015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
EIT(L{) 
Bittoo Kanwar, MD (Printed) 
Medical Monitor 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
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Appendix 2.
Study Procedures Table
Appendix Table 1.
PK Lead-in: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X j
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Vital Signsa
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X
Subject Dosing Diary
X
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X


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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
HCV RNA
X
X
X
X
Viral Sequencing c
X
X
X
Serum or Urine Pregnancy Testinge
X
X
X
Urinalysis
X
X
X
Urine Drug Screen
X
Intensive PK
X d
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
Alpha fetoprotein
X
Alpha-1 anti-trypsin
X
a.
Vital signs include blood pressure, pulse, respiratory rate and temperature, body weight, and height
b.
Day 1 assessments must be performed prior to dosing
c.
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
d.
For Cohorts 1 and 2, plasma samples will be collected for PK analyses following dosing of study drug on Day 10 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours post-dose.
e.
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test. 
f.
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status). 
g.
h.
Swallowability can occur at Day 1 if not completed during screening.
i.
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
j.
Parental height will be collected (if available)
PPD
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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
Xi
Complete Physical Examination
X
X
Xj
X
X
Symptom-Directed Physical Examination
X
X
X
X
Xk
X
X
Tanner Pubertal Stage Assessment
X
Xj
X
X
Vital Signsa
X
X
X
X
X
X
X
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling g
X
Xj
X
X
LDV/SOF FDC Swallowability 
Assessment
X
Xh
Quality of Life Survey e
X
Xj
X
X
Review of Study Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xk
X
X
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
X
X
X
X
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
X


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Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early Termination
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testingl
X
X
X
X
X
X
X
X
X
Single PK
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Urine Drug Test
X
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
Xj
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
a.
Vital signs include blood pressure, pulse, respiratory rate and temperature, and body weight and height
b.
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
c.
Subjects rolling over from PK Lead-in will not be required to repeat screening, Day 1 or Week 1 visits during the on Treatment Phase  
d.
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
e.
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
f.
g.
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
h.
Swallowability can occur at Day 1 if not completed during screening.
i.
Parental height will be collected (if available) 
j.
Subjects on 12 Week Treatment regimen only
k.
Subjects on 24 Week Treatment regimen only
l.
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test
PPD
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 94
28 May 2015
Appendix Table 3.
Treatment Phase: Post Treatment Visits Following Primary Study
4 Weeks Post Treatment
12 Weeks Post Treatment
24 Weeks Post Treatment
Clinical Assessments
Vital Signs, Body weight and Height
X
X
X
Symptom-directed Physical Exam
X
X
X
AEs
X
Xc
Xc
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counselingd
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Test
X
X
Xe
a.
Quality of life survey will be completed by all subjects at 12-Week and 24-Week Post Treatment visits if a site is approved to use the survey.  Subject is to review 
questionnaire with a parent/guardian and write/mark answers directly onto the questionnaire.
b.
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
c.
At Post Treatment Week 12 and 24, only SAEs will be captured
d.
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
e.
GT-3 subjects only: Female subjects of childbearing potential should be provided with Urine Pregnancy Test Kits, instructed on their use and requested to continue to 
self-monitor for pregnancy for 6 months after their last dose of RBV. If required by regulations, additional pregnancy tests beyond 6 months may be added. The subject 
should be contacted every 4 weeks and asked to report results of the urine pregnancy tests. If a positive urine pregnancy test is reported, the subject should return to the clinic 
for a serum pregnancy test.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 95
28 May 2015
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 96
28 May 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count  
(ANC)
Adult and Pediatric, 
≥ 7 Months# 
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 97
28 May 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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% 
# An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 98
28 May 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 99
28 May 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                          
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL                      
1.51 to < 1.74 mmolL
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 100
28 May 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
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28 May 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 102
28 May 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*Calcium should be corrected for albumin if albumin is < 4.0 g/dL
** An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 103
28 May 2015
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 104
28 May 2015
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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Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


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Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
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RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)


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Final
Gilead Sciences, Inc
Amendment 3.0
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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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Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


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Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
Page 110
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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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Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
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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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Gilead Sciences, Inc
Amendment 3.0
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Page 112
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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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Final
Gilead Sciences, Inc
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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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Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
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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


LDV/SOF FDC
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Final
Gilead Sciences, Inc
Amendment 3.0
CONFIDENTIAL
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SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
laryngeal edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic self-
care functions OR 
Hospitalization (other than ER 
visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight from 
baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  Aggressive 
intervention indicated [eg, 
tube feeding or total parenteral 
nutrition]


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


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Final
Gilead Sciences, Inc
Amendment 3.0
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ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social &
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


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


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Appendix 4.
Tanner Stages*
1. Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2. Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of testes and scrotum and increased darkening 
of scrotal skin (13.5-15)
Tanner V 
Genitalia adult in size and shape
3. Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen 
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with 
surrounding breast 
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V 
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. 
*Chart referenced from Marshall WA, Tanner JM, variations in the pattern of pubertal changes in boys and girls {34663}, {34664}


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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Background
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Pregnancy must be excluded before the start of 
treatment with study drugs and prevented thereafter by reliable contraceptive methods. 
Pregnancy tests will be performed regularly throughout this study. Furthermore, RBV is known 
to accumulate intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, 
extreme care must be taken to avoid pregnancy during RBV therapy and for up to 6 months 
following completion of treatment (7 months for males). Please refer to the latest version of the 
product insert for additional information.
Non-clinical toxicity studies of LDV/SOF FDC demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of LDV/SOF FDC 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)
For the purpose of this trial, all post-menarchal females will be considered to be of childbearing 
potential, unless there is documentation of irreversible ovarian failure or surgical sterilization.
Post-menarchal females must have a negative serum pregnancy test at Screening and a negative 
urine pregnancy test on the Day 1 visit prior to dosing. They must also agree to one of the 
following from 3 weeks prior to Day 1 until 6 months after last dose of RBV or 30 days after last 
dose of LDV/SOF FDC if not taking RBV:

Complete abstinence from intercourse. Abstinence is acceptable method of contraception 
only when it is in line with the subject’s preferred and usual lifestyle. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
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 
6 months after last dose of RBV or 30 days  after the last dose of LDV/SOF FDC if not 
taking RBV:
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization


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vasectomy in male partner
implants of levonorgestrel
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 Day 1
until 7 months after last dose of RBV or 90 days after the last dose of LDV/SOF FDC if not 
taking RBV. If their female partner is of childbearing potential (as defined above), their female 
partner must use 1 of the methods of birth control listed above from the date of Screening until 
7 months after last dose of RBV or 90 days after last dose of LDV/SOF FDC if not taking RBV.
Male subjects must agree to refrain from sperm donation for at least 7 months after last dose of 
RBV or 90 days after the last dose of LDV/SOF FDC if not taking RBV.
4. Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 6 months (7 months for partners of male subjects) of 
last RBV dose or 30 days (90 days for partners of male subjects) of last LDV/SOF FDC dose if 
not taking RBV. 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 8.5.2.1.

Prot_005.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT Number: 
Indication: 
Protocol ID: 
Gilead Sciences Medical 
Monitor and Study 
Director: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-coh01i Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir 
Fixed Dose Combination +/- Ribavirin in Adolescents and 
Children with Chronic HCV-Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
115268 
2014-003578-17 
Hepatitis C Vims Infection 
GS-US-337-1116 
Name: 
Telephone: 
Fax: 
E-mail: 
Original: 
Amendment 1.0: 
Amendment 2.0: 
Amendment 2.1: 
Amendment 2.2: 
Amendment 3.0: 
Amendment 4.0: 
Amendment 5.0: 
Benedetta Massetto, 
~:~ 
I"'U 
10 July 2014 
08 October 2014 
08 December 2014 
09 Janumy 2015 (United Kingdom Only) 
01 April 2015 (United Kingdom Only) 
28 May2015 
15 Mm·ch 2016 
04 November 2016 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this docmnent, particularly unpublished data, is the property or under 
control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable Institutional Review Boar·d or 
Independent Ethics Committee. The info1mation 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 
info1mation to others without written authorization from Gilead Sciences, Inc., except to the extent 
necessa1y to obta.in info1med consent from those persons to whom the dmg may be administered. 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................18
1.
INTRODUCTION ..............................................................................................................................................21
1.1.
Background ............................................................................................................................................21
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................22
1.2.1.
Summary of Additional Clinical Experience with Ledipasvir/Sofosbuvir 
Fixed-Dose Combination .....................................................................................................22
1.3.
Ribavirin (RBV).....................................................................................................................................29
1.4.
Rationale for the Current Study .............................................................................................................29
1.5.
Rationale for Dose Selection of LDV/SOF FDC ...................................................................................30
1.6.
Overall Risk/Benefit Assessment...........................................................................................................33
2.
OBJECTIVES.....................................................................................................................................................34
3.
STUDY DESIGN................................................................................................................................................35
3.1.
Treatment Plan and Regimen .................................................................................................................35
3.1.1.
PK Lead-in Phase.................................................................................................................35
3.1.2.
Treatment Phase ...................................................................................................................36
3.2.
Visit Schedule ........................................................................................................................................38
3.2.1.
PK Lead-in ...........................................................................................................................38
3.2.2.
Treatment Phase ...................................................................................................................39
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................39
3.4.
Treatment Discontinuations Criteria ......................................................................................................39
3.5.
Discontinuations.....................................................................................................................................40
3.6.
Pharmacogenomic Substudy ..................................................................................................................40
3.7.
Long-Term Follow-Up...........................................................................................................................40
3.8.
Breakthrough Futility Assessment .........................................................................................................40
3.9.
Reconsent...............................................................................................................................................41
4.
SUBJECT POPULATION..................................................................................................................................42
4.1.
Number of Subjects and Subject Selection ............................................................................................42
4.2.
Inclusion Criteria....................................................................................................................................42
4.3.
Exclusion Criteria...................................................................................................................................43
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................45
5.1.
Randomization and Blinding..................................................................................................................45
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................45
5.2.1.
Description and Handling.....................................................................................................45
5.2.2.
Storage and Handling...........................................................................................................47
5.2.3.
Dosage and Administration of LDV/SOF FDC ...................................................................47
5.3.
Ribavirin (GT-3 Subjects Only).............................................................................................................48
5.3.1.
Description and Handling of RBV .......................................................................................48
5.3.2.
Dosage and Administration of RBV (GT-3 Subjects Only).................................................49
5.4.
Co-administration of LDV/SOF FDC and RBV (GT-3 Subjects Only).................................................49
5.5.
Study Drug Compliance.........................................................................................................................50
5.6.
Prior and Concomitant Medications.......................................................................................................50


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6.
STUDY PROCEDURES ....................................................................................................................................52
6.1.
Subject Enrollment.................................................................................................................................52
6.2.
Screening Assessments ..........................................................................................................................52
6.2.1.
Screening Visit (Day –28 to Day 0) .....................................................................................52
6.3.
PK Lead-in: Treatment Assessments .....................................................................................................54
6.3.1.
Day 1 ....................................................................................................................................54
6.3.2.
Day 3 ....................................................................................................................................55
6.3.3.
Day 10 – Intensive PK..........................................................................................................55
6.4.
Treatment Phase: Treatment Assessments .............................................................................................57
6.4.1.
Day 1 ....................................................................................................................................57
6.4.2.
Weeks 1 and 2 (3 days) .....................................................................................................58
6.4.3.
Weeks 4 and 8 (3 days) .....................................................................................................59
6.4.4.
Week 12 (3 days) - Subjects on 12 Week Treatment Regimen Only................................60
6.4.5.
Week 12 (3 days) - Subjects on 24 Week Treatment Regimen Only................................61
6.4.6.
Week 16 and 20 (3 days) – Subjects on 24 Week Treatment Regimen 
Only......................................................................................................................................61
6.4.7.
Week 24 (3 days) – Subjects on 24 Week Treatment Regimen Only ...............................62
6.4.8.
Unscheduled Visit/Early Termination Visit .........................................................................63
6.5.
Post-Treatment Assessments..................................................................................................................64
6.5.1.
4-Week Post-Treatment Visit (5 days)..............................................................................64
6.5.2.
12-Week Post-Treatment Visit (5 days)............................................................................65
6.5.3.
24-Week Post-Treatment Visit (5 days)............................................................................65
6.6.
Procedures and Specifications................................................................................................................66
6.6.1.
Clinical Laboratory Analytes ...............................................................................................66
6.6.2.
Medical History....................................................................................................................67
6.6.3.
Complete Physical Examination...........................................................................................67
6.6.4.
Tanner Pubertal Stage Assessment.......................................................................................67
6.6.5.
Height & Weight Measurement............................................................................................67
6.6.6.
Bone Age Assessment..........................................................................................................67
6.6.7.
Swallowability Assessment..................................................................................................67
6.6.8.
Vital Signs............................................................................................................................68
6.6.9.
Estimated Glomerular Filtration Rate (GFR) .......................................................................68
6.6.10.
Viral Sequencing (Archive)..................................................................................................68
6.6.11.
Pregnancy Testing................................................................................................................68
6.6.12.
Quality of Life Survey (PedsQL™).......................................................................................69
7.
TOXICITY MANAGEMENT............................................................................................................................70
7.1.
Modification of Dose/Schedule Due to Toxicity....................................................................................70
7.2.
Subject Stopping Rules for LDV/SOF FDC and RBV...........................................................................70
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................71
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................71
8.1.1.
Adverse Events.....................................................................................................................71
8.1.2.
Serious Adverse Events........................................................................................................71
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................72
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................72
8.2.1.
Assessment of Causality for Study Drug and Procedures ....................................................72
8.2.2.
Assessment of Severity ........................................................................................................73
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................73
8.4.
Gilead Reporting Requirements.............................................................................................................75
8.5.
Special Situations Reports......................................................................................................................75


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8.5.1.
Definitions of Special Situations..........................................................................................75
8.5.2.
Instructions for Reporting Special Situations.......................................................................76
9.
STATISTICAL CONSIDERATIONS................................................................................................................78
9.1.
Analysis Objectives and Endpoints........................................................................................................78
9.1.1.
Analysis Objectives..............................................................................................................78
9.1.2.
Primary Endpoints................................................................................................................79
9.1.3.
Secondary Endpoints............................................................................................................79
9.2.
Analysis Conventions.............................................................................................................................79
9.2.1.
Analysis Sets ........................................................................................................................79
9.2.2.
Data Handling Conventions .................................................................................................80
9.2.3.
Interim Analysis ...................................................................................................................81
9.3.
Demographic Data and Baseline Characteristics ...................................................................................81
9.4.
Pharmacokinetic Analysis......................................................................................................................81
9.5.
Safety Analysis.......................................................................................................................................83
9.5.1.
Extent of Exposure...............................................................................................................83
9.5.2.
Adverse Events.....................................................................................................................83
9.5.3.
Laboratory Evaluations ........................................................................................................84
9.5.4.
Other Safety Evaluations......................................................................................................84
9.6.
Efficacy Analysis ...................................................................................................................................85
9.6.1.
Key Efficacy Analysis..........................................................................................................85
9.6.2.
Secondary Efficacy Analysis................................................................................................85
9.6.3.
Subgroup Analysis ...............................................................................................................85
9.7.
Quality of Life Analysis.........................................................................................................................86
9.8.
Data Monitoring Committee ..................................................................................................................86
9.9.
Sample Size............................................................................................................................................86
10.
RESPONSIBILITIES..........................................................................................................................................87
10.1.
Investigator Responsibilities ..................................................................................................................87
10.1.1.
Good Clinical Practice..........................................................................................................87
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................87
10.1.3.
Informed Consent/Assent.....................................................................................................88
10.1.4.
Confidentiality......................................................................................................................88
10.1.5.
Study Files and Retention of Records ..................................................................................88
10.1.6.
Case Report Forms...............................................................................................................89
10.1.7.
Drug Accountability.............................................................................................................90
10.1.8.
Inspections............................................................................................................................90
10.1.9.
Protocol Compliance............................................................................................................90
10.2.
Sponsor Responsibilities ........................................................................................................................90
10.2.1.
Protocol Modifications.........................................................................................................90
10.2.2.
Study Report and Publications .............................................................................................91
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................91
10.3.1.
Access to Information for Monitoring..................................................................................91
10.3.2.
Access to Information for Auditing or Inspections ..............................................................91
10.3.3.
Study Discontinuation..........................................................................................................92
11.
REFERENCES ...................................................................................................................................................93
12.
APPENDICES ....................................................................................................................................................96
Appendix 1.
Investigator Signature Page....................................................................................................97
Appendix 2.
Study Procedures Table..........................................................................................................98
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............104


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Appendix 4.
Tanner Stages* .....................................................................................................................128
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................129
LIST OF IN-TEXT TABLES
Table 1-1.
Statistical Comparison of Pharmacokinetic Parameters for Formulation Comparison 
- Test versus Reference Treatments (Primary PK analysis Set) .............................................25
Table 1-2.
Statistical Comparison of Pharmacokinetic Parameters for Food Effect Comparison 
- Test versus Reference Treatments (Primary PK analysis Set) .............................................26
Table 1-3.
Steady-state PK and Statistical Comparisons of LDV, SOF and GS-331007 PK in 
Adolescent Subjects (PK Lead-in) and Adult Subjects (Phase 2/3 Population PK 
Analysis).................................................................................................................................28
Table 1-4.
Steady-state PK and Statistical Comparisons of LDV, SOF and GS-331007 PK in 
Pediatric Cohort 2 Subjects (6 to <12 years old; PK Lead-in) and Adult Subjects 
(Phase 2/3 Population PK Analysis).......................................................................................28
Table 3-1.
Subject Enrollment by HCV Genotype, Country, and Treatment Duration ...........................37
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................51
Table 7-1.
RBV Dose Reduction Guidelines...........................................................................................70
Table 9-1.
GS-331007, SOF, and LDV PK Parameters after Once-Daily Administration of 
LDV/SOF FDC in HCV-Infected Adults Subjects (Population PK Analysis from 
Phase 2 and 3 Studies)............................................................................................................83
LIST OF IN-TEXT FIGURES
Figure 1-1.
Predicted LDV, SOF, and GS-331007 AUCtau following administration of 
LDV/SOF FDC 45 mg/ 200 mg or LDV/SOF FDC 33.75 mg/ 150 mg (3 to < 6 
years of age) ...........................................................................................................................32
Figure 3-1.
PK Lead-in Phase Study Schema ...........................................................................................36


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc. 
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed 
Dose Combination +/- Ribavirin in Adolescents and Children with 
Chronic HCV Infection
IND Number:
EudraCT Number:
115268
2014-003578-17
Study Centers:
Approximately 30 sites in the United States, Europe, Australia, and 
New Zealand
Number of Subjects:
Approximately 200 subjects
Target Population:
Adolescents and children (aged 3 to < 18 years) chronic hepatitis C 
virus (HCV) infection
Treatment Duration:
PK Lead-in – 10 days
Treatment Phase – 12 or 24 weeks
Objectives:
The primary objective of the PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm 
the dose of LDV/SOF FDC in chronic HCV-infected pediatric 
subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 
10 days of dosing of LDV/SOF FDC in chronic HCV infected 
pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV 
for 12 or 24 weeks in chronic HCV -infected pediatric subjects. 


LDVISOFFDC 
Protocol GS-US-337-1116 
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Study Design: 
CONFIDENTIAL 
Final 
Amendment 5.0 
The seconda!y objectives of the Treatment Phase ofthis study are: 
• 
To detennine the antiviral efficacy of 12 or 24 weeks of 
LDV/SOF FDC +/- RBV u·eatment in chronic HCV infected 
subjects (including the impact of HCV genotype, IL28B 
genotype, and prior u·eatment experience), as assessed by the 
prop01iion of subjects with sustained virological response (SVR) 
12 weeks after completion ofu·eatment (SVR12) 
• 
To determine the antiviral efficacy of 12 or 24 weeks of 
LDV/SOF FDC +/- RBV u·eatment in chronic HCV -infected 
subjects, as assessed by the prop01iion of subjects with SVR 4 and 
24 weeks after completion ofu·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during 
u·eatment and after completion of u·eatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF 
during u·eatment and after completion of u·eatment 
• 
To evaluate the effect of growth and development on pediau·ic 
subjects during and after u·eatlnent 
The explorat01y objective of this study is: 
• 
PD 
Open-label, multi-coh01i, two-part study evaluating the PK, safety, 
and antiviral activity ofLDV/SOF FDC +/- RBV in chronic 
HCV -infected pediau·ic subjects. 
The study commenced with GT-1 , -3 and -4 HCV-infected pediau·ic 
subjects. Subjects with GT-5 and -6 are cunently eligible for 
inclusion into actively emolling groups/coh01is following the 
demonsu·ation ofbenefit:risk in the adult population. Subjects with 
GT-2 will be included once adult data are available, if appropriate. 
PK Lead-in Phase: PK Lead-in will evaluate and/or confnm age 
appropriate LDV/SOF FDC doses by analyzing PK, safety, and 
antiviral activity of LDV /SOF FDC tluough 10 days of dosing for 
each of the three coh01is. Children aged 3 to < 6, children aged 
6 to < 12 years, and adolescents aged 12 to < 18 years with evidence 
of cluonic HCV and HCV RNA ~ 1000 IU/mL at study enby will be 
evaluated. Subjects must be tt·eabnent na'ive without hist01y of 
cinhosis to pruiicipate in the PK Lead-in Phase. 
Page7 
04 November 2016 


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Three cohorts of at least 10 subjects each will be sequentially 
enrolled: 

Cohort 1: 12 to < 18 years old, weighing ≥ 45kg

Cohort 2: 6 to < 12 years old, weighing ≥ 17 kg and < 45 kg

Cohort 3: 3 to < 6 years old 
The study will start with Cohort 1. Subjects will receive LDV/SOF 
FDC (90 mg/ 400 mg fixed dose combination tablet or 
4 x 22.5 mg/ 100 mg based on LDV/SOF FDC swallowability 
assessment) for 10 days with intensive PK conducted on Day 10.
Once Cohort 1 data is analyzed and a Cohort 2 dose is determined, 
Cohort 2 will open for screening. Cohort 2 subjects will receive 
45 mg/ 200 mg LDV/SOF FDC (2 x 22.5 mg/ 100 mg tablets) for 10 
days with intensive PK conducted on Day 10. Cohort 3 subjects will 
receive LDV/SOF FDC oral granules formulation; subjects weighing 
≥17 kg will receive 45 mg/ 200 mg LDV/SOF FDC (4 x 11.25 mg/
50 mg packets) and subjects weighing <17 kg will receive 33.75 mg/ 
150 mg LDV/SOF FDC (3 x 11.25 mg/ 50 mg packets) for 10 days 
with intensive PK conducted on Day 10. 
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 10
of the PK Lead-in Phase. They will continue dosing with LDV/SOF 
FDC with no interruption of study drug administration. Subjects 
rolling over from the PK Lead-in will not be required to perform 
Treatment Phase Screening, Day 1, or Week 1 visits in the Treatment 
Phase.  
Following completion of study treatment in the PK Lead-in of each 
Cohort, intensive PK and safety results of study treatment will be 
reviewed to confirm the appropriateness of the evaluated LDV/SOF 
FDC dose for the Treatment Phase of that Cohort as well as to 
determine the age-appropriate dose to be evaluated in the PK Lead-in 
of the next Cohort.
Treatment Phase: Treatment Phase will be initiated sequentially by 
cohort after confirmation of age-appropriate LDV/SOF FDC dosage 
levels. Subjects who participate in PK Lead-in Phase will 
immediately rollover into Treatment Phase, with no interruption of 
study drug administration, until the appropriateness of the dose is 
confirmed by PK and safety data from the PK Lead-In Phase. These 
subjects will start at the Week 2 visit of the Treatment Phase. 
Additional subjects will be enrolled in the Treatment Phase of each 
Cohort upon confirmation of the appropriateness of the dose.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 9
04 November 2016
Children aged 3 to < 12 years and adolescents aged 12 to < 18 years 
with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study 
entry (those who were dosed in the PK Lead-in Phase will have met 
these criteria prior to enrollment) will be evaluated. The study 
commenced with GT-1, -3 and -4 HCV-infected pediatric subjects. 
Subjects with GT-5 and -6 are currently eligible for inclusion into 
actively enrolling groups/cohorts following the demonstration of 
benefit:risk in the adult population. Subjects with GT-2 will be 
included once adult data are available, if appropriate.
Subjects enrolled in the study will receive the following regimen:

United Kingdom:
GT-1, GT-4, GT-5, and GT-6 treatment-naïve with or without 
cirrhosis: LDV/SOF FDC for 12 weeks
GT-1, GT-4, GT-5, and GT-6 treatment-experienced without 
cirrhosis: LDV/SOF FDC for 12 weeks
GT-1, GT-4, GT-5, and GT-6 treatment-experienced with 
cirrhosis: LDV/SOF FDC for 24 weeks
GT-3 treatment-experienced with or without cirrhosis: 
LDV/SOF FDC + RBV for 24 weeks

United States/Australia/New Zealand:
GT-1 treatment-naïve with or without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1 treatment-experienced without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1 treatment-experienced with cirrhosis: LDV/SOF FDC 
for 24 weeks
GT-4, GT-5, and GT-6 treatment-naïve or treatment-
experienced with or without cirrhosis: LDV/SOF FDC for 
12 weeks
The study will enroll both treatment-naïve and treatment-experienced 
pediatric subjects, with up to 40 subjects allowed to be treatment 
experienced. Approximately 200 total subjects, including subjects 
that participated in the PK Lead-in Phase, will be enrolled in the 
Treatment Phase as follows:

Group 1: Approximately 100 adolescent subjects (12 to < 18 years 
of age)

Group 2: Approximately 100 pediatric subjects (3 to < 12 years of 
age)


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Substudy and Long-
Tenn Follow-Up 
Study: 
Diagnosis and Main 
Eligibility Criteria: 
CONFIDENTIAL 
Final 
Amendment 5.0 
The following defmitions will be used for u·eatment-experienced 
subjects: 
• 
Interferon intolerant: Subject who discontinued therapy 
(:::; 12 weeks total) due to:=::: 1 adverse event 
• 
Interferon non-responder: Subject who did not achieve 
undetectable HCV RNA levels while on u·eatment 
• 
Relapse/breakthrough: Subject who achieved undetectable 
HCV RNA during u·eatment or within 4 weeks of the end of 
u·eatment but did not achieve a sustained virologic response 
(SVR) 
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, and 12 (and Weeks 16, 20, and 24 for subjects 
requiring 24 weeks of u·eatment) dm'ing the u·eatment phase followed 
by post-u·eatment visits 4, 12, and 24 weeks after discontinuation of 
therapy. 
All subjects who do not attain SVR or have viral relapse will be 
encouraged to discuss u·eahnent with standard-of-care (SOC) therapy 
with their healthcare provider. 
Pharmacogenomics (PG) Substudy 
PD 
Long-Term Follow-up 
Subjects who attain SVR24 or those who do not attain SVR24 and do 
not initiate other experimental or approved anti-HCV therapy will be 
followed eve1y 6 months for the first 2 years followed by eve1y 
12 months for assessments of growth, quality of life, and long-te1m 
viral suppression (if applicable) in a separate protocol 
(GS-US-334-1113). This follow-up will continue for 5 years. 
Chronic HCV-infected, u·eatment-nai've and u·eatment experienced 
(up to 40 subjects); male and female subjects aged 3 to < 18 as 
detennined at Day 1. The study commenced with GT-1, -3, and -4 
HCV -infected pediau·ic subjects. Subjects with GT-5 and -6 are 
cmTently eligible for inclusion into actively enrolling groups/coh01is 
following the demonsu·ation of beneflt:risk in the adult population. 
Subjects with GT-2 will be included once adult data are available, if 
appropriate. 
Page 10 
04 November 2016 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 11
04 November 2016
Inclusion Criteria:

Chronic HCV infection documented by either:
A) positive anti-HCV antibody test or positive HCV RNA or 
positive HCV genotyping test at least 6 months prior to the 
Day 1 visit, or
B) liver biopsy performed prior to the Day 1 visit with evidence 
of chronic HCV- infection

HCV RNA ≥ 1000 IU/mL at Screening 

PK Lead-in Only: subjects in Cohort 1 (age 12 to < 18 years 
of age) must weigh ≥ 45 kg

PK Lead-in Only: subjects in Cohort 2 (age 6 to < 12 years of 
age) must weigh ≥ 17 kg and < 45 kg

Females of childbearing potential (as defined in Appendix 5) 
must have a negative pregnancy test at Screening and Day 1.

Hematologic or biochemical parameters at screening within 
the protocol-specified requirements
Exclusion Criteria:

HIV, acute hepatitis A virus (HAV) or chronic HBV infection

History of or current decompensated liver disease

Hepatocellular carcinoma or other malignancy (with exception 
of certain resolved skin cancers)

Chronic liver disease of a non-HCV etiology 
(e.g., hemochromatosis, Wilson’s disease, alpha-1 antitrypsin 
deficiency)

Systemic corticosteroid use for > 2 weeks (pulmonary/nasal 
administration is permitted)

Active or recent history (≤ 1 year) of drug or alcohol abuse

History or current evidence of any condition, therapy, 
laboratory abnormality or other circumstance that might 
confound the results of the study, or interfere with the 
subject’s participation for the full duration of  the study, such 
that it is not in the best interest of the subject to participate.

Sexually active subjects who are not willing to use 2 forms of 
an effective method of contraception, as referenced in 
Appendix 5
See Sections 4.2 and 4.3 of the protocol for full eligibility criteria.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 12
04 November 2016
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the Day 1 
visit. 
Screening assessments will include: informed consent, medical 
history (including parental height, if available), complete physical 
examination, vital signs (including body height and weight), 
concomitant medications, LDV/SOF FDC Swallowability 
Assessment, as applicable (may be performed at screening up to Day 
1), hematology, safety laboratory tests, coagulation tests, HCV RNA, 
serum β-human chorionic gonadotropin (hCG - females of 
childbearing potential only), urinalysis, urine drug screen, IL28B 
genotyping, serology (HIV, HAV, HCV, and HBV, HCV 
genotyping), HbA1c, thyroid stimulating hormone (TSH), alpha 
fetoprotein, alpha-1 anti-trypsin.
For subjects continuing from PK Lead-in into the Treatment Phase, a 
screening visit for the Treatment Phase will not be required.
PK Lead-in Phase: 
Study Visits will occur at Day 1, Day 3, and Day 10.
On-Treatment assessments include physical examination, Tanner 
Pubertal Stage Assessment (Day 1 only), vital signs (including body 
height and weight), bone age assessment (Day 1 only), adverse events 
(AEs), concomitant medications, pregnancy prevention counseling 
(Day 1 only; all subjects ≥ 12 years of age and subjects 
< 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status), quality of life survey (Day 1 only), safety 
laboratory tests, HCV RNA, viral sequencing sampling and 
urinalysis. Coagulation testing and urine pregnancy tests (females of 
child bearing potential only) will be performed at Day 1 and Day 10 
only. LDV/SOF FDC swallowability assessment as applicable with 
placebo will be performed (if not performed at Screening) on Day 1 
to assess a subject’s ability to swallow the 90 mg/ 400 mg or 22.5 mg/
100 mg tablet, as applicable (only subjects administered LDV/SOF 
FDC in tablet form). 
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in 
Phase will participate in an intensive PK evaluation on Day 10. 
Following completion of the Day 10 intensive PK visit, subjects will 
then return for scheduled study visits outlined in the Treatment Phase 
and will continue dosing with LDV/SOF FDC with no interruption of 
study drug administration. Subjects will be administered a dosing 
diary with instructions.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 13
04 November 2016
Treatment Phase: 
Study visits will occur at Day 1, and at the end of Weeks 1, 2, 4, 8, 
and 12 (and Weeks 16, 20, and 24 for subjects requiring 24 weeks of 
treatment). All Treatment Phase subjects will then return for 
follow-up visits at 4, 12, and 24 weeks after discontinuation of 
therapy. 
On-treatment assessments will include physical examination, vital 
signs (including body height and weight), AEs, concomitant 
medications, pregnancy prevention counseling (all subjects 
≥12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status), safety laboratory
tests, coagulation tests, HCV RNA, HBV DNA for HBcAb positive 
subjects, viral sequencing, urine pregnancy tests (females of 
childbearing potential only), PK samples, a quality of life survey, and 
urinalysis. Tanner Pubertal Stage assessment will be performed at 
Day 1 and end of treatment visits; parental heights will be recorded at 
Day 1. The Bone Age Assessment will be performed at the Day 1 
visit. LDV/SOF FDC swallowability assessment as applicable will be 
performed (if not performed at Screening) on Day 1 to assess a 
subject’s ability to swallow a placebo to match the 90 mg/ 400 mg or 
22.5 mg/ 100 mg LDV/SOF FDC tablet, as applicable (only subjects 
administered LDV/SOF FDC in tablet form). For subjects continuing 
from the PK Lead-in, the screening, Day 1, and Week 1 visits of the 
Treatment Phase will not be required. Samples for viral RNA 
sequencing/phenotyping will be collected at Day 1 and every visit 
thereafter.
Post-treatment assessments will include vital signs (including body 
weight and height), symptom-directed physical examination, AEs 
(only SAEs will be captured at post-treatment Week 12 and 
post-treatment Week 24), concomitant medications (only 
post-treatment Week 4), safety laboratory tests, HCV RNA, HBV 
DNA for HBcAb positive subjects, Tanner Pubertal Stage assessment
(only post-treatment Week 12 and post-treatment Week 24), Bone 
Age Assessment (only post-treatment Week 24) and urine pregnancy 
tests (as defined in Appendix 5).  


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
CONFIDENTIAL 
PD 
PKLead-in: 
Final 
Amendment 5.0 
(Coh01i 1) LDV/SOF FDC is manufactured as a tablet, consisting of 
400 mg SOF and 90 mg LDV, for oral administration. LDV/SOF 
FDC tablets will be administered once daily. Subjects unable to 
swallow the LDV/SOF FDC 90 mg/ 400 mg adult tablet (as 
detennined by LDV /SOF FDC Swallowability Assessment at 
Screening or at Day 1) will be re-assigned to 4 x 22.5 mg/ 100 mg 
LDV /SOF FDC tablets daily. 
(Coh01i 2) LDV/SOF FDC 45 mg/ 200 mg (2 x 22.5 mg/ 100 mg) 
will be administered once daily. 
(Coh01i 3) LDV/SOF FDC oral granules will be administered once 
daily for 10 days. Subjects who weigh ::::17kg will receive 45 mg/ 
200 mg LDV/SOF FDC (4 x 11.25 mg/ 50 mg packets) and subjects 
who weigh <17kg will receive 33.75 mg/ 150 mg LDV/SOF FDC 
(3 x 11.25 mg/ 50 mg packets). 
Intensive PK and safety results fi:om the PK Lead-in of each Coh01t 
will be reviewed to confnm the appropriateness of the evaluated 
LDV/SOF FDC dose for the Treatment Phase of that Coh01t as well 
as to dete1mine the age-appropriate dose to be evaluated in the PK 
Lead-in of the next Coh01t. 
Page 14 
04 November 2016 


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 15
04 November 2016
Treatment Phase: 
Subjects who participated in PK Lead-in of each Cohort will continue 
in the Treatment Phase with no interruption of study drug 
administration until the appropriateness of the dose is confirmed by 
PK and safety data from the PK-Lead-in. Additional subjects will be 
enrolled in the Treatment Phase of each Cohort upon confirmation of 
the appropriateness of the dose.
RBV Weight-Based Dosing (GT-3 Subjects only):
The RBV dose is:
Body Weight kg
(lbs.)
RBV Daily 
Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution.  Divided dose in the 
morning and evening.
47-49 (103-108)
600 mg/day
1 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
50-65 (110 – 143)
800 mg/day
2 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
66-80 (145 – 176)
1000 mg/day
2 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
81-105 (178-231)
1200 mg/day
3 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
>105 (>231)
1400 mg/day
3 x 200-mg capsules A.M.
4 x 200-mg capsules P.M.
*
Note:  Subjects with a body weight greater than or equal to 47 kg may utilize the RBV 
oral solution if necessary.
The morning dose of RBV will be taken with food and a weight 
and/or age-appropriate dose of LDV/SOF FDC. The evening dose of 
RBV will be taken with food.
Reference Therapy:
None
Evaluation Criteria:
Safety:
AEs, laboratory tests, physical examinations, and vital sign 
measurements will be collected throughout the study. 
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using COBAS® AmpliPrep/COBAS® TaqMan®
HCV Test.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 16
04 November 2016
PK:
For subjects in the PK Lead-in, the steady-state PK of LDV, SOF,
and its major metabolites (GS-331007 and GS-566500) will be 
assessed at Day 10. For Cohorts 1 and 2, plasma samples will be 
collected for PK analyses following dosing of study drug on Day 10
at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, and 
12 hours postdose (with predose also serving as t= 24). For Cohort 3, 
plasma samples for PK analyses will be collected at the following 
time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours postdose (with 
predose also serving as t = 24).
Plasma PK parameters such as Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, and 
t1/2 will be estimated. 
For all subjects in the Treatment Phase, a single PK blood sample will 
be collected at all visits while on treatment. The PK of GS-331007,
SOF and LDV will be assessed.
The effect of age and LDV/SOF FDC dose on PK (GS-331007, SOF, 
and LDV) will be explored.
Statistical Methods:
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, Ctau, 
AUCtau, AUClast, and t1/2 will be estimated. The PK parameters will be 
summarized by cohort. The effect of age and LDV/SOF FDC dose on 
PK (GS-331007, SOF, and LDV) will be explored.
For the Treatment Phase, the primary safety endpoint is any AE 
leading to permanent discontinuation of study. The key efficacy 
endpoint is SVR12 in all enrolled and treated subjects. Point estimate 
of SVR12 rate and its 95% confidence interval will be provided for 
each age group. 
Clinically relevant subgroup analysis on SVR12 may be conducted as 
appropriate (i.e., assuming that adequate numbers of patients in the 
subsets are available for analysis). 
All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation, median, Q1, Q3, minimum, 
and maximum). All categorical endpoints will be summarized by 
number and percentage of subjects who meet the endpoint definition.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 17
04 November 2016
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.
With approximately 100 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 
SVR12 rate will extend at most 5.9% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 90%.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 18
04 November 2016
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
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)
BLQ
below the lower limit of quantification
BMI
body mass index
CK
creatine kinase
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
dL
Deciliter
DNA
deoxyribonucleic acid
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
EMA
Electronic case report form(s)
European Medicines Agency
ESA
Erythropoiesis stimulating agent
ESPGHAN
European Society for Paediatric Gastroenterology
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed-Dose Combination
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 19
04 November 2016
HAV
Hepatitis A Virus
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HBsAb
Hepatitis B surface antibody
HBcAb
Hepatitis B core antibody
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
peginterferon alfa-2a
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
QD
once daily (use only in tables)
RBC
Red blood cell count
RBV
ribavirin


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 20
04 November 2016
RNA
ribonucleic acid
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard-of-Care
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TSH
Thyroid stimulating hormone
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant 
(λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 21
04 November 2016
1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease worldwide 
and accounts for 70% of cases of chronic hepatitis in industrialized countries. The global 
prevalence of chronic hepatitis C is estimated to average 3% {Esteban et al 2008}. 
The natural history of chronic HCV-infection in children differs from that in adults since 
HCV-infection in children is relatively benign. Most children chronically infected with HCV are 
asymptomatic or have mild nonspecific symptoms. Clinical symptoms are present in 
approximately 20% of children in the first 4 years of life, with hepatomegaly being the most 
frequent sign (10%). Many, but not all, perinatally infected children will have intermittently or 
persistently abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
levels, particularly in the first 2 years of life. In children with vertical HCV-infection who have 
undergone liver biopsy, the histological spectrum is usually mild, although severe liver disease is 
encountered {Mohan et al 2010}. Despite the overall more favorable prognosis compared to 
adults, approximately 4% to 6% of children with chronic HCV-infection have evidence of 
advanced fibrosis or cirrhosis and some children eventually require liver transplantation for end-
stage liver disease as a consequence of HCV-infection {Hu et al 2010}.
The goal of HCV treatment in both pediatric and adult populations is eradication of the virus, 
thereby preventing hepatic inflammation, hepatic fibrosis, cirrhosis, and liver failure resulting in 
either death or need for liver transplantation. This goal, however, is limited by the nature of the 
disease and the fact that not all patients are suitable candidates for currently approved treatments. 
In addition, pediatric treatment is controversial as the current treatment options are limited and 
severe side effects and tolerability can significantly limit or preclude their use. Despite 
well-established guidelines for the treatment of HCV in adults, there is no universal consensus 
on when or if to treat chronic HCV-infection in children. In 2010, the European Society for 
Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) issued guidance for clinical 
trial development for chronic HCV-infection in children {Wirth et al 2010}. In the guideline, the 
ESPGHAN suggested that the primary goal of treatment in children is to eradicate the infection 
to prevent late complications. Hence, the goal is not the treatment of an ongoing liver disease, 
but rather the prevention of a future one.
PEG and weight-based RBV are currently considered the SOC for the treatment of 
HCV-infection in children. Current recommendations are that patients with GT-2 or GT-3 be 
treated with PEG+RBV for 24 weeks and those with GT-1 or GT-4 should receive 48 weeks of 
therapy. Successful treatment of GT-1, however, has proved very difficult to achieve in spite of 
additional therapy or increased duration of treatment. A number of pediatric studies have 
reported that despite 48 weeks of treatment, sustained virologic response (SVR24) was observed 
in only 36% to 53% of subjects with GT-1, while response rates were > 80% in subjects with 
GT-2 or GT-3 {Wirth 2012}. Safety and efficacy data in pediatric patients with GT-5 or GT-6 
are limited.


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Amendment 5.0
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Most children treated with PEG+RBV experience at least 1 adverse event due to treatment 
{Wirth 2012}. Although most of these events are mild to moderate in severity, many of them 
result in dose reductions of 1 or both of the drugs. The most common adverse events have 
consisted of influenza-like illness (91%), headache (62%), and injection site reactions (45%), 
often leading to poor compliance and/or discontinuation from treatment.
Additionally, the concern for growth and development in this age group and the role that both 
PEG and RBV potentially play in reducing growth rates has initiated significant debate among 
pediatric hepatologists as to whether these treatments should even be considered in the pediatric 
population {Serranti et al 2011}. Many pediatricians currently advocate delay of treatment past 
adolescence or even into adulthood when options with DAAs are possible {Serranti et al 2011}. 
Unfortunately, in the 25% of pediatric patients who do meet the criteria for treatment (elevated 
transaminases and viral loads), the option of PEG+RBV therapy remains inadequate in regard to 
both efficacy in GT-1 and safety due to the many risks associated with this treatment.
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
Ledipasvir/Sofosbuvir fixed-dose combination (LDV/SOF FDC) combines two HCV specific 
direct acting antiviral (DAA) agents into a single tablet for the treatment of chronic 
HCV-infection. SOF is a nucleotide analog that is a potent and selective inhibitor of 
NS5B-directed HCV replication with demonstrated activity against GT 1-6 HCV-infection. 
Ledipasvir (LDV) is a novel HCV NS5A inhibitor that has demonstrated potent anti-HCV 
activity, with the highest activity against GT-1 HCV-infection. 
Harvoni® (LDV/SOF FDC) is approved in the United States (US) by the Food and Drug 
Administration (FDA) and in the European Union by the European Medicines Agency (EMA) 
for treatment of GT-1, GT-4, GT-5, and GT-6 HCV infection in both treatment-naïve and 
treatment-experienced adult patients with or without cirrhosis. Additionally, LDV/SOF FDC + 
RBV is approved for treatment of GT-3 HCV infection in treatment-experienced adult patients 
with or without cirrhosis. The recommended treatment regimens depend on HCV genotype, 
presence or absence of cirrhosis, and prior treatment experience. 
1.2.1.
Summary of Additional Clinical Experience with Ledipasvir/Sofosbuvir 
Fixed-Dose Combination
The LDV/SOF FDC phase 3 program consisted of 3 clinical studies: GS-US-337-0102 {Afdhal 
et al 2014b}, GS-US-337-0109 {Afdhal et al 2014a}, and GS-US-337-0108 {Kowdley et al 
2014}. Studies GS-US-337-0102 and GS-US-337-0109 evaluated treatment with LDV/SOF FDC 
RBV for 12 or 24 weeks in treatment-naïve and treatment-experienced subjects, respectively, 
infected with GT-1 HCV. Both studies enrolled up to 20% of HCV-infected subjects who had 
documented compensated cirrhosis. GS-US-337-0108 evaluated LDV/SOF FDC ± RBV 
treatment for 8 weeks and LDV/SOF FDC treatment for 12 weeks in non-cirrhotic 
treatment-naïve subjects with GT-1 HCV-infection. Across these 3 clinical studies, LDV/SOF 
FDC demonstrated a high degree of efficacy (> 93%) for treatment-naïve and treatment
experienced subjects with GT-1 HCV-infection in subjects with and without cirrhosis and
achieved their primary efficacy endpoints {Afdhal et al 2014b}; {Afdhal et al 2014a}; {Kowdley 
et al 2014}. Additionally, treatment with LDV/SOF FDC ± RBV was safe and well tolerated in 
the Phase 3 studies {Afdhal et al 2014b}; {Afdhal et al 2014a}; {Kowdley et al 2014}.  The 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 23
04 November 2016
inclusion of RBV to the treatment regimen was associated with an increase in the total incidence
of adverse events and in graded laboratory abnormalities of anemia and increased bilirubin. 
LDV/SOF FDC indication in GT-3 HCV infection is supported by the Phase 2 Study 
GS-US-337-0122 (ELECTRON-2). In this Phase 2 open-label study, the safety and efficacy of 
LDV/SOF FDC were evaluated with or without RBV in 51 treatment-naïve patients with GT-3 
HCV infection, with or without cirrhosis. Subjects were treated with LDV/SOF FDC (n = 25) or 
LDV/SOF FDC + RBV (n = 26) for 12 weeks. SVR12 rates were 64% (16/25) and 100% (26/26) 
in the LDV/SOF FDC and LDV/SOF FDC + RBV treatment groups, respectively. The relative 
efficacy of a 12-week regimen consisting of LDV/SOF FDC + RBV, compared to a 24-week 
regimen of SOF + RBV has not been investigated. Therefore, 24 weeks of therapy is advised in 
all treatment-experienced GT-3 patients and those treatment-naïve GT-3 patients with cirrhosis 
to maximize therapeutic benefit to achieve SVR.
Both nonclinical and clinical data support the inclusion of GT-4 HCV-infected subjects in the 
Study GS-US-337-1116. LDV displays potent antiviral activity against GT-4. In the replicon 
system the EC50 value of LDV for GT-4d HCV was 0.60 nM and 0.39 nM for GT-4a HCV. For 
reference, the EC50 values of LDV for GT-1a and GT-1b is 0.031 nM and 0.004 nM, 
respectively.
In the Phase 3 Study GS-US-337-0102 (ION-1), 2 subjects with GT-4d HCV infection were 
inadvertently randomized in violation of the protocol inclusion/exclusion criteria. Both subjects 
achieved SVR12. Subject 
 was treated for 12 weeks with LDV/SOF FDC and 
Subject 
 was treated for 24 weeks with LDV/SOF FDC + RBV.
Data from Study GS-US-337-1119 support the inclusion of GT-4 as well as GT-5 HCV-infected 
subjects within the current study. Study GS-US-337-1119 was a European study that investigated
the efficacy and safety of LDV/SOF FDC in treatment-naive and treatment-experienced subjects 
with chronic GT-4 or GT-5 HCV infection. A total of 44 subjects with GT-4 HCV infection, of 
whom 10 (23%) had cirrhosis and 22 (50%) were treatment experienced, were enrolled to 
receive LDV/SOF FDC for 12 weeks. SVR12 was achieved by 41 (93%) of the GT-4 HCV
infection subjects including 21 (96%) who were treatment-naïve and 20 (91%) who were 
treatment-experienced subjects. In addition, a total of 41 subjects with GT-5 HCV infection were 
enrolled, of whom 9 (22%) had cirrhosis and 20 (49%) were treatment-experienced, and received 
LDV/SOF FDC for 12 weeks. SVR12 was achieved by 39 (95%) including 19 (95%) who were 
treatment-experienced and 8 (89%) with cirrhosis.
In addition, data are available from the NIAID/NIH collaborative Study CO-US-337-0117. In 
this study, 21 subjects with GT-4 HCV infection received 12 weeks of LDV/SOF FDC 
treatment. SVR12 was achieved by 20 of 21 subjects including 6 subjects with cirrhosis.
Inclusion of subjects with GT-6 HCV in the current study is supported by data from the 
ELECTRON-2 study (GS-US-337-0122).  In ELECTRON-2, treatment-naïve or treatment-
experienced adult subjects with GT-6 HCV infection with or without cirrhosis (n = 25) received 
LDV/SOF FDC for 12 weeks. In this study, 96% (24/25) of patients achieved SVR12.
PPD
PPD


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
1.2.1.1. 
GS-US-337-2091 
Final 
Amendment 5.0 
Study GS-US-337-2091 was a single dose, randomized, 3-period crossover Phase 1 study in 
healthy adult subjects conducted to evaluate relative bioavailability and the effect of food on 
LDV/SOF FDC oral granules. Subjects were administered the following treatments in a 
randomized order with a 9 day washout between doses: 1 x 90 mg/ 400 mg LDV/SOF FDC 
tablet (adult fonnulation) in the fasted state (Treatment A), 90 mg/ 400 mg LDV/SOF FDC oral 
granules (8 x 11.25 mg/ 50 mg packets) in a fasted state (Treatment B), and 90 mg/ 400 mg 
LDV /SOF oral granules (8 x 11.25 mg/ 50 mg packets) after a standardized high-fat meal 
(Treatment C). F01iy-two healthy subjects were emolled and completed all u·eatments. Overall, 
both LDV/SOF FDC f01mulations were well tolerated. No subjects experienced a serious 
adverse event (SAE) or a Grade 3/4 u·eatment emergent adverse event (AE), and no subjects 
required u·eatment discontinuation for an AE. Grade 3/4laboratOiy abn01m alities were seen in 1 
subject who had a u·ansient Grade 4 lipase elevation (481 UIL) prior to the 3rd dose, followed by 
progressive decrease through 3 weeks after the dose. The subject was asymptomatic and had a 
medical hist01y notable for isolated lipase elevation. 
In accordance with the FDA and EU guidance for Bioavailability and Bioequivalence studies the 
primaty PK analysis set consisted of subjects with pre-dose concenu·ations < 5% of Cmax for each 
period (Guidance for Industry: Bioavailability and Bioequivalence Studies Submitted in NDAs 
or INDs - General Considerations [FDA], Guideline on the Investigation of Bioequivalence EU] 
{U.S. Department of Health and Human Services 2014}, {European Medicines Agency (EMEA) 
2010}). A sensitivity analysis including PK data from all subjects was also conducted. 
1.2.1.1.1. 
GS-US-337-2091 F01mulation Comparison 
Statistical compat·isons of the primaty PK paratneters AUCinf, AUC1ast> Cmax for LDV, and 
GS-331 007 (the primruy circulating metabolite of SOF) are presented below following 
adminisu·ation of90 mg/ 400 mg LDV/SOF FDC oral granules (8 x 11.25 mg/ 50 mg) fasted 
(Treatment B; Test) relative to 90 rng/ 400 mg LDV/SOF FDC tablets (1 x 90 mg/ 400 mg). 
fasted Treatment A; Reference . PO 
CONFIDENTIAL 
Page 24 
04 November 2016 


LDVISOFFDC 
Protocol GS-US-337-1116 
Final 
Gilead Sciences, Inc. 
Amendment 5.0 
Table 1-1. 
Statistical Comparison of Pharmacokinetic Parameters for 
Formulation Comparison- Test versus Reference Treatments 
(Primary PK analysis Set) 
Mean (o/oCV) 
o/oGLSM Ratio (90% CI) 
LDV/SOF 
LDV/SOF FDC 
FDC Tablet 
Oral Granules 
LDV/SOF FDC Oral Granules 
90 mg/ 400 mg 
Sx 11.25 mg/50 mg 
VS 
PK Parameter 
(Reference) 
(Test) 
LDV/SOF FDC Tablet 
LDV (N=42 reference/N=39 test) 
AUC~as~ (h*ng/mL) 
7362.3 (48.3) 
6242.5 (40.7) 
87.76 (77.94, 98.82) 
AUCinf (h *ng/mL) 
8467.5 (54.4) 
7088.4 (46.3) 
88.36 (78.43, 99.54) 
Cmax (ng/mL) 
261.3 (43.5) 
214.8 (38.2) 
84.59 (74.69, 95.81) 
GS-331007 (N=42 reference/N=42 test) 
AUC~as~ (h*ng/mL) 
11146.3 (26.9) 
11525.8 (26.3) 
103.14 (96.71, 110.00) 
AUCinf (h *ng/mL) 
11720.0 (26.1) 
12095.0 (24.4) 
103.64 (98.48, 109.07) 
Cmax (ng/mL) 
833.9 (23.6) 
951.9 (27 .0) 
112.81 (104. 12, 122.22) 
SOF (N=42 reference/N=42 test) 
AUC~as~ (h*ng/mL) 
1559.8 (40.5) 
1676.9 (43.7) 
102.13 (87.16, 119.67) 
AUCinf (h *ng/mL) 
1580.8 (40.2) 
1684.1 (43.5) 
101.60 (86.67, 119.10) 
Cmax (ng/mL) 
1221.0 (38.5) 
1266.7 (46.6) 
95.98 (78.00, 118.11) 
GS-566500 (N=42 reference/N=42 test) 
AUC~as~ (h*ng/mL) 
1846.6 (31.4) 
1952.9 (33.5) 
100.59 (88.89, 113.83) 
AUCinf (h *ng/mL) 
1894.9 (30.8) 
2009.7 (33.0) 
101.37 (90.17, 113.96) 
cmax (ng/mL) 
475.1 (33.9) 
511.3 (34.9) 
103.04 (91.06, 116.60) 
* Prin1a1y PK analysis set excluded subjects with pre-dose concentrations > 5% of Cmax for each period 
Data from the primruy analysis demonstrated modestly lower LDV exposure (~ 1 2%) in the 
LDV /SOF FDC oral granules as compared with the LDV /SOF FDC tablet, with the lower 
bounds of the 90% CI being approximately 75-78%. A slightly larger (20%) reduction in LDV 
was observed using sensitivity analysis that included data from all subjects. These modest 
decreases in exposure ru·e not considered to be clinically relevant based on the established 
exposure/efficacy relationship for LDV and LDV/SOF. 
GS-331007 exposure in the LDV/SOF FDC oral granules was bioequivalent to the LDV/SOF 
FDC tablets. PO 
CONFIDENTIAL 
Page 25 
04 November 2016 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
1.2.1.1.2. 
GS-US-337-2091 - Food Effect Evaluation 
Final 
Amendment 5.0 
Statistical comparisons of the primmy PK parameters AUCinf and AUC1ast for LDV, and 
GS-331 007 (the primmy circulating metabolite of SOF) are presented below following 
administration ofLDV/SOF oral granules (8 x 11.25 mg/50 
in fed state 
relative to a fasted state 
Table 1-2. 
Statistical Comparison of Pharmacokinetic Parameters for Food 
Effect Comparison - Test versus Reference Treatments (Primary PK 
analysis Set) 
Mean (OfoCV) 
OfoGLSM Ratio (90% CI) 
LDV/SOF FDC 
LDV/SOF FDC 
LDV/SOFFDC 
Oral Granules 
Oral Granules 
Oral Granules + 
High-Fat Meal 
Fasted 
High-Fat Meal 
VS 
PK Parameter 
(Reference) 
(Test) 
Fasted 
LDV(N=39 reference/N=40 test) 
AUC~as~ (h*ng/mL) 
6242.5 (40.7) 
5149.6 (26.2) 
87.62 (79.65, 96.39) 
AUCinf (h *ng/mL) 
7088.4 (46.3) 
5748.3 (29.0) 
87.06 (78.95, 96.00) 
Cmax (ng/mL) 
214.8 (38.2) 
159.8 (28.9) 
78.15 (71.26, 85.71) 
GS-331007 (N=42 reference/N=42 test) 
AUC1as1 (h*ng/mL) 
11525.8 (26.3) 
11653.6 (18.9) 
103.12 (97.61, 108.94) 
AUCinf (h *ng/mL) 
12095.0 (24.4) 
12220.6 (18.3) 
102.26 (98.18, 106.52) 
cmax (ng/mL) 
951.9 (27.0) 
583.1 (24.2) 
62.01 (56.90, 67.59) 
SOF (N=42 reference/N=42 test) 
AUC~as~ (h*ng/mL) 
1676.9 (43.7) 
2577.2 (33.1) 
166.11 (145.00, 190.30) 
AUCinf (h *ng/mL) 
1684.1 (43.5) 
2597.7 (32.9) 
166.18 (145.56, 189.71) 
Cmax (ng/mL) 
1266.7 (46.6) 
1236.3 (49.0) 
100.32 (84.83, 118.65) 
GS-566500 (N=42 reference/N=42 test) 
AUC~as~ (h*ng/mL) 
1952.9 (33.5) 
2931.7 (19.1) 
163.23 (144.62, 184.23) 
AUCinf (h *ng/mL) 
2009.7 (33.0) 
2988.8 (18.7) 
160.65 (143.40, 179.99) 
Cmax (ng/mL) 
511.3 (34.9) 
593.9 (31.0) 
122.12 (108.28, 137.73) 
* Prin1a1y PK analysis set excluded subjects with pre-dose concentrations > 5% of Cmax for each period 
CONFIDENTIAL 
Page 26 
04 November 2016 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Final 
Amendment 5.0 
With regards to food effect, the primruy and sensitivity analyses demonsu·ated that the 
prespecified equivalence criteria for LDV (70-143%) and GS-331007 (80-125%) AUC!astand 
AUCinrafter adminisu·ation ofLDV/SOF FDC oral granules with a high-fat/hi h-calorie meal 
comj)ru·ed with fasted adminisu·ation were met. PO 
1.2.1.2. 
GS-US-337-1116 
Preliminruy data are available for the cunent study in adolescent subjects Coh01i 1 (12 to < 18 
yeru·s of age; N=10) and pediau·ic subjects Cohort 2 (6 to <12 yeru·s of age; N=12) who enrolled 
in the PK Lead-in Phase and received an adult clinical dose ofLDV/SOF FDC 90 mg/ 400 mg or 
a reduced dose ofLDV/SOF FDC 45 mg/200 mg, respectively. Of note, 2 out of 12 subjects 
(subjectPPO 
and PO 
in Coh01i 2 en oneously received a dose of90 mg/ 400 mg LDV/SOF 
FDC dming the PK Lead-in Phase: Subject PO 
received 90 mg/ 400 mg from Day 1 through 
Day 10 and Subject P O 
received 90 mg/ 400 mg from Day 1 through Day 4 followed by the 
con ect dose of 45 mg/ 200 mg for the remainder of the PK Lead-in Phase (Day 5 through Day 
10). 
Evaluation of PK in Coh01i 2 subjects was conducted using data from all 12 subjects; observed 
LDV, SOF, and GS-331007 (primruy SOF metabolite) exposmes on Day 10 were used for 
Subject P O 
and exposmes were scaled to 45 mg/ 200 mg for Subject PPO 
(Table 1-4). 
Mean exposmes of LDV, SOF, and GS-331007 in Coh01i 1 and 2 subjects were compru·able to 
observed exposmes in the adult subjects in the Phase 2/3 LDV/SOF FDC clinical progrrun; 
thereby confirming the appropriateness of the adult dose (90 mg/ 400 mg) in the adolescent 
population (12 to < 18 yeru·s of age) and 45 mg/ 200 mg in pediau·ic patients (6 to < 12 yeru·s of 
age) Table 1-3 and Table 1-4. The appropriateness of the 90 mg/ 400 mg LDV/SOF FDC dose in 
adolescents and 45 mg/ 200 mg LDV /SOF FDC dose in the pediau·ic patients is fmi her 
supported by available safety and efficacy data in the u·eatment phases of the study. 
CONFIDENTIAL 
Page 27 
04 November 2016 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 28
04 November 2016
Table 1-3.
Steady-state PK and Statistical Comparisons of LDV, SOF and 
GS-331007 PK in Adolescent Subjects (PK Lead-in) and Adult 
Subjects (Phase 2/3 Population PK Analysis)
Mean (%CV)
Adolescents (N=10)
Phase 2/3 (N=2113)
GMR% (90% CI)
LDV
AUCtau (ng*hr/ml)
10200 (50.9)
8530 (60.8)
127 (94.9, 170)
Cmax (ng/ml)
564 (41.2)
364 (51.4)
162 (125, 209)
Ctau (ng/ml)
319 (71.5)
247 (59.2)
128 (95.2, 172)
SOF*
AUCtau (ng*hr/ml)
2180 (26.6)
1380 (34.0)
160 (138, 185)
Cmax (ng/ml)
1140 (57.2)
659 (34.0)
156 (127, 190)
GS-331007
AUCtau (ng*hr/ml)
12700 (13.7)
12500 (29.2)
105 (90.6, 122)
Cmax (ng/ml)
1010 (21.5)
736 (28.2)
139 (120, 161)
Data reported to 3 significant figures; *N=1542
Table 1-4.
Steady-state PK and Statistical Comparisons of LDV, SOF and 
GS-331007 PK in Pediatric Cohort 2 Subjects (6 to <12 years old; PK 
Lead-in) and Adult Subjects (Phase 2/3 Population PK Analysis)
Mean (%CV)
Pediatrics (N=12)**
Phase 2/3 (N=2113)
GMR% (90% CI)
LDV
AUCtau (ng*hr/ml)
7520 (58.0)
8530 (60.8)
86.9 (66.5, 114)
Cmax (ng/ml)
432 (51.3)
364 (51.4)
116 (92.1, 147)
Ctau (ng/ml)
248 (67.5)
247 (59.2)
91.1 (69.5, 120)
SOF*
AUCtau (ng*hr/ml)
1600 (29.7)
1380 (34.0)
116 (101, 133)
Cmax (ng/ml)
906 (36.0)
659 (34.0)
139 (116, 167)
GS-331007
AUCtau (ng*hr/ml)
8140 (31.6)
12500 (29.2)
65.2 (56.9, 74.7)
Cmax (ng/ml)
772 (24.4)
736 (28.2)
106 (92.8, 122)
Data reported to 3 significant figures; *N=1542 (Phase 2/3), ** Similar results were observed following exclusion of subjects 
 and 
 who received LDV/SOF 90 mg/400 mg during the PK-Lead-in
PPD
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 29
04 November 2016
Please refer to the Investigator’s Brochure (IB) for additional information on the LDV/SOF FDC 
including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA 
and DNA viruses {Roche Laboratories Inc. 2010}, {Roche Products Limited 2010}. Ribavirin 
monotherapy has little or no effect on the replication of HCV but can result in normalization of 
serum ALT activity and improvement in liver histology. When combined with interferon or PEG 
therapy, RBV decreases substantially the relapse rate seen after cessation of interferon therapy 
{Poynard et al 1998}, {McHutchison et al 1998}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to accumulate 
intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, extreme care 
must be taken to avoid pregnancy during RBV therapy and for up to 7 months following 
completion of treatment.  A comprehensive review of RBV is contained in the package 
insert/SmPC.
1.4.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy, pharmacokinetics, and safety of treatment 
with LDV/SOF FDC +/- RBV for adolescents and children with chronic HCV-infection. 
Currently PEG and weight-based RBV are considered the SOC for the treatment of 
HCV-infection in children. Therefore, there is a need for new treatments for HCV in the 
pediatric population that combine potent and sustained efficacy with improved tolerability and 
safety. The primary aim for new treatments of pediatric patients with HCV is to eliminate the 
need to use PEG. In this way, pediatric patients would be able to avoid the necessity of weekly 
injections which can be traumatic and burdensome, and significantly reduce the serious adverse 
events seen with PEG administration. The secondary aim is to eliminate RBV and the adverse 
events seen with its administration within HCV infected subjects.
Harvoni® (LDV/SOF FDC) is approved in the US and EU for the treatment of adults with 
chronic HCV infection. LDV/SOF FDC +/- RBV would provide an all-oral, IFN-free regimen 
with a shorter treatment duration (12 or 24 weeks of LDV/SOF FDC +/- RBV treatment versus 
standard-of-care 24 to 48 weeks of treatment) for GT-1, -3, -4, -5, and -6 HCV infected patients
and would offer another important option in the treatment of HCV infection in the pediatric 
population.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 30
04 November 2016
In vitro viral replicon assay has data demonstrating LDV has potent, antiviral activity against all 
HCV genotypes. In the LDV/SOF FDC phase 3 program, LDV/SOF FDC without RBV has 
been shown to have good efficacy and safety in adults infected with GT-1 HCV infection.  In the 
GS-US-337-0102 (ION-1), GS-US-337-1119, and CO-US-337-0117 studies, LDV/SOF FDC 
without RBV has been shown to have good efficacy and safety in adults infected with GT-4
HCV-infection. In study GS-US-337-0122, a phase 2 open-label study of GT-3 treatment-naïve
adult subjects with and without cirrhosis, LDV/SOF FDC for 12 weeks resulted in an SVR12 of 
64% whereas LDV/SOF + RBV for 12 weeks resulted in an SVR of 100% {Gane et al 2014}. 
The clinical data to support the use of Harvoni® in patients infected with HCV GT-3 are limited.
As a result, the current study includes a 24-week RBV treatment regimen for only treatment-
experienced pediatric subjects with GT-3 HCV-infection.
Considering that SOF has pan-genotypic activity and LDV has in vitro, picomolar to nanomolar 
antiviral activity against certain subtypes within GT 4-6 and sub-micromolar antiviral activity 
against certain subtypes within GT-2, studies in patients with GT-5 and GT-6 HCV have been 
completed and used to support treatment recommendations for the use of LDV/SOF FDC in 
adults infected with GT-5 and GT-6 HCV in both the US and EU. In studies GS-US-337-1119 
and GS-US-337-0122, LDV/SOF FDC for 12 weeks resulted in SVR12 rates of 93% and 96% in 
GT-5 and GT-6 HCV, respectively. Based on these clinical data pediatric subjects with GT-5 and 
GT-6 infection are eligible for enrollment into this clinical study.
If emerging LDV/SOF FDC data in GT-2 HCV infected subjects support treatment in adults,
pediatric subjects with GT-2, will be enrolled in the current study.  Of note, there is an ongoing 
study enrolling GT-2 (and GT-3) pediatric patients, GS-US-334-1112, for treatment with SOF + 
RBV for 12 and 24 weeks, respectively.
1.5.
Rationale for Dose Selection of LDV/SOF FDC
Ledipasvir /Sofosbuvir (90 mg/ 400 mg) fixed-dose combination tablet +/- RBV has 
demonstrated favorable safety and efficacy profiles in over 3000 HCV-infected subjects across 
different patient populations in Phase 2 and 3 clinical trials. These doses represent the marketed 
dose of a ledipasvir/sofosbuvir fixed-dose combination tablet for the treatment of HCV-infection
in adults.
Selection of doses of LDV/SOF FDC +/- RBV for adolescents and younger age groups will 
target systemic exposures similar to those observed in adults at the proposed marketed dose. 
LDV and SOF are substrates for efflux drug transporters P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP). LDV is also a subject to slow oxidative metabolism via an unknown 
mechanism. SOF is extensively metabolized to the pharmacologically active nucleoside analog 
phosphate. The activation pathway involves hydrolysis by intestinal and hepatically expressed 
carboxylesterase (CES1) and Cathepsin A (CatA) enzymes {Yang et al 2009}, {Zhu et al 2009}.  
SOF is also converted to GS-331007, an inactive circulating metabolite, which is eliminated 
renally by active tubular secretion and glomerular filtration.  Available data suggest comparable 
hepatic expression of CES1 in adolescents and adults with modestly decreased expression in 
children.  However, little is known about the developmental regulation of Pgp, CES, and CatA.  


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 31
04 November 2016
When adjusted for BSA, the processes of active secretion and glomerular filtration approximate 
adult activity by 6 to 12 months of age {Kearns et al 2003}. 
The adult clinical dose of LDV/SOF FDC (90 mg/ 400 mg) was evaluated in adolescent subjects 
(12 to <18 years old) while a lower LDV/SOF FDC (45 mg/ 200 mg) is being evaluated in 
children (6 to <12 years old), respectively.  The appropriateness of these doses are supported by 
data from the Cohort 1 and Cohort 2 PK Lead-in Phase which demonstrated comparable LDV, 
SOF, and GS-331007 exposures in adolescent subjects who received LDV/SOF FDC (90 mg/
400 mg) or children who received LDV/SOF FDC (45 mg/ 200 mg) compared to adult subjects 
in Phase 2/3 population PK analyses.
In Cohort 3 (3 to < 6 years of age), a dose of LDV/SOF FDC (45 mg/ 200 mg) administered as 
granules is proposed for evaluation in children weighing ≥ 17 kg, whereas a lower LDV/SOF
FDC granules dose (33.75 mg/ 150 mg) is proposed for evaluation in children weighing < 17 kg. 
These proposed doses are supported by scaling of adult exposures based on correlations between 
body weight and clearance capacity (liver volume/size for LDV and SOF, and renal capacity for 
GS-331007) for the expected body weight range in children (3 to < 6  years of age), and the 
results of the relative bioavailability Phase 1 evaluation of LDV/SOF FDC oral granules  
(GS-US-337-2091), as presented in Figure 1-1 {Fanta et al 2007}, {Kearns et al 2003}. Based on 
this scaling approach, doses of LDV/SOF FDC oral granules (45 mg/ 200 mg) in children
≥17 kg and LDV/SOF FDC granules (33.75 mg/ 150 mg) in children < 17 kg are expected to 
achieve mean systemic exposures of LDV, SOF, and GS-331007 within the range of those
observed in the Phase 2/3 population (Figure 1-1). Safety and PK data in children (3 to < 6 years 
of age) who enroll in the PK-Lead-in Phase will be evaluated to confirm the appropriateness of 
the dose for this age group.


LDVISOFFDC 
Protocol GS-US-337-1116 
Final 
Gilead Sciences, Inc. 
Amendment 5.0 
Figure 1-1. 
Predicted LDV, SOF, and GS-331007 AUCtau following 
administration ofLDV/SOF FDC 45 mg/ 200 mg or LDV/SOF FDC 
33.75 mg/ 150 mg (3 to< 6 years of age) 
~ 
Cl> 
iii 
u 
~ 
-!!!.e 
"1:: 
S.c: 
g •CI 
<(.S 
u. 
0 
5000 
Predicted SOF exposure 
150 mg SOF 
200 mg SOF 
(<17 kg) 
(;:::17 kg) 
•••••••••·t•·•••••••••••••••••••••••••••••••••••••••••• max 
I 
I 
95th %ile 
C/) 
1000 
Q3 
median 
Q1 
~ 
.S! 
"' 
u 
.!!!.. 
5th%ile 
500 
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10 12 14 161718 20 22 24 26 28 30 32 34 36 38 40 42 44 
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CONFIDENTIAL 
Page 32 
04 November 2016 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Predicted LDV exposure 
33.75 mg LDV 
45 mg LDV 
50000 
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(2:17 kg) 
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Overall Risk/Benefit Assessment 
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Final 
Amendment 5. 0 
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Although the majority of pediatric patients infected with HCV exhibit minimal hepatic sequelae 
despite active viral replication and inflammation, a subset of children and adolescents will 
require treatment. Studies suggest that 3 major categories of disease can occur within 10 years 
after putative HCV exposure: (1) undetectable viremia and nmmal ALT, (2) persistent yet 
uncomplicated mild liver disease, and (3) progression to end-stage liver disease {Bertolotti et al 
2008}. It is the last two groups of children in whom therapy may be indicated to prevent end-
stage disease, either during childhood/adolescence or in eady adulthood. 
Given that the ClUTent SOC for the treatment of children infected with HCV is PEG and RBV 
and these regimens aTe long in duration, relatively toxic, and not well tolerated, there continues 
to be a need for new treatments for HCV that combine potent and sustained efficacy with 
improved tolerability and safety. 
The combination ofLDV plus SOF is anticipated to offer greater antiviral efficacy which could 
result in a shmier treatment duration and/or lead to a regimen without RBV or interferon. These 
in tum could result in reduction in adverse events. LDV/SOF FDC could also potentially be of 
benefit in patients who have failed prior treatment with SOF+/-RBV+/- PEG. 
If high rates of SVR can be obtained with shmt, well-tolerated regimens, the anticipated 
improvements in safety and tolerability would offer a favorable risk-benefit detetmination for 
individuals with chronic HCV-infection. 
CONFIDENTIAL 
Page 33 
04 November 2016 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
2. 
OBJECTIVES 
The prima1y objective of the PK Lead-in Phase of this study is: 
Final 
Amendment 5.0 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose ofLDV/SOF FDC 
in chronic HCV-infected pediatric subjects 
The secondruy objective of the PK Lead-in Phase of this study is: 
• 
To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing ofLDV/SOF 
FDC in chronic HCV -infected pediatric subjects 
The primary objective of the Treatment Phase of this study is: 
• 
To evaluate the safety and tolerability ofLDV/SOF FDC +/- RBV for 12 or 24 weeks in 
chronic HCV -infected pediatric subjects 
The secondruy objectives of the Treatment Phase of this study ru·e: 
• 
To dete1mine the antiviral efficacy of 12 or 24 weeks ofLDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects (including the impact of HCV genotype, IL28B genotype, 
and prior treatment experience), as assessed by the prop01iion of subjects with SVR 
12 weeks after completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of 12 or 24 weeks ofLDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment 
• 
To evaluate the effect of growth and development on pediatric subjects during and after 
treatment 
The explorat01y objective of this study is: 
• 
PD 
CONFIDENTIAL 
Page 34 
04 November 2016 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 35
04 November 2016
3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and antiviral 
activity of LDV/SOF FDC +/- RBV in chronic HCV-infected pediatric subjects.
3.1.1.
PK Lead-in Phase
The PK Lead-in Phase will evaluate and/or confirm the age appropriate LDV/SOF FDC dose by 
analyzing PK, safety, and antiviral activity of LDV/SOF FDC through 10 days of dosing for each 
cohort. Children aged 3 to < 6 years, children aged 6 to < 12 years, and adolescents 
aged 12 to < 18 years with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry 
will be evaluated. Subjects must be treatment naïve without history of cirrhosis to participate in 
the PK Lead-in Phase. Three cohorts of at least 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old, weighing ≥45kg

Cohort 2:  6 to < 12 years old, weighing ≥ 17 kg and < 45 kg

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive LDV/SOF FDC (90 mg/ 400 mg 
adult tablet or 4 x 22.5 mg/100 mg tablets if determined necessary based on LDV/SOF FDC
swallowability assessment) for 10 days with intensive PK conducted on Day 10. 
Cohort 2: Subjects will receive LDV/SOF FDC 45 mg/ 200 mg (2 x 22.5 mg/ 100 mg tablets) for 
10 days with intensive PK conducted on Day 10.
Cohort 3: Subjects will receive LDV/SOF FDC oral granules; subjects weighing ≥17 kg will 
receive LDV/SOF FDC 45 mg/ 200 mg (4 x 11.25 mg/ 50 mg packets) and subjects weighing 
<17 kg will receive LDV/SOF FDC 33.75 mg/ 150 mg (3 x 11.25 mg/ 50 mg packets) for 
10 days with intensive PK assessments conducted on Day 10.
Subjects enrolled in the PK Lead-in Phase of each cohort (Cohorts 1, 2, and 3) will immediately 
enroll in the Treatment Phase as they complete Day 10 of PK Lead-in Phase.  They will continue 
dosing with LDV/SOF FDC with no interruption of study drug administration.  Subjects rolling 
over from the PK Lead-in Phase will not be required to perform the screening, Day 1, or Week 1 
visit of the Treatment Phase.


LDV/SOF FDC
Protocol GS-US-337-1116
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Gilead Sciences, Inc.
Amendment 5.0
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Figure 3-1.
PK Lead-in Phase Study Schema
3.1.2.
Treatment Phase
The Treatment Phase will be initiated sequentially by age group as defined in Cohort 1, 2, and 3 
of the PK Lead-in. Subjects who participated in PK Lead-in phase will immediately rollover into 
Treatment Phase with no interruption of study drug administration until the appropriateness of 
the dose has been confirmed by PK and safety results from the PK Lead-in.  The first visit in the 
Treatment Phase for these subjects will be the Week 2 visit.  Additional subjects will be enrolled 
in the Treatment Phase of each Cohort upon confirmation of the appropriateness of the dose from 
the PK Lead-in.
Children aged 3 to < 12 years (Group 2) and adolescents aged 12 to < 18 years (Group 1) with 
chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry (those who were dosed in 
the PK Lead-in phase will have met this criteria prior to enrollment) will be evaluated.
Subjects enrolled in the Treatment Phase will receive the following regimen:
a) United Kingdom:
GT-1, GT-4, GT-5, & GT-6 treatment-naïve subjects with or without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1, GT-4, GT-5, & GT-6 treatment-experienced subjects without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1, GT-4, GT-5, & GT-6 treatment-experienced subjects with cirrhosis: LDV/SOF 
FDC for 24 weeks
GT-3 treatment-experienced subjects with or without cirrhosis: LDV/SOF FDC + RBV 
for 24 weeks


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Gilead Sciences, Inc.
Amendment 5.0
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b) United States/Australia/New Zealand:
GT-1 treatment-naïve subjects with or without cirrhosis: LDV/SOF FDC for 12 weeks
GT-1 treatment-experienced subjects without cirrhosis: LDV/SOF FDC for 12 weeks
GT-1 treatment-experienced subjects with cirrhosis: LDV/SOF FDC for 24 weeks
GT-4, GT-5, & GT-6 treatment-naïve or treatment-experienced subjects with or without 
cirrhosis: LDV/SOF FDC for 12 weeks
Table 3-1.
Subject Enrollment by HCV Genotype, Country, and Treatment 
Duration
GT-1
GT-3
GT-4, GT-5, & GT-6
Cirrhotic 
or 
Non-
cirrhotic 
Subjects 
(TN)
Non -
cirrhotic 
Subjects 
(TE)
Cirrhotic 
Subjects 
(TE)
Non-
cirrhotic 
or 
Cirrhotic 
Subjects 
(TE)
Cirrhotic 
or 
Non-
cirrhotic 
Subjects 
(TN)
Non-
cirrhotic 
Subjects 
(TE)
Cirrhotic 
Subjects 
(TE)
United 
States
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
N/A
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
Australia
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
N/A
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
New 
Zealand
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
N/A
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
United 
Kingdom
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC + 
RBV
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
TN = Treatment Naïve, TE = Treatment Experienced, N/A = Not Applicable


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
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04 November 2016
Subjects with GT -1, -3, and -4 were enrolled initially. GT-5 and GT-6 subjects will be included 
in those groups/cohorts actively enrolling subjects given confirmation of benefit:risk in adult 
patients has been obtained. If emerging LDV/SOF FDC data in GT-2 support treatment in adults,
pediatric subjects with GT-2 will be subsequently enrolled.  
The study will enroll both treatment naïve and treatment experienced pediatric subjects with up 
to 40 subjects allowed to be treatment experienced. Approximately 200 total subjects, including 
subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as follows:

Group 1: Approximately 100 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 100 pediatric subjects (3 to < 12 years of age)
The following definitions will be used for treatment experienced subjects:

Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to ≥1 adverse 
event

Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels while 
on treatment

Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment or 
within 4 weeks of the end of treatment but did not achieve a sustained virologic response 
(SVR)
All subjects who do not attain SVR or have viral relapse will be encouraged to discuss treatment 
with SOC therapy with their healthcare provider.
3.2.
Visit Schedule
3.2.1.
PK Lead-in
Screening assessments will be completed within 28 days of the Day 1 visit. 
Study Visits will occur at Screening, Day 1, Day 3, and Day 10.
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in Phase will participate in an 
intensive PK evaluation on Day 10. Subjects will be administered a dosing diary with 
instructions.  
Following completion of the Day 10 intensive PK visit, subjects will then return for scheduled 
study visits outlined in the Treatment Phase and continue dosing with LDV/SOF FDC with no 
interruption of study drug administration.  Subjects rolling over from the PK Lead-in Phase will 
not be required to perform the screening, Day 1, or Week 1 visits of the Treatment Phase.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 39
04 November 2016
3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. Subjects continuing 
from the PK Lead-in Phase will not be required to complete Screening, Day 1, and Week 1 visits 
of the Treatment Phase.

Subjects requiring 12 weeks of treatment: Study visits will occur at Screening, Day 1, and 
the end of weeks 1, 2, 4, 8, and 12.

Subjects requiring 24 weeks of treatment: Study visits will occur at Screening, Day 1, and 
the end of weeks 1, 2, 4, 8, 12, 16, 20, and 24.
All subjects will then return for follow-up visits at 4, 12, and 24 weeks after discontinuation of
therapy.
The total time to complete all study visits is approximately 40 or 52 weeks including:

28 day (4 week) screening period

12 or 24 week treatment period

24 week post-treatment period
The assessments performed at each visit are described in Section 6.
3.3.
Virologic Response-Based Stopping Criteria
HCV RNA will be unblinded to the Investigator and Sponsor.
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 from nadir 

HCV RNA ≥LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination of 
initial observation.  Subjects that meet the virologic response-based stopping criteria above will 
be notified of their eligibility to participate in the Long-Term Follow-Up Study 
(GS-US-334-1113).
3.4.
Treatment Discontinuations Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances:

Unacceptable toxicity (as defined in Section 7) 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.


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
• 
Pregnancy of female subject or female partner of male subject. 
• 
Efficacy failure as defined in Section 3.3. 
Final 
Amendment 5.0 
• 
Significant protocol violation including non-compliance with study assessments. 
• 
Subject request to discontinue for any reason; it is imp01t ant to detennine 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, regulat01y agency, or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). 
3.5. 
Discontinuations 
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Termination visit as described in the Section 6.4.8. 
Subjects who pennanently discontinue the study dmg for any reason including safety and/or 
tolerability concems prior to completion of the assigned dosing period will be followed 
according to the post-u·eatment study assessments described in Section 6.5. 
3.6. 
Pharmacogenomic Substudy 
3.7. 
Long-Term Follow-Up 
All subjects (those who do or do not attain SVR24) who do not initiate other experimental or 
approved anti-HCV therapy will be followed eve1y 6 months for the first 2 years followed by 
every 12 months for assessments of growth, quality of life, and long-te1m viral suppression (if 
applicable) in a separate protocol (GS-US-334-1113). This follow-up study will continue for 5 
years. 
3.8. 
Breakthrough Futility Assessment 
A futility assessment will be perf01m ed after the first 10 subjects complete Week 8 on study or 
have viral breakthrough at or prior to Week 8. If3 or more of the first 10 subjects emolled have 
viral breakthrough at or prior to Week 8 or are non-responders (HCV RNA 2: LLOQ through 
8 weeks of u·eahnent) then fmther emollment of subjects will be suspended. Virologic 
breakthrough is defined as confnmed HCV RNA 2: LLOQ while on u·eatment after 
two consecutive visits with HCV RNA < LLOQ. 
CONFIDENTIAL 
Page40 
04 November 2016 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 41
04 November 2016
If a holding rule has been met and following an internal safety review it is deemed appropriate to 
restart enrollment, a request to restart enrollment with pertinent data will be submitted to the 
appropriate regulatory agencies.  Enrollment will only resume after review by the appropriate 
regulatory agencies.  Any subject on treatment when a holding rule has been met will be allowed 
to continue to treatment.
Subjects with known or suspected study drug non-adherence will not be considered to meet the 
definition of virologic breakthrough, relapse, or non-responder. 
3.9.
Reconsent
When a subject reaches the age of consent in their country/region, they will be invited to consent 
as an adult to allow them to continue participating in the clinical trial.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 42
04 November 2016
4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 200 subjects will be enrolled in this study.
In order to manage the total study enrollment, Gilead Sciences, Inc. at its sole discretion, may 
suspend screening and/or discontinue the enrollment at any site at any time (upon written notice 
to the site). Discontinuation of the enrollment phase may result in the immediate ineligibility of 
all subjects screened but not yet enrolled, regardless of the progress or outcome of the screening 
assessments performed.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1. Parent or legal guardian able to provide written informed consent prior to any screening 
evaluations and willing to comply with study requirements.  Subjects will provide assent if 
possible.
2. 3 years to < 18 years of age as determined at Day 1 (consent of parent or legal guardian 
required)
3. PK Lead-in phase only: subjects in Cohort 1 (age 12 to <18 years of age) must weigh 45 kg
4. PK Lead-in phase only: subjects in Cohort 2 (age 6 to <12 years of age) must weigh 17 kg
and < 45 kg
5. PK Lead-in phase only: all subjects must be treatment naïve: no prior exposure to any IFN, 
RBV, or other approved or experimental HCV-specific DAA agent
6. Treatment experienced subjects:  prior treatment failure to a regimen including interferon 
either with or without RBV that was completed at least 8 weeks prior to Day 1.
i.
Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to 
≥1 adverse event
ii.
Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels 
while on treatment
iii.
Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment 
or within 4 weeks of the end of treatment but did not achieve a sustained virologic 
response (SVR)
7. 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 Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV-infection


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 43
04 November 2016
8. Infection with HCV as determined at Screening:
a) United Kingdom Only: As of Protocol Amendment 4.0, the study is enrolling GT-1, -3, -
4, -5, and -6 HCV-infected pediatric subjects and will subsequently enroll subjects with 
GT-2 once adult data is available, if appropriate.
b) United States/ Australia/ New Zealand Only: As of Protocol Amendment 4.0, the study is 
enrolling GT-1, -4, -5, and -6 HCV-infected pediatric subjects and will subsequently 
enroll subjects with GT-2 once adult data is available, if appropriate.
9. HCV RNA ≥1000 IU/mL at Screening
10. Adequate hematologic function (absolute neutrophil count 1,500/mm3; 
hemoglobin 11 g/dL or 12 g/dL for GT-3 males only).
11. Negative serum -HCG pregnancy test (for females of childbearing potential only, as defined 
in Appendix 5)
12. Subject able to provide written assent, if they have the ability to read and write, as 
determined by IRB/IEC/local requirements and Investigator’s discretion
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Pregnant or lactating subjects
2. Sexually-active males or females of childbearing potential who are not willing to use an 
effective method of contraception during the study (see Appendix 5 for further details)
3. Treatment-naïve subjects with GT-3 HCV infection as determined at Screening. Treatment 
naïve is define by no prior exposure to any IFN, RBV, or other approved or experimental 
HCV-specific DAA agent
4. Decompensated liver disease defined as INR 1.2 ULN, platelets 50,000/mm3, serum 
albumin 3.5 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, 
jaundice, encephalopathy, variceal hemorrhage)
5. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
6. -fetoprotein 50 ng/mL
7. Serum creatinine > 1.5 mg/dL
8. Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 44
04 November 2016
9. Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of 
certain resolved skin cancers)
10. Co-infection with HIV, acute HAV, or HBV (i.e Hepatitis B Surface Ag positive at 
screening)
11. Significant cardiovascular, pulmonary, or neurological disease
12. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications
13. History of solid organ or bone marrow transplantation
14. Chronic daily non-steroidal anti-inflammatory drug therapy
15. Systemic corticosteroid use for > 2 weeks (pulmonary/nasal administration is permitted)
16. Investigational agents taken within the past 28 days (except with the expressed approval of 
the Sponsor)
17. Clinically-relevant alcohol or drug abuse within 12 months of screening.  A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator
18. Known hypersensitivity to the study drug, the metabolites, or formulation excipients
19. Any other condition (including alcohol or substance abuse) or prior therapy that, in the 
opinion of the Investigator, would make the subject unsuitable for the study or unable to 
comply with dosing requirements
20. Use of any prohibited concomitant medications as described in Section 5.6
21. PK Lead-in phase only: subjects with history of cirrhosis (as determined by liver biopsy)
22. 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 enrollment or has not required medication in the last 12 months may be 
included.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 5.0
CONFIDENTIAL
Page 45
04 November 2016
5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
5.2.1.
Description and Handling 
5.2.1.1.
Formulations
5.2.1.1.1.
LDV/SOF FDC 90 mg/ 400 mg tablets
LDV/SOF FDC 90 mg/400 mg tablets are orange, diamond-shaped, film-coated tablets 
containing 90 mg of LDV and 400 mg of SOF. The tablets are debossed with “GSI” on one side 
and “7985” on the other side. The LDV/SOF 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.
Placebo to match LDV/SOF FDC 90 mg/ 400 mg tablets for the Swallowability Assessment are 
orange, diamond-shaped, film-coated tablets debossed with “GSI” on one side and “7985” on the 
other side. The tablets contain lactose monohydrate, copovidone, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, 
polyethylene glycol, FD&C yellow # 6 /sunset yellow FCF aluminum lake.
5.2.1.1.2.
LDV/SOF FDC 22.5 mg/ 100 mg tablets 
Age-appropriate formulations of LDV/SOF FDC have been developed for subjects who are 
unable to swallow the LDV/SOF FDC 90 mg/ 400 mg tablets which include a lower dose 
strength tablet (LDV/SOF FDC 22.5 mg/100 mg) formulation. LDV/SOF FDC lower dose 
strength tablets are round, plain-faced, white film-coated tablets containing 22.5 mg of LDV and 
100 mg of SOF. The LDV/SOF FDC lower dose strength tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc,
and polyethylene glycol.
Placebo to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for the Swallowability Assessment 
are round, plain-faced, white film-coated tablets. The placebo tablets contain the following 
inactive ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc and 
polyethylene glycol.


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Amendment 5.0
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5.2.1.1.3.
LDV/SOF FDC Oral Granules
The LDV/SOF FDC oral granules 11.25 mg/ 50 mg are orange, round, film-coated granules. The 
LDV/SOF FDC oral granules contain the following inactive ingredients: lactose monohydrate, 
copovidone, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, hypromellose, talc, polyethylene glycol, titanium dioxide, iron oxide 
yellow, iron oxide red, and amino methacrylate copolymer.
5.2.1.2.
Packaging and Labeling
5.2.1.2.1.
LDV/SOF FDC 90 mg/ 400 mg tablets
LDV/ SOF FDC 90 mg/ 400 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 or 30 tablets, a silica gel desiccant, and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child resistant screw 
cap with an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 90 mg/ 400 mg tablets for the Swallowability 
Assessment are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 30 tablets, a silica gel desiccant and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child resistant screw cap with an induction-sealed, aluminum 
faced liner.
5.2.1.2.2.
LDV/SOF FDC 22.5 mg/ 100 mg tablets
LDV/SOF FDC 22.5 mg/ 100 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets, a silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child resistant screw cap with 
an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
a silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant screw cap with an induction-sealed, aluminum faced liner.
5.2.1.2.3.
LDV/SOF FDC oral granules
The LDV/SOF FDC 11.25 mg/ 50 mg oral granules are packaged in aluminum foil packets. A 
prespecified number of packets will be packaged into cartons for dispensation to subjects at 
clinical sites.
All LDV/SOF FDC tablets, oral granules, and placebo to match LDV/SOF FDC bottles to be 
distributed in the US, EU, and the rest of the countries shall be labeled to meet all applicable 
requirements of the US Food and Drug Administration (FDA), Annex 13 of Good Manufacturing 
Practices: Manufacture of investigational medicinal products (February 2010), and/or other local 
regulations as applicable.


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Amendment 5.0
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5.2.2.
Storage and Handling
LDV/ SOF FDC 90 mg/ 400 mg tablets, 22.5 mg/ 100 mg tablets, and 11.25 mg/ 50 mg packets
should be stored at controlled room temperature until required for administration. Controlled 
room temperature is defined as 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C 
(59 °F to 86 °F).
Placebo to match LDV/SOF FDC tablets, 90 mg/ 400 mg, and 22.5 mg/ 100 mg, for the 
Swallowability Assessment should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25 °C (77 °F); excursions are 
permitted between 15 °C and 30 °C (59 °F to 86 °F).  
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the 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 
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 
LDV/SOF FDC.
Sufficient quantities of LDV/SOF FDC tablets, oral granule packets, and placebo tablets will be 
shipped to the investigator or qualified designee from Gilead Sciences (or its designee).
5.2.3.
Dosage and Administration of LDV/SOF FDC
PK Lead-in Phase: 
Cohort 1: LDV/SOF FDC 90 mg/ 400 mg tablets will be administered once daily with or without 
food. Subjects determined unable to swallow the placebo to match the 90 mg/ 400 mg LDV/SOF 
FDC tablet (via LDV/SOF FDC Placebo Swallowability Assessment at Screening up to Day 1) 
will be re-assigned to 4 x 22.5 mg/ 100 mg tablets daily.  Subjects who weigh < 45 kg will be 
excluded.
Cohort 2: LDV/SOF FDC 2 x 22.5 mg/ 100 mg tablets will be administered once daily with or 
without food. Subjects must weigh ≥ 17 kg and < 45 kg.
Cohort 3: LDV/SOF FDC oral granules 45 mg/ 200 mg (4 x 11.25 mg/ 50 mg packets) will be 
administered once daily with or without food for subjects weighing ≥17kg. LDV/SOF FDC oral
granules 33.75 mg/ 150 mg (3 x 11.25 mg/ 50 mg packets) will be administered once daily with 
or without food for subjects weighing <17 kg.
Intensive PK and safety results from the PK Lead-in Phase of each cohort will be reviewed to 
confirm the appropriateness of the evaluated LDV/SOF FDC dose for the Treatment Phase of 
that cohort as well as to determine the age-appropriate dose to be evaluated in the PK Lead-in
phase of the next cohort.
Treatment Phase: Subjects who participated in the PK Lead-in Phase of each cohort will continue 
in the Treatment Phase with no interruption of study drug administration until the 


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appropriateness of the dose is confirmed by PK and safety data from the PK-Lead-in Phase.  
Additional subjects will be enrolled in the Treatment Phase of each cohort upon confirmation of 
the appropriateness of the dose.  
Subjects should be instructed that if vomiting occurs within 5 hours of dosing an additional tablet 
should be taken.  If vomiting occurs more than 5 hours after dosing, no further dose is needed.
If a dose is missed and it is within 18 hours of the normal time, subjects should be instructed to 
take the tablet as soon as possible and then subjects should take the next dose at the usual time.  
If it is after 18 hours then subjects should be instructed to wait and take the next dose at the usual 
time.  Subjects should be instructed not to take a double dose.
5.3.
Ribavirin (GT-3 Subjects Only)
5.3.1.
Description and Handling of RBV
5.3.1.1.
Formulation
REBETOL capsules consist of a white powder in a white, opaque, gelatin capsule. Each capsule 
contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose, lactose 
monohydrate (40 mg), croscarmellose sodium, and magnesium stearate. The capsule shell 
contains gelatin, titanium dioxide. The capsule shell imprint contains shellac, propylene glycol, 
ammonium hydroxide, coloring agent (E 132).The hard capsule is imprinted with blue ink.
REBETOL RBV Oral Solution 40 mg per mL is a clear, colorless to pale or light yellow bubble 
gum-flavored liquid. In addition to the active ingredient, RBV oral solution contains the 
following inactive ingredients: sucrose, glycerin, sorbitol, propylene glycol, sodium citrate, citric 
acid, sodium benzoate, natural and artificial flavor for bubble gum #15864, and water.
5.3.1.2.
Packaging and Labeling
The RBV capsules are packaged in blisters. Each blister card contains 20 capsules and seven 
cards (140 capsules) per carton.
The RBV oral solution is packaged in 4-oz amber glass bottles (100 mL/bottle) with 
child-resistant closures.
RBV capsules and oral solution to be distributed to centers in the US, EU and the rest of the 
countries shall be labeled to meet all applicable requirements of the US Food and Drug 
Administration (FDA) and Annex 13 of Good Manufacturing Practices: Manufacture of 
investigational medicinal products (February 2010) and/or other local regulations as applicable.
5.3.1.3.
Storage and Handling
RBV capsules should not be stored above 30C (86 F).
RBV oral solution should not be stored above 30°C (86°F).


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Amendment 5.0
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5.3.2.
Dosage and Administration of RBV (GT-3 Subjects Only)
RBV dose will be administered by weight as follows:
Body Weight kg (lbs.)
RBV Daily Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution.  Divided dose in the 
morning and evening.
47-49 (103-108)
600 mg/day
1 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
50-65 (110 – 143)
800 mg/day
2 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
66-80 (145 – 176)
1000 mg/day
2 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
81-105 (178-231)
1200 mg/day
3 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
>105 (>231)
1400 mg/day
3 x 200-mg capsules A.M.
4 x 200-mg capsules P.M.
*
Note:  Subjects with a body weight greater than or equal to 47 kg may utilize the RBV oral solution if necessary.
The morning dose of RBV will be taken with food and LDV/SOF FDC. The evening dose of 
RBV will be taken with food.
RBV will be supplied by Gilead Sciences for all subjects.
5.4.
Co-administration of LDV/SOF FDC and RBV (GT-3 Subjects Only)
In the Treatment Phase of the study, each subject will be given instructions to maintain 
approximately the same daily dosing interval between study drug doses.
For morning doses, subjects will be instructed to take study drugs as follows:

LDV/SOF FDC

Weight-based RBV (as per Section 5.3.2).
For evening doses, subjects will be instructed to take study drug as follows:

Weight-based RBV (as per Section 5.3.2).
If a subject forgets to take the study medication at the correct time, it may be taken later in the 
day; however, no more than the protocol specified dose of LDV/SOF FDC should be taken on 
any calendar day.  The subject should resume the standing dosing schedule on the next day. 
Study medications should not be cut or split.  


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Amendment 5.0
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5.5.
Study Drug Compliance
Subjects will be instructed to return any unused LDV/SOF FDC and/or RBV in the original 
container on Day 3 (PK Lead-in), Day 10 (PK Lead-in), and/or at study treatment visits every 
4 weeks (Treatment Phase).  
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.6.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 30 days 
after the last dose of study drug, need to be recorded in the source documents and electronic case 
report form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment:

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

Drugs disallowed per prescribing information of REBETOL® for GT-3 subjects only
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters i.e., P-gp) with study drug(s) may result in PK interactions resulting in 
increases or decreases in exposure of study drug(s). Examples of representative medications 
which are prohibited from 21 days prior to Day 1 through the end of treatment are listed 
below (Table 5-1). In addition, the use of amiodarone is prohibited from 60 days prior to 
Baseline/Day 1 through the end of treatment.


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Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton- Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsc
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Cardiac Medications
Amiodaronee
Digoxinb, Dabigatranb
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinaccea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsd
Rosuvastatin
Atorvastatin, Simvastatin, Pravastatin, 
Pitavastatin, Fluvastatin, Lovastatin
a.
It is recommended to separate antacid and LDV/SOF FDC administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF FDC at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with LDV/SOF FDC or up to 2 hours after taking LDV/SOF FDC. Proton-pump inhibitors should not be 
taken before LDV/SOF FDC. 
b.
May result in an increase in the concentration of study drug and/or concomitant medications. Co-administration of 
LDV/SOF FDC with digoxin or dabigatran may increase the concentration of digoxin or dabigatran. Caution is warranted 
and therapeutic concentration monitoring of digoxin or clinical monitoring of dabigatran is recommended when 
co-administered with LDV/SOF FDC. 
c.
May result in a decrease in the concentrations of study drug.
d.
Use with study drug 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.
e.
May result in symptomatic bradycardia. Mechanism is not currently known. The use of amiodarone is prohibited from 
60 days prior to Baseline/Day 1 through the end of treatment.
Medications for disease conditions excluded from the protocol (e.g., active cancer, 
transplantation) are not listed under this Concomitant Medication section and are disallowed in 
the study.


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Amendment 5.0
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6.
STUDY PROCEDURES
All subjects will complete screening, on-treatment, and post-treatment assessments. Screening 
assessments will be completed within 28 days of the Day 1 visit. The end of study will occur at 
the 24-week Post-Treatment visit. The schedule of assessments is described below. 
Information on the specific laboratory parameters to be measured and clinical assessments to be 
performed are provided in Section 6.6.
6.1.
Subject Enrollment 
Each candidate’s parent or legal guardian must sign an Informed Consent Form prior to the
conduct of any screening procedures. Each study candidate who has the ability to read and write
must sign an Assent Form, as required by IRB/IEC/local requirements, prior to the conduct of 
any study procedures. Screening evaluations will be used to determine the eligibility of each 
candidate for study enrollment. Candidates who fail to meet eligibility criteria by screening 
evaluations may be re-screened once ≥ 30 days after the initial screen if there is a reasonable 
expectation that the candidate will be eligible after repeat screening.
6.2.
Screening Assessments
6.2.1.
Screening Visit (Day –28 to Day 0)
Subjects will complete all screening assessments within 28 days of the Day 1 visit. The screening 
window can be extended to 42 days for subjects requiring additional HCV GT testing or for 
extenuating circumstances.
The following procedures will be performed and documented:

Written informed consent from parent or legal guardian and assent from subject, if applicable 
(see above)

Medical history, including:
Hepatitis C history
Hepatitis C treatment history
Family history (including height of parents, if known)
Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate) and body weight and height


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
Obtain blood samples for tests as listed in Section 6.6.1:
Hematology
Chemistry
Coagulation tests
HCV RNA
Determination of HCV viral GT and subtype
HCV antibody, HIV 1/2 antibody, HBV surface antigen (HBsAg), HBV surface antibody 
(HBsAb), HBV core antibody (HBcAb), and HAV antibody
HbA1c
TSH
IL28B
Serum -hCG pregnancy test for females of childbearing potential only
Alpha fetoprotein (AFP)
Alpha-1 anti-trypsin (ATT)

Obtain urine sample for:
Urinalysis
Urine Drug Screen

Review of concomitant medications

Ask subject and/or parent/legal guardian if the subject is able to swallow and tolerate taking 
pills.

Review of all inclusion and exclusion criteria

Perform LDV/SOF FDC swallowability assessment, as applicable 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the Day 1 visit assessments.


LDVISOFFDC 
Protocol GS-US-337-1116 
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6.3. 
PK Lead-in: Treatment Assessments 
6.3.1. 
Day l 
Final 
Amendment 5.0 
After confi1mation of eligibility has been evaluated, the following tests and procedures must be 
completed prior to emollment and dosing/dispensing on Day 1: 
• 
Perf01m complete physical examination 
• 
Tanner Pubertal Stage Assessment 
• 
Vital signs, including body weight and height measurements 
• 
A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pruiicipants (all subj ects ~ 12 yeru·s of age and subjects < 12 yeru·s of age at the discretion of 
the Investigator based on subject's pubertal status) 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (ru·chive) 
-
HBV DNA testing for subjects HBcAb positive at Screening 
_ 
PD 
• 
Obtain urine samples for the following procedures: 
-
Urinalysis 
-
~-hCG pregnancy test for females of childbearing potential only 
CONFIDENTIAL 
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
Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.
6.3.1.1.
Drug Administration

Dispense study drug(s) as directed by the IWRS

Instruct the subject on the packaging, storage and administration of study drug

Perform LDV/SOF FDC swallowability assessment (for subjects administered LDV/SOF 
FDC in tablet form only if not previously completed at screening).  Observe the subject 
taking the first dose of study drug (with or without food) and record the time of first dose

Subjects will be administered a dosing diary with instructions.
6.3.2.
Day 3
The following procedures/assessments are to be completed on Day 3:

Perform a symptom-directed physical examination as needed

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Review medication compliance with subject and/or subject’s parent/guardian

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 10 – Intensive PK 
The Day 10 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 10 Intensive PK visit may 
be performed within +3 days of the protocol-specified visit date (subjects will continue 
daily dosing through the Intensive PK Visit).


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Subjects should come in a fasted state for the Day 10 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 10 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 10 dose of LDV/SOF FDC must not be taken 
until the evaluations listed below are completed. 
If the subject has already dosed prior to the Day 10 clinic visit or is not in a fasted state, the 
Day 10 intensive PK assessments must not be completed. The subject and/or parents/guardians 
should be instructed to return in a fasted state within 3 days (Days 11, 12, or 13) for the intensive 
PK visit. 
If dosing non-compliance is identified as per subject dosing diary and study drug count on or 
prior to the Day 10 visit, the Day 10 intensive PK assessments must not be completed. The 
subject and/or parents/guardians should be counseled regarding proper dosing and be scheduled 
to return for the Day 10 intensive PK visit no sooner than 3 days following compliant dosing and 
no later than Day 14 (i.e., return on Day 13 or Day 14).  If dosing non-compliance is due to an 
AE, consultation with the Gilead Medical Monitor is required regarding the potential of 
rescheduling the Day 10 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded not 
to take the LDV/SOF FDC prior to arriving at the clinic on the day of the re-scheduled intensive 
PK visit. All Day 10 intensive PK assessments listed below should be completed when the 
subject returns.
The following evaluations are to be completed at the Day 10 Intensive PK visit:

Perform a symptom-directed physical examination 

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Perform study drug accountability 

Review Subject Dosing Diary

Review medication compliance with subject and/or parent/guardian.

Obtain urine samples for the following procedures:
Urinalysis
Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test 
is positive, the Intensive PK sampling will not be completed. The positive result will be 
confirmed with a serum pregnancy test. 

Obtain blood samples for the following laboratory analyses:


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Hematology 
Chemistry 
Coagulation tests
HCV RNA
Viral sequencing (archive)

Perform intensive PK sampling: 
Blood samples will be collected at 0 (predose, ≤30 minutes prior to dosing). After 
collection of the predose sample, subjects will be provided a standardized meal. Within 
5 minutes after consuming the standardized meal, subjects will be dosed with 
LDV/SOF FDC per dosing requirements.
Post-dose blood samples will be collected as follows: 
■
For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 5, 8, and 12 hours post-dose (with predose also 
serving as t= 24).
■
For Cohort 3 only: 0.5, 2, 4, 8, and 12 hours post-dose (with predose also serving as 
t = 24).
Subjects will be restricted from food intake until after collection of the 4-hour post dose 
blood sample, except for subjects in Cohort 3. Please also refer to the PK manual for 
details about standardized meals and PK sample processing instructions.
After completing the Day 10 intensive PK visit subjects will then continue to the Week 2 visit in 
Treatment Phase (described in Section 6.4.2) with no interruption in dosing.
6.4.
Treatment Phase: Treatment Assessments 
6.4.1.
Day 1
After confirmation of eligibility has been evaluated, the following tests and procedures must be 
completed prior to enrollment and dosing/dispensing on Day 1:

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements 

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Review of AEs and concomitant medications


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Amendment 5.0 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pmiicipants (all subj ects ~ 12 years of age and subjects < 12 yem·s of age at the discretion of 
the Investigator based on subject's pubertal status). 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemis1:Iy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (m·chive) 
-
HBV DNA testing for subjects HBcAb positive at Screening 
_ 
PD 
• 
Obtain urine sample for: 
-
Urinalysis 
-
~ -hCG pregnancy test for females of childbem·ing potential only 
• 
Subject completes quality of life survey: Subject is to review questionnaire with a 
pm·ent/gum·dian and write/mm·k answers directly onto the questionnaire 
• 
Perf01m LDV/SOF FDC swallowability assessment (for subjects administered 
LDV /SOF FDC in tablet f01m only if not previously completed at screening) 
6.4.1.1. 
Dmg Adminisu·ation 
• 
Dispense study dm g as directed by the IWRS 
• 
GT-3 subjects only: Ins1:Iuct the subject on the appropriate RBV dose after weight-based 
dosage is calculated using Day 1 weight 
• 
Ins1:Iuct the subject on the packaging, storage, and adminisu·ation of study dm g 
• 
Observe the subject taking the first dose of study dm g (with or without food) and record the 
time of fu st dose 
6.4.2. 
Weeks 1 and 2 (± 3 days) 
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Subjects who participated in the PK Lead-in phase will start study visits in the Treatment Phase
at Week 2.  The following procedures/assessments are to be completed at these visits:

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 
6.4.3.
Weeks 4 and 8 (3 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 
HBV DNA testing for subjects HBcAb positive at Screening


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
Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS
6.4.4.
Week 12 (3 days) - Subjects on 12 Week Treatment Regimen Only

Perform complete physical examination

Tanner Pubertal Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 
HBV DNA testing for subjects HBcAb positive at Screening

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.


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
Subjects should return all bottles of study drug at the Week 12 Visit
6.4.5.
Week 12 (3 days) - Subjects on 24 Week Treatment Regimen Only

Perform symptom-directed physical examination

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 
HBV DNA testing for subjects HBcAb positive at Screening

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS  
6.4.6.
Week 16 and 20 (3 days) – Subjects on 24 Week Treatment Regimen Only

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
Hematology
Chemistry
Coagulation tests
HCV RNA


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Viral sequencing (archive)
Single PK 
HBV DNA testing for subjects HBcAb positive at Screening

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS
6.4.7.
Week 24 (3 days) – Subjects on 24 Week Treatment Regimen Only

Perform complete physical examination

Tanner Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 
HBV DNA testing for subjects HBcAb positive at Screening

Obtain urine sample for:


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-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles and blister cards (if applicable) of study drug at the 
Week 24 Visit
6.4.8.
Unscheduled Visit/Early Termination Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments are at the investigator’s discretion.
The Sponsor/CRO should be informed when a subject comes off treatment due to an adverse 
event. If a subject discontinues treatment then the assessments outlined below should be 
performed.

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 
HBV DNA testing for subjects HBcAb positive at Screening


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
Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles and/or blister cards (if applicable) of study drug at the Early 
Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as described in 
Section 6.5.
6.5.
Post-Treatment Assessments
6.5.1.
4-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for: 
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)
HBV DNA testing for subjects HBcAb positive at Screening

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status) 
Female subjects of childbearing potential on treatment with LDV/SOF FDC + RBV should be 
provided with Urine Pregnancy Test-Kits, instructed on their use, and requested to continue to 
self-monitor for pregnancy for 6-months after their last dose of RBV. If required by local 


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regulations, additional pregnancy tests beyond 6 months may be added.  The subject should be 
contacted every 4 weeks and asked to report results of the urine pregnancy tests. If a positive 
urine pregnancy test is reported, the subject should return to the clinic for a serum pregnancy 
test.
6.5.2.
12-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements

Perform symptom-directed physical examination

Assessment of SAEs

Perform Tanner Pubertal Stage assessment

Obtain blood samples for 
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)
HBV DNA testing for subjects HBcAb positive at Screening

GT-3 subjects only: Obtain urine sample for -hCG pregnancy test for females of 
childbearing potential only

GT-3 subjects only: Pregnancy prevention counseling including partner pregnancy 
prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age 
at the discretion of the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire
6.5.3.
24-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of SAEs

Tanner Pubertal Stage Assessment

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Obtain blood samples for 


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HCV RNA
Viral sequencing (archive)
HBV DNA testing for subjects HBcAb positive at Screening

GT-3 subjects only: Obtain urine sample for -hCG pregnancy test for females of 
childbearing potential only

GT-3 subjects only: Pregnancy prevention counseling including partner pregnancy 
prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age 
at the discretion of the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire.
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed every 6 months for the first 
2 years followed by every 12 months for assessments of growth, quality of life, and long-term 
viral suppression (if applicable) in a separate protocol (GS-US-334-1113). This follow-up will 
continue for 5 years.
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), Glucose, 
Lipase, Potassium, Sodium, Gamma-glutamyl transferase (GGT), alpha fetoprotein (AFP), 
alpha-1 anti-trypsin, creatine kinase (CK) and amylase.
Urinalysis: Appearance, Blood, Color, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV and HBV (HBsAg, HBsAb, HBcAb) and HAV; serology 
for HIV (including reflex testing as necessary). HCV RNA will be measured using the COBAS®
AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System. HCV GT
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 GT should the 
above assays become unavailable.


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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 alternate assays 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum -hCG, Urine -hCG (if positive, requires immediate confirmation with 
Serum -hCG)
Additional Tests: Urine Drug Screen (for amphetimines, cocaine, methadone, opiates), 
Hemoglobin A1c (HbA1c), TSH (reflex Free T4), Alfa fetoprotein (AFP), Alpha-1 anti-trypsin
(AAT).
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. Parental heights will be recorded at Screening.
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; and neurological. 
6.6.4.
Tanner Pubertal Stage Assessment
The Tanner Stage scale is available in Appendix 4.  All subjects will receive a baseline Tanner 
Pubertal Stage Assessment. If the assessment determines that the subject is at a Tanner 5 at 
Day 1, no further Tanner Pubertal Stage Assessments are to be completed. 
6.6.5.
Height & Weight Measurement
Height and weight measurement will be collected at each study visit. The difference in body 
weight and height measurements between Day 1 and End of Treatment, post-treatment Week 12, 
and post-treatment Week 24 will be calculated.  
6.6.6.
Bone Age Assessment
A single X-ray of the left wrist, hand, and fingers will be performed at Day 1 Visit and 
post-treatment Week 24.  Local radiologist will determine bone age from x-ray.
6.6.7.
Swallowability Assessment
A LDV/SOF FDC swallowability assessment as applicable will be performed at screening up to 
Day 1. Subjects who have indicated that they can take tablets will be observed taking a placebo 
to match the 90 mg/ 400 mg LDV/SOF FDC tablet. This will confirm the swallowability of the 
90 mg/ 400 mg tablet size. If a subject is unable to swallow the 90 mg/ 400 mg LDV/SOF FDC 
tablet size, he/she will repeat the assessment with a placebo for the 22.5 mg/ 100 mg 


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LDV/SOF FDC tablet. If unable to swallow the 22.5 mg/ 100 mg LDV/SOF FDC tablet, the 
subject will be dosed with the oral granule formulation.
6.6.8.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.6.9.
Estimated Glomerular Filtration Rate (GFR)
Estimated Glomerular Filtration Rate (GFR) using Schwartz Formula (mL/min/1.73m2) = 
k L/Scr [(k is a proportionality constant, for adolescent females ≥12 years old is 0.55; for 
adolescent males ≥12 years old is 0.70; and for female and male children 3 to < 12 years old is 
0.55); L is height in centimeters (cm); and Scr is serum creatinine (mg/dL)]
6.6.10.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
Unused samples may be archived.
6.6.11.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every 4 weeks during the 
dosing period and for a minimum of 6 months following the last dose of RBV or for a minimum 
of 30 days following the last dose of LDV/SOF FDC if not taking RBV. If required by local 
regulations, additional pregnancy tests beyond 6 months for RBV or 30 days for subjects not 
taking RBV may be added. In the event of a positive urine pregnancy result, subjects will be 
instructed to stop study drug immediately (if applicable) and return to the clinic as soon as 
possible for a serum pregnancy test.
GT-3 subjects only: Pregnancy test kits will be dispensed to female subjects of child bearing 
potential at the 4 Week Post-Treatment visit. The subject will be contacted by telephone monthly 
to confirm that urine pregnancy testing has been performed post-treatment and to record the 
outcome. Alternatively, if required by local regulations or preferred by the investigator or 
subject, the subject may return to the clinic for urine pregnancy tests.


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6.6.12.
Quality of Life Survey (PedsQL™)
The PedsQL ™Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be completed at 
Day 1, End of Treatment, Early Termination (if applicable), 12-Week Post-Treatment, and 
24-Week Post-Treatment visits.  
The PedsQL ™  has separate survey instruments administered by age group, including the
Teen Report (ages 13-18), Child Report (ages 8-12), Young Child Report (ages 5-7), and 
Toddlers (ages 2-4).  Each survey accompanied by the respective parent proxy survey will be 
administered to the subject and their parent/legal guardian (with the exception of the Toddlers 
Report which will only be completed by the parent/legal guardian) for the current age group at 
the time of survey administration.  


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7.
TOXICITY MANAGEMENT
7.1.
Modification of Dose/Schedule Due to Toxicity
Dose reduction of RBV (GT-3 subjects only) due to toxicity should be performed according to 
the product label. Information is provided in Table 7-1.
Table 7-1.
RBV Dose Reduction Guidelines
Laboratory Values
Reduce RBV Dose by 200 mg/daya if:
Discontinue RBV if:
Hemoglobin in subjects with no 
cardiac disease
<10 g/dL
<8.5 g/dL
Hemoglobin in subjects with 
history of stable cardiac disease
2 g/dL decrease in hemoglobin during any 
4 week period treatment
<12 g/dL despite 4 weeks at 
reduced dose
a.
Dose reduction in pediatric patients taking the oral solution is accomplished by modifying the recommended RBV dose from 
original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed.
7.2.
Subject Stopping Rules for LDV/SOF FDC and RBV
The Gilead Medical Monitor should be consulted prior to dose discontinuation of LDV/SOF 
FDC unless the investigator believes that immediate action is warranted to ensure the continued 
safety of the subject.
Administration of LDV/SOF FDC may be discontinued due to a clinical or laboratory event. 
There is no option for LDV/SOF FDC dose reduction. If LDV/SOF FDC is stopped for toxicity, 
it should not be restarted, RBV should be stopped (GT-3 subjects only), and the subject should
complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria must stop treatment with LDV/SOF 
FDC:

Elevation of ALT and/or AST >5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT >3x Day 1 and total bilirubin >2 x ULN, confirmed by 
immediate repeat testing

Confirmed elevation of ALT >15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with LDV/SOF FDC


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8.
ADVERSE EVENTS MANAGEMENT
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
8.1.1.
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-mandated procedures, 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 8.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history CRF
8.1.2.
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.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., 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 (e.g., 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 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
8.2.
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.
8.2.1.
Assessment of Causality for Study Drug and Procedures
The investigator or qualified sub-investigator 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 investigational 
medicinal product. For SAEs, an alternative causality must be provided (e.g., pre-existing 
condition, underlying disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures (e.g.., venipuncture)
8.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4 weeks after last administration of study drug 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 protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of causal relationship, that occurs after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required 24-week 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
after informed consent is signed.


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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. Investigators are not 
obligated to actively seek SAEs after the 24 week post-treatment follow-up period.  However, if 
the investigator learns of any SAEs that occur after study participation has concluded and/or if 
patient is enrolled into the long term follow-up registry study (GS-US-334-1113), and/or eCRF 
database has been locked, and the event is deemed relevant to the use of IMP, he/she should 
promptly document on paper SAE form and report the event directly to Gilead DSPH within 24 
hours of awareness. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com; or
Fax: +1 (650) 522-5477
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, i.e., the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours to:
Gilead Sciences, Drug Safety and 
Public Health:
Fax:
E-mail:
+1 650 522-5477
Safety_FC@gilead.com

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.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
report form.


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8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
8.5.
Special Situations Reports
8.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging or distribution of the medicinal product.  


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8.5.2.
Instructions for Reporting Special Situations
8.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (i.e., signs the informed consent) and throughout the study, including the 
post-treatment follow-up period, to Gilead DSPH using the pregnancy report form within 
24 hours of becoming aware of the pregnancy.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., 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 
Sections 8.1 and 8.3. Furthermore, any SAE occurring as an adverse pregnancy outcome 
post study must be reported directly to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 or Fax: +1 (650) 522-5477.
Pregnancies of female partners of male study subjects exposed to Gilead or other study drug
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy report form and pregnancy outcome report forms within 24 hours. Monitoring of the 
partner pregnancy 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. 
Clinical staff should also report any pregnancies to the Ribavirin Pregnancy Registry at 
1 800-593-2214 (see also http://www.ribavirinpregnancyregistry.com ).
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
8.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 


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Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management and outcome will be reported, when available.


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Objectives and Endpoints 
9.1.1. 
Analysis Objectives 
The prima1y objective of PK Lead-in Phase of this study is: 
Final 
Amendment 5.0 
• 
To evaluate the steady state phrum acokinetics (PK) and confm n the dose ofLDV/SOF FDC 
in chronic HCV-infected pediatric subjects 
The secondruy objective ofPK Lead-in Phase of this study is: 
• 
To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing of 
LDV/SOF FDC in chronic HCV-infected pediatric subjects 
The primru·y objective of Treatment Phase of this study is: 
• 
To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV for 12 or 24 weeks in 
chronic HCV -infected pediatric subjects 
The secondruy objectives of Treatment Phase of this study are: 
• 
To dete1mine the antiviral efficacy of 12 and 24 weeks ofLDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects (including the impact of HCV genotype, IL28B genotype, 
and prior treatment experience), as assessed by the prop01iion of subjects with SVR 
12 weeks after completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of 12 and 24 weeks ofLDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment 
• 
To evaluate the effect of growth and development on pediatric subjects during and after 
treatment 
The explorat01y objective ofthis study is: 
• 
PD 
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9.1.2.
Primary Endpoints
For the PK Lead-in Phase, the appropriateness of the LDV/SOF FDC dose will be assessed by 
evaluating the steady-state PK of the LDV/SOF FDC. The primary endpoint for determining 
steady state PK is AUCtau of GS-331007, SOF, and LDV. Additional steady-state PK parameters 
of GS-331007, SOF, and LDV (e.g., AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½)
will be estimated and summarized as described in Section 9.4.
For the Treatment Phase, the primary safety endpoint is any AE leading to permanent 
discontinuation of study drug (s). 
9.1.3.
Secondary Endpoints
For the PK Lead-in Phase, the secondary endpoint will include antiviral activity measurements, 
including assessment of HCV RNA. AEs leading to permanent discontinuation of study drug will 
be evaluated as a secondary safety endpoint.
For the Treatment Phase, the key efficacy endpoint is SVR12 and secondary efficacy endpoints 
include SVR4, SVR24, breakthrough and relapse. Additional efficacy evaluations may include 
HCV RNA change from Day 1; ALT normalization; and viral kinetic parameters. Secondary 
safety endpoints of growth and development measurements will be assessed (e.g. height, weight, 
and Tanner Stage Assessment).
9.2.
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).
9.2.1.
Analysis Sets 
9.2.1.1.
Pharmacokinetics (PK) Analysis Sets
Intensive PK Analysis Set 
The intensive PK analysis set will include all PK Lead-in phase subjects who received at least 
one dose of study drug and for whom at least one non-missing PK concentration data, during the 
intensive sampling period, reported by PK lab. The PK analysis set will be used for detailed 
pharmacokinetic analysis of LDV, SOF, and metabolites.  
Sparse PK Analysis Set 
The PK analysis set will include all enrolled subjects who received at least one dose of study 
drug and for whom at least one observed concentration data of LDV, SOF, or GS-331007 are 
available. The PK analysis set will be used for analysis of general PK and single sample plasma
concentrations.


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9.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses will include subjects who have 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 last dose of study drug plus 30 days.
9.2.1.3.
Efficacy Analysis Set
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which includes 
HCV-infected subjects who were enrolled and have received at least one dose of study drug.
9.2.2.
Data Handling Conventions
Natural logarithm transformation for key PK parameters, such as Cmax and AUCtau, will be 
applied for pharmacokinetic analysis.
The PK concentration values below the limit of quantitation (BLQ) will be treated as zero for the 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing and will be excluded in any calculation of geometric 
means or ratios. For the presentation of summary and order statistics, if at least 1 subject has a 
concentration value BLQ for the time point, then the minimum value will be displayed as 
“BLQ”. If more than 50% of the subjects have a concentration data value BLQ for the time 
point, then the minimum and median values will be displayed as “BLQ”. If all subjects have 
concentration data values BLQ for the time point, then all order statistics (minimum, first 
quartile [Q1], median, third quartile [Q3], maximum) will be displayed as “BLQ”.
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, 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 
preceded and followed in time by values that are deem 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 medication will be 
considered a failure at the time points subsequent to 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.


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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).
9.2.3.
Interim Analysis
Interim analyses may be performed to provide treatment regimen and duration recommendations
for adolescent subjects (12 to < 18 years of age).
There will be no changes to the study design, study conduct, or the sample size as a result of the 
interim analysis.
9.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by age group and overall for PK Lead-in phase and for Treatment Phase, respectively. 
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight, height, body mass index, HCV RNA level 
(log10 IU/mL), HCV genotype, prior treatment experience, and additional endpoints as necessary.
9.4.
Pharmacokinetic Analysis
PK analysis will be performed for PK Lead-in phase using the intensive PK analysis set. The 
concentration data of LDV, SOF, and metabolites (GS-331007 and GS-566500) over sampling 
time will be listed and summarized by nominal time and cohort. Pharmacokinetic parameters 
(e.g., AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½) will be listed and 
summarized for LDV, SOF,  and metabolites (as applicable) using descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean and its 95% confidence interval, coefficient 
of variation %, standard deviation, median, Q1, Q3, minimum, and maximum) by cohort and 
overall. Plasma concentrations over time will be plotted in semilogarithmic and linear formats as 
mean ± standard deviation and median (Q1, Q3).
To evaluate if the steady-state PK of GS-331007, SOF, and LDV achieved in pediatric subjects 
of this study are similar to the exposures observed in adult subjects (Table 9-1), the GS-331007, 


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SOF, and LDV exposure data from this study will be compared to the integrated adult data. The
primary endpoint of this analysis will be evaluated by carrying out an analysis of variance 
(ANOVA) for log-transformed GS-331007, SOF, and LDV AUCtau. The 90% confidence 
intervals will be constructed for the ratio of geometric means of each PK parameters. The 
equivalence boundary is set as 50% to 200%.  
Given that dose ranging studies for SOF established that a dose of 200 mg results in suboptimal 
exposure compared to the 400 mg dose, and the lack of clinically significant exposure-safety 
relationships observed across a broad range of GS-331007 and SOF exposure, bounds of 50% to 
200% for GS-331007 and SOF AUCtau will allow identification of a clinically relevant difference 
in exposure in the pediatric population.
A phase 2 study evaluating LDV doses of 30 or 90 mg LDV in combination with DAAs 
VDV+TGV+RBV suggested LDV exposure may be suboptimal at the 30 mg dose based on the 
incidence of virologic breakthrough being approximately half in the 90 mg arm; as such the 
90 mg dose was selected for further development.  In the 90 mg LDV arm of this study, the LDV 
AUCtau at the 25 percentile was 3230 hr*ng/mL.  While this value is 62% lower than the mean 
LDV AUCtau (8530 hr*ng/mL) observed in adult HCV-infected subjects in the LDV/SOF FDC 
Phase 2/3 population, it provides ~99.8% of maximal viral load reduction (exposure-response 
model established in the monotherapy proof of concept study).  In the Phase 2/3 population when 
administered the LDV/SOF FDC, there was a lack of clinically significant exposure-efficacy or 
safety relationships observed across the broad range of LDV exposure.  Taken together these 
data support the utility of bounds of 50% to 200% for LDV AUCtau to identify a clinically 
relevant difference in LDV exposure in the pediatric population.
In all pediatric age groups, the targeted exposures for GS-331007, SOF, and LDV are the adult 
equivalent for which safety and efficacy has been established.  In the absence of any pediatric 
PK information (i.e., variability and exposure of GS-331007, SOF, or LDV is unknown) 
assuming a 2-fold higher variability, or a 30 % difference in GS-331007, SOF, or LDV AUCtau
in the pediatric population compared to adults, the predicted 90% CIs of the geometric mean 
ratio (GMR) will be contained within the bounds of 50% to 200%.
Individual patient management will be performed by maintaining exposures comparable to 
adults.  In the event more than one subject in each cohort exhibits GS-331007, SOF, or LDV 
exposures (AUCtau) less than the 2.5th percentile of adult values, a dose assessment may be 
require for the cohort as appropriate.
The effect of age and LDV/SOF FDC dose on PK (LDV, SOF and GS-331007) will be assessed.


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Table 9-1.
GS-331007, SOF, and LDV PK Parameters after Once-Daily 
Administration of LDV/SOF FDC in HCV-Infected Adults Subjects 
(Population PK Analysis from Phase 2 and 3 Studies)
Mean (%CV) PK Parametera
GS-331007 (N=2113)
SOF (N=1542)
LDV (N=2113)
AUCtau (ng•h/mL)
12,500 (29.2)
1380 (34.0)
8530 (60.8)
Cmax (ng/mL)
736 (28.2)
659 (34.0)
364 (51.4)
Ctau (ng/mL)
N/A
N/A
247 (59.2)
a.
Pharmacokinetic parameters are presented as mean (%CV) and are shown to 3 significant digits.
9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in Phase and for Treatment Phase respectively. 
Safety data will be summarized by age group and overall for PK Lead-in Phase and by treatment
regimen for each age group for the Treatment Phase.
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements, and by the documentation of AEs.
All safety data collected while on or after the first dose of study drug administration up to 
30 days after the last dose of study drug will be summarized according to the study drug 
received.
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.
9.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the CRF. Exposure data will be summarized.
9.5.2.
Adverse Events
Clinical and laboratory AEs 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 adverse event with an onset date on or after the study drug 
start date and no later than 30 days after permanent discontinuation of the study drug or any 
adverse event leading to premature discontinuation of the study drug. 


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Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC 
and preferred term) will be provided by cohort:

All AEs,

All treatment-related AEs,

Combined Grade 2, 3 and 4 AEs,

Combined Grade 3 and 4 AEs,

Combined Grade 2, 3 and 4 treatment-related AEs,

Combined Grade 3 and 4 treatment-related AEs,

All AEs that caused permanent discontinuation from study drug,

All AEs that caused change in dose or temporary interruption of study drug,

All SAEs,

All treatment-related SAEs
All AEs collected during the course of the study will be presented in data listings.
9.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled visits will be summarized. Graded laboratory 
abnormalities will be defined using the grading scheme in Grading of Laboratory Abnormalities 
provided in Appendix 3. 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 
and including the date of last dose of study drug plus 30 days, will be summarized by age group 
and overall. If baseline data are missing, then any graded abnormality (i.e., at least a Grade 1) 
will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
9.5.4.
Other Safety Evaluations
9.5.4.1.
Tanner Pubertal Stage Assessment
Tanner Stages (Appendix 4) will be summarized by baseline Tanner Stage using frequency and 
percentage. 


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9.5.4.2. 
Vital Signs (including Body Weight and Height) 
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Vital signs including body weight and height and change from baseline will be summarized at 
each visit. 
9.6. 
Efficacy Analysis 
Efficacy will be evaluated using scheduled assessments of HCV RNA perf01m ed using CO BAS® 
TaqMan® HCV Test, v2.0 for use with the High Pure System. 
Efficacy analysis will be perf01m ed by u·eatment regimen for each age group for Treatment 
Phase. 
All continuous endpoints will be summarized using an 8-number summruy (n, mean, standru·d 
deviation, median, Ql , Q3, minimum, maximum). All categorical endpoints will be summru·ized 
by number and percentage of subjects who meet the endpoint definition. 
9.6.1. 
Key Efficacy Analysis 
The key efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
u·eatment) in the F AS population. Point estimate and its 95% confidence interval will be 
provided. 
9.6.2. 
Secondary Efficacy Analysis 
For the PK Lead-in Phase, senun HCV RNA actual values and change from baseline will be 
summarized at each visit. 
For the Treatment Phase, the proportion of subjects with HCV RNA below LLOQ over time 
(including SVR endpoints SVR4 and SVR24) will be presented in tabulru· and graphical f01m . In 
addition, descriptive summaries and listings will be provided for additional efficacy evaluations 
including senun HCV RNA actual values and change from baseline, prop01iion of subjects with 
virologic failures, and other endpoints of interest including ALT n01m alization. 
PD 
9.6.3. 
Subgroup Analysis 
Subgroup analysis on SVR12 will be perf01m ed by u·eatment experience and cinhosis status, by 
IL28B genotype, and by HCV genotype. Other clinically relevant subgroup analyses may be 
conducted as appropriate (i.e., assuming that adequate numbers of subjects in these subsets ru·e 
available for analysis). 
Details on efficacy analyses will be described in the statistical analysis plan. 
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9.7.
Quality of Life Analysis
The data from PedsQL ™ Pediatric Quality of Life survey will be summarized by visit and 
age group and overall.
9.8.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety and provide recommendation to Gilead about 
whether the nature, frequency, and severity of adverse effects associated with study treatment 
warrant the early termination of the study in the best interests of the participants, whether the 
study should continue as planned, or the study should continue with modifications. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
9.9.
Sample Size
With approximately 100 subjects enrolled into each age group of Treatment Phase, a two-sided 
95.0% confidence interval of the SVR12 rate will extend at most 5.9% in both directions from 
the observed SVR12 rate, assuming the expected SVR12 rate is 90%.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
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 Harmonization (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. For studies conducted under a United States IND, the investigator 
will ensure that 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, are adhered to.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Gilead Sciences, or proprietary interests in the drug being studied. 
This documentation must be provided before participation of the investigator and any 
sub-investigator. The investigator and sub-investigator agree to notify Gilead Sciences of any 
change to reportable interests during the study and for one year following completion of the 
study. Study completion is defined as the date that the last subject has completed 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.”
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
This protocol 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/assent) will be submitted by the investigator to an IRB (for studies conducted in the 
United States) or IEC (for studies conducted outside of the United States). Approval from the 
IRB or IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. Additionally, modifications 
should be submitted to competent authorities, as necessary.


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10.1.3.
Informed Consent/Assent
The investigator is responsible for obtaining written informed consent from the parent/legal 
guardian of the subject participating in this study after adequate explanation to the parent/legal 
guardian and subject of the aims, methods, objectives, and potential hazards of the study and 
before undertaking any study-related procedures. Written assent should be obtained from the 
subject as required by IRB/IEC/local requirements for this age population.  The investigator must 
utilize an IRB- or IEC-approved consent/assent form for documenting written informed 
consent/assent. Each informed consent/assent will be appropriately signed and dated by the 
subject or the subject’s parent/legally authorized representative and the person obtaining 
consent/assent.
10.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, and an 
identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the Sponsor, IRB or IEC, or laboratory. The investigator must keep a screening log 
showing codes, names, and addresses for all subjects screened and for all subjects enrolled in the 
trial.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational new drug, and any 
other study information, remain the sole and exclusive property of Gilead Sciences during the 
conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Gilead Sciences. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data are listed in the Source Data verification Plan, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Participation in trial (including trial number);


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
Trial 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 trial medication (preferably drug dispensing 
and return should be documented as well);

Record of all AEs and other safety parameters (start and end date, and preferably including 
causality and intensity);

Concomitant medication (including start and end date, dose if relevant; dose changes should 
be motivated);

Date of trial completion and reason for early discontinuation, if applicable.
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) 
and until there are no pending or contemplated 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 required by applicable regulatory requirements, by local 
regulations, or by an agreement with Gilead Sciences. The investigator must notify 
Gilead Sciences 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 Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences 
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period up to 15 years for purposes of this study.
10.1.6.
Case Report Forms
For each subject enrolled, a CRF (or eCRF) must be completed and signed by the principal 
investigator or sub-investigator (as appropriate) within a reasonable time period after data 
collection. This also applies to records for those subjects who fail to complete the study 
(even during a pre-randomization screening period if a CRF was initiated). If a subject 


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withdraws from the study, the reason must be noted on the CRF. If a subject is withdrawn from 
the study because of a treatment-limiting adverse event, thorough efforts should be made to 
clearly document the outcome.
10.1.7.
Drug Accountability
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product, and comparators. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), subject 
dispensing records, and returned or destroyed study product. Dispensing records will document 
quantities received from Gilead Sciences and quantities dispensed to subjects, including lot 
number, date dispensed, subject identifier number, subject initials, and the initials of the person 
dispensing the medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRBs or IECs, 
or to regulatory authority or health authority inspectors.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB, IEC, or 
competent authorities in accordance with local requirements. Approval must be obtained before 
changes can be implemented.


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10.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency (ies). 
Gilead Sciences 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.
After conclusion of the study and without prior written approval from Gilead Sciences, 
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 Sciences in an abstract, manuscript, or presentation form; or

the study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).
The investigator will submit 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. The investigator will comply with Gilead Sciences’ 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.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the CRFs for consistency.
The monitor is responsible for routine review of the CRFs 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 CRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences 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 Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.


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10.3.3.
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 Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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11.
REFERENCES
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and 
sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 
2014a;370 (16):1483-93.
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for 
untreated HCV genotype 1 infection. N Engl J Med 2014b;370 (20):1889-98.
Bortolotti F, Verucchi G, Camma C, Cabibbo G, Zancan L, Indolfi G, et al. Long-term course of 
chronic hepatitis C in children: from viral clearance to end-stage liver disease. 
Gastroenterology 2008;134 (7):1900-7.
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus infection in 
Europe. J Hepatol 2008;48 (1):148-62.
European Medicines Agency (EMEA). Committee for Medicinal Products for Human Use 
(CHMP). Guideline on the Investigation of Bioequivalence. 2010.
Fanta S, Jonsson S, Backman JT, Karlsson MO, Hoppu K. Developmental pharmacokinetics of 
ciclosporin--a population pharmacokinetic study in paediatric renal transplant 
candidates. Br J Clin Pharmacol 2007;64 (6):772-84.
Gane E, Hyland RH, An D, Pang PS, Symonds WT, McHutchison JG, et al. 
Ledipasvir/Sofosbuvir Fixed-Dose Combination Is Safe and Effective in Difficult-
to-Treat Populations Including GT 3 Patients, Decompensated GT 1 Patients, and 
GT 1 Patients With Prior Sofosbuvir Experience [Oral Presentation 6]. 49th 
Annual Meeting of The European Association for the Study of the Liver (EASL); 
2014 April 9-13; London, UK. 
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. U.S. 
Prescribing Information. Foster City, CA.  Revised June.  2016:
Gilead Sciences International Ltd. HARVONI (ledipasvir/sofosbuvir) 90 mg/400 mg Film-
Coated Tablets. Summary of Product Characteristics. Cambridge, UK. Revised 
April.  2016:
Hu J, Doucette K, Hartling L, Tjosvold L, Robinson J. Treatment of hepatitis C in children: a 
systematic review. PLoS ONE 2010;5 (7):e11542.
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. 
Developmental pharmacology--drug disposition, action, and therapy in infants 
and children. N Engl J Med 2003;349 (12):1157-67.


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Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and 
sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 
2014;370 (20):1879-88.
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of disease 
in childhood 1969;44 (235):291-303.
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of 
disease in childhood 1970;45 (239):13-23.
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon 
alfa-2b alone or in combination with ribavirin as initial treatment for chronic 
hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339 
(21):1485-92.
Mohan N, Gonzalez-Peralta RP, Fujisawa T, Chang MH, Heller S, Jara P, et al. Chronic hepatitis 
C virus infection in children. J Pediatr Gastroenterol Nutr 2010;50 (2):123-31.
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of 
interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon 
alpha2b plus placebo for 48 weeks for treatment of chronic infection with 
hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). 
Lancet 1998;352 (9138):1426-32.
Roche Laboratories Inc. COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. 
Nutley, NJ. Revised: January 2010.
Roche Products Limited. Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Welwyn Garden City, United Kingdom. Revised: March 2010.
Serranti D, Buonsenso D, Ceccarelli M, Gargiullo L, Ranno O, Valentini P. Pediatric hepatitis C 
infection: to treat or not to treat...what's the best for the child? European review 
for medical and pharmacological sciences 2011;15 (9):1057-67.
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Guidance for Industry. Bioavailability 
and Bioequivalence Studies Submitted in NDAs or INDs — General 
Considerations [Draft Guidance].  March, 2014.
Wirth S. Current treatment options and response rates in children with chronic hepatitis C. World 
J Gastroenterol 2012;18 (2):99-104.
Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti F, Zancan L, Jara P, et al. High sustained 
virologic response rates in children with chronic hepatitis C receiving 
peginterferon alfa-2b plus ribavirin. J Hepatol 2010;52 (4):501-7.


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Yang D, Pearce RE, Wang X, Gaedigk R, Wan YJ, Yan B. Human carboxylesterases HCE1 and 
HCE2: ontogenic expression, inter-individual variability and differential 
hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem 
Pharmacol 2009;77 (2):238-47.
Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and sex-related expression and activity of 
carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos 2009;37 
(9):1819-25.


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12.
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.
Tanner Stages*
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


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Appendix l. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety and 
Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination +/- Ribavirin in Adolescents 
and Children with Chronic HCV-infection 
GS-US-337-1116, Protocol Amendment 5.0, 04 November 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
S.E?t.J~~firl~ 
Tt.A-S~E""tTO 
Benedetta Massetto, MD (Printed) 
Medical Monitor 
Nov~ 
<tt"UJJG 
Date 
PD 
Signature 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 97 
04 November 2016 


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Appendix 2.
Study Procedures Table
Appendix Table 1.
PK Lead-in: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X j
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Vital Signsa
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X
Subject Dosing Diary
X
X
X


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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
Viral Sequencing c
X
X
X
Serum or Urine Pregnancy Testinge
X
X
X
Urinalysis
X
X
X
Urine Drug Screen
X
Intensive PK
X d
HCV Genotyping, IL28B
X
HCV antibody, HIV antibody, HBs antigen, 
HBs antibody, HBc antibody, and HAV 
antibody
X
HbA1c
X
TSH
X
Alpha fetoprotein
X
Alpha-1 anti-trypsin
X
HBV DNAk
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, body weight, and height
b
Day 1 assessments must be performed prior to dosing
PPD


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c
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
d
For Cohorts 1 and 2, plasma samples will be collected for PK analyses following dosing of study drug on Day 10 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours post-dose.
e
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test. 
f
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status). 
g
study.
h
Swallowability, for subjects on tablet formulation, can occur at Day 1 if not completed during screening.
i
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
j
Parental height will be collected (if available)
k
Only subjects HBcAb positive at Screening
PPD


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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
Xi
Complete Physical Examination
X
X
Xj
X
X
Symptom-Directed Physical Examination
X
X
X
X
Xk
X
X
Tanner Pubertal Stage Assessment
X
Xj
X
X
Vital Signsa
X
X
X
X
X
X
X
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling g
X
Xj
X
X
LDV/SOF FDC Swallowability 
Assessment
X
Xh
Quality of Life Survey e
X
Xj
X
X
Review of Study Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xk
X
X
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
X
X
X
X
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
X
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X


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Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early Termination
Serum or Urine Pregnancy Testingl
X
X
X
X
X
X
X
X
X
Single PK
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Urine Drug Test
X
HCV Genotyping, IL28B
X
HCV antibody, HIV antibody, HBs 
antigen, HBs antibody, HBc antibody, and 
HAV antibody
X
HbA1c
X
TSH
X
Xj
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
HBV DNAm
X
X
X
X
X
X
X
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, and body weight and height
b
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
c
Subjects rolling over from PK Lead-in phase will not be required to repeat screening, Day 1 or Week 1 visits during the on Treatment Phase  
d
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
e
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
f
g
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
h
Swallowability, for subjects on tablet formulation, can occur at Day 1 if not completed during screening.
i
Parental height will be collected (if available) 
j
Subjects on 12 Week Treatment regimen only
k
Subjects on 24 Week Treatment regimen only
l
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test
m
Only subjects with positive HBcAb at Screening
PPD
PPD


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Appendix Table 3.
Treatment Phase: Post Treatment Visits Following Primary Study
4 Weeks Post Treatment
12 Weeks Post Treatment
24 Weeks Post Treatment
Clinical Assessments
Vital Signs, Body weight and Height
X
X
X
Symptom-directed Physical Exam
X
X
X
AEs
X
Xc
Xc
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counselingd
X
Xf
Xf
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Test
X
Xe
Xe
HBV DNAg
X
X
X
a
Quality of life survey will be completed by all subjects at 12-Week and 24-Week Post Treatment visits if a site is approved to use the survey.  Subject is to review 
questionnaire with a parent/guardian and write/mark answers directly onto the questionnaire.
b
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
c
At Post Treatment Week 12 and 24, only SAEs will be captured
d
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
e
GT-3 subjects only: Female subjects of childbearing potential should be provided with Urine Pregnancy Test Kits, instructed on their use and requested to continue to 
self-monitor for pregnancy for 6 months after their last dose of RBV. If required by regulations, additional pregnancy tests beyond 6 months may be added. The subject 
should be contacted every 4 weeks and asked to report results of the urine pregnancy tests. If a positive urine pregnancy test is reported, the subject should return to the clinic 
for a serum pregnancy test.
f
GT-3 subjects only
g
Only subjects HBcAb positive at Screening


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 5.0
CONFIDENTIAL
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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 5.0
CONFIDENTIAL
Page 105
04 November 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count  
(ANC)
Adult and Pediatric, 
≥ 7 Months# 
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 5.0
CONFIDENTIAL
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04 November 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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% 
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.  


LDV/SOF FDC
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Gilead Sciences, Inc
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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 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L


LDV/SOF FDC
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Gilead Sciences, Inc
Amendment 5.0
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04 November 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                          
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL                      
1.51 to < 1.74 mmolL
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 5.0
CONFIDENTIAL
Page 109
04 November 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days 
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L


LDV/SOF FDC
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Gilead Sciences, Inc
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04 November 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 5.0
CONFIDENTIAL
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04 November 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
** An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


LDV/SOF FDC
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04 November 2016
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 5.0
CONFIDENTIAL
Page 113
04 November 2016
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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04 November 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


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


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


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


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


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


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


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


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


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


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


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Appendix 4.
Tanner Stages*
1. Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2. Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of testes and scrotum and increased darkening 
of scrotal skin (13.5-15)
Tanner V 
Genitalia adult in size and shape
3. Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen 
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with 
surrounding breast 
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V 
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. 
*
Chart referenced from Marshall WA, Tanner JM, variations in the pattern of pubertal changes in boys and girls {Marshall et al 1970}, {Marshall et al 1969}


LDV/SOF FDC
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Amendment 5.0
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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Background
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Pregnancy must be excluded before the start of 
treatment with study drugs and prevented thereafter by reliable contraceptive methods. 
Pregnancy tests will be performed regularly throughout this study. Furthermore, RBV is known 
to accumulate intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, 
extreme care must be taken to avoid pregnancy during RBV therapy and for up to 6 months 
following completion of treatment (7 months for males). Please refer to the latest version of the 
product insert for additional information.
Non-clinical toxicity studies of LDV/SOF FDC demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of LDV/SOF FDC 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)
For the purpose of this trial, all post-menarchal females will be considered to be of childbearing 
potential, unless there is documentation of irreversible ovarian failure or surgical sterilization.
Post-menarchal females must have a negative serum pregnancy test at Screening and a negative 
urine pregnancy test on the Day 1 visit prior to dosing. They must also agree to one of the 
following from 3 weeks prior to Day 1 until 6 months after last dose of RBV or 30 days after last 
dose of LDV/SOF FDC if not taking RBV:

Complete abstinence from intercourse. Abstinence is acceptable method of contraception 
only when it is in line with the subject’s preferred and usual lifestyle. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
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 
6 months after last dose of RBV or 30 days  after the last dose of LDV/SOF FDC if not 
taking RBV:
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization


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vasectomy in male partner
implants of levonorgestrel
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 Day 1
until 7 months after last dose of RBV or 90 days after the last dose of LDV/SOF FDC if not 
taking RBV. If their female partner is of childbearing potential (as defined above), their female 
partner must use 1 of the methods of birth control listed above from the date of Screening until 
7 months after last dose of RBV or 90 days after last dose of LDV/SOF FDC if not taking RBV.
Male subjects must agree to refrain from sperm donation for at least 7 months after last dose of 
RBV or 90 days after the last dose of LDV/SOF FDC if not taking RBV.
4. Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 6 months (7 months for partners of male subjects) of 
last RBV dose or 30 days (90 days for partners of male subjects) of last LDV/SOF FDC dose if 
not taking RBV. 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 8.5.2.1.

Prot_002.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT Number: 
Indication: 
Protocol ID: 
Gilead Sciences Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-coh01i Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir 
Fixed Dose Combination in Adolescents and Children with 
Chronic HCV-Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
115268 
2014-003578-17 
Hepatitis C Vims Infection 
GS-US-337-1116 
Name: 
Telephone: 
Mobile: 
Fax: 
E-mail: 
Bittoo Kanwar, MD 
PPD 
rpo 
rpo 
PD 
Original: 
10 July 2014 
Amendment 1.0: 08 October 2014 
Amendment 2.0: 08 December 2014 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmiicularly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board 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 necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 2
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................16
1.
INTRODUCTION ..............................................................................................................................................19
1.1.
Background ............................................................................................................................................19
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................20
1.2.1.
Summary of Additional Clinical Experience with Ledipasvir/Sofosbuvir 
Fixed-Dose Combination .....................................................................................................20
1.3.
Rationale for the Current Study .............................................................................................................21
1.4.
Rationale for Dose Selection of LDV/SOF FDC ...................................................................................22
1.5.
Overall Risk/Benefit Assessment...........................................................................................................22
2.
OBJECTIVES.....................................................................................................................................................24
3.
STUDY DESIGN................................................................................................................................................25
3.1.
Treatment Plan and Regimen .................................................................................................................25
3.1.1.
PK Lead-in ...........................................................................................................................25
3.1.2.
Treatment Phase ...................................................................................................................26
3.2.
Visit Schedule ........................................................................................................................................27
3.2.1.
PK Lead-in ...........................................................................................................................27
3.2.2.
Treatment Phase ...................................................................................................................28
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................28
3.4.
Treatment Discontinuations Criteria ......................................................................................................29
3.5.
Discontinuations.....................................................................................................................................29
3.6.
Pharmacogenomic Substudy ..................................................................................................................29
3.7.
Long-Term Follow-Up...........................................................................................................................29
3.8.
Breakthrough Futility Assessment .........................................................................................................30
3.9.
Reconsent...............................................................................................................................................30
4.
SUBJECT POPULATION..................................................................................................................................31
4.1.
Number of Subjects and Subject Selection ............................................................................................31
4.2.
Inclusion Criteria....................................................................................................................................31
4.3.
Exclusion Criteria...................................................................................................................................32
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................34
5.1.
Randomization and Blinding..................................................................................................................34
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................34
5.2.1.
Description and Handling.....................................................................................................34
5.2.2.
Storage and Handling...........................................................................................................35
5.2.3.
Dosage and Administration of LDV/SOF FDC ...................................................................36
5.3.
Study Drug Compliance.........................................................................................................................37
5.4.
Prior and Concomitant Medications.......................................................................................................37
6.
STUDY PROCEDURES ....................................................................................................................................39
6.1.
Subject Enrollment.................................................................................................................................39
6.2.
Screening Assessments ..........................................................................................................................39
6.2.1.
Screening Visit (Day –28 to Day 0) .....................................................................................39


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6.3.
PK Lead-in: Treatment Assessments .....................................................................................................41
6.3.1.
Day 1 ....................................................................................................................................41
6.3.2.
Day 3 ....................................................................................................................................42
6.3.3.
Day 10 – Intensive PK..........................................................................................................42
6.4.
Treatment Phase: Treatment Assessments .............................................................................................44
6.4.1.
Day 1 ....................................................................................................................................44
6.4.2.
Weeks 1 and 2 (3 days) .....................................................................................................45
6.4.3.
Weeks 4 and 8 (3 days) .....................................................................................................46
6.4.4.
Week 12 (3 days) - Subjects on 12 Week Treatment Regimen Only................................47
6.4.5.
Week 12 (3 days) - Subjects on 24 Week Treatment Regimen Only................................47
6.4.6.
Week 16 and 20 (3 days) – Subjects on 24 Week Treatment Regimen 
Only......................................................................................................................................48
6.4.7.
Week 24 (3 days) – Subjects on 24 Week Treatment Regimen Only ...............................49
6.4.8.
Unscheduled Visit/Early Termination Visit .........................................................................50
6.5.
Post-Treatment Assessments..................................................................................................................51
6.5.1.
4-Week Post-Treatment Visit (5 days)..............................................................................51
6.5.2.
12-Week Post-Treatment Visit (5 days)............................................................................51
6.5.3.
24-Week Post-Treatment Visit (5 days)............................................................................52
6.6.
Procedures and Specifications................................................................................................................53
6.6.1.
Clinical Laboratory Analytes ...............................................................................................53
6.6.2.
Medical History....................................................................................................................53
6.6.3.
Complete Physical Examination...........................................................................................53
6.6.4.
Tanner Pubertal Stage Assessment.......................................................................................54
6.6.5.
Height & Weight Measurement............................................................................................54
6.6.6.
Bone Age Assessment..........................................................................................................54
6.6.7.
Swallowability Assessment..................................................................................................54
6.6.8.
Vital Signs............................................................................................................................54
6.6.9.
Estimated Glomerular Filtration Rate (GFR) .......................................................................55
6.6.10.
Viral Sequencing (Archive)..................................................................................................55
6.6.11.
Pregnancy Testing................................................................................................................55
6.6.12.
Quality of Life Survey (PedsQL™).......................................................................................55
7.
TOXICITY MANAGEMENT............................................................................................................................56
7.1.
Subject Stopping Rules for LDV/SOF FDC ..........................................................................................56
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................57
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................57
8.1.1.
Adverse Events.....................................................................................................................57
8.1.2.
Serious Adverse Events........................................................................................................57
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................58
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................58
8.2.1.
Assessment of Causality for Study Drug and Procedures ....................................................58
8.2.2.
Assessment of Severity ........................................................................................................59
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................59
8.4.
Gilead Reporting Requirements.............................................................................................................61
8.5.
Special Situations Reports......................................................................................................................61
8.5.1.
Definitions of Special Situations..........................................................................................61
8.5.2.
Instructions for Reporting Special Situations.......................................................................62
9.
STATISTICAL CONSIDERATIONS................................................................................................................64
9.1.
Analysis Objectives and Endpoints........................................................................................................64


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9.1.1.
Analysis Objectives..............................................................................................................64
9.1.2.
Primary Endpoints................................................................................................................65
9.1.3.
Secondary Endpoints............................................................................................................65
9.2.
Analysis Conventions.............................................................................................................................65
9.2.1.
Analysis Sets ........................................................................................................................65
9.2.2.
Data Handling Conventions .................................................................................................66
9.2.3.
Interim Analysis ...................................................................................................................67
9.3.
Demographic Data and Baseline Characteristics ...................................................................................67
9.4.
Pharmacokinetic Analysis......................................................................................................................67
9.5.
Safety Analysis.......................................................................................................................................70
9.5.1.
Extent of Exposure...............................................................................................................70
9.5.2.
Adverse Events.....................................................................................................................70
9.5.3.
Laboratory Evaluations ........................................................................................................71
9.5.4.
Other Safety Evaluations......................................................................................................71
9.6.
Efficacy Analysis ...................................................................................................................................72
9.6.1.
Key Efficacy Analysis..........................................................................................................72
9.6.2.
Secondary Efficacy Analysis................................................................................................72
9.6.3.
Subgroup Analysis ...............................................................................................................72
9.7.
Quality of Life Analysis.........................................................................................................................73
9.8.
Data Monitoring Committee ..................................................................................................................73
9.9.
Sample Size............................................................................................................................................73
10.
RESPONSIBILITIES..........................................................................................................................................74
10.1.
Investigator Responsibilities ..................................................................................................................74
10.1.1.
Good Clinical Practice..........................................................................................................74
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................74
10.1.3.
Informed Consent/Assent.....................................................................................................75
10.1.4.
Confidentiality......................................................................................................................75
10.1.5.
Study Files and Retention of Records ..................................................................................75
10.1.6.
Case Report Forms...............................................................................................................77
10.1.7.
Drug Accountability.............................................................................................................77
10.1.8.
Inspections............................................................................................................................77
10.1.9.
Protocol Compliance............................................................................................................77
10.2.
Sponsor Responsibilities ........................................................................................................................78
10.2.1.
Protocol Modifications.........................................................................................................78
10.2.2.
Study Report and Publications .............................................................................................78
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................78
10.3.1.
Access to Information for Monitoring..................................................................................78
10.3.2.
Access to Information for Auditing or Inspections ..............................................................79
10.3.3.
Study Discontinuation..........................................................................................................79
11.
REFERENCES ...................................................................................................................................................80
12.
APPENDICES ....................................................................................................................................................82
Appendix 1.
Investigator Signature Page....................................................................................................83
Appendix 2.
Study Procedures Table..........................................................................................................84
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............89
Appendix 4.
Tanner Stages .......................................................................................................................113
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................114


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Final
Gilead Sciences, Inc.
Amendment 2.0
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Page 5
08 December 2014
LIST OF IN-TEXT TABLES
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................38
Table 9-1.
GS-331007, SOF, and LDV PK Parameters after Once-Daily Administration of 
SOF/LDV FDC in HCV-Infected Adults Subjects (Population PK Analysis from 
Phase 2 and 3 Studies)............................................................................................................70
LIST OF IN-TEXT FIGURES
Figure 3-1.
PK Lead-in Phase Study Schema ...........................................................................................26
Figure 3-2.
Treatment Phase Study Schema .............................................................................................27


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 2.0
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08 December 2014
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed 
Dose Combination in Adolescents and Children with Chronic 
HCV-Infection
IND Number:
EudraCT Number:
115268
2014-003578-17
Study Centers:
Approximately 30 sites in the United States, Europe, Australia, and 
New Zealand
Number of Subjects:
Approximately 200 subjects
Target Population:
Adolescents and children (aged 3 to < 18) chronic hepatitis C virus 
(HCV) infection
Treatment Duration:
PK Lead-in – 10 days
Treatment Phase – 12 or 24 weeks
Objectives:
The primary objective of the PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm 
the dose of LDV/SOF FDC in chronic HCV-infected pediatric 
subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 
10 days of dosing of LDV/SOF FDC in chronic HCV infected 
pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC for 12 or 
24 weeks in chronic HCV-infected pediatric subjects. 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
Final 
Amendment 2.0 
The seconda!y objectives of the Treatment Phase ofthis study are: 
• 
To detennine the antiviral efficacy of 12 or 24 weeks of 
LDV /SOF FDC treatment in chronic HCV infected subjects 
(including the impact of HCV genotype, IL28B genotype, and 
prior treatment experience), as assessed by the prop01iion of 
subjects with sustained virological response (SVR) 12 weeks after 
completion of treatment (SVR12) 
• 
To determine the antiviral efficacy of 12 or 24 weeks of 
LDV/SOF FDC treatment in chronic HCV-infected subjects, as 
assessed by the prop01iion of subjects with SVR 4 and 24 weeks 
after completion of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during 
treatment and after completion of treatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF 
during treatment and after completion of treatment 
• 
To evaluate the effect of growth and development on pediatric 
subjects during and after treatment 
The explorat01y objective of this study is: 
• 
PD 
Open-label, multi-coh01i, two-part study evaluating the PK, safety, 
and antiviral activity ofLDV/SOF FDC in chronic HCV-infected 
pediatric subjects. 
The study will be divided into 2 parts and will commence with GT -1 
HCV-infected pediatric subjects as follows (subjects with 
GT-2, -4, -5, and -6 will be included once adult data is available, if 
appropriate): 
PK Lead-in Phase: PK Lead-in will evaluate and/or confnm age 
appropriate LDV/SOF FDC doses by analyzing PK, safety, and 
antiviral activity of LDV /SOF FDC tluough 10 days of dosing for 
each of the three coh01is. Children aged 3 to < 6, children aged 
6 to < 12 years, and adolescents aged 12 to < 18 years with evidence 
of cluonic HCV and HCV RNA~ 1000 IU/mL at study entiy will be 
evaluated. Subjects must be treatment na'ive without hist01y of 
cinhosis to pruiicipate in the PK Lead-in Phase. 
Page7 
08 December 2014 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 8
08 December 2014
Three cohorts of at least 10 subjects each will be sequentially 
enrolled: 

Cohort 1: 12 to < 18 years old, weighing ≥ 45kg

Cohort 2: 6 to < 12 years old 

Cohort 3: 3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive LDV/SOF 
FDC (90 mg/ 400 mg fixed dose combination tablet or 4 x 22.5 mg/ 
100 mg based on LDV/SOF FDC swallowability assessment) for 
10 days with intensive PK conducted on Day 10.
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 10
of the PK Lead-in Phase. They will continue dosing with LDV/SOF 
FDC with no interruption of study drug administration. Subjects 
rolling over from the PK Lead-in will not be required to perform 
Treatment Phase Screening, Day 1, or Week 1 visits in the Treatment 
Phase.  
Following completion of study treatment in the PK Lead-in of each 
Cohort, intensive PK and safety results of study treatment will be 
reviewed to confirm the appropriateness of the evaluated LDV/SOF 
FDC dose for the Treatment Phase of that Cohort as well as to 
determine the age-appropriate dose to be evaluated in the PK Lead-in 
of the next Cohort.
Treatment Phase: Treatment Phase will be initiated sequentially by 
cohort after confirmation of age-appropriate LDV/SOF FDC dosage 
levels. Subjects who participate in PK Lead-in Phase will 
immediately rollover into Treatment Phase, with no interruption of 
study drug administration, until the appropriateness of the dose is 
confirmed by PK and safety data from the PK Lead-In Phase.  These 
subjects will start at the Week 2 visit of the Treatment Phase. 
Additional subjects will be enrolled in the Treatment Phase of each 
Cohort upon confirmation of the appropriateness of the dose.
Children aged 3 to < 12 years and adolescents aged 12 to < 18 years 
with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study 
entry (those who were dosed in the PK Lead-in Phase will have met 
these criteria prior to enrollment) will be evaluated. The study will 
commence with GT-1 HCV infected pediatric subjects and will 
subsequently enroll subjects with GT-2, -4, -5, and -6 once adult data 
is available, if appropriate.


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Substudy and Long-
Tenn Follow-Up 
Study: 
CONFIDENTIAL 
Final 
Amendment 2.0 
Subjects enrolled in the study will receive the following regimen: 
• 
Treatment-naive with or without cinhosis: LDV/SOF FDC for 
12 weeks 
• 
Treatment-experienced without cinhosis: LDV/SOF FDC for 
12 weeks 
• 
Treatment-experienced with cinhosis (as determined by liver 
biopsy): LDV/SOF FDC for 24 weeks 
The study will enroll both u·eatment-nai:ve and u·eahnent experienced 
pediau·ic subjects, with up to 40 subjects allowed to be u·eatment 
experienced. Approximately 200 total subjects, including subjects 
that pmiicipated in the PK Lead-in Phase, will be enrolled in 
Treatment Phase as follows: 
• 
Group 1: Approximately 100 adolescent subjects (12 to < 18 yem·s 
of age) 
• 
Group 2: Approximately 100 pediau·ic subjects (3 to < 12 yem·s of 
age) 
The following defmitions will be used for u·eatment experienced 
subjects: 
• 
Interferon intolerant: Subject who discontinued therapy 
(:::; 12 weeks total) due to :=::: 1 adverse event 
• 
Interferon non-responder: Subject who did not achieve 
undetectable HCV RNA levels while on u·eatment 
• 
Relapse/breakthrough: Subject who achieved undetectable HCV 
RNA dming u·eatment or within 4 weeks of the end of u·eatment 
but did not achieve a sustained virologic response (SVR) 
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, and 12 (and Weeks 16, 20, and 24 for 
treatment-experienced subjects with cinhosis) dming the u·eatment 
phase followed by post-u·eatment visits 4, 12 and 24 weeks after 
discontinuation of therapy. 
All subjects who do not attain SVR or have viral relapse will be 
encomaged to discuss u·eatment with standard-of-care (SOC) therapy 
with their healthcm·e provider. 
Pharmacogenomics (PG) Substudy 
PD 
Page9 
08 December 2014 


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Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 10
08 December 2014
Long-Term Follow-up
Subjects who attain SVR24 or those who do not attain SVR24 and do 
not initiate other experimental or approved anti-HCV therapy will be 
followed every 6 months for assessments of growth, quality of life, 
and long-term viral suppression (if applicable) in a separate protocol 
(GS-US-334-1113). This follow-up will continue for 5 years.
Diagnosis and Main 
Eligibility Criteria: 
Chronic HCV-infected, treatment-naïve and treatment experienced
(up to 40 subjects); male and female subjects aged 3 to < 18 as 
determined at Day 1. The study will commence with GT-1 
HCV-infected pediatric subjects and will subsequently enroll subjects 
with GT-2, -4, -5 and -6 once adult data is available, if appropriate. 
Inclusion Criteria:

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 
Day 1 visit, or
B) a liver biopsy performed prior to the Day 1 visit with evidence 
of chronic HCV- infection

HCV RNA ≥ 1000 IU/mL at Screening 

For the PK Lead-in Phase:  subjects in Cohort 1 (age 12 to 
< 18 years of age) must weigh ≥ 45 kg

Females of childbearing potential (as defined in Appendix 5) must 
have a negative pregnancy test at Screening and Day 1.

Hematologic or biochemical parameters at screening within the 
protocol-specified requirements
Exclusion Criteria:

HIV, acute hepatitis A virus (HAV) or chronic HBV infection

History of or current decompensated liver disease

Hepatocellular carcinoma or other malignancy (with exception of 
certain resolved skin cancers)

Chronic liver disease of a non-HCV etiology 
(e.g., hemochromatosis, Wilson’s disease, alpha-1 antitrypsin 
deficiency)

Systemic corticosteroid use for > 2 weeks (pulmonary/nasal 
administration is permitted)

Active or recent history (≤ 1 year) of drug or alcohol abuse


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 11
08 December 2014

History or current evidence of any condition, therapy, laboratory 
abnormality or other circumstance that might confound the results 
of the study, or interfere with the subject’s participation for the
full duration of  the study, such that it is not in the best interest of 
the subject to participate.

Sexually active subjects must agree to use 2 forms of highly 
effective contraception, as referenced in Appendix 5, for the 
duration of the study and for 30 days (for female subjects) or 
90 days (for male subjects) after the last dose of study medication.
See Sections 4.2 and 4.3 of the protocol for full eligibility criteria.
Study Procedures/
Frequency:
PK Lead-in Phase: 
Screening assessments will be completed within 28 days of the Day 1 
visit. 
Screening assessments will include: medical history (including 
parental height, if available), complete physical examination, vital 
signs (including body height and weight), concomitant medications,
LDV/SOF FDC Swallowability Assessment (may be performed at 
screening up to Day 1), hematology, safety laboratory tests, 
coagulation tests, HCV RNA, serum β-human chorionic gonadotropin 
(hCG - females of childbearing potential only), urinalysis, and urine 
drug screen, IL28B genotyping, serology (HIV, HAV, HCV, and 
HBV, HCV genotyping), HbA1c, thyroid stimulating hormone
(TSH), alpha fetoprotein, alpha-1 anti-trypsin.
Study Visits will occur at Screening, Day 1, Day 3, and Day 10.
On-Treatment assessments include physical examination, Tanner 
Pubertal Stage Assessment (Day 1 only), vital signs (including body 
height and weight), bone age assessment (Day 1 only), adverse events 
(AEs), concomitant medications, pregnancy prevention counseling 
(Day 1 only; all subjects ≥ 12 years of age and subjects < 12 years of 
age at the discretion of the Investigator based on subject’s pubertal 
status), quality of life survey (Day 1 only), safety laboratory tests, 
HCV RNA, viral sequencing sampling and urinalysis. Coagulation 
testing and urine pregnancy tests (females of child bearing potential 
only) will be performed at Day 1 and Day 10 only. LDV/SOF FDC 
swallowability assessment with placebo will be performed at 
Screening or up to Day 1 to assess a subject’s ability to swallow the 
90 mg/ 400 mg or 22.5 mg/ 100 mg FDC tablet (only subjects 
administered LDV/SOF FDC in tablet form). 
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in 
Phase will participate in an intensive PK evaluation on Day 10. 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 12
08 December 2014
Following completion of the Day 10 intensive PK visit, subjects will 
then return for scheduled study visits outlined in the Treatment Phase 
and will continue dosing with LDV/SOF FDC with no interruption of 
study drug administration. Subjects will be administered a dosing 
diary with instructions.
Treatment Phase: 
Screening assessments will be completed within 28 days of the Day 1 
visit. For subjects continuing from PK Lead-in, screening for 
Treatment Phase will not be required.
Screening assessments will include medical history (including 
parental height, if available), complete physical examination, vital 
signs (including body height and weight), AEs, concomitant 
medications, coagulation, safety laboratory tests, HCV RNA, serum 
β-human chorionic gonadotropin (hCG- females of childbearing 
potential only), urinalysis, urine drug screen, serology (HIV, HAV, 
HCV, HBV), IL28B genotyping, HbA1c, TSH, alpha fetoprotein,
alpha-1 anti-trypsin. LDV/SOF FDC swallowability assessment with 
placebo will be performed at Screening or up to Day 1 to assess a 
subject’s ability to swallow the 90 mg/ 400 mg or 22.5 mg/ 100 mg
FDC tablet (only subjects administered LDV/SOF FDC in tablet 
form).
Study visits will occur at Screening, Day 1, and at the end of 
Weeks 1, 2, 4, 8, and 12 (and Weeks 16, 20, and 24 for 
treatment-experienced subjects with cirrhosis). All Treatment Phase 
subjects will then return for follow-up visits at 4, 12 and 24 weeks 
after discontinuation of therapy. 
On-treatment assessments will include physical examination, vital 
signs (including body height and weight), AEs, concomitant 
medications, pregnancy prevention counseling (all subjects ≥12 years 
of age and subjects < 12 years of age at the discretion of the 
Investigator based on subject’s pubertal status), safety laboratory 
tests, coagulation tests, HCV RNA, viral sequencing, urine pregnancy 
tests (females of childbearing potential only), PK samples, a quality 
of life survey, and urinalysis. Tanner Pubertal Stage assessment will 
be performed at Day 1 and end of treatment visits; parental heights 
will be recorded at Day 1. The Bone Age Assessment will be 
performed at the Day 1 visit. If available, results from liver biopsies 
will be collected at screening. LDV/SOF FDC swallowability 
assessment will be performed at screening or up to Day 1 to assess a 
subject’s ability to swallow a placebo to match the 90 mg/ 400 mg or 
22.5 mg/ 100 mg LDV/SOF FDC tablet (only subjects administered 
LDV/SOF FDC in tablet form). For subjects continuing from the 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Final 
Amendment 2.0 
PK Lead-in, the screening, Day 1, and Week 1 visits of the Treatment 
Phase will not be required. Samples for viral RNA 
sequencing/phenotyping will be collected at Day 1 and eve1y visit 
thereafter. 
Post-treatment assessments will include vital signs (including body 
weight and height), symptom-directed physical examination, AEs 
(only SAEs will be captured at post-treatment Week 12 and 
post-treatment Week 24), concomitant medications (only 
post-treatment Week 4), safety laborat01y tests, HCV RNA, Tanner 
Pubertal Stage assessment (only post-treatment Week 12 and 
post-treatment Week 24), Bone Age Assessment (only post-treatment 
Week 24) and mine pregnancy tests (only females of childbearing 
potential at post-treatment Week 4 and post-treatment Week 12). 
PD 
PKLead-in: 
(Coh01i 1) LDV/SOF FDC is manufactmed as a tablet, consisting of 
400 mg SOF and 90 mg LDV, for oral administration. LDV/SOF 
FDC tablets will be administered once daily. Subjects unable to 
swallow the LDV/SOF FDC 90 mg/ 400 mg adult tablets (as 
detennined by LDV /SOF FDC Placebo swallowability assessment at 
Screening or at any time dming the study) will be re-assigned to 
4 x 22.5 mg/ 100 mg LDV/SOF FDC tablets daily. 
Intensive PK and safety results from the PK Lead-in of each Coh01t 
will be reviewed to confnm the appropriateness of the evaluated 
LDV/SOF FDC dose for the Treatment Phase of that Coh01t as well 
as to dete1mine the age-appropriate dose to be evaluated in the PK 
Lead-in of the next Cohort. 
Treatment Phase: 
Subjects who pruticipated in PK Lead-in of each Coh01t will continue 
in the Treatment Phase with no intenuption of study dmg 
administration until the appropriateness of the dose is confi1med by 
PK and safety data from the PK-Lead-in. Additional subjects will be 
em olled in the Treatment Phase of each Coh01t upon confmnation of 
the appropriateness of the dose. 
Reference Therapy: 
None 
CONFIDENTIAL 
Page 13 
08 December 2014 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 14
08 December 2014
Evaluation Criteria:
Safety:
AEs, laboratory tests, physical examinations, and vital sign 
measurements will be collected throughout the study. 
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using COBAS® AmpliPrep/COBAS® TaqMan®
HCV Test.
PK:
For subjects in the PK Lead-in, the steady-state PK of LDV, SOF,
and its major metabolites (GS-331007 and GS-566500) will be 
assessed at Day 10. For Cohorts 1 and 2, plasma samples will be 
collected for PK analyses following dosing of study drug on Day 10
at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, and 12 
hours postdose (with predose also serving as t= 24). For Cohort 3, 
plasma samples for PK analyses will be collected at the following 
time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours postdose (with 
predose also serving as t = 24).
Plasma PK parameters such as Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, and 
t1/2 will be estimated. 
For all subjects in the Treatment Phase, a single PK blood sample will 
be collected at all visits while on treatment. The PK of GS-331007,
SOF and LDV will be assessed.
The effect of age and LDV/SOF FDC dose on PK (GS-331007, SOF, 
and LDV) will be explored.
Statistical Methods:
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, Ctau, 
AUCtau, AUClast, and t1/2 will be estimated. The PK parameters will be 
summarized by cohort. The effect of age and LDV/SOF FDC dose on 
PK (GS-331007, GS-566500, SOF, and LDV) will be explored.
For the Treatment Phase, the primary safety endpoint is any AE 
leading to permanent discontinuation of study drug and will be 
summarized by treatment-experience and cirrhosis status, by age 
group, by GT, and by overall. The key efficacy endpoint is SVR12 in 
all enrolled and treated subjects and will be summarized by 
treatment-experience and cirrhosis status, by age group, by GT, by 
overall, and by age group and GT. Point estimate and its 
95% confidence interval will be provided. 
Subgroup analysis on SVR12 will be performed by 
treatment-experience and cirrhosis status, by IL28B genotype, and by 
GT. Other clinically relevant subgroup analyses may be conducted as 
appropriate (i.e., assuming that adequate numbers of patients in these 
subsets are available for analysis). 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 15
08 December 2014
All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation, median, Q1, Q3, minimum, 
and maximum). 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 by treatment-experience 
and cirrhosis status, by age group, by GT, by overall, and by age 
group and GT.
With approximately 100 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 
SVR12 rate will extend at most 5.9% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 90%.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 16
08 December 2014
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
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)
BLQ
below the lower limit of quantification
BMI
body mass index
CK
creatine kinase
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
dL
Deciliter
DNA
deoxyribonucleic acid
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
ESA
Erythropoiesis stimulating agent
ESPGHAN
European Society for Paediatric Gastroenterology
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed-Dose Combination
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
HAV
Hepatitis A Virus


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 17
08 December 2014
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
peginterferon alfa-2a
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
QD
once daily (use only in tables)
RBC
Red blood cell count
RBV
ribavirin
RNA
ribonucleic acid
SADR
Serious adverse drug reaction


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 18
08 December 2014
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
SAE
serious adverse event
SD
Standard deviation
SOC
Standard-of-Care
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TSH
Thyroid stimulating hormone
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant 
(λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 19
08 December 2014
1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease worldwide 
and accounts for 70% of cases of chronic hepatitis in industrialized countries. The global 
prevalence of chronic hepatitis C is estimated to average 3% {19705}. 
The natural history of chronic HCV-infection in children differs from that in adults since 
HCV-infection in children is relatively benign. Most children chronically infected with HCV are 
asymptomatic or have mild nonspecific symptoms. Clinical symptoms are present in 
approximately 20% of children in the first 4 years of life, with hepatomegaly being the most 
frequent sign (10%). Many, but not all, perinatally infected children will have intermittently or 
persistently abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
levels, particularly in the first 2 years of life. In children with vertical HCV-infection who have 
undergone liver biopsy, the histological spectrum is usually mild, although severe liver disease is 
encountered {19801}. Despite the overall more favorable prognosis compared to adults, 
approximately 4% to 6% of children with chronic HCV-infection have evidence of advanced 
fibrosis or cirrhosis and some children eventually require liver transplantation for end-stage liver 
disease as a consequence of HCV-infection {19799}.
The goal of HCV treatment in both pediatric and adult populations is eradication of the virus, 
thereby preventing hepatic inflammation, hepatic fibrosis, cirrhosis, and liver failure resulting in 
either death or need for liver transplantation. This goal, however, is limited by the nature of the 
disease and the fact that not all patients are suitable candidates for currently approved treatments. 
In addition, pediatric treatment is controversial as the current treatment options are limited and 
severe side effects and tolerability can significantly limit or preclude their use. Despite 
well-established guidelines for the treatment of HCV in adults, there is no universal consensus 
on when or if to treat chronic HCV-infection in children. In 2010, the European Society for 
Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) issued guidance for clinical 
trial development for chronic HCV-infection in children {20286}. In the guideline, the 
ESPGHAN suggested that the primary goal of treatment in children is to eradicate the infection 
to prevent late complications. Hence, the goal is not the treatment of an ongoing liver disease, 
but rather the prevention of a future one.
PEG and weight-based RBV are currently considered the SOC for the treatment of 
HCV-infection in children. Current recommendations are that patients with GT-2 or GT-3 be 
treated with PEG+RBV for 24 weeks and those with GT-1 or GT-4 should receive 48 weeks of 
therapy. Successful treatment of GT-1, however, has proved very difficult to achieve in spite of 
additional therapy or increased duration of treatment. A number of pediatric studies have 
reported that despite 48 weeks of treatment, sustained virologic response (SVR24) was observed 
in only 36% to 53% of subjects with GT-1, while response rates were > 80% in subjects with 
GT-2 or GT-3 {20285}.


LDV/SOF FDC
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Amendment 2.0
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Most children treated with PEG+RBV experience at least 1 adverse event due to treatment 
{20285}. Although most of these events are mild to moderate in severity, many of them result in 
dose reductions of 1 or both of the drugs. The most common adverse events have consisted of 
influenza-like illness (91%), headache (62%), and injection site reactions (45%), often leading to 
poor compliance and/or discontinuation from treatment.
Additionally, the concern for growth and development in this age group and the role that both 
PEG and RBV potentially play in reducing growth rates has initiated significant debate among 
pediatric hepatologists as to whether these treatments should even be considered in the pediatric 
population {20282}. Many pediatricians currently advocate delay of treatment past adolescence 
or even into adulthood when options with DAAs are possible {20282}. Unfortunately, in the 
25% of pediatric patients who do meet the criteria for treatment (elevated transaminases and viral 
loads), the option of PEG+RBV therapy remains inadequate in regard to both efficacy in GT-1 
and safety due to the many risks associated with this treatment.
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
Ledipasvir/Sofosbuvir fixed-dose combination (LDV/SOF FDC) combines two HCV specific 
direct acting antiviral (DAA) agents into a single tablet for the treatment of chronic 
HCV-infection. SOF is a nucleotide analog that is a potent and selective inhibitor of 
NS5B-directed HCV replication with demonstrated activity against GT 1-6 HCV-infection. 
Ledipasvir (LDV) is a novel HCV NS5A inhibitor that has demonstrated potent anti-HCV 
activity, with the highest activity against GT1 HCV-infection. Harvoni® (LDV/SOF FDC) has 
been approved in the United States by the Food and Drug Administration (FDA) for treatment of 
HCV infection GT-1 adult patients. Harvoni® is indicated for either treatment-naïve or 
treatment-experienced subjects with or without cirrhosis with a 12 or 24 week treatment 
duration. For treatment-experienced subjects with cirrhosis a 24 week treatment duration is 
recommended. Harvoni® is also approved in the EU for treatment of HCV infection GT-1 and 
GT-4 adult patients as outlined above and for GT-3 treatment-experienced adults with cirrhosis 
and/or prior treatment failure subjects for 24 weeks treatment duration with ribavirin (RBV).
1.2.1.
Summary of Additional Clinical Experience with Ledipasvir/Sofosbuvir 
Fixed-Dose Combination
The LDV/SOF FDC phase 3 program consisted of 3 clinical studies: GS-US-337-0102 {28583}, 
GS-US-337-0109 {28585}, and GS-US-337-0108 {28587}. Studies GS-US-337-0102 and 
GS-US-337-0109 evaluated treatment with LDV/SOF FDC RBV for 12 or 24 weeks in 
treatment-naïve and treatment experienced subjects, respectively, infected with GT-1 HCV. Both 
studies enrolled up to 20% of HCV-infected subjects who had documented compensated 
cirrhosis. GS-US-337-0108 evaluated LDV/SOF FDC ± RBV treatment for 8 weeks and 
LDV/SOF FDC treatment for 12 weeks in non-cirrhotic treatment-naïve subjects with GT-1 
HCV-infection. Across these 3 clinical studies, LDV/SOF FDC demonstrated a high degree of 
efficacy (> 93%) for treatment-naïve and treatment experienced subjects with GT-1 
HCV-infection in subjects with and without cirrhosis and achieved their primary efficacy 
endpoints {28583}; {28585}; {28587}. Additionally, treatment with LDV/SOF FDC ± RBV was 
safe and well tolerated in the Phase 3 studies {28583}; {28585}; {28587}.  The inclusion of RBV 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 21
08 December 2014
to the treatment regimen was associated with an increase in the total incidence of adverse events 
and in graded laboratory abnormalities of anemia and increased bilirubin. 
Please refer to the Investigator’s Brochure (IB) for additional information on the LDV/SOF FDC 
including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.3.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with LDV/SOF 
FDC for adolescents and children with chronic HCV-infection. 
Currently PEG and weight-based RBV are considered the SOC for the treatment of 
HCV-infection in children. Therefore, there is a need for new treatments for HCV in the 
pediatric population that combine potent and sustained efficacy with improved tolerability and 
safety. The primary aim for new treatments of pediatric patients with HCV is to eliminate the 
need to use PEG. In this way, pediatric patients would be able to avoid the necessity of weekly 
injections which can be traumatic and burdensome, and significantly reduce the serious adverse 
events seen with PEG administration. The secondary aim is to eliminate RBV and the adverse 
events seen with its administration.
Harvoni® (LDV/SOF FDC) is approved in the US and EU for the treatment of adults with 
chronic HCV infection. LDV/SOF FDC would provide an all-oral, IFN-free regimen with a 
shorter treatment duration (12 or 24 weeks of LDV/SOF FDC treatment versus standard-of-care 
24 to 48 weeks of treatment) for GT-1 HCV infection subjects and would offer another important 
option in the treatment of HCV infection in the pediatric population.
In vitro viral replicon assay have data demonstrated that LDV has potent, picomolar antiviral 
activity against GT-1a and GT-1b HCV-infection. In the LDV/SOF FDC phase 3 program, 
LDV/SOF FDC without RBV has been shown to have good efficacy and safety in adults infected 
with GT-1 HCV-infection.  In study GS-US-337-0122, a phase 2 open-label study of GT-3 
treatment-naïve adult subjects with and without cirrhosis, LDV/SOF FDC for 12 weeks resulted 
in an SVR12 of 64% whereas LDV/SOF + RBV for 12 weeks resulted in an SVR of 100% 
{29292}.  As a result, the current study which does not include RBV in the treatment regimen 
will initially only enroll pediatric subjects with GT-1 HCV-infection and will not enroll subjects 
with GT-3.


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 2.0
CONFIDENTIAL
Page 22
08 December 2014
Considering that SOF has pan-genotypic activity and LDV has in vitro, picomolar to nanomolar 
antiviral activity against certain subtypes within GT 4-6 and sub-micromolar antiviral activity 
against certain subtypes within GT-2, studies have been planned and/or initiated with LDV/SOF 
FDC in adult subjects with GT-2, -4, -5, and -6.  If emerging LDV/SOF FDC data in these 
additional GTs support treatment in these genotypes in adults, pediatric subjects with 
GT-2, -4, -5 and -6 will be enrolled in the current study.  Of note, there is an ongoing study 
enrolling GT-2 and -3 pediatric patients, GS-US-334-1112, for treatment with SOF + RBV for 
12 and 24 weeks, respectively.
1.4.
Rationale for Dose Selection of LDV/SOF FDC
Ledipasvir /Sofosbuvir (90 mg/400 mg) fixed-dose combination tablet, administered once daily, 
has demonstrated favorable safety and efficacy profiles in over 1952 HCV-infected subjects 
across different patient populations in phase 2 and 3 clinical trials. This is the marketed dose of a 
ledipasvir/sofosbuvir fixed-dose combination tablet for the treatment of HCV-infection in adults.
Selection of doses of LDV/SOF FDC for adolescents and younger age groups will target 
systemic exposures similar to those observed in adults at the proposed marketed dose and taking 
into account body weight/body surface area, the potential ontogenic changes in intestinal and 
hepatically expressed carboxylesterase (CES1) and Cathepsin A (CatA) enzymes, the drug 
transporter p-glycoprotein (Pgp), and the results obtained in older age groups.  Available data 
suggests comparable hepatic expression of CES1 in adolescents and adults with modestly 
decreased expression in children.  However, little is known about the developmental regulation 
of Pgp, CES, and CatA.  As such, the adult clinical doses (90 mg/ 400 mg) will be evaluated in 
adolescents (12 to <18 years old).  Safety and PK data in the adolescent group (Cohort 1) in the 
PK Lead-in, in addition to body weight/body surface area will inform dose selection for the 
younger age groups.
Age-appropriate formulations of LDV/SOF FDC (a smaller, 22.5 mg/ 100 mg strength tablet and 
a non-tablet formulation currently under development) that offer an important option in the 
treatment of HCV-infection in the pediatric population are planned for evaluation in children 
below 12 years of age or children who are unable to swallow the adult dose tablet formulation.
1.5.
Overall Risk/Benefit Assessment
Although the majority of pediatric patients infected with HCV exhibit minimal hepatic sequelae 
despite active viral replication and inflammation, a subset of children and adolescents will 
require treatment. Studies suggest that 3 major categories of disease can occur within 10 years 
after putative HCV exposure: (1) undetectable viremia and normal ALT, (2) persistent yet 
uncomplicated mild liver disease, and (3) progression to end-stage liver disease {20273}. It is the 
last two groups of children in whom therapy may be indicated to prevent end-stage disease, 
either during childhood/adolescence or in early adulthood.


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 2.0
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Page 23
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Given that the current SOC for the treatment of children infected with HCV is PEG and RBV 
and these regimens are long in duration, relatively toxic, and not well tolerated, there continues 
to be a need for new treatments for HCV that combine potent and sustained efficacy with 
improved tolerability and safety. 
The combination of LDV plus SOF is anticipated to offer greater antiviral efficacy which could 
result in a shorter treatment duration and/or lead to a regimen without RBV or interferon. These 
in turn could result in reduction in adverse events.  LDV/SOF FDC could also potentially be of 
benefit in patients who have failed prior treatment with SOF+/-RBV+/- PEG.
If high rates of SVR can be obtained with short, well-tolerated regimens, the anticipated 
improvements in safety and tolerability would offer a favorable risk-benefit determination for 
individuals with chronic HCV-infection.


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
2. 
OBJECTIVES 
The prima1y objective of the PK Lead-in Phase of this study is: 
Final 
Amendment 2.0 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose ofLDV/SOF FDC 
in chronic HCV-infected pediatric subjects 
The secondruy objective of the PK Lead-in Phase of this study is: 
• 
To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing ofLDV/SOF 
FDC in chronic HCV -infected pediatric subjects 
The primary objective of the Treatment Phase of this study is: 
• 
To evaluate the safety and tolerability ofLDV/SOF FDC for 12 or 24 weeks in chronic 
HCV -infected pediatric subjects 
The secondruy objectives of the Treatment Phase of this study ru·e: 
• 
To dete1mine the antiviral efficacy of 12 or 24 weeks ofLDV/SOF FDC treatment in chronic 
HCV-infected subjects (including the impact ofHCV genotype, IL28B genotype, and prior 
treatment experience), as assessed by the proportion of subjects with SVR 12 weeks after 
completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of 12 or 24 weeks ofLDV/SOF FDC treatment in chronic 
HCV -infected subjects, as assessed by the prop01iion of subjects with SVR 4 and 24 weeks 
after completion of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment 
• 
To evaluate the effect of growth and development on pediatric subjects during and after 
treatment 
The explorat01y objective of this study is: 
• 
PD 
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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and antiviral 
activity of LDV/SOF FDC in chronic HCV-infected pediatric subjects.
3.1.1.
PK Lead-in
The PK Lead-in Phase will evaluate and/or confirm the age appropriate LDV/SOF FDC dose by 
analyzing PK, safety, and antiviral activity of LDV/SOF FDC through 10 days of dosing for each 
cohort. Children aged 3 to < 6 years, children aged 6 to < 12 years, and adolescents aged 12 to 
< 18 years with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry will be 
evaluated. Subjects must be treatment naïve without history of cirrhosis to participate in the PK 
Lead-in Phase. Three cohorts of at least 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old, weighing ≥45kg

Cohort 2:  6 to < 12 years old 

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive LDV/SOF FDC (90 mg/ 400 mg 
adult tablet or 4 x 22.5 mg/100 mg tablets if determined necessary based on LDV/SOF FDC
swallowability assessment) for 10 days with intensive PK conducted on Day 10. 
Following completion of study treatment in the PK Lead-in of Cohort 1 and pending PK and 
safety results, the PK Lead-in of Cohort 2 will initiate and receive study treatment 
(age appropriate dose and formulation). Following completion of study treatment in the PK 
Lead-in of Cohort 2 and pending PK and safety results, the PK Lead-in of Cohort 3 will initiate 
and receive study treatment (age-appropriate dose and formulation). 
Subjects enrolled in the PK Lead-in of each cohort (Cohorts 1, 2 and 3) will immediately enroll 
in the Treatment Phase as they complete Day 10 of PK Lead-in.  They will continue dosing with 
LDV/SOF FDC with no interruption of study drug administration.  Subjects rolling over from the 
PK Lead-in Phase will not be required to perform the screening, Day 1, or Week 1 visit of the 
Treatment Phase.


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Figure 3-1.
PK Lead-in Phase Study Schema
3.1.2.
Treatment Phase
The Treatment Phase will be initiated sequentially by age group as defined in Cohort 1, 2, and 3 
of the PK Lead-in. Subjects who participated in PK Lead-in will immediately rollover into 
Treatment Phase with no interruption of study drug administration until the appropriateness of 
the dose has been confirmed by PK and safety results from the PK Lead-in.  The first visit in the 
Treatment Phase for these subjects will be the Week 2 visit.  Additional subjects will be enrolled 
in the Treatment Phase of each Cohort upon confirmation of the appropriateness of the dose from 
the PK Lead-in.
Children aged 3 to < 12 years (Group 2) and adolescents aged 12 to < 18 years (Group 1) with 
chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry (those who were dosed in 
the PK Lead-in will have met this criteria prior to enrollment) will be evaluated.
Subjects enrolled in the Treatment Phase will receive the following regimen:

Treatment-naïve with or without cirrhosis: LDV/SOF FDC for 12 weeks

Treatment-experienced without cirrhosis: LDV/SOF FDC for 12 weeks

Treatment-experienced with cirrhosis: LDV/SOF FDC for 24 weeks
Subjects with GT 1 will be enrolled first.  If emerging LDV/SOF FDC data in GT-2, -4, -5, 
and -6 support treatment in these GTs in adults, pediatric subjects with GT-2, -4, -5, and -6 will 
be subsequently enrolled.  


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The study will enroll both treatment naïve and treatment experienced pediatric subjects with up 
to 40 subjects allowed to be treatment experienced. Approximately 200 total subjects, including 
subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as follows:

Group 1: Approximately 100 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 100 pediatric subjects (3 to < 12 years of age)
The following definitions will be used for treatment experienced subjects:

Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to 
≥1 adverse event

Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels 
while on treatment

Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment 
or within 4 weeks of the end of treatment but did not achieve a sustained virologic 
response (SVR)
All subjects who do not attain SVR or have viral relapse will be encouraged to discuss treatment 
with SOC therapy with their healthcare provider.
Figure 3-2.
Treatment Phase Study Schema
3.2.
Visit Schedule
3.2.1.
PK Lead-in
Screening assessments will be completed within 28 days of the Day 1 visit. 
Study Visits will occur at Screening, Day 1, Day 3, and Day 10.


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Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in Phase will participate in an 
intensive PK evaluation on Day 10. Subjects will be administered a dosing diary with 
instructions.  
Following completion of the Day 10 intensive PK visit, subjects will then return for scheduled 
study visits outlined in the Treatment Phase and continue dosing with LDV/SOF FDC with no 
interruption of study drug administration.  Subjects rolling over from the PK Lead-in Phase will 
not be required to perform the screening, Day 1, or Week 1 visits of the Treatment Phase.
3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. Subjects continuing 
from the PK Lead-in Phase will not be required to complete Screening, Day 1, and Week 1 visits 
of the Treatment Phase.

Treatment-naïve (with or without cirrhosis) and treatment-experienced (without 
cirrhosis) subjects: Study visits will occur at Screening, Day 1, and the end of weeks 1, 2, 4, 
8, and 12.

Treatment-experienced (with cirrhosis) subjects: Study visits will occur at Screening, 
Day 1, and the end of weeks 1, 2, 4, 8, 12, 16, 20, and 24.
All subjects will then return for follow-up visits at 4, 12, and 24 weeks after discontinuation of
therapy.
The total time to complete all study visits is approximately 40 or 52 weeks including:

28 day (4 week) screening period

12 or 24 week treatment period

24 week post-treatment period
The assessments performed at each visit are described in Section 6.
3.3.
Virologic Response-Based Stopping Criteria
HCV RNA will be unblinded to the Investigator and Sponsor.
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 from nadir 

HCV RNA ≥LLOQ through 8 weeks of treatment


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Amendment 2.0 
Confinnation should be perf01m ed as soon as possible but within 2 weeks after dete1mination of 
initial observation. Subjects that meet the virologic response-based stopping criteria above will 
be notified of their eligibility to pmiicipate in the Long-T enn Follow-Up Study 
(GS-US-334-1113). 
3.4. 
Treatment Discontinuations Criteria 
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances: 
• 
Unacceptable toxicity (as defmed in Section 7 of the protocol) or toxicity that, in the 
judgment of the investigator, compr01nises the ability to continue study-specific procedures 
or is considered to not be in the subject's best interest. 
• 
Pregnancy of female subject or female pminer of male subject. 
• 
Efficacy failure as defmed in Section 3.3. 
• 
Significant protocol violation including non-compliance with study assessments. 
• 
Subject request to discontinue for any reason; it is imp01i ant to dete1mine 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, regulat01y agency, or an Institutional 
Review Bom·d (IRB)/Independent Ethics Committee (IEC). 
3.5. 
Discontinuations 
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Em·ly Te1mination visit as described in the Section 6.4.8. 
Subjects who pennanently discontinue the study dmg for any reason including safety and/or 
tolerability concems prior to completion of the assigned dosing period will be followed 
according to the post-treatment study assessments described in Section 6.5. 
3.6. 
Pharmacogenomic Substudy 
PD 
3.7. 
Long-Term Follow-Up 
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed eve1y 6 months for 
assessments of growth, quality of life, and long-te1m viral suppression (if applicable) in a 
separate protocol (GS-US-334-1113). This follow-up study will continue for 5 years. 
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3.8.
Breakthrough Futility Assessment
A futility assessment will be performed after the first 10 subjects complete Week 8 on study or 
have viral breakthrough at or prior to Week 8. If 3 or more of the first 10 subjects enrolled have 
viral breakthrough at or prior to Week 8 or are non-responders (HCV RNA > LLOQ through 
8 weeks of treatment) then further enrollment of subjects will be suspended. Virologic 
breakthrough is defined as confirmed HCV RNA > LLOQ while on treatment after 
two consecutive visits with HCV RNA < LLOQ.
Subjects with known or suspected study drug non-adherence will not be considered to meet the 
definition of virologic breakthrough, relapse, or non-responder. 
3.9.
Reconsent
When a subject reaches the age of consent in their country/region, they will be invited to consent 
as adults to allow them to continue participating in the clinical trial.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 200 subjects will be enrolled in this study.
In order to manage the total study enrollment, Gilead Sciences, Inc. at its sole discretion, may 
suspend screening and/or discontinue the enrollment at any site at any time (upon written notice 
to the site). Discontinuation of the enrollment phase may result in the immediate ineligibility of 
all subjects screened but not yet enrolled, regardless of the progress or outcome of the screening 
assessments performed.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1. Parent or legal guardian able to provide written informed consent prior to any screening 
evaluations and willing to comply with study requirements.  Subjects will provide assent if 
possible.
2. 3 years to < 18 years of age as determined at Day 1 (consent of parent or legal guardian 
required)
3. PK Lead-in only: subjects in Cohort 1 (age 12 to <18 years of age) must weigh 45 kg
4. PK Lead-in only: all subjects must be treatment naïve: no prior exposure to any IFN, RBV, 
or other approved or experimental HCV-specific DAA agent
5. Treatment experienced subjects:  prior treatment failure to a regimen including interferon 
either with or without RBV that was completed at least 8 weeks prior to Day 1.
i.
Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to 
≥1 adverse event
ii.
Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels 
while on treatment
iii.
Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment 
or within 4 weeks of the end of treatment but did not achieve a sustained virologic 
response (SVR)


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6. 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 Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV-infection
7. Infection with HCV as determined at Screening. The study will commence with GT-1 
HCV-infected pediatric subjects and will subsequently enroll subjects with GT-2, -4, -5 
and -6 once adult data is available, if appropriate. 
8. HCV RNA ≥1000 IU/mL at Screening
9. Adequate hematologic function (absolute neutrophil count 1,500/mm3; 
hemoglobin 11 g/dL).
10. Negative serum -HCG pregnancy test (for females of childbearing potential only, as defined 
in Appendix 5)
11. Subject able to provide written assent, if they have the ability to read and write, as 
determined by IRB/IEC/local requirements and Investigator’s discretion
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Pregnant or lactating subjects
2. Sexually-active males or females of childbearing potential who are not willing to use an 
effective method of contraception during the study (see Appendix 5 for further details)
3. Infection with GT-3 HCV as determined at Screening.
4. Decompensated liver disease defined as INR 1.2 ULN, platelets 50,000/mm3, serum 
albumin 3.5 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, 
jaundice, encephalopathy, variceal hemorrhage)
5. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
6. -fetoprotein 50 ng/mL
7. Serum creatinine > 1.5 mg/dL
8. Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula


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9. Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of 
certain resolved skin cancers)
10. Co-infection with HIV, acute HAV, or HBV
11. Significant cardiovascular, pulmonary, or neurological disease
12. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications
13. History of solid organ or bone marrow transplantation
14. Chronic daily non-steroidal anti-inflammatory drug therapy
15. Systemic corticosteroid use for > 2 weeks (pulmonary/nasal administration is permitted)
16. Investigational agents taken within the past 28 days (except with the expressed approval of 
the Sponsor)
17. Clinically-relevant alcohol or drug abuse within 12 months of screening.  A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator
18. Known hypersensitivity to the study drug, the metabolites, or formulation excipients
19. Any other condition (including alcohol or substance abuse) or prior therapy that, in the
opinion of the Investigator, would make the subject unsuitable for the study or unable to 
comply with dosing requirements
20. Use of any prohibited concomitant medications as described in Section 5.4
21. PK Lead-in only: subjects with history of cirrhosis 


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
5.2.1.
Description and Handling 
5.2.1.1.
Formulation
LDV/ SOF FDC tablets are orange, diamond-shaped, film-coated tablets containing 90 mg of 
LDV and 400 mg of SOF. The tablets are debossed with “GSI” on one side and “7985” on the 
other side. The LDV/SOF 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.
Placebo to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment are 
orange, diamond-shaped, film-coated tablets debossed with “GSI” on one side and “7985” on the 
other side. The tablets contain lactose monohydrate, copovidone, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, 
polyethylene glycol, FD&C yellow # 6 /sunset yellow FCF aluminum lake.
Age-appropriate formulations of LDV/SOF FDC have been developed for subjects who are 
unable to swallow the LDV/SOF FDC 90 mg/ 400 mg tablets which include a lower dose 
strength tablet (LDV/SOF FDC 22.5 mg/ 100 mg) formulation. LDV/ SOF FDC lower dose 
strength tablets are round, plain-faced, white film-coated tablets containing 22.5 mg of LDV and 
100 mg of SOF. The LDV/SOF FDC lower dose strength tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc 
and polyethylene glycol.
Placebos to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment are 
round, plain-faced, white film-coated tablets. The placebo tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc and polyethylene glycol.
The non-tablet LDV/SOF FDC formulation will be based on the PK results obtained from 
cohorts 1 and/or 2 of this study. The formulation, composition, acceptability (including 
palatability) will be available and reflected in a protocol amendment which will be submitted for 
approval prior to dosing subjects who are unable to swallow tablets.


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5.2.1.2.
Packaging and Labeling
LDV/ SOF FDC 90 mg/ 400 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 or 30 tablets, a silica gel desiccant, and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child resistant screw 
cap with an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
a silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant screw cap with an induction-sealed, aluminum faced liner.
LDV/SOF FDC 22.5 mg/ 100 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets, a silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child resistant screw cap with 
an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
a silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant screw cap with an induction-sealed, aluminum faced liner.
The packaging and labeling of the non-tablet LDV/SOF FDC formulation will be based on the 
chosen formulation. The packaging and labeling will be available and reflected in a protocol 
amendment which will be submitted for approval prior to dosing subjects who are unable to 
swallow tablets.
All LDV/SOF FDC and placebo to match LDV/SOF FDC bottles to be distributed in the US, 
EU, and the rest of the countries shall be labeled to meet all applicable requirements of the 
US Food and Drug Administration (FDA), Annex 13 of Good Manufacturing Practices: 
Manufacture of investigational medicinal products (February 2010), and/or other local 
regulations as applicable.
5.2.2.
Storage and Handling
LDV/ SOF FDC tablets, 90 mg/ 400 mg, should be stored at controlled room temperature until 
required for administration. Controlled room temperature is defined as 25 °C (77 °F); excursions 
are permitted between 15 °C and 30 °C (59 °F to 86 °F).
Placebo to match LDV/ SOF FDC tablets, 90 mg/ 400 mg, for Swallowability Assessment 
should be stored at controlled room temperature until required for administration. Controlled 
room temperature is defined as 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C 
(59 °F to 86 °F).  
LDV/SOF FDC tablets, 22.5 mg/ 100 mg, should be stored at controlled room temperature until 
required for administration. Controlled room temperature is defined as 25 °C (77 °F); excursions 
are permitted between 15 °C and 30 °C (59 °F to 86 °F).


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Placebo to match LDV/ SOF FDC tablets, 22.5 mg/ 100 mg, for Swallowability Assessment 
should be stored at controlled room temperature until required for administration. Controlled 
room temperature is defined as 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C 
(59 °F to 86 °F).
The storage and handling of the non-tablet LDV/SOF FDC formulation will be based on the 
chosen formulation. The storage and handling will be available and reflected in a protocol 
amendment implemented prior to dosing subjects who are unable to swallow tablets.
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 
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 
LDV/SOF FDC.
Sufficient quantities of LDV/SOF FDC tablets, non-tablet LDV/SOF FDC formulation, and 
placebo tablets will be shipped to the investigator or qualified designee from Gilead Sciences 
(or its designee).
5.2.3.
Dosage and Administration of LDV/SOF FDC
PK Lead-in: (Cohort 1) LDV/SOF FDC 90 mg/ 400 mg tablets will be administered once daily 
with or without food. Subjects determined unable to swallow the placebo to match the 
90 mg/ 400 mg LDV/SOF FDC tablet (by LDV/SOF FDC Placebo Swallowability Assessment 
at Screening up to Day 1) will be re-assigned to 4 x 22.5 mg/ 100 mg tablets daily.  Subjects who 
weigh < 45 kg will be excluded.
Intensive PK and safety results from the PK Lead-in of each Cohort will be reviewed to confirm 
the appropriateness of the evaluated LDV/SOF FDC dose for the Treatment Phase of that Cohort 
as well as to determine the age-appropriate dose to be evaluated in the PK Lead-in of the 
next Cohort.
Treatment Phase: Subjects who participated in the PK Lead-in of each Cohort will continue in 
the Treatment Phase with no interruption of study drug administration until the appropriateness 
of the dose is confirmed by PK and safety data from the PK-Lead-in.  Additional subjects will be 
enrolled in the Treatment Phase of each Cohort upon confirmation of the appropriateness of the 
dose.  
An additional age-appropriate formulation for LDV/SOF FDC Oral Granulates is currently under 
development. The dose for this formulation will be dependent on the PK results obtained from 
Cohorts 1 and/or 2 of this study. The strength, composition, and dosing administration will be 
available and reflected in a protocol amendment which will be submitted for approval prior to 
dosing subjects who are unable to swallow tablets.


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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.
5.3.
Study Drug Compliance
Subjects will be instructed to return any unused LDV/SOF FDC in the original container on 
Day 3 (PK Lead-in), Day 10 (PK Lead-in), and/or at study treatment visits every 4 weeks
(Treatment Phase).  
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.4.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 30 days 
after the last dose of study drug, need to be recorded in the source documents and electronic case 
report form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment:

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 i.e., P-gp) with study drug(s) may result in PK interactions resulting in 
increases or decreases in exposure of study drug(s). Examples of representative medications 
which are prohibited from 21 days prior to 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
Anticonvulsantsc
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Cardiac Medications b
Digoxin, Dabigatran
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinaccea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsd
Rosuvastatin
Atorvastatin, Simvastatin, Pravastatin, 
Pitavastatin, Fluvastatin, Lovastatin
a
It is recommended to separate antacid and LDV/SOF FDC administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF FDC at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with LDV/SOF FDC or up to 2 hours after taking LDV/SOF FDC. Proton-pump inhibitors should not be 
taken before LDV/SOF FDC. 
b
May result in an increase in the concentration of study drug and/or concomitant medications. Co-administration of 
LDV/SOF FDC with digoxin or dabigatran may increase the concentration of digoxin or dabigatran. Caution is warranted 
and therapeutic concentration monitoring of digoxin or clinical monitoring of dabigatran is recommended when 
co-administered with LDV/SOF FDC. 
c
May result in a decrease in the concentrations of study drug.
d
Use with study drug 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 (e.g., active cancer, 
transplantation) are not listed under this Concomitant Medication section and are disallowed in 
the study.


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6.
STUDY PROCEDURES
All subjects will complete screening, on-treatment, and post-treatment assessments. Screening 
assessments will be completed within 28 days of the Day 1 visit. The end of study will occur at 
the 24-week Post-Treatment visit. The schedule of assessments is described below. 
Information on the specific laboratory parameters to be measured and clinical assessments to be 
performed are provided in Section 6.6.
6.1.
Subject Enrollment 
Each candidate’s parent or legal guardian must sign an Informed Consent Form prior to the
conduct of any screening procedures. Each study candidate who has the ability to read and write
must sign an Assent Form, as required by IRB/IEC/local requirements, prior to the conduct of 
any study procedures. Screening evaluations will be used to determine the eligibility of each 
candidate for study enrollment. Candidates who fail to meet eligibility criteria by screening 
evaluations may be re-screened once ≥ 30 days after the initial screen if there is a reasonable 
expectation that the candidate will be eligible after repeat screening.
6.2.
Screening Assessments
6.2.1.
Screening Visit (Day –28 to Day 0)
Subjects will complete all screening assessments within 28 days of the Day 1 visit. The screening 
window can be extended to 42 days for subjects requiring additional HCV GT testing or for 
extenuating circumstances.
The following procedures will be performed and documented:

Written informed consent from parent or legal guardian and assent from subject, if applicable 
(see above)

Medical history, including:
— Hepatitis C history
— Hepatitis C treatment history
— Family history, including height of parents
— Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate) and body weight and height


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
Obtain blood samples for tests as listed in Section 6.6.1:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Determination of HCV viral GT and subtype
— HCV antibody, HIV 1/2 antibody, and HBs antigen, HAV antibody
— HbA1c
— TSH
— IL28B
— Serum -hCG pregnancy test for females of childbearing potential only
— Alpha fetoprotein (AFP)
— Alpha-1 anti-trypsin (ATT)

Obtain urine sample for:
— Urinalysis
— Urine Drug Screen

Review of concomitant medications

Ask subject and/or parent/legal guardian if the subject is able to swallow and tolerate taking 
pills.

Review of all inclusion and exclusion criteria

Perform LDV/SOF FDC swallowability assessment 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the Day 1 visit assessments.


LDVISOFFDC 
Protocol GS-US-337-1116 
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6.3. 
PK Lead-in: Treatment Assessments 
6.3.1. 
Day l 
Final 
Amendment 2.0 
After confnmation of eligibility has been evaluated, the following tests and procedmes must be 
completed prior to emollment and dosing/dispensing on Day 1: 
• 
Perf01m complete physical examination 
• 
Tanner Pubertal Stage Assessment 
• 
Vital signs, including body weight and height measmements 
• 
A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pruiicipants (all subj ects ~ 12 yeru·s of age and subjects < 12 yeru·s of age at the discretion of 
the Investigator based on subject's pube1i al status) 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (ru·chive) 
_ 
PD 
• 
Obtain mine samples for the following procedmes: 
-
Urinalysis 
-
~ -hCG pregnancy test for females of childberu·ing potential only 
• 
Subject completes quality of life smvey: Subject is to review questionnaire with a 
parent/guardian and write/mru·k answers directly onto the questionnaire. 
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08 December 2014 


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6.3.1.1.
Drug Administration

Dispense study drug as directed by the IWRS

Instruct the subject on the packaging, storage and administration of study drug

Perform LDV/SOF FDC swallowability assessment (for subjects administered LDV/SOF 
FDC in tablet form only if not previously completed at screening).  Observe the subject 
taking the first dose of study drug (with or without food) and record the time of first dose

Subjects will be administered a dosing diary with instructions.
6.3.2.
Day 3
The following procedures/assessments are to be completed on Day 3:

Perform a symptom-directed physical examination as needed

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Review medication compliance with subject and/or subject’s parent/guardian

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 10 – Intensive PK 
The Day 10 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 10 Intensive PK visit may 
be performed within +3 days of the protocol-specified visit date (subjects will continue 
daily dosing through the Intensive PK Visit).
Subjects should come in a fasted state for the Day 10 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 10 Intensive PK visit). Subjects and/or
parents/guardians should be instructed that the Day 10 dose of LDV/SOF FDC must not be taken 
until the evaluations listed below are completed. 


LDV/SOF FDC
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Amendment 2.0
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If the subject has already dosed prior to the Day 10 clinic visit or is not in a fasted state, the 
Day 10 intensive PK assessments must not be completed. The subject and/or parents/guardians 
should be instructed to return in a fasted state within 3 days (Days 11, 12, or 13) for the intensive 
PK visit. 
If dosing non-compliance is identified as per subject dosing diary and pill count on or prior to the 
Day 10 visit, the Day 10 intensive PK assessments must not be completed. The subject and/or 
parents/guardians should be counseled regarding proper dosing and be scheduled to return for the 
Day 10 intensive PK visit no sooner than 3 days following compliant dosing and no later than 
Day 14 (i.e., return on Day 13 or Day 14).  If dosing non-compliance is due to an AE, 
consultation with the Gilead Medical Monitor is required regarding the potential of rescheduling 
the Day 10 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded not 
to take the LDV/SOF FDC prior to arriving at the clinic on the day of the re-scheduled intensive 
PK visit. All Day 10 intensive PK assessments listed below should be completed when the 
subject returns.
The following evaluations are to be completed at the Day 10 Intensive PK visit:

Perform a symptom-directed physical examination 

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Perform study drug accountability 

Review Subject Dosing Diary

Review medication compliance with subject and/or parent/guardian.

Obtain urine samples for the following procedures:
— Urinalysis
— Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test 
is positive, the Intensive PK sampling will not be completed. The positive result will be 
confirmed with a serum pregnancy test. 

Obtain blood samples for the following laboratory analyses:
— Hematology 
— Chemistry 
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)


LDV/SOF FDC
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
Perform intensive PK sampling: 
Blood samples will be collected at 0 (predose, ≤30 minutes prior to dosing). After 
collection of the predose sample, subjects will be provided a standardized meal. Within 
5 minutes after consuming the standardized meal, subjects will be dosed with LDV/SOF 
FDC per dosing requirements.
Post-dose blood samples will be collected as follows: 
■
For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 5, 8, and 12 hours post-dose (with predose also 
serving as t= 24).
■
For Cohort 3 only: 0.5, 2, 4, 8, and 12 hours post-dose (with predose also serving as 
t = 24).
Subjects will be restricted from food intake until after collection of the 4-hour post dose 
blood sample, except for subjects in Cohort 3. Please also refer to the PK manual for 
details about standardized meals and PK sample processing instructions.
After completing the Day 10 intensive PK visit subjects will then continue to the Week 2 visit in 
Treatment Phase (described in Section 6.4.2) with no interruption in dosing.
6.4.
Treatment Phase: Treatment Assessments 
6.4.1.
Day 1
After confirmation of eligibility has been evaluated, the following tests and procedures must be 
completed prior to enrollment and dosing/dispensing on Day 1:

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements 

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Review of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status). 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (archive) 
_ 
PD 
• 
Obtain urine sample for: 
-
Urinalysis 
-
~ -hCG pregnancy test for females of childbearing potential only 
Final 
Amendment 2.0 
• 
Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire 
• 
Perf01m LDV/SOF FDC swallowability assessment (for subjects administered 
LDV /SOF FDC in tablet f01m only if not previously completed at screening) 
6.4.1.1. 
Dmg Adminisu·ation 
• 
Dispense study dmg as directed by the IWRS 
• 
lnstiuct the subject on the packaging, storage, and adminisu·ation of study dmg 
• 
Observe the subject taking the first dose of study dmg (with or without food) and record the 
time of fust dose 
6.4.2. 
Weeks 1 and 2 (± 3 days) 
Subjects who participated in the PK Lead-in will start study visits in the Treatment Phase at 
Week 2. The following procedures/assessments are to be completed at these visits: 
• 
Vital signs, including body weight and height measurements 
• 
Perf01m symptom-directed physical examination 
• 
Assessment of AEs and concomitant medications 
CONFIDENTIAL 
Page45 
08 December 2014 


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Amendment 2.0
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08 December 2014

Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— Single PK 
6.4.3.
Weeks 4 and 8 (3 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— Single PK 

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS


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Amendment 2.0
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6.4.4.
Week 12 (3 days) - Subjects on 12 Week Treatment Regimen Only

Perform complete physical examination

Tanner Pubertal Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— TSH
— Single PK 

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles of study drug at the Week 12 Visit
6.4.5.
Week 12 (3 days) - Subjects on 24 Week Treatment Regimen Only

Perform symptom-directed physical examination

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications


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Amendment 2.0
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
Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— Single PK 

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS  
6.4.6.
Week 16 and 20 (3 days) – Subjects on 24 Week Treatment Regimen Only

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only


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Amendment 2.0
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
Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS
6.4.7.
Week 24 (3 days) – Subjects on 24 Week Treatment Regimen Only

Perform complete physical examination

Tanner Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles of study drug at the Week 24 Visit


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6.4.8.
Unscheduled Visit/Early Termination Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments are at the investigator’s discretion.
The Sponsor/CRO should be informed when a subject comes off treatment due to an adverse 
event. If a subject discontinues treatment then the assessments outlined below should be 
performed.

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— TSH
— Single PK 

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles of study drug at the Early Termination Visit


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Amendment 2.0
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All subjects should complete Post-Treatment assessments after early termination, as described in 
Section 6.5.
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
experimental or approved anti-HCV therapy will be followed every 6 months for assessments of 
growth, quality of life, and long-term viral suppression (if applicable) in a separate protocol 
(GS-US-334-1113). This follow-up will continue for 5 years.
6.5.
Post-Treatment Assessments
6.5.1.
4-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for: 
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status) 
6.5.2.
12-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements

Perform symptom-directed physical examination

Assessment of SAEs

Perform Tanner Pubertal Stage assessment


LDV/SOF FDC
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Amendment 2.0
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
Obtain blood samples for 
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire
6.5.3.
24-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of SAEs

Tanner Pubertal Stage Assessment

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Obtain blood samples for 
— HCV RNA
— Viral sequencing (archive)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire.
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed every 6 months for 
assessments of growth, quality of life, and long-term viral suppression (if applicable) in a 
separate protocol (GS-US-334-1113). This follow-up will continue for 5 years.


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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), Glucose, 
Lipase, Potassium, Sodium, Gamma-glutamyl transferase (GGT), alpha fetoprotein (AFP), 
alpha-1 anti-trypsin, creatine kinase (CK) and amylase.
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® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System. 
HCV GT 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 GT should the above assays become unavailable.
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 alternate assays 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum -hCG, Urine -hCG (if positive, requires immediate confirmation with 
Serum -hCG)
Additional Tests: Urine Drug Screen (for amphetimines, cocaine, methadone, opiates), 
Hemoglobin A1c (HbA1c), TSH (reflex Free T4), Alfa fetoprotein (AFP), Alpha-1 anti-trypsin
(AAT).
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. Parental heights will be recorded at Screening.
6.6.3.
Complete Physical Examination
A complete physical examination must include source documentation of general appearance, and 
the following body systems: Head, neck and thyroid; eyes, ears, nose, throat, mouth and tongue; 
chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological. 


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Amendment 2.0
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6.6.4.
Tanner Pubertal Stage Assessment
The Tanner Stage scale is available in Appendix 4.  All subjects will receive a baseline Tanner 
Pubertal Stage Assessment. If the assessment determines that the subject is at a Tanner 5 at 
Day 1, no further Tanner Pubertal Stage Assessments are to be completed. Date of first menses 
will be documented. 
6.6.5.
Height & Weight Measurement
Height and weight measurement will be collected at each study visit. The difference in body 
weight and height measurements between Day 1 and End of Treatment, post-treatment Week 12, 
and post-treatment Week 24 will be calculated.  
6.6.6.
Bone Age Assessment
A single X-ray of the left wrist, hand, and fingers will be performed at Day 1 Visit and 
post-treatment Week 24.  Local radiologist will determine bone age from x-ray.
6.6.7.
Swallowability Assessment
A LDV/SOF FDC swallowability assessment will be performed at screening up to Day 1.  
Subjects who have indicated that they can take pills will be observed taking a placebo to match 
the 90 mg/ 400 mg LDV/SOF FDC tablet. This will confirm the swallowability of the 
90 mg/ 400 mg tablet size. If a subject is unable to swallow the 90 mg/ 400 mg LDV/SOF FDC 
tablet size, he/she will repeat the assessment with a placebo for the 22.5 mg/ 100 mg 
LDV/SOF FDC tablet. If unable to swallow the 22.5 mg/ 100 mg LDV/SOF FDC tablet, 
enrollment of the subject will be deferred until the granule formulation is available.
6.6.8.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.


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6.6.9.
Estimated Glomerular Filtration Rate (GFR)
Estimated Glomerular Filtration Rate (GFR) using Schwartz Formula (mL/min/1.73m2) = 
k L/Scr [(k is a proportionality constant, for adolescent females ≥12 years old is 0.55; and for 
adolescent males ≥12 years old is 0.70); L is height in centimeters (cm); and Scr is serum 
creatinine (mg/dL)]
6.6.10.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
Unused samples may be archived.
6.6.11.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every 4 weeks during the 
dosing period and for a minimum of 30 days following the last dose of LDV/SOF FDC. If 
required by local regulations, additional pregnancy tests beyond 30 days may be added. In the 
event of a positive urine pregnancy result, subjects will be instructed to stop study drug
immediately (if applicable) and return to the clinic as soon as possible for a serum pregnancy 
test.
6.6.12.
Quality of Life Survey (PedsQL™)
The PedsQL ™ Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be completed 
in Treatment Phase of the study at Day 1, End of Treatment, Early Termination (if applicable), 
12-Week Post-Treatment, and 24-Week Post-Treatment visits.  
The PedsQL ™  has separate survey instruments administered by age group, including the
Teen Report (ages 13-18), Child Report (ages 8-12), Young Child Report (ages 5-7), and 
Toddlers (ages 2-4).  Each survey will be administered to the subject for the current age group at 
the time of survey administration.  


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Amendment 2.0
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7.
TOXICITY MANAGEMENT
7.1.
Subject Stopping Rules for LDV/SOF FDC
The Gilead Medical Monitor should be consulted prior to dose discontinuation of LDV/SOF 
FDC unless the investigator believes that immediate action is warranted to ensure the continued 
safety of the subject.
Administration of LDV/SOF FDC may be discontinued due to a clinical or laboratory event. 
There is no option for LDV/SOF FDC dose reduction. If LDV/SOF FDC is stopped for toxicity, 
it should not be restarted.
Subjects who meet any of the following laboratory criteria must stop treatment with LDV/SOF 
FDC:

Elevation of ALT and/or AST >5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT >3x Day 1 and total bilirubin >2 x ULN, confirmed by 
immediate repeat testing

Confirmed elevation of ALT >15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with LDV/SOF FDC


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8.
ADVERSE EVENTS MANAGEMENT
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
8.1.1.
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-mandated procedures, 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 8.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history CRF
8.1.2.
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

Persistent or significant disability/incapacity


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
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.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., 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 (e.g., 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 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
8.2.
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.
8.2.1.
Assessment of Causality for Study Drug and Procedures
The investigator or qualified sub-investigator 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 investigational 
medicinal product. For SAEs, an alternative causality must be provided (e.g., 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 AE reporting.


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The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures (e.g.., venipuncture)
8.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4 weeks after last administration of study drug 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 protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of causal relationship, that occurs after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required 24-week 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
after informed consent is signed 
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. Investigators are not 
obligated to actively seek SAEs after the 24 week post-treatment follow-up period.  However, if 


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the investigator leams of any SAEs that occur after study pruticipation has concluded and the 
event is deemed relevant to the use of IMP, he/she should promptly document and rep01i the 
event directly to Gilead DSPH. 
Electronic Serious Adverse Event (eSAE) Rep01ting Process 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infonnation 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 infonnation electr·onically, i.e., the 
eCRF database is not ftmctioning, record the SAE on the paper serious adverse event 
rep01ting f01m and submit within 24 hours to: 
Gilead Sciences, Dmg 
Safety and Public 
Health: 
Gilead Sciences, 
Medical Monitor: 
Fax: 
E-mail: 
Name: 
Phone: 
Mobile: 
Fax: 
E-mail: 
+ 1 650 522-5477 
Safety _FC@gilead.com 
Bittoo Kanwru·, MD 
PO 
PPD 
PPD 
PPD 
• 
As soon as it is possible to do so, any SAE rep01ted via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been rep01ted via a paper fonn because the eCRF database has been locked, 
no ftnther action is necessruy. 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
• 
For fatal or life-threatening events, copies of hospital case reports, autopsy rep01ts, and other 
documents ru·e also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the tr·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
rep01ts. 
• 
Any medications necessruy for tr·eatlnent 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 
rep01i f01m. 
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8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
8.5.
Special Situations Reports
8.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging or distribution of the medicinal product.  


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8.5.2.
Instructions for Reporting Special Situations
8.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (i.e., signs the informed consent) and throughout the study, including the 
post-treatment follow-up period, to Gilead DSPH using the pregnancy report form within 
24 hours of becoming aware of the pregnancy.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., 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 
Sections 8.1 and 8.3. Furthermore, any SAE occurring as an adverse pregnancy outcome 
post study must be reported directly to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 or Fax: +1 (650) 522-5477.
Pregnancies of female partners of male study subjects exposed to Gilead or other study drug
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy report form and pregnancy outcome report forms within 24 hours. Monitoring of the 
partner pregnancy 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 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.


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8.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management and outcome will be reported, when available.


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Objectives and Endpoints 
9.1.1. 
Analysis Objectives 
The prima1y objective of PK Lead-in Phase of this study is: 
Final 
Amendment 2.0 
• 
To evaluate the steady state phrum acokinetics (PK) and confmn the dose ofLDV/SOF FDC 
in chronic HCV-infected pediatric subjects 
The secondruy objective ofPK Lead-in Phase of this study is: 
• 
To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing ofLDV/SOF 
FDC in chronic HCV -infected pediatric subjects 
The primru·y objective of Treatment Phase of this study is: 
• 
To evaluate the safety and tolerability of LDV/SOF FDC for 12 or 24 weeks in chronic 
HCV -infected pediatric subjects 
The secondruy objectives of Treatment Phase of this study ru·e: 
• 
To dete1mine the antiviral efficacy of 12 and 24 weeks ofLDV/SOF FDC treatment in 
chronic HCV-infected subjects (including the impact ofHCV genotype, IL28B genotype, 
and prior treatment experience), as assessed by the prop01iion of subjects with SVR 
12 weeks after completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of 12 and 24 weeks ofLDV/SOF FDC treatment in 
chronic HCV-infected subjects, as assessed by the prop01iion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment 
• 
To evaluate the effect of growth and development on pediatric subjects during and after 
treatment 
The explorat01y objective ofthis study is: 
• 
PD 
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9.1.2.
Primary Endpoints
For the PK Lead-in Phase, the appropriateness of the LDV/SOF FDC dose will be assessed by 
evaluating the steady-state PK of the LDV/SOF FDC. The primary endpoint for determining 
steady state PK is AUCtau of GS-331007, SOF, and LDV. Additional steady-state PK parameters 
of GS-331007, SOF, and LDV (e.g., AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½)
will be estimated and summarized as described in Section 9.4.
For the Treatment Phase, the primary safety endpoint is any AE leading to permanent 
discontinuation of study drug (s). 
9.1.3.
Secondary Endpoints
For the PK Lead-in Phase, the secondary endpoint will include antiviral activity measurements, 
including assessment of HCV RNA. AEs leading to permanent discontinuation of study drug will 
be evaluated as a secondary safety endpoint.
For the Treatment Phase, the key efficacy endpoint is SVR12 and secondary efficacy endpoints 
include SVR4, SVR24, breakthrough and relapse. Additional efficacy evaluations may include 
HCV RNA change from Day 1; ALT normalization; and viral kinetic parameters. Secondary 
safety endpoints of growth and development measurements will be assessed (e.g. height, weight, 
and Tanner Stage Assessment).
9.2.
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).
9.2.1.
Analysis Sets 
9.2.1.1.
Pharmacokinetics (PK) Analysis Sets
Intensive PK Analysis Set 
The intensive PK analysis set will include all PK Lead-in subjects who received at least one dose 
of study drug and for whom at least one non-missing PK concentration data, during the intensive 
sampling period, reported by PK lab. The PK analysis set will be used for detailed 
pharmacokinetic analysis of LDV, SOF, and metabolites.  
Sparse PK Analysis Set 
The PK analysis set will include all enrolled subjects who received at least one dose of study 
drug and for whom at least one observed concentration data of LDV, SOF, or GS-331007 are 
available. The PK analysis set will be used for analysis of general PK and single sample plasma
concentrations.
9.2.1.2.
Safety Analysis Set


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The primary analysis set for safety analyses will include subjects who were enrolled and have 
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 last dose of study drug plus 30 days.
9.2.1.3.
Efficacy Analysis Set
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which includes 
HCV-infected subjects who were enrolled and have received at least one dose of study drug.
9.2.2.
Data Handling Conventions
Natural logarithm transformation for key PK parameters, such as Cmax and AUCtau, will be 
applied for pharmacokinetic analysis.
The PK concentration values below the limit of quantitation (BLQ) will be treated as zero for the 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing and will be excluded in any calculation of geometric 
means or ratios. For the presentation of summary and order statistics, if at least 1 subject has a 
concentration value BLQ for the time point, then the minimum value will be displayed as 
“BLQ”. If more than 50% of the subjects have a concentration data value BLQ for the time 
point, then the minimum and median values will be displayed as “BLQ”. If all subjects have 
concentration data values BLQ for the time point, then all order statistics (minimum, first 
quartile [Q1], median, third quartile [Q3], maximum) will be displayed as “BLQ”.
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, 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 
preceded and followed in time by values that are deem 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 medication will be 
considered a failure at the time points subsequent to 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. 


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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).
9.2.3.
Interim Analysis
No formal interim analyses are planned for this study.
9.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by age group and overall for PK Lead-in and by treatment experience and cirrhosis 
status, age group and overall for Treatment Phase respectively. 
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight, height, body mass index, HCV RNA level 
(log10 IU/mL), HCV GT, prior treatment experience, and additional endpoints as necessary.
9.4.
Pharmacokinetic Analysis
PK analysis will be performed for PK Lead-in using the intensive PK analysis set. The 
concentration data of LDV, SOF, and metabolites (GS-331007 and GS-566500) over sampling 
time will be listed and summarized by nominal time and cohort. Pharmacokinetic parameters 


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(e.g., AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½) will be listed and 
summarized for LDV, SOF,  and metabolites (as applicable) using descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean and its 95% confidence interval, coefficient 
of variation %, standard deviation, median, Q1, Q3, minimum, and maximum) by cohort and 
overall. Plasma concentrations over time will be plotted in semilogarithmic and linear formats as 
mean ± standard deviation and median (Q1, Q3).
To evaluate if the steady-state PK of GS-331007, SOF, and LDV achieved in pediatric subjects 
of this study are similar to the exposures observed in adult subjects (Table 9-1), the GS-331007, 
SOF, and LDV exposure data from this study will be compared to the integrated adult data. The 
primary endpoint of this analysis will be evaluated by carrying out an analysis of variance 
(ANOVA) for log-transformed GS-331007, SOF, and LDV AUCtau. The 90% confidence 
intervals will be constructed for the ratio of geometric means of each PK parameters. The 
equivalence boundary is set as 50% to 200%.  
Given that dose ranging studies for SOF established that a dose of 200 mg results in suboptimal 
exposure compared to the 400 mg dose, and the lack of clinically significant exposure-safety 
relationships observed across a broad range of GS-331007 and SOF exposure, bounds of 50% to 
200% for GS-331007 and SOF AUCtau will allow identification of a clinically relevant difference 
in exposure in the pediatric population.
A phase 2 study evaluating LDV doses of 30 or 90 mg LDV in combination with DAAs 
VDV+TGV+RBV suggested LDV exposure may be suboptimal at the 30 mg dose based on the 
incidence of virologic breakthrough being approximately half in the 90 mg arm; as such the 
90 mg dose was selected for further development.  In the 90 mg LDV arm of this study, the LDV 
AUCtau at the 25 percentile was 3230 hr*ng/mL.  While this value is 62% lower than the mean 
LDV AUCtau (8530 hr*ng/mL) observed in adult HCV-infected subjects in the LDV/SOF FDC 
Phase 2/3 population, it provides ~99.8% of maximal viral load reduction (exposure-response 
model established in the monotherapy proof of concept study).  In the Phase 2/3 population when 
administered the LDV/SOF FDC, there was a lack of clinically significant exposure-efficacy or 
safety relationships observed across the broad range of LDV exposure.  Taken together these 
data support the utility of bounds of 50% to 200% for LDV AUCtau to identify a clinically 
relevant difference in LDV exposure in the pediatric population.
In all pediatric age groups, the targeted exposures for GS-331007, SOF, and LDV are the adult 
equivalent for which safety and efficacy has been established.  In the absence of any pediatric 
PK information (i.e., variability and exposure of GS-331007, SOF, or LDV is unknown) 
assuming a 2-fold higher variability, or a 30 % difference in GS-331007, SOF, or LDV AUCtau
in the pediatric population compared to adults, the predicted 90% CIs of the geometric mean 
ratio (GMR) will be contained within the bounds of 50% to 200%.
Individual patient management will be performed by maintaining exposures comparable to 
adults.  In the event more than one subject in each cohort exhibits GS-331007, SOF, or LDV 
exposures (AUCtau) less than the 2.5th percentile of adult values, a dose assessment may be 
require for the cohort as appropriate.


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The effect of age and LDV/SOF FDC dose on PK (LDV, SOF and GS-331007) will be assessed.


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Table 9-1.
GS-331007, SOF, and LDV PK Parameters after Once-Daily 
Administration of SOF/LDV FDC in HCV-Infected Adults Subjects 
(Population PK Analysis from Phase 2 and 3 Studies) 
Mean (%CV) PK 
Parametera
GS-331007 (N=2113)
SOF (N=1542)
LDV (N=2113)
AUCtau (ng•h/mL)
12,500 (29.2)
1380 (34.0)
8530 (60.8)
Cmax (ng/mL)
736 (28.2)
659 (34.0)
364 (51.4)
Ctau (ng/mL)
N/A
N/A
247 (59.2)
a
Pharmacokinetic parameters are presented as mean (%CV) and are shown to 3 significant digits.
9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in and overall study Treatment Phase
respectively. Safety data will be summarized by age group and overall for PK Lead-in Phase and 
by treatment experience and cirrhosis status, age group, by GT, and by overall for the Treatment 
Phase respectively.
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements, and by the documentation of AEs.
All safety data collected while on or after the first dose of study drug administration up to 
30 days after the last dose of study drug will be summarized by cohort according to the study 
drug received.
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.
9.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the CRF. Exposure data will be summarized.
9.5.2.
Adverse Events
Clinical and laboratory AEs 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 study drug up to the date of last dose of study drug plus 30 days. 


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Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC 
and preferred term) will be provided by cohort:

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,

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.
9.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled visits will be summarized. Graded laboratory 
abnormalities will be defined using the grading scheme in Grading of Laboratory Abnormalities 
provided in Appendix 3. 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 
and including the date of last dose of study drug plus 30 days, will be summarized by age group 
and overall. If baseline data are missing, then any graded abnormality (i.e., at least a Grade 1) 
will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
9.5.4.
Other Safety Evaluations
9.5.4.1.
Tanner Pubertal Stage Assessment
Tanner Stages (Appendix 4) will be summarized by baseline Tanner Stage using frequency and 
percentage. Age of first menses will be summarized descriptively.


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9.5.4.2. 
Vital Signs (including Body Weight and Height) 
Final 
Amendment 2.0 
Vital signs including body weight and height and change from baseline will be summarized at 
each visit. 
9.6. 
Efficacy Analysis 
Efficacy will be evaluated using scheduled assessments of HCV RNA perf01m ed using CO BAS® 
TaqMan® HCV Test, v2.0 for use with the High Pure System. 
Efficacy analysis will be perf01m ed by u·eatment experience and cinhosis status, by age group, 
by GT, by overall, and by age group and GT for Treatment Phase. 
All continuous endpoints will be summarized using an 8-number summruy (n, mean, standru·d 
deviation, median, Ql , Q3, minimum, maximum). All categorical endpoints will be summru·ized 
by number and percentage of subjects who meet the endpoint definition. 
9.6.1. 
Key Efficacy Analysis 
The key efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
u·eatment) in the F AS population. Point estimate and its 95% confidence interval will be 
provided. 
9.6.2. 
Secondary Efficacy Analysis 
For the PK Lead-in Phase, senun HCV RNA actual values and change from baseline will be 
summarized at each visit. 
For the Treatment Phase, the proportion of subjects with HCV RNA below LLOQ over time 
(including SVR endpoints SVR4 and SVR24) will be presented in tabulru· and graphical f01m . In 
addition, descriptive summaries and listings will be provided for additional efficacy evaluations 
including senun HCV RNA actual values and change from baseline, prop01iion of subjects with 
virologic failures, and other endpoints of interest including ALT n01m alization. 
PD 
9.6.3. 
Subgroup Analysis 
Subgroup analysis on SVR12 will be perf01m ed by u·eatment experience and cinhosis status, by 
IL28B genotype, and by GT. Other clinically relevant subgroup analyses may be conducted as 
appropriate (i.e., assuming that adequate numbers of subjects in these subsets are available for 
analysis). 
Details on efficacy analyses will be described in the statistical analysis plan. 
CONFIDENTIAL 
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9.7.
Quality of Life Analysis
The data from PedsQL ™ Pediatric Quality of Life survey will be summarized by visit and 
age group and overall.
9.8.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety and provide recommendation to Gilead about 
whether the nature, frequency, and severity of adverse effects associated with study treatment 
warrant the early termination of the study in the best interests of the participants, whether the 
study should continue as planned, or the study should continue with modifications. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
9.9.
Sample Size
With approximately 100 subjects enrolled into each age group of Treatment Phase, a two-sided 
95.0% confidence interval of the SVR12 rate will extend at most 5.9% in both directions from 
the observed SVR12 rate, assuming the expected SVR12 rate is 90%.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
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 Harmonization (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. For studies conducted under a United States IND, the investigator 
will ensure that 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, are adhered to.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Gilead Sciences, or proprietary interests in the drug being studied. 
This documentation must be provided before participation of the investigator and any 
sub-investigator. The investigator and sub-investigator agree to notify Gilead Sciences of any 
change to reportable interests during the study and for one year following completion of the 
study. Study completion is defined as the date that the last subject has completed 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.”
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
This protocol 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/assent) will be submitted by the investigator to an IRB (for studies conducted in the
United States) or IEC (for studies conducted outside of the United States). Approval from the 
IRB or IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation.


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10.1.3.
Informed Consent/Assent
The investigator is responsible for obtaining written informed consent from the parent/legal 
guardian of the subject participating in this study after adequate explanation to the parent/legal 
guardian and subject of the aims, methods, objectives, and potential hazards of the study and 
before undertaking any study-related procedures. Written assent should be obtained from the 
subject as required by IRB/IEC/local requirements for this age population.  The investigator must 
utilize an IRB- or IEC-approved consent/assent form for documenting written informed 
consent/assent. Each informed consent/assent will be appropriately signed and dated by the 
subject or the subject’s parent/legally authorized representative and the person obtaining 
consent/assent.
10.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, and an 
identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the Sponsor, IRB or IEC, or laboratory. The investigator must keep a screening log 
showing codes, names, and addresses for all subjects screened and for all subjects enrolled in the 
trial.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational new drug, and any 
other study information, remain the sole and exclusive property of Gilead Sciences during the 
conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Gilead Sciences. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data are listed in the Source Data verification Plan, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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
Participation in trial (including trial number);

Trial 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 trial medication (preferably drug dispensing 
and return should be documented as well);

Record of all AEs and other safety parameters (start and end date, and preferably including 
causality and intensity);

Concomitant medication (including start and end date, dose if relevant; dose changes should 
be motivated);

Date of trial completion and reason for early discontinuation, if applicable.
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) 
and until there are no pending or contemplated 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 required by applicable regulatory requirements, by local 
regulations, or by an agreement with Gilead Sciences. The investigator must notify 
Gilead Sciences 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 Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences 
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period up to 15 years for purposes of this study.


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10.1.6.
Case Report Forms
For each subject enrolled, a CRF (or eCRF) must be completed and signed by the principal 
investigator or sub-investigator (as appropriate) within a reasonable time period after data 
collection. This also applies to records for those subjects who fail to complete the study 
(even during a pre-randomization screening period if a CRF was initiated). If a subject 
withdraws from the study, the reason must be noted on the CRF. If a subject is withdrawn from 
the study because of a treatment-limiting adverse event, thorough efforts should be made to 
clearly document the outcome.
10.1.7.
Drug Accountability
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product, and comparators. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), subject 
dispensing records, and returned or destroyed study product. Dispensing records will document 
quantities received from Gilead Sciences and quantities dispensed to subjects, including lot 
number, date dispensed, subject identifier number, subject initials, and the initials of the person 
dispensing the medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRBs or IECs, 
or to regulatory authority or health authority inspectors.
10.1.9.
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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10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB, IEC, or 
competent authorities in accordance with local requirements. Approval must be obtained before 
changes can be implemented.
10.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies). 
Gilead Sciences 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.
After conclusion of the study and without prior written approval from Gilead Sciences, 
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 Sciences in an abstract, manuscript, or presentation form; or

the study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).
The investigator will submit 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. The investigator will comply with Gilead Sciences’ 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.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the CRFs for consistency.
The monitor is responsible for routine review of the CRFs 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 CRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.


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10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences 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 Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
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 Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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11.
REFERENCES
19705
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48 (1):148-62.
19799
Hu J, Doucette K, Hartling L, Tjosvold L, Robinson J. Treatment of hepatitis C in 
children: a systematic review. PLoS ONE 2010;5 (7):e11542.
19801
Mohan N, Gonzalez-Peralta RP, Fujisawa T, Chang MH, Heller S, Jara P, et al. 
Chronic hepatitis C virus infection in children. J Pediatr Gastroenterol Nutr 
2010;50 (2):123-31.
20273
Bortolotti F, Verucchi G, Camma C, Cabibbo G, Zancan L, Indolfi G, et al. Long-
term course of chronic hepatitis C in children: from viral clearance to end-stage 
liver disease. Gastroenterology 2008;134 (7):1900-7.
20282
Serranti D, Buonsenso D, Ceccarelli M, Gargiullo L, Ranno O, Valentini P. 
Pediatric hepatitis C infection: to treat or not to treat...what's the best for the 
child? European review for medical and pharmacological sciences 2011;15 
(9):1057-67.
20285
Wirth S. Current treatment options and response rates in children with chronic 
hepatitis C. World J Gastroenterol 2012;18 (2):99-104.
20286
Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti F, Zancan L, Jara P, et al. 
High sustained virologic response rates in children with chronic hepatitis C 
receiving peginterferon alfa-2b plus ribavirin. J Hepatol 2010;52 (4):501-7.
28583
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and 
sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370 
(20):1889-98.
28585
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. 
Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N 
Engl J Med 2014;370 (16):1483-93.
28587
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. 
Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N 
Engl J Med 2014;370 (20):1879-88.


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29292
Gane E, Hyland RH, An D, Pang PS, Symonds WT, McHutchison JG, et al. 
Ledipasvir/Sofosbuvir Fixed-Dose Combination Is Safe and Effective in Difficult-
to-Treat Populations Including GT 3 Patients, Decompensated GT 1 Patients, and 
GT 1 Patients With Prior Sofosbuvir Experience [Oral Presentation 6]. 49th 
Annual Meeting of The European Association for the Study of the Liver (EASL); 
2014 April 9-13; London, UK. 


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12.
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.
Tanner Stages
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety and 
Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination in Adolescents and Children 
with Chronic HCV-infection 
GS-US-337-1116, Protocol Amendment 2, 08 December 2014 
This protocol has been approved by Gilead Sciences.lnc....I.®..foJlo.Yi.ing.s.ir.matur_e docu ents 
h. 
l 
IPPD 
t IS approva . 
Bittoo Kanwar, MD (Printed) 
Medical Monitor 
Date 
1gnaror 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
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Appendix 2.
Study Procedures Table
Appendix Table 1.
PK Lead-in: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X j
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Vital Signsa
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X
Subject Dosing Diary
X
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X


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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
HCV RNA
X
X
X
X
Viral Sequencing c
X
X
X
Serum or Urine Pregnancy Testinge
X
X
X
Urinalysis
X
X
X
Urine Drug Screen
X
Intensive PK
X d
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
Alpha fetoprotein
X
Alpha-1 anti-trypsin
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, body weight, and height
b
Day 1 assessments must be performed prior to dosing
c
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
d
For Cohorts 1 and 2, plasma samples will be collected for PK analyses following dosing of study drug on Day 10 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours post-dose.
e
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test. 
f
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status). 
g
h
Swallowability can occur at Day 1 if not completed during screening.
i
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
j
Parental height will be collected (if available)
PPD
PPD


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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early 
Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
Xi
Complete Physical Examination
X
X
Xj
X
X
Symptom-Directed Physical Examination
X
X
X
X
Xk
X
X
Tanner Pubertal Stage Assessment
X
Xj
X
X
Vital Signsa
X
X
X
X
X
X
X
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling g
X
Xj
X
X
LDV/SOF FDC Swallowability 
Assessment
X
Xh
Quality of Life Survey e
X
Xj
X
X
Review of Study Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
  Xk
X
X
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
X
X
X
X
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
X


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 87
08 December 2014
Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early 
Termination
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testingl
X
X
X
X
X
X
X
X
X
Single PK
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Urine Drug Test
X
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
Xj
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, and body weight and height
b
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
c
Subjects rolling over from PK Lead-in will not be required to repeat screening, Day 1 or Week 1 visits during the on Treatment Phase  
d
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
e
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
f
g
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
h
Swallowability can occur at Day 1 if not completed during screening.
i
Parental height will be collected (if available) 
j
Subjects on 12 Week Treatment regimen only
k
Subjects on 24 Week Treatment regimen only
l
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test
PPD
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 88
08 December 2014
Appendix Table 3.
Treatment Phase: Post Treatment Visits Following Primary Study
4 Weeks Post Treatment
12 Weeks Post Treatment
24 Weeks Post Treatment
Clinical Assessments
Vital Signs, Body weight and Height
X
X
X
Symptom-directed Physical Exam
X
X
X
AEs
X
Xc
Xc
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counselingd
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Test
X
X
a
Quality of life survey will be completed by all subjects at 12-Week and 24-Week Post Treatment visits if a site is approved to use the survey.  Subject is to review 
questionnaire with a parent/guardian and write/mark answers directly onto the questionnaire.
b
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
c
At Post Treatment Week 12 and 24, only SAEs will be captured
d
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 89
08 December 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 90
08 December 2014
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 91
08 December 2014
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 92
08 December 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 93
08 December 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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 94
08 December 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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 95
08 December 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 96
08 December 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 97
08 December 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 98
08 December 2014
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 
Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to Dipstick 
Hematuria.
With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for the 
AE.


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


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Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 100
08 December 2014
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


LDV/SOF FDC
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Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 101
08 December 2014
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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Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 102
08 December 2014
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or  
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 103
08 December 2014
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


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Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 104
08 December 2014
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated 
(eg, IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)


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Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 105
08 December 2014
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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Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 106
08 December 2014
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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Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 107
08 December 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 108
08 December 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 109
08 December 2014
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]


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 110
08 December 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 111
08 December 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 112
08 December 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
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08 December 2014
Appendix 4.
Tanner Stages
1. Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2. Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of testes and scrotum and increased darkening 
of scrotal skin (13.5-15)
Tanner V 
Genitalia adult in size and shape
3. Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen 
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with 
surrounding breast 
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V 
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 114
08 December 2014
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Background
Non-clinical toxicity studies of LDV/SOF FDC demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of LDV/SOF FDC 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)
For the purpose of this trial, all post-menarchal females will be considered to be of childbearing 
potential, unless there is documentation of irreversible ovarian failure or surgical sterilization.
Post-menarchal females must have a negative serum pregnancy test at Screening and a negative 
urine pregnancy test on the Day 1 visit prior to randomization. They must also agree to one of 
the following from 3 weeks prior to Day 1 until 30 days after last dose of LDV/SOF FDC:

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 the last dose of LDV/SOF FDC:
— 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
— implants of levonorgestrel
— injectable progesterone
— oral contraceptives (either combined or progesterone only)
— contraceptive vaginal ring 
— transdermal contraceptive patch


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 2.0
CONFIDENTIAL
Page 115
08 December 2014
3. Contraceptive Requirements for Male Subjects (and their female partners)
All male study participants must agree to consistently and correctly use a condom from Day 1
until 90 days after the last dose of LDV/SOF FDC. If their female partner is of childbearing 
potential (as defined above), their female partner must use 1 of the methods of birth control listed 
above from the date of Screening until 90 days after last dose of LDV/SOF FDC.
Male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of 
LDV/SOF FDC.
4. Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days (90 days for partners of male subjects) of 
last LDV/SOF FDC 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 8.5.2.1.

Prot_004.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT Number: 
Indication: 
Protocol ID: 
Gilead Study Director: 
Gilead Sciences Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-coh01i Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir 
Fixed Dose Combination +/- Ribavirin in Adolescents and 
Children with Chronic HCV-Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
115268 
2014-003578-17 
Hepatitis C Vims Infection 
GS-US-337-1116 
Name: 
Telephone: 
Fax: 
E-mail: 
Name: 
Telephone: 
Fax: 
E-mail: 
Original: 
Amendment 1.0: 
Amendment 2.0: 
Amendment 2.1: 
Amendment 2.2: 
Amendment 3.0: 
Amendment 4.0: 
r
PD 
I"'U 
rpo 
I"'U 
Theo Brandt-Sarif, MD, 
PD 
10 July 2014 
08 October 2014 
08 December 2014 
09 Janumy 2015 (United Kingdom Only) 
01 April 2015 (United Kingdom Only) 
28 May2015 
15 Mm·ch 2016 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmi iculm·ly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board 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 necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 2
15 March 2016
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................18
1.
INTRODUCTION ..............................................................................................................................................21
1.1.
Background ............................................................................................................................................21
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................22
1.2.1.
Summary of Additional Clinical Experience with Ledipasvir/Sofosbuvir 
Fixed-Dose Combination .....................................................................................................22
1.3.
Ribavirin (RBV).....................................................................................................................................25
1.4.
Rationale for the Current Study .............................................................................................................26
1.5.
Rationale for Dose Selection of LDV/SOF FDC ...................................................................................27
1.6.
Overall Risk/Benefit Assessment...........................................................................................................30
2.
OBJECTIVES.....................................................................................................................................................31
3.
STUDY DESIGN................................................................................................................................................32
3.1.
Treatment Plan and Regimen .................................................................................................................32
3.1.1.
PK Lead-in ...........................................................................................................................32
3.1.2.
Treatment Phase ...................................................................................................................33
3.2.
Visit Schedule ........................................................................................................................................35
3.2.1.
PK Lead-in ...........................................................................................................................35
3.2.2.
Treatment Phase ...................................................................................................................36
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................36
3.4.
Treatment Discontinuations Criteria ......................................................................................................36
3.5.
Discontinuations.....................................................................................................................................37
3.6.
Pharmacogenomic Substudy ..................................................................................................................37
3.7.
Long-Term Follow-Up...........................................................................................................................37
3.8.
Breakthrough Futility Assessment .........................................................................................................37
3.9.
Reconsent...............................................................................................................................................38
4.
SUBJECT POPULATION..................................................................................................................................39
4.1.
Number of Subjects and Subject Selection ............................................................................................39
4.2.
Inclusion Criteria....................................................................................................................................39
4.3.
Exclusion Criteria...................................................................................................................................40
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................42
5.1.
Randomization and Blinding..................................................................................................................42
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................42
5.2.1.
Description and Handling.....................................................................................................42
5.2.2.
Storage and Handling...........................................................................................................43
5.2.3.
Dosage and Administration of LDV/SOF FDC ...................................................................44
5.3.
Ribavirin (GT-3 Subjects Only).............................................................................................................45
5.3.1.
Description and Handling of RBV .......................................................................................45
5.3.2.
Dosage and Administration of RBV (GT-3 Subjects Only).................................................46
5.4.
Co-administration of LDV/SOF FDC and RBV (GT-3 Subjects Only).................................................46
5.5.
Study Drug Compliance.........................................................................................................................47
5.6.
Prior and Concomitant Medications.......................................................................................................47


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Gilead Sciences, Inc.
Amendment 4.0
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6.
STUDY PROCEDURES ....................................................................................................................................49
6.1.
Subject Enrollment.................................................................................................................................49
6.2.
Screening Assessments ..........................................................................................................................49
6.2.1.
Screening Visit (Day –28 to Day 0) .....................................................................................49
6.3.
PK Lead-in: Treatment Assessments .....................................................................................................51
6.3.1.
Day 1 ....................................................................................................................................51
6.3.2.
Day 3 ....................................................................................................................................52
6.3.3.
Day 10 – Intensive PK..........................................................................................................52
6.4.
Treatment Phase: Treatment Assessments .............................................................................................54
6.4.1.
Day 1 ....................................................................................................................................54
6.4.2.
Weeks 1 and 2 (3 days) .....................................................................................................55
6.4.3.
Weeks 4 and 8 (3 days) .....................................................................................................56
6.4.4.
Week 12 (3 days) - Subjects on 12 Week Treatment Regimen Only................................57
6.4.5.
Week 12 (3 days) - Subjects on 24 Week Treatment Regimen Only................................57
6.4.6.
Week 16 and 20 (3 days) – Subjects on 24 Week Treatment Regimen 
Only......................................................................................................................................58
6.4.7.
Week 24 (3 days) – Subjects on 24 Week Treatment Regimen Only ...............................59
6.4.8.
Unscheduled Visit/Early Termination Visit .........................................................................60
6.5.
Post-Treatment Assessments..................................................................................................................61
6.5.1.
4-Week Post-Treatment Visit (5 days)..............................................................................61
6.5.2.
12-Week Post-Treatment Visit (5 days)............................................................................61
6.5.3.
24-Week Post-Treatment Visit (5 days)............................................................................62
6.6.
Procedures and Specifications................................................................................................................63
6.6.1.
Clinical Laboratory Analytes ...............................................................................................63
6.6.2.
Medical History....................................................................................................................63
6.6.3.
Complete Physical Examination...........................................................................................64
6.6.4.
Tanner Pubertal Stage Assessment.......................................................................................64
6.6.5.
Height & Weight Measurement............................................................................................64
6.6.6.
Bone Age Assessment..........................................................................................................64
6.6.7.
Swallowability Assessment..................................................................................................64
6.6.8.
Vital Signs............................................................................................................................64
6.6.9.
Estimated Glomerular Filtration Rate (GFR) .......................................................................65
6.6.10.
Viral Sequencing (Archive)..................................................................................................65
6.6.11.
Pregnancy Testing................................................................................................................65
6.6.12.
Quality of Life Survey (PedsQL™).......................................................................................65
7.
TOXICITY MANAGEMENT............................................................................................................................66
7.1.
Modification of Dose/Schedule Due to Toxicity....................................................................................66
7.2.
Subject Stopping Rules for LDV/SOF FDC and RBV...........................................................................66
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................67
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................67
8.1.1.
Adverse Events.....................................................................................................................67
8.1.2.
Serious Adverse Events........................................................................................................67
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................68
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................68
8.2.1.
Assessment of Causality for Study Drug and Procedures ....................................................68
8.2.2.
Assessment of Severity ........................................................................................................69
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................69
8.4.
Gilead Reporting Requirements.............................................................................................................71
8.5.
Special Situations Reports......................................................................................................................71


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Amendment 4.0
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8.5.1.
Definitions of Special Situations..........................................................................................71
8.5.2.
Instructions for Reporting Special Situations.......................................................................72
9.
STATISTICAL CONSIDERATIONS................................................................................................................74
9.1.
Analysis Objectives and Endpoints........................................................................................................74
9.1.1.
Analysis Objectives..............................................................................................................74
9.1.2.
Primary Endpoints................................................................................................................75
9.1.3.
Secondary Endpoints............................................................................................................75
9.2.
Analysis Conventions.............................................................................................................................75
9.2.1.
Analysis Sets ........................................................................................................................75
9.2.2.
Data Handling Conventions .................................................................................................76
9.2.3.
Interim Analysis ...................................................................................................................77
9.3.
Demographic Data and Baseline Characteristics ...................................................................................77
9.4.
Pharmacokinetic Analysis......................................................................................................................77
9.5.
Safety Analysis.......................................................................................................................................79
9.5.1.
Extent of Exposure...............................................................................................................79
9.5.2.
Adverse Events.....................................................................................................................79
9.5.3.
Laboratory Evaluations ........................................................................................................80
9.5.4.
Other Safety Evaluations......................................................................................................80
9.6.
Efficacy Analysis ...................................................................................................................................81
9.6.1.
Key Efficacy Analysis..........................................................................................................81
9.6.2.
Secondary Efficacy Analysis................................................................................................81
9.6.3.
Subgroup Analysis ...............................................................................................................81
9.7.
Quality of Life Analysis.........................................................................................................................82
9.8.
Data Monitoring Committee ..................................................................................................................82
9.9.
Sample Size............................................................................................................................................82
10.
RESPONSIBILITIES..........................................................................................................................................83
10.1.
Investigator Responsibilities ..................................................................................................................83
10.1.1.
Good Clinical Practice..........................................................................................................83
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................83
10.1.3.
Informed Consent/Assent.....................................................................................................84
10.1.4.
Confidentiality......................................................................................................................84
10.1.5.
Study Files and Retention of Records ..................................................................................84
10.1.6.
Case Report Forms...............................................................................................................85
10.1.7.
Drug Accountability.............................................................................................................86
10.1.8.
Inspections............................................................................................................................86
10.1.9.
Protocol Compliance............................................................................................................86
10.2.
Sponsor Responsibilities ........................................................................................................................86
10.2.1.
Protocol Modifications.........................................................................................................86
10.2.2.
Study Report and Publications .............................................................................................87
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................87
10.3.1.
Access to Information for Monitoring..................................................................................87
10.3.2.
Access to Information for Auditing or Inspections ..............................................................87
10.3.3.
Study Discontinuation..........................................................................................................88
11.
REFERENCES ...................................................................................................................................................89
12.
APPENDICES ....................................................................................................................................................91
Appendix 1.
Investigator Signature Page....................................................................................................92
Appendix 2.
Study Procedures Table..........................................................................................................93
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............98


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 5
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Appendix 4.
Tanner Stages* .....................................................................................................................122
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................123
LIST OF IN-TEXT TABLES
Table 1-1.
Steady-state PK and Statistical Comparisons of LDV, SOF and GS-331007 PK in 
Adolescent Subjects (PK Lead-in) and Adult Subjects (Phase 2/3 Population PK 
Analysis).................................................................................................................................24
Table 1-2.
Steady-state PK and Statistical Comparisons of LDV, SOF and GS-331007 PK in 
Pediatric Cohort 2 Subjects (6 to <12 years old; PK Lead-in) and Adult Subjects 
(Phase 2/3 Population PK Analysis).......................................................................................25
Table 3-1.
Subject Enrollment by HCV Genotype, Country, and Treatment Duration ...........................34
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................48
Table 7-1.
RBV Dose Reduction Guidelines...........................................................................................66
Table 9-1.
GS-331007, SOF, and LDV PK Parameters after Once-Daily Administration of 
SOF/LDV FDC in HCV-Infected Adults Subjects (Population PK Analysis from 
Phase 2 and 3 Studies)............................................................................................................79
LIST OF IN-TEXT FIGURES
Figure 1-1.
Predicted LDV, SOF and GS-331007 AUCtau following administration of LDV/SOF 
FDC 45 mg/ 200 mg in Children or LDV/SOF FDC 33.75 mg/ 150 mg (3 to < 6 
years of age) ...........................................................................................................................28
Figure 3-1.
PK Lead-in Phase Study Schema ...........................................................................................33


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 6
15 March 2016
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed 
Dose Combination +/- Ribavirin in Adolescents and Children with 
Chronic HCV -Infection
IND Number:
EudraCT Number:
115268
2014-003578-17
Study Centers:
Approximately 30 sites in the United States, Europe, Australia, and 
New Zealand
Number of Subjects:
Approximately 200 subjects
Target Population:
Adolescents and children (aged 3 to < 18) chronic hepatitis C virus 
(HCV) infection
Treatment Duration:
PK Lead-in – 10 days
Treatment Phase – 12 or 24 weeks
Objectives:
The primary objective of the PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm 
the dose of LDV/SOF FDC in chronic HCV-infected pediatric 
subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 
10 days of dosing of LDV/SOF FDC in chronic HCV infected 
pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV 
for 12 or 24 weeks in chronic HCV -infected pediatric subjects. 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
Final 
Amendment 4.0 
The seconda!y objectives of the Treatment Phase ofthis study are: 
• 
To detennine the antiviral efficacy of 12 or 24 weeks of 
LDV/SOF FDC +/- RBV u·eatment in chronic HCV infected 
subjects (including the impact of HCV genotype, IL28B 
genotype, and prior u·eatment experience), as assessed by the 
prop01iion of subjects with sustained virological response (SVR) 
12 weeks after completion ofu·eatment (SVR12) 
• 
To determine the antiviral efficacy of 12 or 24 weeks of 
LDV/SOF FDC +/- RBV u·eatment in chronic HCV -infected 
subjects, as assessed by the prop01iion of subjects with SVR 4 and 
24 weeks after completion ofu·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during 
u·eatment and after completion of u·eatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF 
during u·eatment and after completion of u·eatment 
• 
To evaluate the effect of growth and development on pediau·ic 
subjects during and after u·eatlnent 
The explorat01y objective of this study is: 
• 
PD 
Open-label, multi-coh01i, two-part study evaluating the PK, safety, 
and antiviral activity ofLDV/SOF FDC +/- RBV in chronic 
HCV -infected pediau·ic subjects. 
The study commenced with GT-1 , -3 and -4 HCV-infected pediau·ic 
subjects. Subjects with GT-5 and -6 are cunently eligible for 
inclusion into actively emolling groups/coh01is following the 
demonsu·ation ofbenefit:risk in the adult population. Subjects with 
GT-2 will be included once adult data are available, if appropriate. 
PK Lead-in Phase: PK Lead-in will evaluate and/or confnm age 
appropriate LDV/SOF FDC doses by analyzing PK, safety, and 
antiviral activity of LDV /SOF FDC tluough 10 days of dosing for 
each of the three coh01is. Children aged 3 to < 6, children aged 
6 to < 12 years, and adolescents aged 12 to < 18 years with evidence 
of cluonic HCV and HCV RNA ~ 1000 IU/mL at study enby will be 
evaluated. Subjects must be tt·eabnent na'ive without hist01y of 
cinhosis to pruiicipate in the PK Lead-in Phase. 
Page7 
15 March 2016 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 8
15 March 2016
Three cohorts of at least 10 subjects each will be sequentially 
enrolled: 

Cohort 1: 12 to < 18 years old, weighing ≥ 45kg

Cohort 2: 6 to < 12 years old, weighing ≥ 17 kg and < 45 kg

Cohort 3: 3 to < 6 years old 
The study will start with Cohort 1. Subjects will receive LDV/SOF 
FDC (90 mg/ 400 mg fixed dose combination tablet or 
4 x 22.5 mg/ 100 mg based on LDV/SOF FDC swallowability 
assessment) for 10 days with intensive PK conducted on Day 10.
Once Cohort 1 data is analyzed and a Cohort 2 dose is determined, 
Cohort 2 will open for screening. Cohort 2 subjects will receive 
45 mg/ 200 mg LDV/SOF FDC (2 x 22.5 mg/ 100 mg tablets) for 10 
days with intensive PK conducted on Day 10. Cohort 3 subjects will 
receive LDV/SOF FDC oral granule formulation; subjects weighing 
≥17 kg will receive 45 mg/ 200 mg LDV/SOF FDC and subjects 
weighing <17 kg will receive 33.75 mg/ 150 mg LDV/SOF FDC for 
10 days with intensive PK conducted on Day 10. Subject enrollment 
for Cohort 3 will be deferred until oral granule formulation is 
available. 
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 10
of the PK Lead-in Phase. They will continue dosing with LDV/SOF 
FDC with no interruption of study drug administration. Subjects 
rolling over from the PK Lead-in will not be required to perform 
Treatment Phase Screening, Day 1, or Week 1 visits in the Treatment 
Phase.  
Following completion of study treatment in the PK Lead-in of each 
Cohort, intensive PK and safety results of study treatment will be 
reviewed to confirm the appropriateness of the evaluated LDV/SOF 
FDC dose for the Treatment Phase of that Cohort as well as to 
determine the age-appropriate dose to be evaluated in the PK Lead-in 
of the next Cohort.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 9
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Treatment Phase: Treatment Phase will be initiated sequentially by 
cohort after confirmation of age-appropriate LDV/SOF FDC dosage 
levels. Subjects who participate in PK Lead-in Phase will 
immediately rollover into Treatment Phase, with no interruption of 
study drug administration, until the appropriateness of the dose is 
confirmed by PK and safety data from the PK Lead-In Phase. These 
subjects will start at the Week 2 visit of the Treatment Phase. 
Additional subjects will be enrolled in the Treatment Phase of each 
Cohort upon confirmation of the appropriateness of the dose.
Children aged 3 to < 12 years and adolescents aged 12 to < 18 years 
with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study 
entry (those who were dosed in the PK Lead-in Phase will have met 
these criteria prior to enrollment) will be evaluated. The study 
commenced with GT-1, -3 and -4 HCV-infected pediatric subjects. 
Subjects with GT-5 and -6 are currently eligible for inclusion into 
actively enrolling groups/cohorts following the demonstration of 
benefit:risk in the adult population. Subjects with GT-2 will be 
included once adult data are available, if appropriate.
Subjects enrolled in the study will receive the following regimen:

United Kingdom:
GT-1, GT-4, GT-5, and GT-6 treatment-naïve with or without 
cirrhosis: LDV/SOF FDC for 12 weeks
GT-1, GT-4, GT-5, and GT-6 treatment-experienced without 
cirrhosis: LDV/SOF FDC for 12 weeks
GT-1, GT-4, GT-5, and GT-6 treatment-experienced with 
cirrhosis: LDV/SOF FDC for 24 weeks
GT-3 treatment-experienced with or without cirrhosis: 
LDV/SOF FDC + RBV for 24 weeks

United States/Australia/New Zealand:
GT-1 treatment-naïve with or without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1 treatment-experienced without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1 treatment-experienced with cirrhosis: LDV/SOF FDC 
for 24 weeks
GT-4, GT-5, and GT-6 treatment-naïve or treatment-
experienced with or without cirrhosis: LDV/SOF FDC for 
12 weeks


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Substudy and Long-
Tenn Follow-Up 
Study: 
CONFIDENTIAL 
Final 
Amendment 4.0 
The study will enroll both u·eatment-na'ive and u·eahnent-experienced 
pediau·ic subjects, with up to 40 subjects allowed to be u·eatment 
experienced. Approximately 200 total subjects, including subjects 
that prui icipated in the PK Lead-in Phase, will be enrolled in the 
Treatment Phase as follows: 
• 
Group 1: Approximately 100 adolescent subjects (12 to < 18 yeru·s 
of age) 
• 
Group 2: Approximately 100 pediau·ic subjects (3 to < 12 yeru·s of 
age) 
The following defmitions will be used for u·eatment-experienced 
subjects: 
• 
Interferon intolerant: Subject who discontinued therapy 
(:::; 12 weeks total) due to:=::: 1 adverse event 
• 
Interferon non-responder: Subject who did not achieve 
undetectable HCV RNA levels while on u·eatment 
• 
Relapse/breakthrough: Subject who achieved undetectable 
HCV RNA during u·eatment or within 4 weeks of the end of 
u·eatment but did not achieve a sustained virologic response 
(SVR) 
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, and 12 (and Weeks 16, 20, and 24 for subjects 
requiring 24 weeks of u·eatment) dm'ing the u·eatment phase followed 
by post-u·eatment visits 4, 12, and 24 weeks after discontinuation of 
therapy. 
All subjects who do not attain SVR or have viral relapse will be 
encouraged to discuss u·eahnent with standard-of-cru·e (SOC) therapy 
with their healthcru·e provider. 
Pharmacogenomics (PG) Substudy 
PD 
Long-Term Follow-up 
Subjects who attain SVR24 or those who do not attain SVR24 and do 
not initiate other experimental or approved anti-HCV therapy will be 
followed eve1y 6 months for the first 2 years followed by eve1y 
12 months for assessments of growth, quality of life, and long-te1m 
viral suppression (if applicable) in a sepru·ate protocol 
(GS-US-334-1113). This follow-up will continue for 5 yeru·s. 
Page 10 
15 March 2016 


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 11
15 March 2016
Diagnosis and Main 
Eligibility Criteria: 
Chronic HCV-infected, treatment-naïve and treatment experienced
(up to 40 subjects); male and female subjects aged 3 to < 18 as 
determined at Day 1. The study commenced with GT-1, -3, and -4
HCV -infected pediatric subjects. Subjects with GT-5 and -6 are 
currently eligible for inclusion into actively enrolling groups/cohorts 
following the demonstration of benefit:risk in the adult population. 
Subjects with GT-2 will be included once adult data are available, if 
appropriate. 
Inclusion Criteria:

Chronic HCV infection documented by either:
A) positive anti-HCV antibody test or positive HCV RNA or 
positive HCV genotyping test at least 6 months prior to the 
Day 1 visit, or
B) liver biopsy performed prior to the Day 1 visit with evidence 
of chronic HCV- infection

HCV RNA ≥ 1000 IU/mL at Screening 

PK Lead-in Only: subjects in Cohort 1 (age 12 to < 18 years 
of age) must weigh ≥ 45 kg

PK Lead-in Only: subjects in Cohort 2 (age 6 to < 12 years of 
age) must weigh ≥ 17 kg and < 45 kg

Females of childbearing potential (as defined in Appendix 5) 
must have a negative pregnancy test at Screening and Day 1.

Hematologic or biochemical parameters at screening within 
the protocol-specified requirements
Exclusion Criteria:

HIV, acute hepatitis A virus (HAV) or chronic HBV infection

History of or current decompensated liver disease

Hepatocellular carcinoma or other malignancy (with exception 
of certain resolved skin cancers)

Chronic liver disease of a non-HCV etiology 
(e.g., hemochromatosis, Wilson’s disease, alpha-1 antitrypsin 
deficiency)

Systemic corticosteroid use for > 2 weeks (pulmonary/nasal 
administration is permitted)

Active or recent history (≤ 1 year) of drug or alcohol abuse


LDV/SOF FDC
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Gilead Sciences, Inc.
Amendment 4.0
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
History or current evidence of any condition, therapy, 
laboratory abnormality or other circumstance that might 
confound the results of the study, or interfere with the 
subject’s participation for the full duration of  the study, such 
that it is not in the best interest of the subject to participate.

Sexually active subjects who are not willing to use 2 forms of 
an effective method of contraception, as referenced in 
Appendix 5
See Sections 4.2 and 4.3 of the protocol for full eligibility criteria.
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the Day 1 
visit. 
Screening assessments will include: informed consent, medical 
history (including parental height, if available), complete physical 
examination, vital signs (including body height and weight), 
concomitant medications, LDV/SOF FDC Swallowability 
Assessment (may be performed at screening up to Day 1), 
hematology, safety laboratory tests, coagulation tests, HCV RNA, 
serum β-human chorionic gonadotropin (hCG - females of 
childbearing potential only), urinalysis, urine drug screen, IL28B 
genotyping, serology (HIV, HAV, HCV, and HBV, HCV 
genotyping), HbA1c, thyroid stimulating hormone (TSH), alpha 
fetoprotein, alpha-1 anti-trypsin.
For subjects continuing from PK Lead-in into the Treatment Phase, a 
screening visit for the Treatment Phase will not be required.
PK Lead-in Phase: 
Study Visits will occur at Day 1, Day 3, and Day 10.
On-Treatment assessments include physical examination, Tanner 
Pubertal Stage Assessment (Day 1 only), vital signs (including body 
height and weight), bone age assessment (Day 1 only), adverse events 
(AEs), concomitant medications, pregnancy prevention counseling 
(Day 1 only; all subjects ≥ 12 years of age and subjects 
< 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status), quality of life survey (Day 1 only), safety 
laboratory tests, HCV RNA, viral sequencing sampling and 
urinalysis. Coagulation testing and urine pregnancy tests (females of 
child bearing potential only) will be performed at Day 1 and Day 10 
only. LDV/SOF FDC swallowability assessment with placebo will be 
performed (if not performed at Screening) on Day 1 to assess a 
subject’s ability to swallow the 90 mg/ 400 mg or 22.5 mg/ 100 mg
FDC tablet, as applicable (only subjects administered LDV/SOF FDC


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 13
15 March 2016
in tablet form). 
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in 
Phase will participate in an intensive PK evaluation on Day 10. 
Following completion of the Day 10 intensive PK visit, subjects will 
then return for scheduled study visits outlined in the Treatment Phase 
and will continue dosing with LDV/SOF FDC with no interruption of 
study drug administration. Subjects will be administered a dosing 
diary with instructions.
Treatment Phase: 
Study visits will occur at Day 1, and at the end of Weeks 1, 2, 4, 8, 
and 12 (and Weeks 16, 20, and 24 for subjects requiring 24 weeks of 
treatment). All Treatment Phase subjects will then return for 
follow-up visits at 4, 12, and 24 weeks after discontinuation of 
therapy. 
On-treatment assessments will include physical examination, vital 
signs (including body height and weight), AEs, concomitant 
medications, pregnancy prevention counseling (all subjects 
≥12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status), safety laboratory
tests, coagulation tests, HCV RNA, viral sequencing, urine pregnancy 
tests (females of childbearing potential only), PK samples, a quality 
of life survey, and urinalysis. Tanner Pubertal Stage assessment will 
be performed at Day 1 and end of treatment visits; parental heights 
will be recorded at Day 1. The Bone Age Assessment will be 
performed at the Day 1 visit. LDV/SOF FDC swallowability 
assessment will be performed (if not performed at Screening) on
Day 1 to assess a subject’s ability to swallow a placebo to match the 
90 mg/ 400 mg or 22.5 mg/ 100 mg LDV/SOF FDC tablet, as 
applicable (only subjects administered LDV/SOF FDC in tablet 
form). For subjects continuing from the PK Lead-in, the screening, 
Day 1, and Week 1 visits of the Treatment Phase will not be required.
Samples for viral RNA sequencing/phenotyping will be collected at 
Day 1 and every visit thereafter.
Post-treatment assessments will include vital signs (including body 
weight and height), symptom-directed physical examination, AEs 
(only SAEs will be captured at post-treatment Week 12 and 
post-treatment Week 24), concomitant medications (only 
post-treatment Week 4), safety laboratory tests, HCV RNA, Tanner 
Pubertal Stage assessment (only post-treatment Week 12 and 
post-treatment Week 24), Bone Age Assessment (only post-treatment 
Week 24) and urine pregnancy tests (as defined in Appendix 5).  


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
CONFIDENTIAL 
PD 
PKLead-in: 
Final 
Amendment 4.0 
(Coh01i 1) LDV/SOF FDC is manufactured as a tablet, consisting of 
400 mg SOF and 90 mg LDV, for oral administration. LDV/SOF 
FDC tablets will be administered once daily. Subjects unable to 
swallow the LDV/SOF FDC 90 mg/ 400 mg adult tablet (as 
detennined by LDV /SOF FDC Swallowability Assessment at 
Screening or at Day 1) will be re-assigned to 4 x 22.5 mg/ 100 mg 
LDV /SOF FDC tablets daily. 
(Coh01i 2) LDV/SOF FDC 45 mg/ 200 mg (2 x 22.5 mg/ 100 mg) 
will be administered once daily. 
(Coh01i 3) LDV/SOF FDC oral granules will be administered once 
daily for 10 days. Subjects who weigh ::::17kg will receive 45 mg/ 
200 mg LDV/SOF FDC and subjects who weigh <17kg will receive 
33.75 mg/ 150 mg LDV/SOF FDC. 
Intensive PK and safety results fi:om the PK Lead-in of each Coh01i 
will be reviewed to confnm the appropriateness of the evaluated 
LDV/SOF FDC dose for the Treatment Phase of that Coh01i as well 
as to dete1mine the age-appropriate dose to be evaluated in the PK 
Lead-in of the next Cohort. 
Page 14 
15 March 2016 


LDV/SOF FDC
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Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 15
15 March 2016
Treatment Phase: 
Subjects who participated in PK Lead-in of each Cohort will continue 
in the Treatment Phase with no interruption of study drug 
administration until the appropriateness of the dose is confirmed by 
PK and safety data from the PK-Lead-in. Additional subjects will be 
enrolled in the Treatment Phase of each Cohort upon confirmation of 
the appropriateness of the dose.
RBV Weight-Based Dosing (GT-3 Subjects only):
The RBV dose is:
Body Weight kg
(lbs.)
RBV Daily 
Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution.  Divided dose in the 
morning and evening.
47-49 (103-108)
600 mg/day
1 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
50-65 (110 – 143)
800 mg/day
2 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
66-80 (145 – 176)
1000 mg/day
2 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
81-105 (178-231)
1200 mg/day
3 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
>105 (>231)
1400 mg/day
3 x 200-mg capsules A.M.
4 x 200-mg capsules P.M.
*
Note:  Subjects with a body weight greater than or equal to 47 kg may utilize the RBV 
oral solution if necessary.
The morning dose of RBV will be taken with food and a weight 
and/or age-appropriate dose of LDV/SOF FDC. The evening dose of 
RBV will be taken with food.
Reference Therapy:
None
Evaluation Criteria:
Safety:
AEs, laboratory tests, physical examinations, and vital sign 
measurements will be collected throughout the study. 
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using COBAS® AmpliPrep/COBAS® TaqMan®
HCV Test.


LDV/SOF FDC
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Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 16
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PK:
For subjects in the PK Lead-in, the steady-state PK of LDV, SOF,
and its major metabolites (GS-331007 and GS-566500) will be 
assessed at Day 10. For Cohorts 1 and 2, plasma samples will be 
collected for PK analyses following dosing of study drug on Day 10
at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, and 
12 hours postdose (with predose also serving as t= 24). For Cohort 3, 
plasma samples for PK analyses will be collected at the following 
time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours postdose (with 
predose also serving as t = 24).
Plasma PK parameters such as Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, and 
t1/2 will be estimated. 
For all subjects in the Treatment Phase, a single PK blood sample will 
be collected at all visits while on treatment. The PK of GS-331007,
SOF and LDV will be assessed.
The effect of age and LDV/SOF FDC dose on PK (GS-331007, SOF, 
and LDV) will be explored.
Statistical Methods:
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, Ctau, 
AUCtau, AUClast, and t1/2 will be estimated. The PK parameters will be 
summarized by cohort. The effect of age and LDV/SOF FDC dose on 
PK (GS-331007, SOF, and LDV) will be explored.
For the Treatment Phase, the primary safety endpoint is any AE 
leading to permanent discontinuation of study drug and will be 
summarized by the 4 regimens based on treatment-experience,
cirrhosis status and genotype, by age group, by regimen and age 
group, and overall. The key efficacy endpoint is SVR12 in all 
enrolled and treated subjects and will be summarized the 4 regimens 
based on by treatment-experience, cirrhosis status and genotype, by 
age group, by regimen and age group, and overall. Point estimate and 
its 95% confidence interval will be provided. 
Subgroup analysis on SVR12 will be performed by 
treatment-experience and cirrhosis status, by IL28B genotype, and by 
GT. Other clinically relevant subgroup analyses may be conducted as 
appropriate (i.e., assuming that adequate numbers of patients in these 
subsets are available for analysis). 
All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation, median, Q1, Q3, minimum, 
and maximum). All categorical endpoints will be summarized by 
number and percentage of subjects who meet the endpoint definition.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 17
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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 by the 4 regimens based on 
treatment-experience, cirrhosis status and GT, by age group, by 
regimen and age group, and overall.
With approximately 100 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 
SVR12 rate will extend at most 5.9% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 90%.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 18
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
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)
BLQ
below the lower limit of quantification
BMI
body mass index
CK
creatine kinase
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
dL
Deciliter
DNA
deoxyribonucleic acid
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
EMA
Electronic case report form(s)
European Medicines Agency
ESA
Erythropoiesis stimulating agent
ESPGHAN
European Society for Paediatric Gastroenterology
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed-Dose Combination
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)


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Amendment 4.0
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Page 19
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HAV
Hepatitis A Virus
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
peginterferon alfa-2a
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
QD
once daily (use only in tables)
RBC
Red blood cell count
RBV
ribavirin
RNA
ribonucleic acid
SADR
Serious adverse drug reaction
SAE
serious adverse event


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Amendment 4.0
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SD
Standard deviation
SOC
Standard-of-Care
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TSH
Thyroid stimulating hormone
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant 
(λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count


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Amendment 4.0
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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease worldwide 
and accounts for 70% of cases of chronic hepatitis in industrialized countries. The global 
prevalence of chronic hepatitis C is estimated to average 3% {19705}. 
The natural history of chronic HCV-infection in children differs from that in adults since 
HCV-infection in children is relatively benign. Most children chronically infected with HCV are 
asymptomatic or have mild nonspecific symptoms. Clinical symptoms are present in 
approximately 20% of children in the first 4 years of life, with hepatomegaly being the most 
frequent sign (10%). Many, but not all, perinatally infected children will have intermittently or 
persistently abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
levels, particularly in the first 2 years of life. In children with vertical HCV-infection who have 
undergone liver biopsy, the histological spectrum is usually mild, although severe liver disease is 
encountered {19801}. Despite the overall more favorable prognosis compared to adults, 
approximately 4% to 6% of children with chronic HCV-infection have evidence of advanced 
fibrosis or cirrhosis and some children eventually require liver transplantation for end-stage liver 
disease as a consequence of HCV-infection {19799}.
The goal of HCV treatment in both pediatric and adult populations is eradication of the virus, 
thereby preventing hepatic inflammation, hepatic fibrosis, cirrhosis, and liver failure resulting in 
either death or need for liver transplantation. This goal, however, is limited by the nature of the 
disease and the fact that not all patients are suitable candidates for currently approved treatments.
In addition, pediatric treatment is controversial as the current treatment options are limited and 
severe side effects and tolerability can significantly limit or preclude their use. Despite 
well-established guidelines for the treatment of HCV in adults, there is no universal consensus 
on when or if to treat chronic HCV-infection in children. In 2010, the European Society for 
Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) issued guidance for clinical 
trial development for chronic HCV-infection in children {20286}. In the guideline, the 
ESPGHAN suggested that the primary goal of treatment in children is to eradicate the infection 
to prevent late complications. Hence, the goal is not the treatment of an ongoing liver disease, 
but rather the prevention of a future one.
PEG and weight-based RBV are currently considered the SOC for the treatment of 
HCV-infection in children. Current recommendations are that patients with GT-2 or GT-3 be 
treated with PEG+RBV for 24 weeks and those with GT-1 or GT-4 should receive 48 weeks of 
therapy. Successful treatment of GT-1, however, has proved very difficult to achieve in spite of 
additional therapy or increased duration of treatment. A number of pediatric studies have 
reported that despite 48 weeks of treatment, sustained virologic response (SVR24) was observed 
in only 36% to 53% of subjects with GT-1, while response rates were > 80% in subjects with 
GT-2 or GT-3 {20285}. Safety and efficacy data in pediatric patients with GT-5 or GT-6 are 
limited.


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Most children treated with PEG+RBV experience at least 1 adverse event due to treatment 
{20285}. Although most of these events are mild to moderate in severity, many of them result in 
dose reductions of 1 or both of the drugs. The most common adverse events have consisted of 
influenza-like illness (91%), headache (62%), and injection site reactions (45%), often leading to 
poor compliance and/or discontinuation from treatment.
Additionally, the concern for growth and development in this age group and the role that both 
PEG and RBV potentially play in reducing growth rates has initiated significant debate among 
pediatric hepatologists as to whether these treatments should even be considered in the pediatric 
population {20282}. Many pediatricians currently advocate delay of treatment past adolescence 
or even into adulthood when options with DAAs are possible {20282}. Unfortunately, in the 
25% of pediatric patients who do meet the criteria for treatment (elevated transaminases and viral 
loads), the option of PEG+RBV therapy remains inadequate in regard to both efficacy in GT-1 
and safety due to the many risks associated with this treatment.
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
Ledipasvir/Sofosbuvir fixed-dose combination (LDV/SOF FDC) combines two HCV specific 
direct acting antiviral (DAA) agents into a single tablet for the treatment of chronic 
HCV-infection. SOF is a nucleotide analog that is a potent and selective inhibitor of 
NS5B-directed HCV replication with demonstrated activity against GT 1-6 HCV-infection. 
Ledipasvir (LDV) is a novel HCV NS5A inhibitor that has demonstrated potent anti-HCV 
activity, with the highest activity against GT-1 HCV-infection. 
Harvoni® (LDV/SOF FDC) is approved in the United States (US) by the Food and Drug 
Administration (FDA) and in the European Union by the European Medicines Agency (EMA) 
for treatment of GT-1, GT-4, GT-5, and GT-6 HCV infection in both treatment-naïve and 
treatment-experienced adult patients with or without cirrhosis. Additionally, LDV/SOF FDC + 
RBV is approved for treatment of GT-3 HCV infection in treatment-experienced adult patients 
with or without cirrhosis. The recommended treatment regimens depend on HCV genotype, 
presence or absence of cirrhosis, and prior treatment experience. 
1.2.1.
Summary of Additional Clinical Experience with Ledipasvir/Sofosbuvir 
Fixed-Dose Combination
The LDV/SOF FDC phase 3 program consisted of 3 clinical studies: GS-US-337-0102 {28583}, 
GS-US-337-0109 {28585}, and GS-US-337-0108 {28587}. Studies GS-US-337-0102 and 
GS-US-337-0109 evaluated treatment with LDV/SOF FDC RBV for 12 or 24 weeks in 
treatment-naïve and treatment-experienced subjects, respectively, infected with GT-1 HCV. Both 
studies enrolled up to 20% of HCV-infected subjects who had documented compensated 
cirrhosis. GS-US-337-0108 evaluated LDV/SOF FDC ± RBV treatment for 8 weeks and 
LDV/SOF FDC treatment for 12 weeks in non-cirrhotic treatment-naïve subjects with GT-1 
HCV-infection. Across these 3 clinical studies, LDV/SOF FDC demonstrated a high degree of 
efficacy (> 93%) for treatment-naïve and treatment experienced subjects with GT-1 
HCV-infection in subjects with and without cirrhosis and achieved their primary efficacy 
endpoints {28583}; {28585}; {28587}. Additionally, treatment with LDV/SOF FDC ± RBV was 
safe and well tolerated in the Phase 3 studies {28583}; {28585}; {28587}.  The inclusion of RBV 


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to the treatment regimen was associated with an increase in the total incidence of adverse events 
and in graded laboratory abnormalities of anemia and increased bilirubin. 
LDV/SOF FDC indication in GT-3 HCV infection is supported by the Phase 2 Study 
GS-US-337-0122 (ELECTRON-2). In this Phase 2 open-label study, the safety and efficacy of 
LDV/SOF FDC were evaluated with or without RBV in 51 treatment-naïve patients with GT-3 
HCV infection, with or without cirrhosis. Subjects were treated with LDV/SOF FDC (n = 25) or 
LDV/SOF FDC + RBV (n = 26) for 12 weeks. SVR12 rates were 64% (16/25) and 100% (26/26) 
in the LDV/SOF FDC and LDV/SOF FDC + RBV treatment groups, respectively. The relative 
efficacy of a 12-week regimen consisting of LDV/SOF FDC + RBV, compared to a 24-week 
regimen of SOF + RBV has not been investigated. Therefore, 24 weeks of therapy is advised in 
all treatment-experienced GT-3 patients and those treatment-naïve GT-3 patients with cirrhosis 
to maximize therapeutic benefit to achieve SVR.
Both nonclinical and clinical data support the inclusion of GT-4 HCV-infected subjects in the 
Study GS-US-337-1116. LDV displays potent antiviral activity against GT-4. In the replicon 
system the EC50 value of LDV for GT-4d HCV was 0.60 nM and 0.39 nM for GT-4a HCV. For 
reference, the EC50 values of LDV for GT-1a and GT-1b is 0.031 nM and 0.004 nM, 
respectively.
In the Phase 3 Study GS-US-337-0102 (ION-1), 2 subjects with GT-4d HCV infection were 
inadvertently randomized in violation of the protocol inclusion/exclusion criteria. Both subjects 
achieved SVR12. Subject 
 was treated for 12 weeks with LDV/SOF FDC and 
Subject 
 was treated for 24 weeks with LDV/SOF FDC + RBV.
Data from GS-US-337-1119 study support the inclusion of GT-4 as well as GT-5 HCV-infected 
subjects within the current study. The GS-US-337-1119 study was a European study that 
investigated the efficacy and safety of LDV/SOF FDC in treatment-naive and treatment-
experienced subjects with chronic GT-4 or GT-5 HCV infection. A total of 44 subjects with GT-
4 HCV infection, of whom 10 (23%) had cirrhosis and 22 (50%) were treatment experienced, 
were enrolled to receive LDV/SOF FDC for 12 weeks. SVR12 was achieved by 41 (93%) of the 
GT-4 HCV infection subjects including 21 (96%) who were treatment-naïve and 20 (91%) who 
were treatment-experienced subjects. In addition, a total of 41 subjects with GT-5 HCV infection
were enrolled, of whom 9 (22%) had cirrhosis and 20 (49%) were treatment-experienced, and
received LDV/SOF FDC for 12 weeks. SVR12 was achieved by 39 (95%) including 19 (95%) 
who were treatment-expereinced and 8 (89%) with cirrhosis.
In addition, data are available from the NIAID/NIH collaborative CO-US-337-0117 study. In this 
study, 21 subjects with GT-4 HCV infection received 12 weeks of LDV/SOF FDC treatment. 
SVR12 was achieved by 20 of 21 subjects including 6 subjects with cirrhosis.
Inclusion of subjects with GT-6 HCV in the current study is supported by data from the 
ELECTRON-2 study (GS-US-337-0122).  In ELECTRON-2, treatment-naïve or treatment-
experienced adult subjects with GT-6 HCV infection with or without cirrhosis (n = 25) received 
LDV/SOF FDC for 12 weeks. In this study, 96% (24/25) of patients achieved SVR12.
PPD
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 24
15 March 2016
Preliminary data are available for the current study in adolescent subjects (12 to < 18 years of 
age; N=10) and pediatric subjects (6 to <12 years of age; N= 12) who enrolled in the PK Lead-in 
Phase and received an adult clinical dose of LDV/SOF FDC 90 mg/ 400 mg or a reduced dose of 
LDV/SOF FDC 45 mg/200 mg, respectively. Of note, 2 out of 12 subjects (subject 
 and 
 in Cohort 2 erroneously received a dose of 90 mg/ 400 mg LDV/SOF FDC during the PK 
Lead-in Phase: Subject 
received 90 mg/ 400 mg from Day 1 through Day 10 and Subject 
 received 90 mg/ 400 mg from Day 1 through Day 4 followed by the correct dose of 45 
mg/ 200 mg for the remainder of the PK Lead-in Phase (Day 5 through Day 10). 
Evaluation of PK in Cohort 2 subjects was therefore conducted using data from all 12 subjects;
observed LDV, SOF, and GS-331007 (primary SOF metabolite) exposures on Day 10 were used 
for Subject 
and exposures were scaled to 45 mg/ 200 mg for Subject 
 (Table 1-2).  
Mean exposures of LDV, SOF, and GS-331007 in Cohort 1 and 2 subjects were comparable to 
observed exposures in the adult subjects in the Phase 2/3 LDV/SOF FDC clinical program; 
thereby confirming the appropriateness of the adult dose (90 mg/ 400 mg) in the adolescent 
population (12 to < 18 years of age) and 45 mg/ 200 mg in pediatric patients (6 to < 12 years of 
age) Table 1-1 and Table 1-2.
Safety data available for adolescent (12 to < 18 years) and pediatric (6 to < 12 years) subjects 
who enrolled in the PK Lead-in Phase resulted in no significant safety concerns in either age 
group.
Table 1-1.
Steady-state PK and Statistical Comparisons of LDV, SOF and 
GS-331007 PK in Adolescent Subjects (PK Lead-in) and Adult 
Subjects (Phase 2/3 Population PK Analysis)
Mean (%CV)
Adolescents (N=10)
Phase 2/3 (N=2113)
GMR% (90% CI)
LDV
AUCtau (ng*hr/ml)
10200 (50.9)
8530 (60.8)
127 (94.9, 170)
Cmax (ng/ml)
564 (41.2)
364 (51.4)
162 (125, 209)
Ctau (ng/ml)
319 (71.5)
247 (59.2)
128 (95.2, 172)
SOF*
AUCtau (ng*hr/ml)
2180 (26.6)
1380 (34.0)
160 (138, 185)
Cmax (ng/ml)
1140 (57.2)
659 (34.0)
156 (127, 190)
GS-331007
AUCtau (ng*hr/ml)
12700 (13.7)
12500 (29.2)
105 (90.6, 122)
Cmax (ng/ml)
1010 (21.5)
736 (28.2)
139 (120, 161)
Data reported to 3 significant figures; *N=1542
PPD
PPD
PPD
PPD
PPD
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 25
15 March 2016
Table 1-2.
Steady-state PK and Statistical Comparisons of LDV, SOF and 
GS-331007 PK in Pediatric Cohort 2 Subjects (6 to <12 years old; PK 
Lead-in) and Adult Subjects (Phase 2/3 Population PK Analysis)
Mean (%CV)
Pediatrics (N=12)**
Phase 2/3 (N=2113)
GMR% (90% CI)
LDV
AUCtau (ng*hr/ml)
7520 (58.0)
8530 (60.8)
86.9 (66.5, 114)
Cmax (ng/ml)
432 (51.3)
364 (51.4)
116 (92.1, 147)
Ctau (ng/ml)
248 (67.5)
247 (59.2)
91.1 (69.5, 120)
SOF*
AUCtau (ng*hr/ml)
1600 (29.7)
1380 (34.0)
116 (101, 133)
Cmax (ng/ml)
906 (36.0)
659 (34.0)
139 (116, 167)
GS-331007
AUCtau (ng*hr/ml)
8140 (31.6)
12500 (29.2)
65.2 (56.9, 74.7)
Cmax (ng/ml)
772 (24.4)
736 (28.2)
106 (92.8, 122)
Data reported to 3 significant figures; *N=1542 (Phase 2/3), ** Similar results were observed following exclusion of subjects 
 and 
 who received LDV/SOF 90 mg/400 mg during the PK-Lead-in
Please refer to the Investigator’s Brochure (IB) for additional information on the LDV/SOF FDC 
including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA 
and DNA viruses {15572}, {15668}. Ribavirin monotherapy has little or no effect on the 
replication of HCV but can result in normalization of serum ALT activity and improvement in 
liver histology. When combined with interferon or PEG therapy, RBV decreases substantially the 
relapse rate seen after cessation of interferon therapy {12557}, {12558}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to accumulate 
intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, extreme care 
must be taken to avoid pregnancy during RBV therapy and for up to 7 months following 
completion of treatment.  A comprehensive review of RBV is contained in the package 
insert/SmPC.
PPD
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 26
15 March 2016
1.4.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with LDV/SOF 
FDC +/- RBV for adolescents and children with chronic HCV-infection. 
Currently PEG and weight-based RBV are considered the SOC for the treatment of 
HCV-infection in children. Therefore, there is a need for new treatments for HCV in the 
pediatric population that combine potent and sustained efficacy with improved tolerability and 
safety. The primary aim for new treatments of pediatric patients with HCV is to eliminate the 
need to use PEG. In this way, pediatric patients would be able to avoid the necessity of weekly 
injections which can be traumatic and burdensome, and significantly reduce the serious adverse 
events seen with PEG administration. The secondary aim is to eliminate RBV and the adverse
events seen with its administration within HCV infected subjects.
Harvoni® (LDV/SOF FDC) is approved in the US and EU for the treatment of adults with 
chronic HCV infection. LDV/SOF FDC +/- RBV would provide an all-oral, IFN-free regimen 
with a shorter treatment duration (12 or 24 weeks of LDV/SOF FDC +/- RBV treatment versus 
standard-of-care 24 to 48 weeks of treatment) for GT-1, -3, -4, -5, and -6 HCV infected patients
and would offer another important option in the treatment of HCV infection in the pediatric 
population.
In vitro viral replicon assay has data demonstrating LDV has potent, antiviral activity against all 
HCV genotypes. In the LDV/SOF FDC phase 3 program, LDV/SOF FDC without RBV has 
been shown to have good efficacy and safety in adults infected with GT-1 HCV infection.  In the 
GS-US-337-0102 (ION-1), GS-US-337-1119, and CO-US-337-0117 studies, LDV/SOF FDC 
without RBV has been shown to have good efficacy and safety in adults infected with GT-4
HCV-infection. In study GS-US-337-0122, a phase 2 open-label study of GT-3 treatment-naïve
adult subjects with and without cirrhosis, LDV/SOF FDC for 12 weeks resulted in an SVR12 of 
64% whereas LDV/SOF + RBV for 12 weeks resulted in an SVR of 100% {29292}. The clinical 
data to support the use of Harvoni® in patients infected with HCV GT-3 are limited. As a result, 
the current study includes a 24-week RBV treatment regimen for only treatment-experienced 
pediatric subjects with GT-3 HCV-infection.
Considering that SOF has pan-genotypic activity and LDV has in vitro, picomolar to nanomolar 
antiviral activity against certain subtypes within GT 4-6 and sub-micromolar antiviral activity 
against certain subtypes within GT-2, studies in patients with GT-5 and GT-6 HCV have been 
completed and used to support treatment recommendations for the use of LDV/SOF FDC in 
adults infected with GT-5 and GT-6 HCV in both the US and EU. In studies GS-US-337-1119 
and GS-US-337-0122, LDV/SOF FDC for 12 weeks resulted in SVR12 rates of 93% and 96% in 
GT-5 and GT-6 HCV, respectively. Based on these clinical data paediatric subjects with GT-5 
and GT-6 infection are eligible for enrollment into this clinical study.
If emerging LDV/SOF FDC data in GT-2 HCV infected subjects support treatment in adults,
pediatric subjects with GT-2, will be enrolled in the current study.  Of note, there is an ongoing 
study enrolling GT-2 (and GT-3) pediatric patients, GS-US-334-1112, for treatment with SOF + 
RBV for 12 and 24 weeks, respectively.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 27
15 March 2016
1.5.
Rationale for Dose Selection of LDV/SOF FDC
Ledipasvir /Sofosbuvir (90 mg/ 400 mg) fixed-dose combination tablet +/- RBV has 
demonstrated favorable safety and efficacy profiles in over 3000 HCV-infected subjects across 
different patient populations in phase 2 and 3 clinical trials. These doses represent the marketed 
dose of a ledipasvir/sofosbuvir fixed-dose combination tablet for the treatment of HCV-infection
in adults.
Selection of doses of LDV/SOF FDC +/- RBV for adolescents and younger age groups will 
target systemic exposures similar to those observed in adults at the proposed marketed dose. 
LDV and SOF are substrates for efflux drug transporters P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP). LDV is also a subject to slow oxidative metabolism via an unknown 
mechanism. SOF is extensively metabolized to the pharmacologically active nucleoside analog 
phosphate. The activation pathway involves hydrolysis by intestinal and hepatically expressed 
carboxylesterase (CES1) and Cathepsin A (CatA) enzymes {20287}, {20288}.  SOF is also 
converted to GS-331007, an inactive circulating metabolite, which is eliminated renally by active 
tubular secretion and glomerular filtration.  Available data suggest comparable hepatic 
expression of CES1 in adolescents and adults with modestly decreased expression in children.  
However, little is known about the developmental regulation of Pgp, CES, and CatA.  When 
adjusted for BSA, the processes of active secretion and glomerular filtration approximate adult 
activity by 6 to 12 months of age {5914}. 
The adult clinical dose of LDV/SOF FDC (90 mg/ 400 mg) is being evaluated in adolescent 
subjects (12 to <18 years old) while a lower LDV/SOF FDC (45 mg/ 200 mg) is being evaluated 
in children (6 to <12 years old), respectively.  The appropriateness of these doses are supported 
by data from the Cohort 1 and Cohort 2 PK Lead-in Phase which demonstrated comparable 
LDV, SOF and GS-331007 exposures in adolescent subjects who received LDV/SOF FDC
(90 mg/ 400 mg) or children who received LDV/SOF FDC (45 mg/ 200 mg) compared to adult 
subjects in Phase 2/3 population PK analyses.
In Cohort 3 (3 to < 6 years of age), a dose of LDV/SOF FDC (45 mg/ 200 mg) is proposed for 
evaluation in children weighing ≥ 17 kg, whereas a lower LDV/SOF FDC dose (33.75 mg/ 150 
mg) is proposed for evaluation in children weighing < 17 kg. These proposed doses are
supported by scaling of adult exposures based on correlations between body weight and 
clearance capacity (liver volume/size for LDV and SOF, and renal capacity for GS-331007) for 
the expected body weight range in children (3 to < 6  years of age) as demonstrated in Figure 1-1
{34882}, {5914}. Based on this scaling approach, doses of LDV/SOF FDC (45 mg/ 200 mg) in 
children ≥ 17 kg and LDV/SOF FDC (33.75 mg/ 150 mg) in children < 17 kg are expected to 
achieve mean systemic exposures of LDV, SOF and GS-331007 within the range of those
observed in the Phase 2/3 population. Safety and PK data in children (3 to < 6 years of age) who 
enroll in the PK-Lead-in Phase will be evaluated to confirm the appropriateness of the dose for 
this age group.


LDVISOFFDC 
Protocol GS-US-337-1116 
Final 
Gilead Sciences, Inc. 
Amendment 4.0 
Figure 1-1. 
Predicted LDV, SOF and GS-331007 AUCtau following administration 
ofLDV/SOF FDC 45 mg/ 200 mg in Children or LDV/SOF FDC 33.75 
mg/ 150 mg (3 to < 6 years of age) 
'S 
..2! 
C1l o.-.. 
Ill-
-E 
ja::: 
! .s:; 
u " 
::::> 
Cl 
<(..:. 
u. 
0 
(/) 
150 mg SOF 
Predicted SOF exposure 
200 mg SOF 
( <17 kg) 
(;~ 1 7 kg) 
.......... t. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
l1l3)(_ 
5000 
• • • • • • • • 
95th %lie 
. ¥ .. ~::.~~~~~J. Q3 
1000 
median 
Q1 
5th %ile 
500 
min 
10 12 14 161718 20 22 24 26 28 30 32 34 36 38 40 42 44 
weight (kg) 
o 
5th percentile o 
0 1 A 
median 
v 03 ¢ 
95th percentile 
CONFIDENTIAL 
Page28 
15 March 2016 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 29
15 March 2016
weight (kg)
GS-331007 AUCtau (scaled)
(ng*hr/ml)
Phase 2/3 Population
LDV/SOF (90 mg/400 mg)
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
10000
min
5th %ile
Q1
median
Q3
95th %ile
max
Predicted GS-331007 exposure
5000
20000
95th percentile
Q3
Q1
5th percentile
median
17
Predicted GS-331007 exposure
150 mg SOF
(<17 kg)
200 mg  SOF
( 17 kg)


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
~ 
(I) 
'jij 
(.) 
~ 
lh - E 
:::.>::: 
~.J: 
u " 
C) 
:::> s 
c{ 
> 
c 
...J 
1.6. 
33.75 mg LDV 
Predicted LDV exposure 
45 mg LDV 
50000 
10000 
1000 
. ~ ~ 1 ?. ~9) .................. {~ 1?. ~9l .................. . 
I 
I 
I 
.................... 
............. 
.................... 
10 12 14 161718 20 22 24 26 28 30 32 34 36 38 40 42 44 
weight (kg) 
o 
5th percentile 
o 
01 
A 
median 
v 
03 
¢ 
95th percentile 
Overall Risk/Benefit Assessment 
Final 
Amendment 4.0 
max 
95th %ile 
r o, 
Q3 
~::r 
(hAl 
OUI 
median 
"TT(I) 
~N 
Q1 
cow 
o., 
3 0 
5th %ile 
(Q"t:J 
~=-
QAI 
o:::: 
3 g 
s. 
min 
Although the majority of pediatric patients infected with HCV exhibit minimal hepatic sequelae 
despite active viral replication and inflammation, a subset of children and adolescents will 
require treatment. Studies suggest that 3 major categories of disease can occur within 10 years 
after putative HCV exposure: (1) undetectable viremia and nmmal ALT, (2) persistent yet 
uncomplicated mild liver disease, and (3) progression to end-stage liver disease {20273}. It is the 
last two groups of children in whom therapy may be indicated to prevent end-stage disease, 
either during childhood/adolescence or in early adulthood. 
Given that the cunent SOC for the treatment of children infected with HCV is PEG and RBV 
and these regimens are long in duration, relatively toxic, and not well tolerated, there continues 
to be a need for new treatments for HCV that combine potent and sustained efficacy with 
improved tolerability and safety. 
The combination of LDV plus SOF is anticipated to offer greater antiviral efficacy which could 
result in a shmter treatment duration and/or lead to a regimen without RBV or interferon. These 
in tum could result in reduction in adverse events. LDV /SOF FDC could also potentially be of 
benefit in patients who have failed prior treatment with SOF+/-RBV+/- PEG. 
If high rates of SVR can be obtained with short, well-tolerated regimens, the anticipated 
improvements in safety and tolerability would offer a favorable risk-benefit detetmination for 
individuals with chronic HCV-infection. 
CONFIDENTIAL 
Page 30 
15 March 2016 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
2. 
OBJECTIVES 
The prima1y objective of the PK Lead-in Phase of this study is: 
Final 
Amendment 4.0 
• 
To evaluate the steady state phrum acokinetics (PK) and confmn the dose ofLDV/SOF FDC 
in chronic HCV-infected pediatric subjects 
The secondruy objective of the PK Lead-in Phase of this study is: 
• 
To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing ofLDV/SOF 
FDC in chronic HCV -infected pediatric subjects 
The primary objective of the Treatment Phase of this study is: 
• 
To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV for 12 or 24 weeks in 
chronic HCV -infected pediatric subjects 
The secondruy objectives of the Treatment Phase of this study ru·e: 
• 
To dete1mine the antiviral efficacy of 12 or 24 weeks ofLDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects (including the impact of HCV genotype, IL28B genotype, 
and prior treatment experience), as assessed by the prop01iion of subjects with SVR 
12 weeks after completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of 12 or 24 weeks ofLDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment 
• 
To evaluate the effect of growth and development on pediatric subjects during and after 
treatment 
The explorat01y objective of this study is: 
• PD 
CONFIDENTIAL 
Page 31 
15 March 2016 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 32
15 March 2016
3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and antiviral 
activity of LDV/SOF FDC +/- RBV in chronic HCV-infected pediatric subjects.
3.1.1.
PK Lead-in
The PK Lead-in Phase will evaluate and/or confirm the age appropriate LDV/SOF FDC dose by 
analyzing PK, safety, and antiviral activity of LDV/SOF FDC through 10 days of dosing for each 
cohort. Children aged 3 to < 6 years, children aged 6 to < 12 years, and adolescents 
aged 12 to < 18 years with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry 
will be evaluated. Subjects must be treatment naïve without history of cirrhosis to participate in 
the PK Lead-in Phase. Three cohorts of at least 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old, weighing ≥45kg

Cohort 2:  6 to < 12 years old, weighing ≥ 17 kg and < 45 kg

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive LDV/SOF FDC (90 mg/ 400 mg 
adult tablet or 4 x 22.5 mg/100 mg tablets if determined necessary based on LDV/SOF FDC
swallowability assessment) for 10 days with intensive PK conducted on Day 10. 
Cohort 2: Subjects will receive LDV/SOF FDC 45 mg/ 200 mg (2 x 22.5 mg/ 100 mg tablets) for 
10 days with intensive PK conducted on Day 10.
Once Cohort 3 is opened, subjects will receive LDV/SOF FDC oral granules; subjects weighing 
≥17 kg will receive LDV/SOF FDC 45 mg/ 200 mg and subjects weighing <17 kg will receive 
LDV/SOF FDC 33.75 mg/ 150 mg for 10 days with intensive PK conducted on Day 10. Subject 
enrollment for Cohort 3 will be deferred until oral granule formulation is available. 
Subjects enrolled in the PK Lead-in of each cohort (Cohorts 1, 2 and 3) will immediately enroll 
in the Treatment Phase as they complete Day 10 of PK Lead-in.  They will continue dosing with 
LDV/SOF FDC with no interruption of study drug administration.  Subjects rolling over from the 
PK Lead-in Phase will not be required to perform the screening, Day 1, or Week 1 visit of the 
Treatment Phase.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 33
15 March 2016
Figure 3-1.
PK Lead-in Phase Study Schema
3.1.2.
Treatment Phase
The Treatment Phase will be initiated sequentially by age group as defined in Cohort 1, 2, and 3 
of the PK Lead-in. Subjects who participated in PK Lead-in will immediately rollover into 
Treatment Phase with no interruption of study drug administration until the appropriateness of 
the dose has been confirmed by PK and safety results from the PK Lead-in.  The first visit in the 
Treatment Phase for these subjects will be the Week 2 visit.  Additional subjects will be enrolled 
in the Treatment Phase of each Cohort upon confirmation of the appropriateness of the dose from 
the PK Lead-in.
Children aged 3 to < 12 years (Group 2) and adolescents aged 12 to < 18 years (Group 1) with 
chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry (those who were dosed in 
the PK Lead-in will have met this criteria prior to enrollment) will be evaluated.
Subjects enrolled in the Treatment Phase will receive the following regimen:
a) United Kingdom:
GT-1, GT-4, GT-5, & GT-6 treatment-naïve subjects with or without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1, GT-4, GT-5, & GT-6 treatment-experienced subjects without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1, GT-4, GT-5, & GT-6 treatment-experienced subjects with cirrhosis: LDV/SOF 
FDC for 24 weeks
GT-3 treatment-experienced subjects with or without cirrhosis: LDV/SOF FDC + RBV 
for 24 weeks


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 34
15 March 2016
b) United States/Australia/New Zealand:
GT-1 treatment-naïve subjects with or without cirrhosis: LDV/SOF FDC for 12 weeks
GT-1 treatment-experienced subjects without cirrhosis: LDV/SOF FDC for 12 weeks
GT-1 treatment-experienced subjects with cirrhosis: LDV/SOF FDC for 24 weeks
GT-4, GT-5, & GT-6 treatment-naïve or treatment-experienced subjects with or without 
cirrhosis: LDV/SOF FDC for 12 weeks
Table 3-1.
Subject Enrollment by HCV Genotype, Country, and Treatment 
Duration
GT-1
GT-3
GT-4, GT-5, & GT-6
Cirrhotic 
or 
Non-
cirrhotic 
Subjects 
(TN)
Non -
cirrhotic 
Subjects 
(TE)
Cirrhotic 
Subjects 
(TE)
Non-
cirrhotic 
or 
Cirrhotic 
Subjects 
(TE)
Cirrhotic 
or 
Non-
cirrhotic 
Subjects 
(TN)
Non-
cirrhotic 
Subjects 
(TE)
Cirrhotic 
Subjects 
(TE)
United 
States
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
N/A
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
Australia
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
N/A
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
New 
Zealand
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
N/A
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
United 
Kingdom
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC + 
RBV
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
12 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
24 Weeks 
of 
treatment 
with 
LDV/SOF 
FDC
TN = Treatment Naïve, TE = Treatment Experienced, N/A = Not Applicable


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Subjects with GT -1, -3, and -4 were enrolled initially. GT-5 and GT-6 subjects will be included 
in those groups/cohorts actively enrolling subjects given confirmation of benefit:risk in adult 
patients has been obtained. If emerging LDV/SOF FDC data in GT-2 support treatment in adults,
pediatric subjects with GT-2 will be subsequently enrolled.  
The study will enroll both treatment naïve and treatment experienced pediatric subjects with up 
to 40 subjects allowed to be treatment experienced. Approximately 200 total subjects, including 
subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as follows:

Group 1: Approximately 100 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 100 pediatric subjects (3 to < 12 years of age)
The following definitions will be used for treatment experienced subjects:

Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to ≥1 adverse 
event

Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels while 
on treatment

Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment or 
within 4 weeks of the end of treatment but did not achieve a sustained virologic response 
(SVR)
All subjects who do not attain SVR or have viral relapse will be encouraged to discuss treatment 
with SOC therapy with their healthcare provider.
3.2.
Visit Schedule
3.2.1.
PK Lead-in
Screening assessments will be completed within 28 days of the Day 1 visit. 
Study Visits will occur at Screening, Day 1, Day 3, and Day 10.
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in Phase will participate in an 
intensive PK evaluation on Day 10. Subjects will be administered a dosing diary with 
instructions.  
Following completion of the Day 10 intensive PK visit, subjects will then return for scheduled 
study visits outlined in the Treatment Phase and continue dosing with LDV/SOF FDC with no 
interruption of study drug administration.  Subjects rolling over from the PK Lead-in Phase will 
not be required to perform the screening, Day 1, or Week 1 visits of the Treatment Phase.


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3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. Subjects continuing 
from the PK Lead-in Phase will not be required to complete Screening, Day 1, and Week 1 visits 
of the Treatment Phase.

Subjects requiring 12 weeks of treatment: Study visits will occur at Screening, Day 1, and 
the end of weeks 1, 2, 4, 8, and 12.

Subjects requiring 24 weeks of treatment: Study visits will occur at Screening, Day 1, and 
the end of weeks 1, 2, 4, 8, 12, 16, 20, and 24.
All subjects will then return for follow-up visits at 4, 12, and 24 weeks after discontinuation of
therapy.
The total time to complete all study visits is approximately 40 or 52 weeks including:

28 day (4 week) screening period

12 or 24 week treatment period

24 week post-treatment period
The assessments performed at each visit are described in Section 6.
3.3.
Virologic Response-Based Stopping Criteria
HCV RNA will be unblinded to the Investigator and Sponsor.
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 from nadir 

HCV RNA ≥LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination of 
initial observation.  Subjects that meet the virologic response-based stopping criteria above will 
be notified of their eligibility to participate in the Long-Term Follow-Up Study 
(GS-US-334-1113).
3.4.
Treatment Discontinuations Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances:

Unacceptable toxicity (as defined in Section 7) 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.


LDVISOFFDC 
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• 
Pregnancy of female subject or female partner of male subject. 
• 
Efficacy failure as defined in Section 3.3. 
Final 
Amendment 4.0 
• 
Significant protocol violation including non-compliance with study assessments. 
• 
Subject request to discontinue for any reason; it is imp01iant to detennine 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, regulat01y agency, or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). 
3.5. 
Discontinuations 
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Termination visit as described in the Section 6.4.8. 
Subjects who pennanently discontinue the study dmg for any reason including safety and/or 
tolerability concems prior to completion of the assigned dosing period will be followed 
according to the post-u·eatment study assessments described in Section 6.5. 
3.6. 
Pharmacogenomic Substudy 
3.7. 
Long-Term Follow-Up 
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed eve1y 6 months for the first 
2 years followed by eve1y 12 months for assessments of growth, quality of life, and long-te1m 
viral suppression (if applicable) in a separate protocol (GS-US-334-1113). This follow-up study 
will continue for 5 years. 
3.8. 
Breakthrough Futility Assessment 
A futility assessment will be perf01m ed after the first 10 subjects complete Week 8 on study or 
have viral breakthrough at or prior to Week 8. If3 or more of the first 10 subjects emolled have 
viral breakthrough at or prior to Week 8 or are non-responders (HCV RNA 2: LLOQ through 
8 weeks of u·eahnent) then fmiher emollment of subjects will be suspended. Virologic 
breakthrough is defined as confnmed HCV RNA .2: LLOQ while on u·eatment after 
two consecutive visits with HCV RNA < LLOQ. 
CONFIDENTIAL 
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If a holding rule has been met and following an internal safety review it is deemed appropriate to 
restart enrollment, a request to restart enrollment with pertinent data will be submitted to the 
appropriate regulatory agencies.  Enrollment will only resume after review by the appropriate 
regulatory agencies.  Any subject on treatment when a holding rule has been met will be allowed 
to continue to treatment.
Subjects with known or suspected study drug non-adherence will not be considered to meet the 
definition of virologic breakthrough, relapse, or non-responder. 
3.9.
Reconsent
When a subject reaches the age of consent in their country/region, they will be invited to consent 
as an adult to allow them to continue participating in the clinical trial.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 200 subjects will be enrolled in this study.
In order to manage the total study enrollment, Gilead Sciences, Inc. at its sole discretion, may 
suspend screening and/or discontinue the enrollment at any site at any time (upon written notice 
to the site). Discontinuation of the enrollment phase may result in the immediate ineligibility of 
all subjects screened but not yet enrolled, regardless of the progress or outcome of the screening 
assessments performed.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1. Parent or legal guardian able to provide written informed consent prior to any screening 
evaluations and willing to comply with study requirements.  Subjects will provide assent if 
possible.
2. 3 years to < 18 years of age as determined at Day 1 (consent of parent or legal guardian 
required)
3. PK Lead-in only: subjects in Cohort 1 (age 12 to <18 years of age) must weigh 45 kg
4. PK Lead-in only: subjects in Cohort 2 (age 6 to <12 years of age) must weigh 17 kg and 
< 45 kg
5. PK Lead-in only: all subjects must be treatment naïve: no prior exposure to any IFN, RBV, 
or other approved or experimental HCV-specific DAA agent
6. Treatment experienced subjects:  prior treatment failure to a regimen including interferon 
either with or without RBV that was completed at least 8 weeks prior to Day 1.
i.
Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to 
≥1 adverse event
ii.
Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels 
while on treatment
iii.
Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment 
or within 4 weeks of the end of treatment but did not achieve a sustained virologic 
response (SVR)
7. 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 Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV-infection


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8. Infection with HCV as determined at Screening:
a) United Kingdom Only: As of Protocol Amendment 4.0, the study is enrolling GT-1, -3, -
4, -5, and -6 HCV-infected pediatric subjects and will subsequently enroll subjects with 
GT-2 once adult data is available, if appropriate.
b) United States/ Australia/ New Zealand Only: As of Protocol Amendment 4.0, the study is 
enrolling GT-1, -4, -5, and -6 HCV-infected pediatric subjects and will subsequently 
enroll subjects with GT-2 once adult data is available, if appropriate.
9. HCV RNA ≥1000 IU/mL at Screening
10. Adequate hematologic function (absolute neutrophil count 1,500/mm3; 
hemoglobin 11 g/dL or 12 g/dL for GT-3 males only).
11. Negative serum -HCG pregnancy test (for females of childbearing potential only, as defined 
in Appendix 5)
12. Subject able to provide written assent, if they have the ability to read and write, as 
determined by IRB/IEC/local requirements and Investigator’s discretion
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Pregnant or lactating subjects
2. Sexually-active males or females of childbearing potential who are not willing to use an 
effective method of contraception during the study (see Appendix 5 for further details)
3. Treatment-naïve subjects with GT-3 HCV infection as determined at Screening. Treatment 
naïve is define by no prior exposure to any IFN, RBV, or other approved or experimental 
HCV-specific DAA agent
4. Decompensated liver disease defined as INR 1.2 ULN, platelets 50,000/mm3, serum 
albumin 3.5 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, 
jaundice, encephalopathy, variceal hemorrhage)
5. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
6. -fetoprotein 50 ng/mL
7. Serum creatinine > 1.5 mg/dL
8. Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula


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9. Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of 
certain resolved skin cancers)
10. Co-infection with HIV, acute HAV, or HBV
11. Significant cardiovascular, pulmonary, or neurological disease
12. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications
13. History of solid organ or bone marrow transplantation
14. Chronic daily non-steroidal anti-inflammatory drug therapy
15. Systemic corticosteroid use for > 2 weeks (pulmonary/nasal administration is permitted)
16. Investigational agents taken within the past 28 days (except with the expressed approval of 
the Sponsor)
17. Clinically-relevant alcohol or drug abuse within 12 months of screening.  A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator
18. Known hypersensitivity to the study drug, the metabolites, or formulation excipients
19. Any other condition (including alcohol or substance abuse) or prior therapy that, in the 
opinion of the Investigator, would make the subject unsuitable for the study or unable to 
comply with dosing requirements
20. Use of any prohibited concomitant medications as described in Section 5.6
21. PK Lead-in only: subjects with history of cirrhosis (as determined by liver biopsy)
22. 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 enrollment or has not required medication in the last 12 months may be 
included.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
5.2.1.
Description and Handling 
5.2.1.1.
Formulation
LDV/ SOF FDC tablets are orange, diamond-shaped, film-coated tablets containing 90 mg of 
LDV and 400 mg of SOF. The tablets are debossed with “GSI” on one side and “7985” on the 
other side. The LDV/SOF 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.
Placebo to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment are 
orange, diamond-shaped, film-coated tablets debossed with “GSI” on one side and “7985” on the 
other side. The tablets contain lactose monohydrate, copovidone, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, 
polyethylene glycol, FD&C yellow # 6 /sunset yellow FCF aluminum lake.
Age-appropriate formulations of LDV/SOF FDC have been developed for subjects who are 
unable to swallow the LDV/SOF FDC 90 mg/ 400 mg tablets which include a lower dose 
strength tablet (LDV/SOF FDC 22.5 mg/ 100 mg) formulation. LDV/ SOF FDC lower dose 
strength tablets are round, plain-faced, white film-coated tablets containing 22.5 mg of LDV and 
100 mg of SOF. The LDV/SOF FDC lower dose strength tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc 
and polyethylene glycol.
Placebos to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment are 
round, plain-faced, white film-coated tablets. The placebo tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc and polyethylene glycol.
The non-tablet LDV/SOF FDC formulation will be based on the PK results obtained from 
cohorts 1 and 2 of this study. The formulation, composition, acceptability (including palatability) 
will be available and reflected in a protocol amendment which will be submitted for approval 
prior to dosing subjects in the PK Lead-in Cohort 3 and/or Treatment Phase (3 to < 6 years old 
age).


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5.2.1.2.
Packaging and Labeling
LDV/ SOF FDC 90 mg/ 400 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 or 30 tablets, a silica gel desiccant, and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child resistant screw 
cap with an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
a silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant screw cap with an induction-sealed, aluminum faced liner.
LDV/SOF FDC 22.5 mg/ 100 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets, a silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child resistant screw cap with 
an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
a silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant screw cap with an induction-sealed, aluminum faced liner.
The packaging and labeling of the non-tablet LDV/SOF FDC formulation will be based on the 
chosen formulation. The packaging and labeling will be available and reflected in a protocol 
amendment which will be submitted for approval prior to dosing subjects who are unable to 
swallow tablets.
All LDV/SOF FDC and placebo to match LDV/SOF FDC bottles to be distributed in the US, 
EU, and the rest of the countries shall be labeled to meet all applicable requirements of the 
US Food and Drug Administration (FDA), Annex 13 of Good Manufacturing Practices: 
Manufacture of investigational medicinal products (February 2010), and/or other local 
regulations as applicable.
5.2.2.
Storage and Handling
LDV/ SOF FDC tablets, 90 mg/ 400 mg, should be stored at controlled room temperature until 
required for administration. Controlled room temperature is defined as 25 °C (77 °F); excursions 
are permitted between 15 °C and 30 °C (59 °F to 86 °F).
Placebo to match LDV/ SOF FDC tablets, 90 mg/ 400 mg, for Swallowability Assessment 
should be stored at controlled room temperature until required for administration. Controlled 
room temperature is defined as 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C 
(59 °F to 86 °F).  
LDV/SOF FDC tablets, 22.5 mg/ 100 mg, should be stored at controlled room temperature until 
required for administration. Controlled room temperature is defined as 25 °C (77 °F); excursions 
are permitted between 15 °C and 30 °C (59 °F to 86 °F).


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Placebo to match LDV/ SOF FDC tablets, 22.5 mg/ 100 mg, for Swallowability Assessment 
should be stored at controlled room temperature until required for administration. Controlled 
room temperature is defined as 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C 
(59 °F to 86 °F).
The storage and handling of the non-tablet LDV/SOF FDC formulation will be based on the 
chosen formulation. The storage and handling will be available and reflected in a protocol 
amendment implemented prior to dosing subjects who are unable to swallow tablets.
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 
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 
LDV/SOF FDC.
Sufficient quantities of LDV/SOF FDC tablets, non-tablet LDV/SOF FDC formulation, and 
placebo tablets will be shipped to the investigator or qualified designee from Gilead Sciences 
(or its designee).
5.2.3.
Dosage and Administration of LDV/SOF FDC
PK Lead-in: 
Cohort 1: LDV/SOF FDC 90 mg/ 400 mg tablets will be administered once daily with or without 
food. Subjects determined unable to swallow the placebo to match the 90 mg/ 400 mg LDV/SOF 
FDC tablet (by LDV/SOF FDC Placebo Swallowability Assessment at Screening up to Day 1) 
will be re-assigned to 4 x 22.5 mg/ 100 mg tablets daily.  Subjects who weigh < 45 kg will be 
excluded.
Cohort 2: LDV/SOF FDC 2 x 22.5 mg/ 100 mg tablets will be administered once daily with or 
without food. Subjects must weigh ≥ 17 kg and < 45 kg.
Cohort 3: LDV/SOF FDC 45 mg/ 200 mg will be administered once daily with or without food
for subjects weighing ≥17kg. LDV/SOF FDC 33.75 mg/ 150 mg will be administered once daily 
with or without food for subjects weighing <17 kg. All subjects enrolled within Cohort 3 will be 
deferred until non-tablet formulation is available.
Intensive PK and safety results from the PK Lead-in of each Cohort will be reviewed to confirm 
the appropriateness of the evaluated LDV/SOF FDC dose for the Treatment Phase of that Cohort 
as well as to determine the age-appropriate dose to be evaluated in the PK Lead-in of the 
next Cohort.


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Treatment Phase: Subjects who participated in the PK Lead-in of each Cohort will continue in 
the Treatment Phase with no interruption of study drug administration until the appropriateness 
of the dose is confirmed by PK and safety data from the PK-Lead-in.  Additional subjects will be 
enrolled in the Treatment Phase of each Cohort upon confirmation of the appropriateness of the 
dose.  
An additional age-appropriate formulation for LDV/SOF FDC is currently under development. 
The strength, composition, and dosing administration will be available and reflected in a protocol 
amendment which will be submitted for approval prior to dosing Cohort 3 subjects and/or 
subjects who are unable to swallow tablets.
Subjects should be instructed that if vomiting occurs within 5 hours of dosing an additional tablet 
should be taken.  If vomiting occurs more than 5 hours after dosing, no further dose is needed.
If a dose is missed and it is within 18 hours of the normal time, subjects should be instructed to 
take the tablet as soon as possible and then subjects should take the next dose at the usual time.  
If it is after 18 hours then subjects should be instructed to wait and take the next dose at the usual 
time.  Subjects should be instructed not to take a double dose.
5.3.
Ribavirin (GT-3 Subjects Only)
5.3.1.
Description and Handling of RBV
5.3.1.1.
Formulation
REBETOL capsules consist of a white powder in a white, opaque, gelatin capsule. Each capsule 
contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose, lactose 
monohydrate (40 mg), croscarmellose sodium, and magnesium stearate. The capsule shell 
contains gelatin, titanium dioxide. The capsule shell imprint contains shellac, propylene glycol, 
ammonium hydroxide, coloring agent (E 132).The hard capsule is imprinted with blue ink.
REBETOL RBV Oral Solution 40 mg per mL is a clear, colorless to pale or light yellow bubble 
gum-flavored liquid. In addition to the active ingredient, RBV oral solution contains the 
following inactive ingredients: sucrose, glycerin, sorbitol, propylene glycol, sodium citrate, citric 
acid, sodium benzoate, natural and artificial flavor for bubble gum #15864, and water.
5.3.1.2.
Packaging and Labeling
The RBV capsules are packaged in blisters. Each blister card contains 20 capsules and seven 
cards (140 capsules) per carton.
The RBV oral solution is packaged in 4-oz amber glass bottles (100 mL/bottle) with 
child-resistant closures.
RBV capsules and oral solution to be distributed to centers in the US, EU and the rest of the 
countries shall be labeled to meet all applicable requirements of the US Food and Drug 
Administration (FDA) and Annex 13 of Good Manufacturing Practices: Manufacture of 
investigational medicinal products (February 2010) and/or other local regulations as applicable.


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5.3.1.3.
Storage and Handling
RBV capsules should not be stored above 30C (86 F).
RBV oral solution should not be stored above 30°C (86°F).
5.3.2.
Dosage and Administration of RBV (GT-3 Subjects Only)
RBV dose will be administered by weight as follows:
Body Weight kg (lbs.)
RBV Daily Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution.  Divided dose in the morning and 
evening.
47-49 (103-108)
600 mg/day
1 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
50-65 (110 – 143)
800 mg/day
2 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
66-80 (145 – 176)
1000 mg/day
2 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
81-105 (178-231)
1200 mg/day
3 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
>105 (>231)
1400 mg/day
3 x 200-mg capsules A.M.
4 x 200-mg capsules P.M.
*
Note:  Subjects with a body weight greater than or equal to 47 kg may utilize the RBV oral solution if necessary.
The morning dose of RBV will be taken with food and LDV/SOF FDC. The evening dose of 
RBV will be taken with food.
RBV will be supplied by Gilead Sciences for all subjects.
5.4.
Co-administration of LDV/SOF FDC and RBV (GT-3 Subjects Only)
In the Treatment Phase of the study, each subject will be given instructions to maintain 
approximately the same daily dosing interval between study drug doses.
For morning doses, subjects will be instructed to take study drugs as follows:

LDV/SOF FDC

Weight-based RBV (as per Section 5.3.2).
For evening doses, subjects will be instructed to take study drug as follows:

Weight-based RBV (as per Section 5.3.2).
If a subject forgets to take the study medication at the correct time, it may be taken later in the 
day; however, no more than the protocol specified dose of LDV/SOF FDC should be taken on 


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any calendar day.  The subject should resume the standing dosing schedule on the next day. 
Study medications should not be cut or split.  
5.5.
Study Drug Compliance
Subjects will be instructed to return any unused LDV/SOF FDC and/or RBV in the original 
container on Day 3 (PK Lead-in), Day 10 (PK Lead-in), and/or at study treatment visits every 
4 weeks (Treatment Phase).  
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.6.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 30 days 
after the last dose of study drug, need to be recorded in the source documents and electronic case 
report form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment:

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

Drugs disallowed per prescribing information of REBETOL® for GT-3 subjects only
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters i.e., P-gp) with study drug(s) may result in PK interactions resulting in 
increases or decreases in exposure of study drug(s). Examples of representative medications 
which are prohibited from 21 days prior to Day 1 through the end of treatment are listed 
below. In addition, the use of amiodarone is prohibited from 60 days prior to 
Baseline/Day 1 through the end of treatment.


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Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton- Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsc
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Cardiac Medications
Amiodaronee
Digoxinb, Dabigatranb
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinaccea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsd
Rosuvastatin
Atorvastatin, Simvastatin, Pravastatin, 
Pitavastatin, Fluvastatin, Lovastatin
a.
It is recommended to separate antacid and LDV/SOF FDC administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF FDC at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with LDV/SOF FDC or up to 2 hours after taking LDV/SOF FDC. Proton-pump inhibitors should not be 
taken before LDV/SOF FDC. 
b.
May result in an increase in the concentration of study drug and/or concomitant medications. Co-administration of 
LDV/SOF FDC with digoxin or dabigatran may increase the concentration of digoxin or dabigatran. Caution is warranted 
and therapeutic concentration monitoring of digoxin or clinical monitoring of dabigatran is recommended when 
co-administered with LDV/SOF FDC. 
c.
May result in a decrease in the concentrations of study drug.
d.
Use with study drug 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.
e.
May result in symptomatic bradycardia. Mechanism is not currently known. The use of amiodarone is prohibited from 
60 days prior to Baseline/Day 1 through the end of treatment.
Medications for disease conditions excluded from the protocol (e.g., active cancer, 
transplantation) are not listed under this Concomitant Medication section and are disallowed in 
the study.


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6.
STUDY PROCEDURES
All subjects will complete screening, on-treatment, and post-treatment assessments. Screening 
assessments will be completed within 28 days of the Day 1 visit. The end of study will occur at 
the 24-week Post-Treatment visit. The schedule of assessments is described below. 
Information on the specific laboratory parameters to be measured and clinical assessments to be 
performed are provided in Section 6.6.
6.1.
Subject Enrollment 
Each candidate’s parent or legal guardian must sign an Informed Consent Form prior to the
conduct of any screening procedures. Each study candidate who has the ability to read and write
must sign an Assent Form, as required by IRB/IEC/local requirements, prior to the conduct of 
any study procedures. Screening evaluations will be used to determine the eligibility of each 
candidate for study enrollment. Candidates who fail to meet eligibility criteria by screening 
evaluations may be re-screened once ≥ 30 days after the initial screen if there is a reasonable 
expectation that the candidate will be eligible after repeat screening.
6.2.
Screening Assessments
6.2.1.
Screening Visit (Day –28 to Day 0)
Subjects will complete all screening assessments within 28 days of the Day 1 visit. The screening 
window can be extended to 42 days for subjects requiring additional HCV GT testing or for 
extenuating circumstances.
The following procedures will be performed and documented:

Written informed consent from parent or legal guardian and assent from subject, if applicable 
(see above)

Medical history, including:
Hepatitis C history
Hepatitis C treatment history
Family history (including height of parents, if known)
Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate) and body weight and height


LDV/SOF FDC
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
Obtain blood samples for tests as listed in Section 6.6.1:
Hematology
Chemistry
Coagulation tests
HCV RNA
Determination of HCV viral GT and subtype
HCV antibody, HIV 1/2 antibody, and HBs antigen, HAV antibody
HbA1c
TSH
IL28B
Serum -hCG pregnancy test for females of childbearing potential only
Alpha fetoprotein (AFP)
Alpha-1 anti-trypsin (ATT)

Obtain urine sample for:
Urinalysis
Urine Drug Screen

Review of concomitant medications

Ask subject and/or parent/legal guardian if the subject is able to swallow and tolerate taking 
pills.

Review of all inclusion and exclusion criteria

Perform LDV/SOF FDC swallowability assessment 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the Day 1 visit assessments.


LDVISOFFDC 
Protocol GS-US-337-1116 
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6.3. 
PK Lead-in: Treatment Assessments 
6.3.1. 
Day l 
Final 
Amendment 4.0 
After confnmation of eligibility has been evaluated, the following tests and procedmes must be 
completed prior to emollment and dosing/dispensing on Day 1: 
• 
Perf01m complete physical examination 
• 
Tanner Pubertal Stage Assessment 
• 
Vital signs, including body weight and height measmements 
• 
A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pruiicipants (all subj ects ~ 12 yeru·s of age and subjects < 12 yeru·s of age at the discretion of 
the Investigator based on subject's pubertal status) 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (ru·chive) 
_ 
PD 
• 
Obtain mine samples for the following procedmes: 
-
Urinalysis 
-
~ -hCG pregnancy test for females of childberu·ing potential only 
• 
Subject completes quality of life smvey: Subject is to review questionnaire with a 
parent/guardian and write/mru·k answers directly onto the questionnaire. 
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Amendment 4.0
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6.3.1.1.
Drug Administration

Dispense study drug(s) as directed by the IWRS

Instruct the subject on the packaging, storage and administration of study drug

Perform LDV/SOF FDC swallowability assessment (for subjects administered LDV/SOF 
FDC in tablet form only if not previously completed at screening).  Observe the subject 
taking the first dose of study drug (with or without food) and record the time of first dose

Subjects will be administered a dosing diary with instructions.
6.3.2.
Day 3
The following procedures/assessments are to be completed on Day 3:

Perform a symptom-directed physical examination as needed

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Review medication compliance with subject and/or subject’s parent/guardian

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 10 – Intensive PK 
The Day 10 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 10 Intensive PK visit may 
be performed within +3 days of the protocol-specified visit date (subjects will continue 
daily dosing through the Intensive PK Visit).
Subjects should come in a fasted state for the Day 10 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 10 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 10 dose of LDV/SOF FDC must not be taken 
until the evaluations listed below are completed. 


LDV/SOF FDC
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If the subject has already dosed prior to the Day 10 clinic visit or is not in a fasted state, the 
Day 10 intensive PK assessments must not be completed. The subject and/or parents/guardians 
should be instructed to return in a fasted state within 3 days (Days 11, 12, or 13) for the intensive 
PK visit. 
If dosing non-compliance is identified as per subject dosing diary and study drug count on or 
prior to the Day 10 visit, the Day 10 intensive PK assessments must not be completed. The 
subject and/or parents/guardians should be counseled regarding proper dosing and be scheduled 
to return for the Day 10 intensive PK visit no sooner than 3 days following compliant dosing and 
no later than Day 14 (i.e., return on Day 13 or Day 14).  If dosing non-compliance is due to an 
AE, consultation with the Gilead Medical Monitor is required regarding the potential of 
rescheduling the Day 10 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded not 
to take the LDV/SOF FDC prior to arriving at the clinic on the day of the re-scheduled intensive 
PK visit. All Day 10 intensive PK assessments listed below should be completed when the 
subject returns.
The following evaluations are to be completed at the Day 10 Intensive PK visit:

Perform a symptom-directed physical examination 

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Perform study drug accountability 

Review Subject Dosing Diary

Review medication compliance with subject and/or parent/guardian.

Obtain urine samples for the following procedures:
Urinalysis
Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test 
is positive, the Intensive PK sampling will not be completed. The positive result will be 
confirmed with a serum pregnancy test. 

Obtain blood samples for the following laboratory analyses:
Hematology 
Chemistry 


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Coagulation tests
HCV RNA
Viral sequencing (archive)

Perform intensive PK sampling: 
Blood samples will be collected at 0 (predose, ≤30 minutes prior to dosing). After 
collection of the predose sample, subjects will be provided a standardized meal. Within 
5 minutes after consuming the standardized meal, subjects will be dosed with 
LDV/SOF FDC per dosing requirements.
Post-dose blood samples will be collected as follows: 
■
For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 5, 8, and 12 hours post-dose (with predose also 
serving as t= 24).
■
For Cohort 3 only: 0.5, 2, 4, 8, and 12 hours post-dose (with predose also serving as 
t = 24).
Subjects will be restricted from food intake until after collection of the 4-hour post dose 
blood sample, except for subjects in Cohort 3. Please also refer to the PK manual for 
details about standardized meals and PK sample processing instructions.
After completing the Day 10 intensive PK visit subjects will then continue to the Week 2 visit in 
Treatment Phase (described in Section 6.4.2) with no interruption in dosing.
6.4.
Treatment Phase: Treatment Assessments 
6.4.1.
Day 1
After confirmation of eligibility has been evaluated, the following tests and procedures must be 
completed prior to enrollment and dosing/dispensing on Day 1:

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements 

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Review of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status). 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (archive) 
PPU 
• 
Obtain urine sample for: 
-
Urinalysis 
-
~ -hCG pregnancy test for females of childbearing potential only 
Final 
Amendment 4.0 
• 
Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire 
• 
Perf01m LDV/SOF FDC swallowability assessment (for subjects administered 
LDV /SOF FDC in tablet f01m only if not previously completed at screening) 
6.4.1.1. 
Dmg Adminisu·ation 
• 
Dispense study dmg as directed by the IWRS 
• 
GT-3 subjects only: Insti11ct the subject on the appropriate RBV dose after weight-based 
dosage is calculated using Day 1 weight 
• 
lnstiuct the subject on the packaging, storage, and adminisu·ation of study dmg 
• 
Observe the subject taking the first dose of study dmg (with or without food) and record the 
time of fust dose 
6.4.2. 
Weeks 1 and 2 (± 3 days) 
Subjects who patticipated in the PK Lead-in will sta1t study visits in the Treatment Phase at 
Week 2. The following procedures/assessments are to be completed at these visits: 
• 
Vital signs, including body weight and height measurements 
• 
Perf01m symptom-directed physical examination 
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Amendment 4.0
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
Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 
6.4.3.
Weeks 4 and 8 (3 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS


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Amendment 4.0
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6.4.4.
Week 12 (3 days) - Subjects on 12 Week Treatment Regimen Only

Perform complete physical examination

Tanner Pubertal Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles of study drug at the Week 12 Visit
6.4.5.
Week 12 (3 days) - Subjects on 24 Week Treatment Regimen Only

Perform symptom-directed physical examination

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications


LDV/SOF FDC
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Amendment 4.0
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
Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS  
6.4.6.
Week 16 and 20 (3 days) – Subjects on 24 Week Treatment Regimen Only

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS


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Amendment 4.0
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6.4.7.
Week 24 (3 days) – Subjects on 24 Week Treatment Regimen Only

Perform complete physical examination

Tanner Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles and blister cards (if applicable) of study drug at the 
Week 24 Visit


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Amendment 4.0
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6.4.8.
Unscheduled Visit/Early Termination Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments are at the investigator’s discretion.
The Sponsor/CRO should be informed when a subject comes off treatment due to an adverse 
event. If a subject discontinues treatment then the assessments outlined below should be 
performed.

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK 

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles and/or blister cards (if applicable) of study drug at the Early 
Termination Visit


LDV/SOF FDC
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Amendment 4.0
CONFIDENTIAL
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15 March 2016
All subjects should complete Post-Treatment assessments after early termination, as described in 
Section 6.5.
6.5.
Post-Treatment Assessments
6.5.1.
4-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for: 
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status) 
Female subjects of childbearing potential on treatment with LDV/SOF FDC + RBV should be 
provided with Urine Pregnancy Test-Kits, instructed on their use and requested to continue to 
self-monitor for pregnancy for 6-months after their last dose of RBV. If required by local 
regulations, additional pregnancy tests beyond 6 months may be added.  The subject should be 
contacted every 4 weeks and asked to report results of the urine pregnancy tests. If a positive 
urine pregnancy test is reported, the subject should return to the clinic for a serum pregnancy 
test.
6.5.2.
12-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements

Perform symptom-directed physical examination

Assessment of SAEs


LDV/SOF FDC
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Final
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Amendment 4.0
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
Perform Tanner Pubertal Stage assessment

Obtain blood samples for 
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

GT-3 subjects only: Obtain urine sample for -hCG pregnancy test for females of 
childbearing potential only

GT-3 subjects only: Pregnancy prevention counseling including partner pregnancy 
prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age 
at the discretion of the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire
6.5.3.
24-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of SAEs

Tanner Pubertal Stage Assessment

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Obtain blood samples for 
HCV RNA
Viral sequencing (archive)

GT-3 subjects only: Obtain urine sample for -hCG pregnancy test for females of 
childbearing potential only

GT-3 subjects only: Pregnancy prevention counseling including partner pregnancy 
prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age 
at the discretion of the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire.


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Amendment 4.0
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All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed every 6 months for the first 
2 years followed by every 12 months for assessments of growth, quality of life, and long-term 
viral suppression (if applicable) in a separate protocol (GS-US-334-1113). This follow-up will 
continue for 5 years.
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), Glucose, 
Lipase, Potassium, Sodium, Gamma-glutamyl transferase (GGT), alpha fetoprotein (AFP), 
alpha-1 anti-trypsin, creatine kinase (CK) and amylase.
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® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System. 
HCV GT 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 GT should the above assays become unavailable.
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 alternate assays 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum -hCG, Urine -hCG (if positive, requires immediate confirmation with 
Serum -hCG)
Additional Tests: Urine Drug Screen (for amphetimines, cocaine, methadone, opiates), 
Hemoglobin A1c (HbA1c), TSH (reflex Free T4), Alfa fetoprotein (AFP), Alpha-1 anti-trypsin
(AAT).
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. Parental heights will be recorded at Screening.


LDV/SOF FDC
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Amendment 4.0
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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.
Tanner Pubertal Stage Assessment
The Tanner Stage scale is available in Appendix 4.  All subjects will receive a baseline Tanner 
Pubertal Stage Assessment. If the assessment determines that the subject is at a Tanner 5 at 
Day 1, no further Tanner Pubertal Stage Assessments are to be completed. 
6.6.5.
Height & Weight Measurement
Height and weight measurement will be collected at each study visit. The difference in body 
weight and height measurements between Day 1 and End of Treatment, post-treatment Week 12, 
and post-treatment Week 24 will be calculated.  
6.6.6.
Bone Age Assessment
A single X-ray of the left wrist, hand, and fingers will be performed at Day 1 Visit and 
post-treatment Week 24.  Local radiologist will determine bone age from x-ray.
6.6.7.
Swallowability Assessment
A LDV/SOF FDC swallowability assessment will be performed at screening up to Day 1. 
Subjects who have indicated that they can take pills will be observed taking a placebo to match 
the 90 mg/ 400 mg LDV/SOF FDC tablet. This will confirm the swallowability of the 
90 mg/ 400 mg tablet size. If a subject is unable to swallow the 90 mg/ 400 mg LDV/SOF FDC 
tablet size, he/she will repeat the assessment with a placebo for the 22.5 mg/ 100 mg 
LDV/SOF FDC tablet. If unable to swallow the 22.5 mg/ 100 mg LDV/SOF FDC tablet, 
enrollment of the subject will be deferred until the granule formulation is available.
6.6.8.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.


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6.6.9.
Estimated Glomerular Filtration Rate (GFR)
Estimated Glomerular Filtration Rate (GFR) using Schwartz Formula (mL/min/1.73m2) = 
k L/Scr [(k is a proportionality constant, for adolescent females ≥12 years old is 0.55; for 
adolescent males ≥12 years old is 0.70; and for female and male children 3 to < 12 years old is 
0.55); L is height in centimeters (cm); and Scr is serum creatinine (mg/dL)]
6.6.10.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
Unused samples may be archived.
6.6.11.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every 4 weeks during the 
dosing period and for a minimum of 6 months following the last dose of RBV or for a minimum 
of 30 days following the last dose of LDV/SOF FDC if not taking RBV. If required by local 
regulations, additional pregnancy tests beyond 6 months for RBV or 30 days for subjects not 
taking RBV may be added. In the event of a positive urine pregnancy result, subjects will be 
instructed to stop study drug immediately (if applicable) and return to the clinic as soon as 
possible for a serum pregnancy test.
GT-3 subjects only: Pregnancy test kits will be dispensed to female subjects of child bearing 
potential at the 4 Week Post-Treatment visit. The subject will be contacted by telephone monthly 
to confirm that urine pregnancy testing has been performed post-treatment and to record the 
outcome. Alternatively, if required by local regulations or preferred by the investigator or 
subject, the subject may return to the clinic for urine pregnancy tests.
6.6.12.
Quality of Life Survey (PedsQL™)
The PedsQL ™Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be completed at 
Day 1, End of Treatment, Early Termination (if applicable), 12-Week Post-Treatment, and 
24-Week Post-Treatment visits.  
The PedsQL ™  has separate survey instruments administered by age group, including the
Teen Report (ages 13-18), Child Report (ages 8-12), Young Child Report (ages 5-7), and 
Toddlers (ages 2-4).  Each survey accompanied by the respective parent proxy survey will be 
administered to the subject and their parent/legal guardian (with the exception of the Toddlers 
Report which will only be completed by the parent/legal guardian) for the current age group at 
the time of survey administration.  


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7.
TOXICITY MANAGEMENT
7.1.
Modification of Dose/Schedule Due to Toxicity
Dose reduction of RBV (GT-3 subjects only) due to toxicity should be performed according to 
the product label. Information is provided in Table 7-1.
Table 7-1.
RBV Dose Reduction Guidelines
Laboratory Values
Reduce RBV Dose by 200 mg/daya if:
Discontinue RBV if:
Hemoglobin in subjects with no 
cardiac disease
<10 g/dL
<8.5 g/dL
Hemoglobin in subjects with 
history of stable cardiac disease
2 g/dL decrease in hemoglobin during any 
4 week period treatment
<12 g/dL despite 4 weeks at 
reduced dose
a.
Dose reduction in pediatric patients taking the oral solution is accomplished by modifying the recommended RBV dose from 
original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed.
7.2.
Subject Stopping Rules for LDV/SOF FDC and RBV
The Gilead Medical Monitor should be consulted prior to dose discontinuation of LDV/SOF 
FDC unless the investigator believes that immediate action is warranted to ensure the continued 
safety of the subject.
Administration of LDV/SOF FDC may be discontinued due to a clinical or laboratory event. 
There is no option for LDV/SOF FDC dose reduction. If LDV/SOF FDC is stopped for toxicity, 
it should not be restarted, RBV should be stopped (GT-3 subjects only), and the subject should
complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria must stop treatment with LDV/SOF 
FDC:

Elevation of ALT and/or AST >5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT >3x Day 1 and total bilirubin >2 x ULN, confirmed by 
immediate repeat testing

Confirmed elevation of ALT >15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with LDV/SOF FDC


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8.
ADVERSE EVENTS MANAGEMENT
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
8.1.1.
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-mandated procedures, 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 8.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history CRF
8.1.2.
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.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., 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 (e.g., 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 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
8.2.
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.
8.2.1.
Assessment of Causality for Study Drug and Procedures
The investigator or qualified sub-investigator 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 investigational 
medicinal product. For SAEs, an alternative causality must be provided (e.g., pre-existing 
condition, underlying disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures (e.g.., venipuncture)
8.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4 weeks after last administration of study drug 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 protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of causal relationship, that occurs after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required 24-week 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
after informed consent is signed.


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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. Investigators are not 
obligated to actively seek SAEs after the 24 week post-treatment follow-up period.  However, if 
the investigator learns of any SAEs that occur after study participation has concluded and/or if 
patient is enrolled into the long term follow-up registry study (GS-US-334-1113), and/or eCRF 
database has been locked, and the event is deemed relevant to the use of IMP, he/she should 
promptly document on paper SAE form and report the event directly to Gilead DSPH within 24 
hours of awareness. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com; or
Fax: +1 (650) 522-5477
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, i.e., the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours to:
Gilead Sciences, Drug Safety and 
Public Health:
Fax:
E-mail:
+1 650 522-5477
Safety_FC@gilead.com

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.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
report form.


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8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
8.5.
Special Situations Reports
8.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging or distribution of the medicinal product.  


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8.5.2.
Instructions for Reporting Special Situations
8.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (i.e., signs the informed consent) and throughout the study, including the 
post-treatment follow-up period, to Gilead DSPH using the pregnancy report form within 
24 hours of becoming aware of the pregnancy.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., 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 
Sections 8.1 and 8.3. Furthermore, any SAE occurring as an adverse pregnancy outcome 
post study must be reported directly to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 or Fax: +1 (650) 522-5477.
Pregnancies of female partners of male study subjects exposed to Gilead or other study drug
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy report form and pregnancy outcome report forms within 24 hours. Monitoring of the 
partner pregnancy 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. 
Clinical staff should also report any pregnancies to the Ribavirin Pregnancy Registry at 
1 800-593-2214 (see also http://www.ribavirinpregnancyregistry.com ).
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
8.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 


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Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management and outcome will be reported, when available.


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Objectives and Endpoints 
9.1.1. 
Analysis Objectives 
The prima1y objective of PK Lead-in Phase of this study is: 
Final 
Amendment 4.0 
• 
To evaluate the steady state phrum acokinetics (PK) and confm n the dose ofLDV/SOF FDC 
in chronic HCV-infected pediatric subjects 
The secondruy objective ofPK Lead-in Phase of this study is: 
• 
To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing of 
LDV/SOF FDC in chronic HCV-infected pediatric subjects 
The primru·y objective of Treatment Phase of this study is: 
• 
To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV for 12 or 24 weeks in 
chronic HCV -infected pediatric subjects 
The secondruy objectives of Treatment Phase of this study are: 
• 
To dete1mine the antiviral efficacy of 12 and 24 weeks ofLDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects (including the impact of HCV genotype, IL28B genotype, 
and prior treatment experience), as assessed by the prop01iion of subjects with SVR 
12 weeks after completion oftreatment (SVR12) 
• 
To dete1mine the antiviral efficacy of 12 and 24 weeks ofLDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment 
• 
To evaluate the effect of growth and development on pediatric subjects during and after 
treatment 
The explorat01y objective ofthis study is: 
• 
PD 
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9.1.2.
Primary Endpoints
For the PK Lead-in Phase, the appropriateness of the LDV/SOF FDC dose will be assessed by 
evaluating the steady-state PK of the LDV/SOF FDC. The primary endpoint for determining 
steady state PK is AUCtau of GS-331007, SOF, and LDV. Additional steady-state PK parameters 
of GS-331007, SOF, and LDV (e.g., AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½)
will be estimated and summarized as described in Section 9.4.
For the Treatment Phase, the primary safety endpoint is any AE leading to permanent 
discontinuation of study drug (s). 
9.1.3.
Secondary Endpoints
For the PK Lead-in Phase, the secondary endpoint will include antiviral activity measurements, 
including assessment of HCV RNA. AEs leading to permanent discontinuation of study drug will 
be evaluated as a secondary safety endpoint.
For the Treatment Phase, the key efficacy endpoint is SVR12 and secondary efficacy endpoints 
include SVR4, SVR24, breakthrough and relapse. Additional efficacy evaluations may include 
HCV RNA change from Day 1; ALT normalization; and viral kinetic parameters. Secondary 
safety endpoints of growth and development measurements will be assessed (e.g. height, weight, 
and Tanner Stage Assessment).
9.2.
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).
9.2.1.
Analysis Sets 
9.2.1.1.
Pharmacokinetics (PK) Analysis Sets
Intensive PK Analysis Set 
The intensive PK analysis set will include all PK Lead-in subjects who received at least one dose 
of study drug and for whom at least one non-missing PK concentration data, during the intensive 
sampling period, reported by PK lab. The PK analysis set will be used for detailed 
pharmacokinetic analysis of LDV, SOF, and metabolites.  
Sparse PK Analysis Set 
The PK analysis set will include all enrolled subjects who received at least one dose of study 
drug and for whom at least one observed concentration data of LDV, SOF, or GS-331007 are 
available. The PK analysis set will be used for analysis of general PK and single sample plasma
concentrations.


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9.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses will include subjects who were enrolled and have 
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 last dose of study drug plus 30 days.
9.2.1.3.
Efficacy Analysis Set
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which includes 
HCV-infected subjects who were enrolled and have received at least one dose of study drug.
9.2.2.
Data Handling Conventions
Natural logarithm transformation for key PK parameters, such as Cmax and AUCtau, will be 
applied for pharmacokinetic analysis.
The PK concentration values below the limit of quantitation (BLQ) will be treated as zero for the 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing and will be excluded in any calculation of geometric 
means or ratios. For the presentation of summary and order statistics, if at least 1 subject has a 
concentration value BLQ for the time point, then the minimum value will be displayed as 
“BLQ”. If more than 50% of the subjects have a concentration data value BLQ for the time 
point, then the minimum and median values will be displayed as “BLQ”. If all subjects have 
concentration data values BLQ for the time point, then all order statistics (minimum, first 
quartile [Q1], median, third quartile [Q3], maximum) will be displayed as “BLQ”.
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, 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 
preceded and followed in time by values that are deem 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 medication will be 
considered a failure at the time points subsequent to 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.


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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).
9.2.3.
Interim Analysis
Two interim analyses will be performed to provide treatment regimen and duration
recommendation for the following age groups:

adolescent subjects (12 to < 18 years of age) 

pediatric subjects (6 to < 12 years of age) 
There will be no changes to the study design, study conduct, or the sample size as a result of the 
interim analyses.
9.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by age group and overall for PK Lead-in and by the 4 regimens based on 
treatment-experience, cirrhosis status and genotype, by age group, by regimen and age group, 
and overall for Treatment Phase respectively. 
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight, height, body mass index, HCV RNA level 
(log10 IU/mL), HCV GT, prior treatment experience, and additional endpoints as necessary.
9.4.
Pharmacokinetic Analysis
PK analysis will be performed for PK Lead-in using the intensive PK analysis set. The 
concentration data of LDV, SOF, and metabolites (GS-331007 and GS-566500) over sampling 
time will be listed and summarized by nominal time and cohort. Pharmacokinetic parameters 
(e.g., AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½) will be listed and
summarized for LDV, SOF,  and metabolites (as applicable) using descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean and its 95% confidence interval, coefficient 


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of variation %, standard deviation, median, Q1, Q3, minimum, and maximum) by cohort and 
overall. Plasma concentrations over time will be plotted in semilogarithmic and linear formats as 
mean ± standard deviation and median (Q1, Q3).
To evaluate if the steady-state PK of GS-331007, SOF, and LDV achieved in pediatric subjects 
of this study are similar to the exposures observed in adult subjects (Table 9-1), the GS-331007, 
SOF, and LDV exposure data from this study will be compared to the integrated adult data. The 
primary endpoint of this analysis will be evaluated by carrying out an analysis of variance 
(ANOVA) for log-transformed GS-331007, SOF, and LDV AUCtau. The 90% confidence 
intervals will be constructed for the ratio of geometric means of each PK parameters. The 
equivalence boundary is set as 50% to 200%.  
Given that dose ranging studies for SOF established that a dose of 200 mg results in suboptimal 
exposure compared to the 400 mg dose, and the lack of clinically significant exposure-safety 
relationships observed across a broad range of GS-331007 and SOF exposure, bounds of 50% to 
200% for GS-331007 and SOF AUCtau will allow identification of a clinically relevant difference 
in exposure in the pediatric population.
A phase 2 study evaluating LDV doses of 30 or 90 mg LDV in combination with DAAs 
VDV+TGV+RBV suggested LDV exposure may be suboptimal at the 30 mg dose based on the 
incidence of virologic breakthrough being approximately half in the 90 mg arm; as such the 
90 mg dose was selected for further development.  In the 90 mg LDV arm of this study, the LDV
AUCtau at the 25 percentile was 3230 hr*ng/mL.  While this value is 62% lower than the mean 
LDV AUCtau (8530 hr*ng/mL) observed in adult HCV-infected subjects in the LDV/SOF FDC 
Phase 2/3 population, it provides ~99.8% of maximal viral load reduction (exposure-response 
model established in the monotherapy proof of concept study).  In the Phase 2/3 population when 
administered the LDV/SOF FDC, there was a lack of clinically significant exposure-efficacy or 
safety relationships observed across the broad range of LDV exposure.  Taken together these 
data support the utility of bounds of 50% to 200% for LDV AUCtau to identify a clinically 
relevant difference in LDV exposure in the pediatric population.
In all pediatric age groups, the targeted exposures for GS-331007, SOF, and LDV are the adult 
equivalent for which safety and efficacy has been established.  In the absence of any pediatric 
PK information (i.e., variability and exposure of GS-331007, SOF, or LDV is unknown) 
assuming a 2-fold higher variability, or a 30 % difference in GS-331007, SOF, or LDV AUCtau
in the pediatric population compared to adults, the predicted 90% CIs of the geometric mean 
ratio (GMR) will be contained within the bounds of 50% to 200%.
Individual patient management will be performed by maintaining exposures comparable to 
adults.  In the event more than one subject in each cohort exhibits GS-331007, SOF, or LDV 
exposures (AUCtau) less than the 2.5th percentile of adult values, a dose assessment may be 
require for the cohort as appropriate.
The effect of age and LDV/SOF FDC dose on PK (LDV, SOF and GS-331007) will be assessed.


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Table 9-1.
GS-331007, SOF, and LDV PK Parameters after Once-Daily 
Administration of SOF/LDV FDC in HCV-Infected Adults Subjects 
(Population PK Analysis from Phase 2 and 3 Studies)
Mean (%CV) PK Parametera
GS-331007 (N=2113)
SOF (N=1542)
LDV (N=2113)
AUCtau (ng•h/mL)
12,500 (29.2)
1380 (34.0)
8530 (60.8)
Cmax (ng/mL)
736 (28.2)
659 (34.0)
364 (51.4)
Ctau (ng/mL)
N/A
N/A
247 (59.2)
a.
Pharmacokinetic parameters are presented as mean (%CV) and are shown to 3 significant digits.
9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in and overall study Treatment Phase 
respectively. Safety data will be summarized by age group and overall for PK Lead-in Phase and 
by the 4 regimens based on treatment-experience, cirrhosis status and genotype, by age group, by 
regimen and age group, and overall for the Treatment Phase respectively.
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements, and by the documentation of AEs.
All safety data collected while on or after the first dose of study drug administration up to 
30 days after the last dose of study drug will be summarized by cohort according to the study 
drug received.
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.
9.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the CRF. Exposure data will be summarized.
9.5.2.
Adverse Events
Clinical and laboratory AEs 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 study drug up to the date of last dose of study drug plus 30 days. 


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Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC 
and preferred term) will be provided by cohort:

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,

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.
9.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled visits will be summarized. Graded laboratory 
abnormalities will be defined using the grading scheme in Grading of Laboratory Abnormalities 
provided in Appendix 3. 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 
and including the date of last dose of study drug plus 30 days, will be summarized by age group 
and overall. If baseline data are missing, then any graded abnormality (i.e., at least a Grade 1) 
will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
9.5.4.
Other Safety Evaluations
9.5.4.1.
Tanner Pubertal Stage Assessment
Tanner Stages (Appendix 4) will be summarized by baseline Tanner Stage using frequency and 
percentage. 


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Vital Signs (including Body Weight and Height) 
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Vital signs including body weight and height and change from baseline will be summarized at 
each visit. 
9.6. 
Efficacy Analysis 
Efficacy will be evaluated using scheduled assessments of HCV RNA perf01m ed using CO BAS® 
TaqMan® HCV Test, v2.0 for use with the High Pure System. 
Efficacy analysis will be perf01m ed by the 4 regimens based on u·eatment-experience, cinhosis 
status and genotype, by age group, by regimen and age group, and overall for Treatment Phase. 
All continuous endpoints will be summarized using an 8-number summruy (n, mean, standru·d 
deviation, median, Ql , Q3, minimum, maximum). All categorical endpoints will be summru·ized 
by number and percentage of subjects who meet the endpoint defmition. 
9.6.1. 
Key Efficacy Analysis 
The key efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
u·eatment) in the F AS population. Point estimate and its 95% confidence interval will be 
provided. 
9.6.2. 
Secondary Efficacy Analysis 
For the PK Lead-in Phase, senun HCV RNA actual values and change from baseline will be 
summarized at each visit. 
For the Treatment Phase, the proportion of subjects with HCV RNA below LLOQ over time 
(including SVR endpoints SVR4 and SVR24) will be presented in tabulru· and graphical f01m . In 
addition, descriptive summaries and listings will be provided for additional efficacy evaluations 
including senun HCV RNA actual values and change from baseline, prop01iion of subjects with 
virologic failures, and other endpoints of interest including ALT n01m alization. 
PD 
9.6.3. 
Subgroup Analysis 
Subgroup analysis on SVR12 will be perf01m ed by u·eatment experience and cinhosis status, by 
IL28B genotype, and by GT. Other clinically relevant subgroup analyses may be conducted as 
appropriate (i.e., assuming that adequate numbers of subjects in these subsets are available for 
analysis). 
Details on efficacy analyses will be described in the statistical analysis plan. 
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9.7.
Quality of Life Analysis
The data from PedsQL ™ Pediatric Quality of Life survey will be summarized by visit and 
age group and overall.
9.8.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety and provide recommendation to Gilead about 
whether the nature, frequency, and severity of adverse effects associated with study treatment 
warrant the early termination of the study in the best interests of the participants, whether the 
study should continue as planned, or the study should continue with modifications. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
9.9.
Sample Size
With approximately 100 subjects enrolled into each age group of Treatment Phase, a two-sided 
95.0% confidence interval of the SVR12 rate will extend at most 5.9% in both directions from 
the observed SVR12 rate, assuming the expected SVR12 rate is 90%.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
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 Harmonization (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. For studies conducted under a United States IND, the investigator 
will ensure that 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, are adhered to.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Gilead Sciences, or proprietary interests in the drug being studied. 
This documentation must be provided before participation of the investigator and any 
sub-investigator. The investigator and sub-investigator agree to notify Gilead Sciences of any 
change to reportable interests during the study and for one year following completion of the 
study. Study completion is defined as the date that the last subject has completed 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.”
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
This protocol 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/assent) will be submitted by the investigator to an IRB (for studies conducted in the 
United States) or IEC (for studies conducted outside of the United States). Approval from the 
IRB or IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. Additionally, modifications 
should be submitted to competent authorities, as necessary.


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10.1.3.
Informed Consent/Assent
The investigator is responsible for obtaining written informed consent from the parent/legal 
guardian of the subject participating in this study after adequate explanation to the parent/legal 
guardian and subject of the aims, methods, objectives, and potential hazards of the study and 
before undertaking any study-related procedures. Written assent should be obtained from the 
subject as required by IRB/IEC/local requirements for this age population.  The investigator must 
utilize an IRB- or IEC-approved consent/assent form for documenting written informed 
consent/assent. Each informed consent/assent will be appropriately signed and dated by the 
subject or the subject’s parent/legally authorized representative and the person obtaining 
consent/assent.
10.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, and an 
identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the Sponsor, IRB or IEC, or laboratory. The investigator must keep a screening log 
showing codes, names, and addresses for all subjects screened and for all subjects enrolled in the 
trial.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational new drug, and any 
other study information, remain the sole and exclusive property of Gilead Sciences during the 
conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Gilead Sciences. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data are listed in the Source Data verification Plan, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Participation in trial (including trial number);


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
Trial 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 trial medication (preferably drug dispensing 
and return should be documented as well);

Record of all AEs and other safety parameters (start and end date, and preferably including 
causality and intensity);

Concomitant medication (including start and end date, dose if relevant; dose changes should 
be motivated);

Date of trial completion and reason for early discontinuation, if applicable.
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) 
and until there are no pending or contemplated 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 required by applicable regulatory requirements, by local 
regulations, or by an agreement with Gilead Sciences. The investigator must notify 
Gilead Sciences 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 Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences 
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period up to 15 years for purposes of this study.
10.1.6.
Case Report Forms
For each subject enrolled, a CRF (or eCRF) must be completed and signed by the principal 
investigator or sub-investigator (as appropriate) within a reasonable time period after data 
collection. This also applies to records for those subjects who fail to complete the study 
(even during a pre-randomization screening period if a CRF was initiated). If a subject 


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withdraws from the study, the reason must be noted on the CRF. If a subject is withdrawn from 
the study because of a treatment-limiting adverse event, thorough efforts should be made to 
clearly document the outcome.
10.1.7.
Drug Accountability
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product, and comparators. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), subject 
dispensing records, and returned or destroyed study product. Dispensing records will document 
quantities received from Gilead Sciences and quantities dispensed to subjects, including lot 
number, date dispensed, subject identifier number, subject initials, and the initials of the person 
dispensing the medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRBs or IECs, 
or to regulatory authority or health authority inspectors.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB, IEC, or 
competent authorities in accordance with local requirements. Approval must be obtained before 
changes can be implemented.


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10.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies). 
Gilead Sciences 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.
After conclusion of the study and without prior written approval from Gilead Sciences, 
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 Sciences in an abstract, manuscript, or presentation form; or

the study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).
The investigator will submit 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. The investigator will comply with Gilead Sciences’ 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.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the CRFs for consistency.
The monitor is responsible for routine review of the CRFs 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 CRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences 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 Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.


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10.3.3.
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 Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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11.
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Yang D, Pearce RE, Wang X, Gaedigk R, Wan YJ, Yan B. Human 
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variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and 
permethrin. Biochem Pharmacol 2009;77 (2):238-47.
20288
Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and sex-related expression and 
activity of carboxylesterase 1 and 2 in mouse and human liver. Drug Metab 
Dispos 2009;37 (9):1819-25.
28583
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and 
sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370 
(20):1889-98.
28585
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. 
Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N 
Engl J Med 2014;370 (16):1483-93.
28587
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. 
Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N 
Engl J Med 2014;370 (20):1879-88.
29292
Gane E, Hyland RH, An D, Pang PS, Symonds WT, McHutchison JG, et al. 
Ledipasvir/Sofosbuvir Fixed-Dose Combination Is Safe and Effective in Difficult-
to-Treat Populations Including GT 3 Patients, Decompensated GT 1 Patients, and 
GT 1 Patients With Prior Sofosbuvir Experience [Oral Presentation 6]. 49th 
Annual Meeting of The European Association for the Study of the Liver (EASL); 
2014 April 9-13; London, UK. 
34663
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. 
Archives of disease in childhood 1970;45 (239):13-23.
34664
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. 
Archives of disease in childhood 1969;44 (235):291-303.
34882
Fanta S, Jonsson S, Backman JT, Karlsson MO, Hoppu K. Developmental 
pharmacokinetics of ciclosporin--a population pharmacokinetic study in 
paediatric renal transplant candidates. Br J Clin Pharmacol 2007;64 (6):772-84.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 91
15 March 2016
12.
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.
Tanner Stages*
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


LDV/SOP FDC 
Prolocol GS .. US-337-Ill6 
Final 
Gilead Sciences, ln(j, 
Amendmenl 4.0 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LA KRSlDE JHUVE 
FOSTEU CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Ot·,en-Label, Multicenter, Multl~cohort Study to Investigate the Safety and 
.Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination+/- Ribavirin in Adolescents 
and Childre11 with Chronic HCV-infection 
GS~US~337~1116, .Protocol Amendment 4.0, 15 March 2016 
This protocol has been approved by Gilead Sciences, Inc. The following sjgnature doctunents 
this approvaL 
-'f~eo & ... .., ... ,H~ )<'i .. :f ~!> 
Theo Brandt-Sarif, MD (l:>rinted) 
Medical Monitor 
(5 
Date 
PD 
INVESTIGATOR STATEMENT 
I have read the pmtocol, inclttdlng aJJ appe.ndi.ces) and J agree that it contains all necessary 
details for tnc and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable eilbl1 to complete the study within the time 
designated. 
J. wm provtae all smay personnel unaet· my sttpervislon coptes or tne prow(~Ol anu l:l.t:cess tu an 
information provided by Gilead Sciences, Inc. I will discuss this materiul with them to ensure 
that they arc fully infom1ed about the drugs and the study. 
Pduc(pa.l lnvestigator Name (Printed) 
Signature 
Date 
Site Number 
CONFlDENTJAL 
Pnge 92 
lS March 2016 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 4.0
CONFIDENTIAL
Page 93
15 March 2016
Appendix 2.
Study Procedures Table
Appendix Table 1.
PK Lead-in: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X j
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Vital Signsa
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X
Subject Dosing Diary
X
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 4.0
CONFIDENTIAL
Page 94
15 March 2016
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
HCV RNA
X
X
X
X
Viral Sequencing c
X
X
X
Serum or Urine Pregnancy Testinge
X
X
X
Urinalysis
X
X
X
Urine Drug Screen
X
Intensive PK
X d
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
Alpha fetoprotein
X
Alpha-1 anti-trypsin
X
a.
Vital signs include blood pressure, pulse, respiratory rate and temperature, body weight, and height
b.
Day 1 assessments must be performed prior to dosing
c.
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
d.
For Cohorts 1 and 2, plasma samples will be collected for PK analyses following dosing of study drug on Day 10 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours post-dose.
e.
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test. 
f.
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status). 
g.
h.
Swallowability can occur at Day 1 if not completed during screening.
i.
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
j.
Parental height will be collected (if available)
PPD
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 4.0
CONFIDENTIAL
Page 95
15 March 2016
Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
Xi
Complete Physical Examination
X
X
Xj
X
X
Symptom-Directed Physical Examination
X
X
X
X
Xk
X
X
Tanner Pubertal Stage Assessment
X
Xj
X
X
Vital Signsa
X
X
X
X
X
X
X
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling g
X
Xj
X
X
LDV/SOF FDC Swallowability 
Assessment
X
Xh
Quality of Life Survey e
X
Xj
X
X
Review of Study Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xk
X
X
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
X
X
X
X
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
X


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 4.0
CONFIDENTIAL
Page 96
15 March 2016
Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early Termination
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testingl
X
X
X
X
X
X
X
X
X
Single PK
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Urine Drug Test
X
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
Xj
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
a.
Vital signs include blood pressure, pulse, respiratory rate and temperature, and body weight and height
b.
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
c.
Subjects rolling over from PK Lead-in will not be required to repeat screening, Day 1 or Week 1 visits during the on Treatment Phase  
d.
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
e.
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
f.
g.
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
h.
Swallowability can occur at Day 1 if not completed during screening.
i.
Parental height will be collected (if available) 
j.
Subjects on 12 Week Treatment regimen only
k.
Subjects on 24 Week Treatment regimen only
l.
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test
PPD
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 4.0
CONFIDENTIAL
Page 97
15 March 2016
Appendix Table 3.
Treatment Phase: Post Treatment Visits Following Primary Study
4 Weeks Post Treatment
12 Weeks Post Treatment
24 Weeks Post Treatment
Clinical Assessments
Vital Signs, Body weight and Height
X
X
X
Symptom-directed Physical Exam
X
X
X
AEs
X
Xc
Xc
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counselingd
X
Xf
Xf
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Test
X
Xe
Xe
a.
Quality of life survey will be completed by all subjects at 12-Week and 24-Week Post Treatment visits if a site is approved to use the survey.  Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire.
b.
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
c.
At Post Treatment Week 12 and 24, only SAEs will be captured
d.
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on subject’s pubertal status).
e.
GT-3 subjects only: Female subjects of childbearing potential should be provided with Urine Pregnancy Test Kits, instructed on their use and requested to continue to self-monitor for pregnancy 
for 6 months after their last dose of RBV. If required by regulations, additional pregnancy tests beyond 6 months may be added. The subject should be contacted every 4 weeks and asked to report 
results of the urine pregnancy tests. If a positive urine pregnancy test is reported, the subject should return to the clinic for a serum pregnancy test.
f.
GT-3 subjects only


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 4.0
CONFIDENTIAL
Page 98
15 March 2016
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 4.0
CONFIDENTIAL
Page 99
15 March 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count  
(ANC)
Adult and Pediatric, 
≥ 7 Months# 
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 4.0
CONFIDENTIAL
Page 100
15 March 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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% 
# An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 4.0
CONFIDENTIAL
Page 101
15 March 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 4.0
CONFIDENTIAL
Page 102
15 March 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                          
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL                      
1.51 to < 1.74 mmolL
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 4.0
CONFIDENTIAL
Page 103
15 March 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L


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


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


LDV/SOF FDC
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Amendment 4.0
CONFIDENTIAL
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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


LDV/SOF FDC
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Gilead Sciences, Inc
Amendment 4.0
CONFIDENTIAL
Page 107
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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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Final
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Amendment 4.0
CONFIDENTIAL
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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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CONFIDENTIAL
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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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Amendment 4.0
CONFIDENTIAL
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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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Final
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SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
laryngeal edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic self-
care functions OR 
Hospitalization (other than ER 
visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight from 
baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  Aggressive 
intervention indicated [eg, 
tube feeding or total parenteral 
nutrition]


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


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


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


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Amendment 4.0
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Appendix 4.
Tanner Stages*
1. Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2. Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of testes and scrotum and increased darkening 
of scrotal skin (13.5-15)
Tanner V 
Genitalia adult in size and shape
3. Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen 
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with 
surrounding breast 
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V 
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. 
*
Chart referenced from Marshall WA, Tanner JM, variations in the pattern of pubertal changes in boys and girls {34663}, {34664}


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Amendment 4.0
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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Background
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Pregnancy must be excluded before the start of 
treatment with study drugs and prevented thereafter by reliable contraceptive methods. 
Pregnancy tests will be performed regularly throughout this study. Furthermore, RBV is known 
to accumulate intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, 
extreme care must be taken to avoid pregnancy during RBV therapy and for up to 6 months 
following completion of treatment (7 months for males). Please refer to the latest version of the 
product insert for additional information.
Non-clinical toxicity studies of LDV/SOF FDC demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of LDV/SOF FDC 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)
For the purpose of this trial, all post-menarchal females will be considered to be of childbearing 
potential, unless there is documentation of irreversible ovarian failure or surgical sterilization.
Post-menarchal females must have a negative serum pregnancy test at Screening and a negative 
urine pregnancy test on the Day 1 visit prior to dosing. They must also agree to one of the 
following from 3 weeks prior to Day 1 until 6 months after last dose of RBV or 30 days after last 
dose of LDV/SOF FDC if not taking RBV:

Complete abstinence from intercourse. Abstinence is acceptable method of contraception 
only when it is in line with the subject’s preferred and usual lifestyle. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
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 
6 months after last dose of RBV or 30 days  after the last dose of LDV/SOF FDC if not 
taking RBV:
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization


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vasectomy in male partner
implants of levonorgestrel
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 Day 1
until 7 months after last dose of RBV or 90 days after the last dose of LDV/SOF FDC if not 
taking RBV. If their female partner is of childbearing potential (as defined above), their female 
partner must use 1 of the methods of birth control listed above from the date of Screening until 
7 months after last dose of RBV or 90 days after last dose of LDV/SOF FDC if not taking RBV.
Male subjects must agree to refrain from sperm donation for at least 7 months after last dose of 
RBV or 90 days after the last dose of LDV/SOF FDC if not taking RBV.
4. Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 6 months (7 months for partners of male subjects) of 
last RBV dose or 30 days (90 days for partners of male subjects) of last LDV/SOF FDC dose if 
not taking RBV. 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 8.5.2.1.

Prot_001.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT Number: 
Indication: 
Protocol ID: 
Gilead Sciences Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-coh01i Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir 
Fixed Dose Combination in Adolescents and Children with 
Chronic HCV-Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
115268 
2014-003578-17 
Hepatitis C Vims Infection 
GS-US-337-1116 
Name: 
Telephone: 
Mobile: 
Fax: 
E-mail: 
Bittoo Kanwar, MD 
PPD 
rpo 
PD 
t-'U 
Original: 
10 July 2014 
Amendment 1.0: 08 October 2014 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pruiicularly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board 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 necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 1.0
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................15
1.
INTRODUCTION ..............................................................................................................................................18
1.1.
Background ............................................................................................................................................18
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................19
1.3.
Rationale for the Current Study .............................................................................................................20
1.4.
Rationale for Dose Selection of LDV/SOF FDC ...................................................................................20
1.5.
Overall Risk/Benefit Assessment...........................................................................................................21
2.
OBJECTIVES.....................................................................................................................................................22
3.
STUDY DESIGN................................................................................................................................................23
3.1.
Treatment Plan and Regimen .................................................................................................................23
3.1.1.
PK Lead-in ...........................................................................................................................23
3.1.2.
Treatment Phase ...................................................................................................................23
3.2.
Visit Schedule ........................................................................................................................................25
3.2.1.
PK Lead-in ...........................................................................................................................25
3.2.2.
Treatment Phase ...................................................................................................................26
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................26
3.4.
Treatment Discontinuations Criteria ......................................................................................................26
3.5.
Discontinuations.....................................................................................................................................27
3.6.
Pharmacogenomic Substudy ..................................................................................................................27
3.7.
Long-Term Follow-Up...........................................................................................................................27
3.8.
Breakthrough Futility Assessment .........................................................................................................27
4.
SUBJECT POPULATION..................................................................................................................................28
4.1.
Number of Subjects and Subject Selection ............................................................................................28
4.2.
Inclusion Criteria....................................................................................................................................28
4.3.
Exclusion Criteria...................................................................................................................................29
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................31
5.1.
Randomization and Blinding..................................................................................................................31
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................31
5.2.1.
Description and Handling.....................................................................................................31
5.2.2.
Storage and Handling...........................................................................................................32
5.2.3.
Dosage and Administration of LDV/SOF FDC ...................................................................33
5.3.
Study Drug Compliance.........................................................................................................................34
5.4.
Prior and Concomitant Medications.......................................................................................................34
6.
STUDY PROCEDURES ....................................................................................................................................36
6.1.
Subject Enrollment.................................................................................................................................36
6.2.
Screening Assessments ..........................................................................................................................36
6.2.1.
Screening Visit (Day –28 to Day 0) .....................................................................................36
6.3.
PK Lead-in: Treatment Assessments .....................................................................................................38
6.3.1.
Day 1 Visit ...........................................................................................................................38
6.3.2.
Day 3 ....................................................................................................................................39


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6.3.3.
Day 10 – Intensive PK..........................................................................................................39
6.4.
Treatment Phase: Treatment Assessments .............................................................................................41
6.4.1.
Day 1 Visit ...........................................................................................................................41
6.4.2.
Weeks 1 and 2 (3 days) .....................................................................................................42
6.4.3.
Weeks 4 and 8 (3 days) .....................................................................................................43
6.4.4.
Week 12 (3 days) ..............................................................................................................44
6.4.5.
Unscheduled Visit/Early Termination Visit .........................................................................44
6.5.
Post-Treatment Assessments..................................................................................................................46
6.5.1.
4-Week Post-Treatment Visit (5 days)..............................................................................46
6.5.2.
12-Week Post-Treatment Visit (5 days)............................................................................46
6.5.3.
24-Week Post-Treatment Visit (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.
Tanner Pubertal Stage Assessment.......................................................................................48
6.6.5.
Height & Weight Measurement............................................................................................49
6.6.6.
Bone Age Assessment..........................................................................................................49
6.6.7.
Swallowability Assessment..................................................................................................49
6.6.8.
Vital Signs............................................................................................................................49
6.6.9.
Estimated Glomerular Filtration Rate (GFR) .......................................................................49
6.6.10.
Viral Sequencing (Archive)..................................................................................................49
6.6.11.
Pregnancy Testing................................................................................................................50
6.6.12.
Quality of Life Survey (PedsQL™).......................................................................................50
7.
TOXICITY MANAGEMENT............................................................................................................................51
7.1.
Subject Stopping Rules for LDV/SOF FDC ..........................................................................................51
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................52
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................52
8.1.1.
Adverse Events.....................................................................................................................52
8.1.2.
Serious Adverse Events........................................................................................................52
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................53
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................53
8.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................53
8.2.2.
Assessment of Severity ........................................................................................................54
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................54
8.4.
Gilead Reporting Requirements.............................................................................................................56
8.5.
Special Situations Reports......................................................................................................................56
8.5.1.
Definitions of Special Situations..........................................................................................56
8.5.2.
Instructions for Reporting Special Situations.......................................................................57
9.
STATISTICAL CONSIDERATIONS................................................................................................................59
9.1.
Analysis Objectives and Endpoints........................................................................................................59
9.1.1.
Analysis Objectives..............................................................................................................59
9.1.2.
Primary Endpoints................................................................................................................60
9.1.3.
Secondary Endpoints............................................................................................................60
9.2.
Analysis Conventions.............................................................................................................................60
9.2.1.
Analysis Sets ........................................................................................................................60
9.2.2.
Data Handling Conventions .................................................................................................61
9.2.3.
Interim Analysis ...................................................................................................................62
9.3.
Demographic Data and Baseline Characteristics ...................................................................................62


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9.4.
Pharmacokinetic Analysis......................................................................................................................62
9.5.
Safety Analysis.......................................................................................................................................64
9.5.1.
Extent of Exposure...............................................................................................................64
9.5.2.
Adverse Events.....................................................................................................................64
9.5.3.
Laboratory Evaluations ........................................................................................................65
9.5.4.
Other Safety Evaluations......................................................................................................65
9.6.
Efficacy Analysis ...................................................................................................................................66
9.6.1.
Primary Efficacy Analysis....................................................................................................66
9.6.2.
Secondary Efficacy Analysis................................................................................................66
9.6.3.
Subgroup Analysis ...............................................................................................................66
9.7.
Quality of Life Analysis.........................................................................................................................67
9.8.
Data Monitoring Committee ..................................................................................................................67
9.9.
Sample Size............................................................................................................................................67
10.
RESPONSIBILITIES..........................................................................................................................................68
10.1.
Investigator Responsibilities ..................................................................................................................68
10.1.1.
Good Clinical Practice..........................................................................................................68
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................68
10.1.3.
Informed Consent/Assent.....................................................................................................69
10.1.4.
Confidentiality......................................................................................................................69
10.1.5.
Study Files and Retention of Records ..................................................................................69
10.1.6.
Case Report Forms...............................................................................................................70
10.1.7.
Drug Accountability.............................................................................................................71
10.1.8.
Inspections............................................................................................................................71
10.1.9.
Protocol Compliance............................................................................................................71
10.2.
Sponsor Responsibilities ........................................................................................................................71
10.2.1.
Protocol Modifications.........................................................................................................71
10.2.2.
Study Report and Publications .............................................................................................72
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................72
10.3.1.
Access to Information for Monitoring..................................................................................72
10.3.2.
Access to Information for Auditing or Inspections ..............................................................72
10.3.3.
Study Discontinuation..........................................................................................................73
11.
REFERENCES ...................................................................................................................................................74
12.
APPENDICES ....................................................................................................................................................75
Appendix 1.
Investigator Signature Page....................................................................................................76
Appendix 2.
Study Procedures Table..........................................................................................................77
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............83
Appendix 4.
Tanner Stages .......................................................................................................................107
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................108


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Amendment 1.0
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LIST OF IN-TEXT TABLES
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................35
Table 9-1.
SOF, GS-331007, and LDV PK Parameters after Once-Daily Administration of 
SOF/LDV in HCV-Infected Adults Subjects (Population PK Analysis from Phase 2 
and 3 Studies) .........................................................................................................................64
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................25


LDV/SOF FDC
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Gilead Sciences, Inc.
Amendment 1.0
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed 
Dose Combination in Adolescents and Children with Chronic 
HCV-Infection
IND Number:
EudraCT Number:
115268
2014-003578-17
Study Centers:
Approximately 30 sites in the United States, Europe, Australia, and 
New Zealand
Number of Subjects:
Approximately 200 subjects
Target Population:
Adolescents and children (aged 3 to < 18) chronic hepatitis C virus 
(HCV) infection
Treatment Duration:
PK Lead-in – 10 days
Treatment Phase – 12 weeks
Objectives:
The primary objective of the PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm 
the dose of LDV/SOF FDC in chronic HCV-infected pediatric 
subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 
10 days of dosing of LDV/SOF FDC in chronic HCV infected 
pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC for 
12 weeks in chronic HCV-infected pediatric subjects. 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
Final 
Amendment 1.0 
The seconda!y objectives of the Treatment Phase ofthis study are: 
• 
To detennine the antiviral efficacy of 12 weeks ofLDV/SOF 
FDC treatment in chronic HCV infected subjects (including the 
impact ofHCV genotype, IL28 genotype, and prior treatment 
experience), as assessed by the prop01i ion of subjects with 
sustained virological response (SVR) 12 weeks after completion 
of treatment (SVR12) 
• 
To determine the antiviral efficacy of 12 weeks ofLDV/SOF 
FDC treatment in chronic HCV-infected subjects, as assessed by 
the prop01iion of subjects with SVR 4 and 24 weeks after 
completion of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during 
treatment and after completion of treatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF 
during treatment and after completion of treatment 
• 
To evaluate the effect of growth and development on pediatric 
subjects during and after treatment 
The explorat01y objective of this study is: 
• 
PD 
Open-label, multi-coh01i, two-part study evaluating the PK, safety, 
and antiviral activity ofLDV/SOF FDC in chronic HCV-infected 
pediatric subjects. 
The study will be divided into 2 parts and will commence with GT -1 
HCV-infected pediatric subjects as follows (subjects with 
GT-2, -4, -5, and -6 will be included once adult data is available, if 
appropriate): 
PK Lead-in Phase: PK Lead-in will evaluate and/or confnm age 
appropriate LDV/SOF FDC doses by analyzing PK, safety, and 
antiviral activity of LDV /SOF FDC through 10 days of dosing for 
each of the three coh01is. Children aged 3 to < 6, children aged 
6 to < 12 years, and adolescents aged 12 to < 18 with years evidence 
of cluonic HCV and HCV RNA ~ 1000 IU/mL at study entiy will be 
evaluated. Subjects must be treatment na'ive to prui icipate in the PK 
Lead-in Phase. 
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Gilead Sciences, Inc.
Amendment 1.0
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Three cohorts of at least 10 subjects each will be sequentially 
enrolled: 

Cohort 1: 12 to < 18 years, old weighing ≥ 45kg

Cohort 2: 6 to < 12 years old 

Cohort 3: 3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive LDV/SOF 
FDC (90 mg/ 400 mg fixed dose combination tablet or 4 x 22.5 mg/ 
100 mg based on LDV/SOF FDC swallowability assessment) for 
10 days with intensive PK conducted on Day 10.
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 10
of the PK Lead-in Phase. They will continue dosing with LDV/SOF 
FDC with no interruption of study drug administration. Subjects 
rolling over from the PK Lead-in will not be required to perform 
Treatment Phase Screening, Day 1, or Week 1 visits in the Treatment 
Phase.  
Following completion of study treatment in the PK Lead-in of each 
Cohort, intensive PK and safety results of study treatment will be 
reviewed to confirm the appropriateness of the evaluated LDV/SOF 
FDC dose for the Treatment Phase of that Cohort as well as to 
determine the age-appropriate dose to be evaluated in the PK Lead-in 
of the next Cohort.
Treatment Phase: Treatment Phase will be initiated sequentially by 
cohort after confirmation of age-appropriate LDV/SOF FDC dosage 
levels. Subjects who participate in PK Lead-in Phase will 
immediately rollover into Treatment Phase, with no interruption of 
study drug administration, until the appropriateness of the dose is 
confirmed by PK and safety data from the PK Lead-In Phase.  These 
subjects will start at the Week 2 visit of the Treatment Phase. 
Additional subjects will be enrolled in the Treatment Phase of each 
Cohort upon confirmation of the appropriateness of the dose.
Children aged 3 to < 12 years and adolescents aged 12 to < 18 years 
with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study 
entry (those who were dosed in the PK Lead-in Phase will have met 
these criteria prior to enrollment) will be evaluated. The study will 
commence with GT-1 HCV infected pediatric subjects and will 
subsequently enroll subjects with GT-2, -4, -5, and -6 once adult data 
is available, if appropriate.


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Final 
Amendment 1.0 
All subjects emolled in the study will receive the following regimen: 
• 
LDV/SOF FDC for 12 weeks 
The study will emoll both u·eatment-na'ive and u·eahnent experienced 
pediau·ic subjects, with up to 40 subjects allowed to be u·eatment 
experienced. Approximately 200 total subjects, including subjects 
that pmiicipated in the PK Lead-in Phase, will be emolled in 
Treatment Phase as follows: 
• 
Group 1: Approximately 100 adolescent subjects (12 to < 18 yem·s 
of age) 
• 
Group 2: Approximately 100 pediau·ic subjects (3 to < 12 yem·s of 
age) 
The following defmitions will be used for u·eatment experienced 
subjects: 
• 
Interferon intolerant: Subject who discontinued therapy 
(:S 12 weeks total) due to:::: 1 adverse event 
• 
Interferon non-responder: Subject who did not achieve 
undetectable HCV RNA levels while on u·eatment 
• 
Relapse/breakthrough: Subject who achieved undetectable HCV 
RNA dming u·eatment or within 4 weeks of the end of u·eatment 
but did not achieve a sustained virologic response (SVR) 
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, and 12 dming the u·eatment phase followed by post-
u·eatment visits 4, 12 and 24 weeks after discontinuation of therapy. 
All subjects who do not attain SVR or have viral relapse will be 
encomaged to discuss u·eahnent with standard-of-cm·e (SOC) therapy 
with their healthcm·e provider. 
Substudy and Long-
Pharmacogenomics (PG) Substudy 
Tenn Follow-Up 
PD 
Study: 
CONFIDENTIAL 
Long-Term Follow-up 
Subjects who attain SVR24 or those who do not attain SVR24 and do 
not initiate experimental or approved anti-HCV therapy will be 
followed eve1y 6 months for assessments of growth, quality of life, 
and long-tenn viral suppression (if applicable) in a sepm·ate protocol 
(GS-US-334-1113). This follow-up will continue for 5 yem·s. 
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Amendment 1.0
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Diagnosis and Main 
Eligibility Criteria: 
Chronic HCV-infected, treatment-naïve and treatment experienced
(up to 40 subjects), male and female subjects aged 3 to < 18 as 
determined at Day 1. The study will commence with GT-1 
HCV-infected pediatric subjects and will subsequently enroll subjects 
with GT-2, -4, -5 and -6 once adult data is available, if appropriate. 
Inclusion Criteria:

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 
Day 1 visit, or
B) a liver biopsy performed prior to the Day 1 visit with evidence 
of chronic HCV- infection

HCV RNA ≥ 1000 IU/mL at Screening

For the PK Lead-in Phase:  subjects in Cohort 1 (age 12 to 
< 18 years of age) must weigh ≥ 45 kg

Sexually active subjects must agree to use 2 forms of highly 
effective contraception, as referenced in Appendix 5, for the 
duration of the study and for 30 days (for female subjects) or 
90 days (for male subjects) after the last dose of study medication. 
Females of childbearing potential (as defined in Appendix 5) must 
have a negative pregnancy test at Screening and Day 1.
Exclusion Criteria:

Hematologic or biochemical parameters at screening outside the 
protocol-specified requirements

HIV, acute hepatitis A virus (HAV) or chronic HBV infection

History of or current decompensated liver disease

Hepatocellular carcinoma or other malignancy (with exception of 
certain resolved skin cancers)

Chronic liver disease of a non-HCV etiology 
(eg, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin 
deficiency)

Systemic corticosteroid use for 2 weeks (pulmonary/nasal 
administration is permitted)

Active or recent history (≤ 1 year) of drug or alcohol abuse


LDV/SOF FDC
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Amendment 1.0
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
History or current evidence of any condition, therapy, laboratory 
abnormality or other circumstance that might confound the results 
of the study, or interfere with the subject’s participation for the 
full duration of  the study, such that it is not in the best interest of 
the subject to participate.
See Sections 4.2 and 4.3 of the protocol for full eligibility criteria.
Study Procedures/
Frequency:
PK Lead-in Phase: 
Screening assessments will be completed within 28 days of the Day 1 
visit. 
Screening assessments will include: complete physical examination, 
vital signs (including body height and weight), adverse events (AEs),
concomitant medications, LDV/SOF FDC Swallowability 
Assessment (may be performed at screening up to Day 1), 
hematology, safety laboratory tests, coagulation tests, HCV RNA, 
serum β-human chorionic gonadotropin (hCG - females of 
childbearing potential only), urinalysis, and urine drug screen, IL28B 
genotyping, serology (HIV, HAV, HCV, and HBV), HbA1c, thyroid 
stimulating hormone (TSH), alpha fetoprotein, alpha-1 anti-trypsin.
Study Visits will occur at Screening, Day 1, Day 3, and Day 10.
On-Treatment assessments include physical examination, Tanner 
Pubertal Stage Assessment (Day 1 only), vital signs (including body 
height and weight), bone age assessment (Day 1 only), adverse events 
(AEs), concomitant medications, pregnancy prevention counseling 
(Day 1 only; all subjects ≥ 12 years of age and subjects < 12 years of 
age at the discretion of the Investigator based on subject’s pubertal 
status), quality of life survey (Day 1 only), safety laboratory tests, 
HCV RNA, viral sequencing sampling, and urinalysis.  Coagulation 
testing and urine pregnancy tests (females of child bearing potential 
only) will be performed at Day 1 and Day 10 only. LDV/SOF FDC 
swallowability assessment with placebo will be performed at 
Screening or up to Day 1 to assess a subject’s ability to swallow the 
90 mg/ 400 mg or 22.5 mg/ 100 mg FDC tablet (only subjects 
administered LDV/SOF FDC in tablet form). 
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in 
Phase will participate in an intensive PK evaluation on Day 10. 
Following completion of the Day 10 intensive PK visit, subjects will 
then return for scheduled study visits outlined in the Treatment Phase 
and will continue dosing with LDV/SOF FDC with no interruption of 
study drug administration. Subjects will be administered a dosing 
diary with instructions.


LDV/SOF FDC
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Gilead Sciences, Inc.
Amendment 1.0
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Treatment Phase: 
Screening assessments will be completed within 28 days of the Day 1 
visit. For subjects continuing from PK Lead-in, screening for 
Treatment Phase will not be required.
Screening assessments will include complete physical examination, 
vital signs (including body height and weight), AEs, concomitant 
medications, coagulation, safety laboratory tests, HCV RNA, serum 
β-human chorionic gonadotropin (hCG- females of childbearing 
potential only), urinalysis, urine drug screen, serology (HIV, HAV, 
HCV, HBV), IL28B genotyping, HbA1c, TSH, alpha fetoprotein,
alpha-1 anti-trypsin. LDV/SOF FDC swallowability assessment with 
placebo will be performed at Screening or up to Day 1 to assess a 
subject’s ability to swallow the 90 mg/ 400 mg or 22.5 mg/ 100 mg
FDC tablet (only subjects administered LDV/SOF FDC in tablet 
form).
Study visits will occur at Screening, Day 1, and at the end of 
Weeks 1, 2, 4, 8, and 12. All Treatment Phase subjects will then 
return for follow-up visits at 4, 12 and 24 weeks after discontinuation 
of therapy. 
On-treatment assessments will include physical examination, vital 
signs (including body height and weight), AEs, concomitant 
medications, pregnancy prevention counseling (all subjects ≥12 years 
of age and subjects < 12 years of age at the discretion of the 
Investigator based on subject’s pubertal status), safety laboratory 
tests, coagulation tests, HCV RNA, viral sequencing, urine pregnancy 
tests (females of childbearing potential only), PK samples, and 
urinalysis. Tanner Pubertal Stage assessment will be performed at 
Day 1, end of treatment, post-treatment Week 12, and post-treatment 
Week 24 visits; parental heights will be recorded at Day 1. The Bone 
Age Assessment will be performed at the Day 1 and post-treatment 
Week 24 visits. If available, results from liver biopsies will be 
collected at screening. LDV/SOF FDC swallowability assessment 
will be performed at screening or up to Day 1 to assess a subject’s 
ability to swallow a placebo to match the 90 mg/ 400 mg or 22.5 mg/
100 mg LDV/SOF FDC tablet (only subjects administered LDV/SOF 
FDC in tablet form). For subjects continuing from the PK Lead-in, 
the screening, Day 1, and Week 1 visits of the Treatment Phase will 
not be required. Samples for viral RNA sequencing/phenotyping will 
be collected at Day 1 and every visit thereafter.
Post-treatment assessments will include vital signs (including body 
weight and height), symptom-directed physical examination, AEs 
(only SAEs will be captured at post-treatment Week 12 and 
post-treatment Week 24), concomitant medications (only 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Final 
Amendment 1.0 
post-treatment Week 4), safety laborat01y tests, HCV RNA, and urine 
pregnancy tests (only females of childbearing potential at 
post-treatment Week 4 and post-u·eatment Week 12). 
PD 
PKLead-in: 
(Coh01i 1) LDV/SOF FDC is manufactured as a tablet, consisting of 
400 mg SOF and 90 mg LDV, for oral adminisu·ation. LDV/SOF 
FDC tablets will be administered once daily. Subjects unable to 
swallow the LDV/SOF FDC 90 mg/ 400 mg adult tablets (as 
detennined by LDV /SOF FDC Placebo swallowability assessment at 
Screening or at any time during the study) will be re-assigned to 
4 x 22.5 mg/ 100 mg LDV/SOF FDC tablets daily. 
Intensive PK and safety results fi:om the PK Lead-in of each Coh01t 
will be reviewed to confnm the appropriateness of the evaluated 
LDV/SOF FDC dose for the Treatment Phase of that Coh01t as well 
as to dete1mine the age-appropriate dose to be evaluated in the PK 
Lead-in of the next Coh01t. 
Treatment Phase: 
Subjects who prut icipated in PK Lead-in of each Coh01t will continue 
in the Treatment Phase with no intenuption of study dmg 
adminisu·ation until the appropriateness of the dose is confi1med by 
PK and safety data from the PK-Lead-in. Additional subjects will be 
emolled in the Treahnent Phase of each Cohort upon confmnation of 
the appropriateness of the dose. 
Reference Therapy: 
None 
Evaluation Criteria: 
Safety: 
Efficacy: 
PK: 
CONFIDENTIAL 
AEs, laborat01y tests, physical examinations, and vital sign 
measurements will be collected throughout the study. 
Efficacy will be evaluated using scheduled assessments ofHCV RNA 
perf01med using COBAS® AmpliPrep/COBAS® TaqMan® 
HCV Test. 
For subjects in the PK Lead-in, a steady-state PK ofLDV, SOF, and 
its major metabolites (GS-566500 and GS-331007) will be assessed at 
Day 10. For Cohorts 1 and 2, plasma srunples will be collected for PK 
analyses following dosing of study diugs on Day 10 at the following 
time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, and 12 hours postdose 
Page 13 
08 October 2014 


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Gilead Sciences, Inc.
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(with predose also serving as t= 24). For Cohort 3, plasma samples 
for PK analyses will be collected at the following time points: 
0 (predose), 0.5, 2, 4, 8, and 12 hours postdose (with predose also 
serving as t = 24).
Plasma PK parameters such as Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, and 
t1/2 will be estimated. 
For all subjects in the Treatment Phase, a single PK blood sample will 
be collected at all visits while on treatment. The PK of SOF, 
GS-566500 and GS-331007, and LDV will be assessed.
The effect of age and LDV/SOF FDC dose on PK (SOF, GS-331007,
and LDV) will be explored.
Statistical Methods:
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, Ctau, 
AUCtau, and t1/2 will be estimated. The PK parameters will be 
summarized by cohort. The effect of age and LDV/SOF FDC dose on 
PK (SOF, GS-331007, and LDV) will be explored.
For the Treatment Phase, the primary safety endpoint is any AE 
leading to permanent discontinuation of study drug and will be 
summarized by age group, by GT, and by overall. Primary efficacy 
endpoint is SVR12 in all enrolled and treated subjects and will be 
summarized by age group, by GT, by overall, and by age group and 
GT. Point estimate and its 95% confidence interval will be provided. 
Subgroup analysis on SVR12 will be performed by prior treatment 
experience (treatment-naïve vs. treatment experienced) and by GT. 
Other clinically relevant subgroup analyses may be conducted as 
appropriate (i.e., assuming that adequate numbers of patients in these 
subsets are available for analysis). 
All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation, median, Q1, Q3, minimum, 
and maximum). 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 by age group, by GT, by 
overall, and by age group and GT.
With approximately 100 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 
SVR12 rate will extend at most 5.9% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 90%.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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Amendment 1.0
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
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)
BLQ
below the lower limit of quantification
BMI
body mass index
CK
creatine kinase
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
dL
Deciliter
DNA
deoxyribonucleic acid
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
ESA
Erythropoiesis stimulating agent
ESPGHAN
European Society for Paediatric Gastroenterology
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed-Dose Combination
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
HAV
Hepatitis A Virus


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Amendment 1.0
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
peginterferon alfa-2a
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
QD
once daily (use only in tables)
RBC
Red blood cell count
RBV
ribavirin
RNA
ribonucleic acid
SADR
Serious adverse drug reaction


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Amendment 1.0
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
SAE
serious adverse event
SD
Standard deviation
SOC
Standard-of-Care
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TSH
Thyroid stimulating hormone
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant 
(λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease worldwide 
and accounts for 70% of cases of chronic hepatitis in industrialized countries. The global 
prevalence of chronic hepatitis C is estimated to average 3% {19705}. 
The natural history of chronic HCV-infection in children differs from that in adults since 
HCV-infection in children is relatively benign. Most children chronically infected with HCV are 
asymptomatic or have mild nonspecific symptoms. Clinical symptoms are present in 
approximately 20% of children in the first 4 years of life, with hepatomegaly being the most 
frequent sign (10%). Many, but not all, perinatally infected children will have intermittently or 
persistently abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
levels, particularly in the first 2 years of life. In children with vertical HCV-infection who have 
undergone liver biopsy, the histological spectrum is usually mild, although severe liver disease is 
encountered {19801}. Despite the overall more favorable prognosis compared to adults, 
approximately 4% to 6% of children with chronic HCV-infection have evidence of advanced 
fibrosis or cirrhosis and some children eventually require liver transplantation for end-stage liver 
disease as a consequence of HCV-infection {19799}.
The goal of HCV treatment in both pediatric and adult populations is eradication of the virus, 
thereby preventing hepatic inflammation, hepatic fibrosis, cirrhosis, and liver failure resulting in 
either death or need for liver transplantation. This goal, however, is limited by the nature of the 
disease and the fact that not all patients are suitable candidates for currently approved treatments. 
In addition, pediatric treatment is controversial as the current treatment options are limited and 
severe side effects and tolerability can significantly limit or preclude their use. Despite 
well-established guidelines for the treatment of HCV in adults, there is no universal consensus 
on when or if to treat chronic HCV-infection in children. In 2010, the European Society for 
Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) issued guidance for clinical 
trial development for chronic HCV-infection in children {20286}. In the guideline, the 
ESPGHAN suggested that the primary goal of treatment in children is to eradicate the infection 
to prevent late complications. Hence, the goal is not the treatment of an ongoing liver disease, 
but rather the prevention of a future one.
PEG and weight-based RBV are currently considered the SOC for the treatment of 
HCV-infection in children. Current recommendations are that patients with GT-2 or GT-3 be 
treated with PEG+RBV for 24 weeks and those with GT-1 or GT-4 should receive 48 weeks of 
therapy. Successful treatment of GT-1, however, has proved very difficult to achieve in spite of 
additional therapy or increased duration of treatment. A number of pediatric studies have 
reported that despite 48 weeks of treatment, sustained virologic response (SVR24) was observed 
in only 36% to 53% of subjects with GT-1, while response rates were > 80% in subjects with 
GT-2 or GT-3 {20285}.


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Most children treated with PEG+RBV experience at least 1 adverse event due to treatment 
{20285}. Although most of these events are mild to moderate in severity, many of them result in 
dose reductions of 1 or both of the drugs. The most common adverse events have consisted of 
influenza-like illness (91%), headache (62%), and injection site reactions (45%), often leading to 
poor compliance and/or discontinuation from treatment.
Additionally, the concern for growth and development in this age group and the role that both 
PEG and RBV potentially play in reducing growth rates has initiated significant debate among 
pediatric hepatologists as to whether these treatments should even be considered in the pediatric 
population {20282}. Many pediatricians currently advocate delay of treatment past adolescence 
or even into adulthood when options with DAAs are possible {20282}. Unfortunately, in the 25% 
of pediatric patients who do meet the criteria for treatment (elevated transaminases and viral 
loads), the option of PEG+RBV therapy remains inadequate in regard to both efficacy in GT-1 
and safety due to the many risks associated with this treatment.
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
Ledipasvir/Sofosbuvir fixed-dose combination (LDV/SOF FDC) combines two HCV specific 
direct acting antiviral (DAA) agents into a single tablet for the treatment of chronic 
HCV-infection. SOF is a nucleotide analog that is a potent and selective inhibitor of 
NS5B-directed HCV replication with demonstrated activity against GT 1-6 HCV-infection. 
Ledipasvir (LDV) is a novel HCV NS5A inhibitor that has demonstrated potent anti-HCV 
activity, with the highest activity against GT1 HCV-infection.  
The LDV/SOF phase 3 program consisted of 3 clinical studies: GS-US-337-0102 {28583}, 
GS-US-337-0109 {28585}, and GS-US-337-0108 {28587}. Studies GS-US-337-0102 and 
GS-US-337-0109 evaluated treatment with LDV/SOF FDC RBV for 12 or 24 weeks in 
treatment-naïve and treatment experienced subjects, respectively, infected with GT-1 HCV. Both 
studies enrolled up to 20% of HCV-infected subjects who had documented compensated 
cirrhosis. GS-US-337-0108 evaluated LDV/SOF FDC ± RBV treatment for 8 weeks and 
LDV/SOF FDC treatment for 12 weeks in non-cirrhotic treatment-naïve subjects with GT-1 
HCV-infection. Across these 3 clinical studies, LDV/SOF FDC demonstrated a high degree of 
efficacy (> 93%) for treatment-naïve and treatment experienced subjects with GT-1 
HCV-infection in subjects with and without cirrhosis and achieved their primary efficacy 
endpoints {28583}; {28585}; {28587}. Additionally, treatment with LDV/SOF FDC ± RBV was 
safe and well tolerated in the Phase 3 studies {28583}; {28585}; {28587}.  The inclusion of RBV 
to the treatment regimen was associated with an increase in the total incidence of adverse events 
and in graded laboratory abnormalities of anemia and increased bilirubin. 
Please refer to the Investigator’s Brochure (IB) for additional information on the LDV/SOF FDC 
including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience


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1.3.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with LDV/SOF 
FDC for adolescents and children with chronic HCV-infection. 
Currently PEG and weight-based RBV are considered the SOC for the treatment of 
HCV-infection in children. Therefore, there is a need for new treatments for HCV in the 
pediatric population that combine potent and sustained efficacy with improved tolerability and 
safety. The primary aim for new treatments of pediatric patients with HCV is to eliminate the 
need to use PEG. In this way, pediatric patients would be able to avoid the necessity of weekly 
injections which can be traumatic and burdensome, and significantly reduce the serious adverse 
events seen with PEG administration. The secondary aim is to eliminate RBV and the adverse 
events seen with its administration. Consequently, LDV/SOF FDC has the potential to be a 
simple and highly effective all-oral treatment regimen for chronic HCV-infection with treatment 
duration of 12 weeks without PEG or RBV for some GTs. 
In vitro viral replicon assay have data demonstrated that LDV has potent, picomolar antiviral 
activity against GT-1a and GT-1b HCV-infection. In the LDV/SOF FDC phase 3 program, 
LDV/SOF FDC without RBV has been shown to have good efficacy and safety in adults infected 
with GT-1 HCV-infection.  In study GS-US-337-0122, a phase 2 open-label study of GT-3 
treatment-naïve adult subjects with and without cirrhosis, LDV/SOF FDC for 12 weeks resulted 
in an SVR12 of 64% whereas LDV/SOF + RBV for 12 weeks resulted in an SVR of 100% 
{29292}.  As a result, the current study which does not include RBV in the treatment regimen 
will initially only enroll pediatric subjects with GT-1 HCV-infection and will not enroll subjects 
with GT-3.
Considering that SOF has pan-genotypic activity and LDV has in vitro, picomolar to nanomolar 
antiviral activity against certain subtypes within GT 4-6 and sub-micromolar antiviral activity 
against certain subtypes within GT-2, studies have been planned and/or initiated with LDV/SOF 
FDC in adult subjects with GT-2, -4, -5, and -6.  If emerging LDV/SOF FDC data in these 
additional GTs support treatment in these genotypes in adults, pediatric subjects with 
GT-2, -4, -5 and -6 will be enrolled in the current study.  Of note, there is an ongoing study 
enrolling GT-2 and -3 pediatric patients, GS-US-334-1112, for treatment with SOF + RBV for 
12 and 24 weeks, respectively.
1.4.
Rationale for Dose Selection of LDV/SOF FDC
Ledipasvir /Sofosbuvir (90 mg/400 mg) fixed-dose combination tablet, administered once daily, 
has demonstrated favorable safety and efficacy profiles in over 1952 HCV-infected subjects 
across different patient populations in phase 2 and 3 clinical trials. These doses are the proposed 
marketed dose of a ledipasvir/sofosbuvir fixed-dose combination tablet for the treatment of 
HCV-infection.
Selection of doses of LDV/SOF FDC for adolescents and younger age groups will target 
systemic exposures similar to those observed in adults at the proposed marketed dose and taking 
into account body weight/body surface area, the potential ontogenic changes in intestinal and 


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hepatically expressed carboxylesterase (CES1) and Cathepsin A (CatA) enzymes, the drug 
transporter p-glycoprotein (Pgp), and the results obtained in older age groups.  Available data 
suggests comparable hepatic expression of CES1 in adolescents and adults with modestly 
decreased expression in children.  However, little is known about the developmental regulation 
of Pgp, CES, and CatA.  As such, the adult clinical doses (90 mg / 400 mg) will be evaluated in 
adolescents (12 to <18 years old).  Safety and PK data in the adolescent group (Cohort 1) in the 
PK Lead-in, in addition to body weight/body surface area will inform dose selection for the
younger age groups.
Age-appropriate formulations of LDV/SOF FDC (a smaller, 22.5 mg / 100 mg strength tablet 
and a non-tablet formulation currently under development) that offer an important option in the 
treatment of HCV-infection in the pediatric population are planned for evaluation in children 
below 12 years of age or children who are unable to swallow the adult dose tablet formulation.
1.5.
Overall Risk/Benefit Assessment
Although the majority of pediatric patients infected with HCV exhibit minimal hepatic sequelae 
despite active viral replication and inflammation, a subset of children and adolescents will 
require treatment. Studies suggest that 3 major categories of disease can occur within 10 years 
after putative HCV exposure: (1) undetectable viremia and normal ALT, (2) persistent yet 
uncomplicated mild liver disease, and (3) progression to end-stage liver disease {20273}. It is the 
last two groups of children in whom therapy may be indicated to prevent end-stage disease, 
either during childhood/adolescence or in early adulthood.
Given that the current SOC for the treatment of children infected with HCV is PEG and RBV 
and these regimens are long in duration, relatively toxic, and not well tolerated, there continues 
to be a need for new treatments for HCV that combine potent and sustained efficacy with 
improved tolerability and safety. 
The combination of LDV plus SOF is anticipated to offer greater antiviral efficacy which could 
result in a shorter treatment duration and/or lead to a regimen without RBV or interferon. These 
in turn could result in reduction in adverse events.  LDV/SOF FDC could also potentially be of 
benefit in patients who have failed prior treatment with SOF+/-RBV+/- PEG.
If high rates of SVR can be obtained with short, well-tolerated regimens, the anticipated 
improvements in safety and tolerability would offer a favorable risk-benefit determination for 
individuals with chronic HCV-infection.


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2. 
OBJECTIVES 
The prima1y objective of the PK Lead-in Phase of this study is: 
Final 
Amendment 1.0 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose ofLDV/SOF FDC 
in chronic HCV-infected pediatric subjects 
The secondruy objective of the PK Lead-in Phase of this study is: 
• 
To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing ofLDV/SOF 
FDC in chronic HCV -infected pediatric subjects 
The primary objective of the Treatment Phase of this study is: 
• 
To evaluate the safety and tolerability ofLDV/SOF FDC for 12 weeks in chronic 
HCV -infected pediatric subjects 
The secondruy objectives of the Treatment Phase of this study ru·e: 
• 
To dete1mine the antiviral efficacy of 12 weeks ofLDV/SOF FDC treatment in chronic 
HCV-infected subjects (including the impact ofHCV genotype, IL28 genotype, and prior 
treatment experience), as assessed by the proportion of subjects with SVR 12 weeks after 
completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of 12 weeks ofLDV/SOF FDC treatment in chronic 
HCV -infected subjects, as assessed by the prop01iion of subjects with SVR 4 and 24 weeks 
after completion of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment 
• 
To evaluate the effect of growth and development on pediatric subjects during and after 
treatment 
The explorat01y objective of this study is: 
• 
PD 
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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and antiviral 
activity of LDV/SOF FDC in chronic HCV-infected pediatric subjects.
3.1.1.
PK Lead-in
The PK Lead-in Phase will evaluate and/or confirm the age appropriate LDV/SOF FDC dose by 
analyzing PK, safety, and antiviral activity of LDV/SOF FDC through 10 days of dosing for each 
cohort. Children aged 3 to < 6 years, children aged 6 to < 12 years, and adolescents aged 12 to 
< 18 years with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry will be 
evaluated. Subjects must be treatment naïve to participate in the PK Lead-in Phase. 
Three cohorts of at least 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old weighing ≥45kg

Cohort 2:  6 to < 12 years old 

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive LDV/SOF FDC (90 mg/400 mg adult 
tablet or 4 x 22.5 mg/100 mg tablets if determined necessary based on LDV/SOF FDC
swallowability assessment) for 10 days with intensive PK conducted on Day 10. 
Following completion of study treatment in the PK Lead-in of Cohort 1 and pending PK and 
safety results, the PK Lead-in of Cohort 2 will initiate and receive study treatment (age 
appropriate dose and formulation). Following completion of study treatment in the PK Lead-in of 
Cohort 2 and pending PK and safety results, the PK Lead-in of Cohort 3 will initiate and receive 
study treatment (age-appropriate dose and formulation). 
Subjects enrolled in the PK Lead-in of each cohort (Cohorts 1, 2 and 3) will immediately enroll 
in the Treatment Phase as they complete Day 10 of PK Lead-in.  They will continue dosing with 
LDV/SOF FDC with no interruption of study drug administration.  Subjects rolling over from the 
PK Lead-in Phase will not be required to perform the screening, Day 1, or Week 1 visit of the 
Treatment Phase.
3.1.2.
Treatment Phase
The Treatment Phase will be initiated sequentially by age group as defined in Cohort 1, 2, and 3 
of the PK Lead-in. Subjects who participated in PK Lead-in will immediately rollover into 
Treatment Phase with no interruption of study drug administration until the appropriateness of 
the dose has been confirmed by PK and safety results from the PK Lead-in.  The first visit in the 
Treatment Phase for these subjects will be the Week 2 visit.  Additional subjects will be enrolled 
in the Treatment Phase of each Cohort upon confirmation of the appropriateness of the dose from 
the PK Lead-in.


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Children aged 3 to < 12 years (Group 2) and adolescents aged 12 to < 18 years (Group 1) with 
chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry (those who were dosed in 
the PK Lead-in will have met this criteria prior to enrollment) will be evaluated.
Subjects enrolled in the Treatment Phase will receive the regimen of LDV/SOF FDC for 
12 weeks. Subjects with GT 1 will be enrolled first.  If emerging LDV/SOF FDC data in 
GT-2, -4, -5, and -6 support treatment in these GTs in adults, pediatric subjects with GT-2, -4, -5, 
and -6 will be subsequently enrolled.  
The study will enroll both treatment naïve and treatment experienced pediatric subjects with up 
to 40 subjects allowed to be treatment experienced. Approximately 200 total subjects, including 
subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as follows:

Group 1: Approximately 100 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 100 pediatric subjects (3 to < 12 years of age)
The following definitions will be used for treatment experienced subjects:

Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to ≥1 adverse 
event

Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels while 
on treatment

Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment or 
within 4 weeks of the end of treatment but did not achieve a sustained virologic response 
(SVR)
All subjects who do not attain SVR or have viral relapse will be encouraged to discuss treatment 
with SOC therapy with their healthcare provider.


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Figure 3-1.
Study Schema
3.2.
Visit Schedule
3.2.1.
PK Lead-in
Screening assessments will be completed within 28 days of the Day 1 visit. 
Study Visits will occur at Screening, Day 1, Day 3, and Day 10.
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in Phase will participate in an 
intensive PK evaluation on Day 10. Subjects will be administered a dosing diary with 
instructions.  
Following completion of the Day 10 intensive PK visit, subjects will then return for scheduled 
study visits outlined in the Treatment Phase and continue dosing with LDV/SOF FDC with no 
interruption of study drug administration.  Subjects rolling over from the PK Lead-in Phase will 
not be required to perform the Treatment Phase screening, Day 1, or Week 1 visits of the 
Treatment Phase.


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3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. Subjects continuing 
from the PK Lead-in Phase will not be required to complete Screening, Day 1, and Week 1 visits 
of the Treatment Phase.
Study visits for all treatment phase subjects will occur at Screening, Day 1, and the end of weeks 
1, 2, 4, 8, and 12. All subjects will then return for follow-up visits at 4, 12, and 24 weeks after 
discontinuation of therapy.
The total time to complete all study visits is approximately 40 weeks including:

28 day (4 week) screening period

12 week treatment period

24 week post-treatment period
The assessments performed at each visit are described in Section 6.
3.3.
Virologic Response-Based Stopping Criteria
HCV RNA will be unblinded to the Investigator and Sponsor.
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 from nadir 

HCV RNA ≥LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination of 
initial observation.  Subjects that meet the virologic response-based stopping criteria above will 
be notified of their eligibility to participate in the Long-Term Follow-Up Study 
(GS-US-334-1113).
3.4.
Treatment Discontinuations Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication 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 or female partner of male subject.

Efficacy failure as defined in Section 3.3.


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• 
Significant protocol violation including non-compliance with study assessments. 
• 
Subject request to discontinue for any reason; it is imp01iant to detennine 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, regulat01y agency, or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). 
3.5. 
Discontinuations 
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Tennination visit as described in the Section 6.4.5. 
Subjects who pennanently discontinue the study dmg for any reason including safety and/or 
tolerability concems prior to completion of the assigned dosing period will be followed 
according to the post-u·eatment study assessments described in Section 6.5. 
3.6. 
Pharmacogenomic Substudy 
PD 
3.7. 
Long-Term Follow-Up 
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed eve1y 6 months for 
assessments of growth, quality of life, and long-te1m viral suppression (if applicable) in a 
separate protocol (GS-US-334-1113). This follow-up study will continue for 5 years. 
3.8. 
Breakthrough Futility Assessment 
A futility assessment will be perf01m ed after the first 10 subjects complete Week 8 on study or 
have viral breakthrough at or prior to Week 8. If3 or more of the first 10 subjects emolled have 
viral breakthrough at or prior to Week 8 or are non-responders (HCV RNA.:::_ LLOQ through 
8 weeks of u·eatment) then fmi her emollment of subjects will be suspended. Virologic 
breakthrough is defined as confnm ed HCV RNA.:::, LLOQ while on u·eatment after two 
consecutive visits with HCV RNA < LLOQ. 
Subjects with known or suspected study dmg non-adherence will not be considered to meet the 
definition of virologic breakthrough, relapse, or non-responder. 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 200 subjects will be enrolled in this study.
In order to manage the total study enrollment, Gilead Sciences, Inc. at its sole discretion, may 
suspend screening and/or discontinue the enrollment at any site at any time (upon written notice 
to the site). Discontinuation of the enrollment phase may result in the immediate ineligibility of 
all subjects screened but not yet enrolled, regardless of the progress or outcome of the screening 
assessments performed.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1. Parent or legal guardian able to provide written informed consent prior to any screening 
evaluations and willing to comply with study requirements.  Subjects will provide assent if 
possible.
2. 3 years to < 18 years of age as determined at Day 1 (consent of parent or legal guardian 
required)
3. PK Lead-in only: subjects in Cohort 1 (age 12 to <18 years of age) must weigh 45 kg
4. PK Lead-in only: all subjects must be treatment naïve: no prior exposure to any IFN, RBV, 
or other approved or experimental HCV-specific DAA agent
5. Treatment experienced subjects:  prior treatment failure to a regimen including interferon 
either with or without RBV that was completed at least 8 weeks prior to Day 1.
i.
Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to 
≥1 adverse event
ii.
Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels 
while on treatment
iii.
Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment 
or within 4 weeks of the end of treatment but did not achieve a sustained virologic 
response (SVR)


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6. 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 Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV-infection
7. Infection with HCV as determined at Screening. The study will commence with GT-1 
HCV-infected pediatric subjects and will subsequently enroll subjects with GT-2, -4, -5 
and -6 once adult data is available, if appropriate. 
8. HCV RNA ≥1000 IU/mL at Screening
9. Adequate hematologic function (absolute neutrophil count 1,500/mm3; 
hemoglobin 11 g/dL).
10. Negative serum -HCG pregnancy test (for females of childbearing potential only, as defined 
in Appendix 5)
11. Subject able to provide written assent, if they have the ability to read and write, as 
determined by IRB/IEC/local requirements and Investigator’s discretion
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Pregnant or lactating subjects
2. Sexually-active males or females of childbearing potential who are not willing to use an 
effective method of contraception during the study (see Appendix 5 for further details)
3. Infection with GT-3 HCV as determined at Screening.
4. Decompensated liver disease defined as INR 1.2 ULN, platelets 50,000/mm3, serum 
albumin 3.5 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, 
jaundice, encephalopathy, variceal hemorrhage)
5. Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
6. -fetoprotein 50 ng/mL
7. Serum creatinine > 1.5 mg/dL
8. Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula


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9. Evidence of hepatocellular carcinoma (HCC)
10. Co-infection with HIV, acute HAV, or HBV
11. Significant cardiovascular, pulmonary, or neurological disease
12. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications
13. History of solid organ or bone marrow transplantation
14. Chronic daily non-steroidal anti-inflammatory drug therapy
15. Systemic corticosteroid use for 2 weeks (pulmonary/nasal administration is permitted)
16. Investigational agents taken within the past 28 days (except with the expressed approval of 
the Sponsor)
17. Clinically-relevant alcohol or drug abuse within 12 months of screening.  A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator
18. Known hypersensitivity to the study drugs, the metabolites, or formulation excipients
19. Any other condition (including alcohol or substance abuse) or prior therapy that, in the 
opinion of the Investigator, would make the subject unsuitable for the study or unable to 
comply with dosing requirements
20. Use of any prohibited concomitant medications as described in Section 5.4 within 28 days of 
the Day 1 visit


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
5.2.1.
Description and Handling 
5.2.1.1.
Formulation
LDV/ SOF FDC tablets are orange, diamond-shaped, film-coated tablets containing 90 mg of 
LDV and 400 mg of SOF. The tablets are debossed with “GSI” on one side and “7985” on the 
other side. The LDV/SOF 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 aluminium lake.
Placebo to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment are 
orange, diamond-shaped, film-coated tablets debossed with “GSI” on one side and “7985” on the 
other side. The tablets contain 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 aluminium 
lake.
Age-appropriate formulations of LDV/SOF FDC have been developed for subjects who are 
unable to swallow the LDV/SOF FDC 90 mg/ 400 mg tablets which include a lower dose 
strength tablet (LDV/SOF FDC 22.5 mg/ 100 mg) formulation. LDV/ SOF FDC lower dose 
strength tablets are round, plain-faced, white film-coated tablets containing 22.5 mg of LDV and 
100 mg of SOF. The LDV/SOF FDC lower dose strength tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc 
and polyethylene glycol.
Placebos to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment are 
round, plain-faced, white film-coated tablets. The placebo tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc and polyethylene glycol.
The non-tablet LDV/SOF FDC formulation will be based on the PK results obtained from 
cohorts 1 and/or 2 of this study. The formulation, composition, acceptability (including 
palatability) will be available and reflected in a protocol amendment which will be submitted for 
approval prior to dosing subjects who are unable to swallow tablets.


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5.2.1.2.
Packaging and Labeling
LDV/ SOF FDC 90 mg/ 400 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 or 30 tablets, a silica gel desiccant, and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child resistant screw 
cap with an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
a silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant screw cap with an induction-sealed, aluminum faced liner.
LDV/SOF FDC 22.5 mg/ 100 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets, a silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child resistant screw cap with 
an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
a silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant screw cap with an induction-sealed, aluminum faced liner.
The packaging and labeling of the non-tablet LDV/SOF FDC formulation will be based on the 
chosen formulation. The packaging and labeling will be available and reflected in a protocol 
amendment which will be submitted for approval prior to dosing subjects who are unable to 
swallow tablets.
All LDV/SOF FDC and placebo to match LDV/SOF FDC bottles to be distributed in the US, 
EU, and the rest of the countries shall be labeled to meet all applicable requirements of the 
US Food and Drug Administration (FDA), Annex 13 of Good Manufacturing Practices: 
Manufacture of investigational medicinal products (February 2010), and/or other local 
regulations as applicable.
5.2.2.
Storage and Handling
LDV/ SOF FDC tablets, 90 mg/ 400 mg, should be stored at controlled room temperature until 
required for administration. Controlled room temperature is defined as 25 °C (77 °F); excursions 
are permitted between 15 °C and 30 °C (59 °F to 86 °F).
Placebo to match LDV/ SOF FDC tablets, 90 mg/ 400 mg, for Swallowability Assessment 
should be stored at controlled room temperature until required for administration. Controlled 
room temperature is defined as 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C 
(59 °F to 86 °F).  
LDV/SOF FDC tablets, 22.5 mg/ 100 mg, should be stored at controlled room temperature until 
required for administration. Controlled room temperature is defined as 25 °C (77 °F); excursions 
are permitted between 15 °C and 30 °C (59 °F to 86 °F).


LDV/SOF FDC
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Amendment 1.0
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Placebo to match LDV/ SOF FDC tablets, 22.5 mg/ 100 mg, for Swallowability Assessment 
should be stored at controlled room temperature until required for administration. Controlled 
room temperature is defined as 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C 
(59 °F to 86 °F).
The storage and handling of the non-tablet LDV/SOF FDC formulation will be based on the 
chosen formulation. The storage and handling will be available and reflected in a protocol 
amendment implemented prior to dosing subjects who are unable to swallow tablets.
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 
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 
LDV/SOF FDC.
Sufficient quantities of LDV/SOF FDC tablets, non-tablet LDV/SOF FDC formulation, and 
placebo tablets will be shipped to the investigator or qualified designee from Gilead Sciences (or 
its designee).
5.2.3.
Dosage and Administration of LDV/SOF FDC
PK Lead-in: (Cohort 1) LDV/SOF FDC 90 mg/ 400 mg tablets will be administered once daily 
with or without food. Subjects determined unable to swallow the placebo to match the 90 mg/ 
400 mg LDV/SOF FDC tablet (by LDV/SOF FDC Placebo Swallowability Assessment at 
Screening up to Day 1) will be re-assigned to 4 x 22.5 mg/ 100 mg tablets daily.  Subjects who 
weigh < 45 kg will be excluded.
Intensive PK and safety results from the PK Lead-in of each Cohort will be reviewed to confirm 
the appropriateness of the evaluated LDV/SOF FDC dose for the Treatment Phase of that Cohort 
as well as to determine the age-appropriate dose to be evaluated in the PK Lead-in of the next 
Cohort.
Treatment Phase: Subjects who participated in the PK Lead-in of each Cohort will continue in 
the Treatment Phase with no interruption of study drug administration until the appropriateness 
of the dose is confirmed by PK and safety data from the PK-Lead-in.  Additional subjects will be 
enrolled in the Treatment Phase of each Cohort upon confirmation of the appropriateness of the 
dose.  
An additional age-appropriate formulation for LDV/SOF FDC Oral Granulates is currently under 
development. The dose for this formulation will be dependent on the PK results obtained from 
Cohorts 1 and/or 2 of this study. The strength, composition, and dosing administration will be 
available and reflected in a protocol amendment which will be submitted for approval prior to 
dosing subjects who are unable to swallow tablets.


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Amendment 1.0
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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.
5.3.
Study Drug Compliance
Subjects will be instructed to return any unused LDV/SOF FDC in the original container on 
Day 10 (PK Lead-in) and/or at study treatment visits every 4 weeks (Treatment Phase).  
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.4.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 30 days 
after the last dose of study drug, need to be recorded in the source documents and electronic case 
report form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment:

Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents (ESAs); granulocyte 
colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Chronic use of systemic immunosuppressants for reasons other than kidney graft 
maintenance 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(s) may result in PK interactions resulting in increases 
or decreases in exposure of study drug(s). Examples of representative medications which are 
prohibited from 21 days prior to Day 1 through the end of treatment are listed below:


LDV/SOF FDC
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Amendment 1.0
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Page 35
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Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton- Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Antiarrhythmics b
Quinidine
Anticonvulsantsc
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Cardiac Medications b
Digoxin, Valsartan, Olmesartan, 
Telmisartan, Ranolazine, Bosentan
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinaccea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsd
Rosuvastatin
Atorvastatin, Simvastatin, Pravastatin, 
Pitavastatin, Fluvastatin, Lovastatin
a
It is recommended to separate antacid and LDV/SOF administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF 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 LDV/SOF or up to 2 hours after taking LDV/SOF. Proton-pump inhibitors should not be taken before 
LDV/SOF. 
b
May result in an increase in the concentration of study drugs and/or concomitant medications. Coadministration of 
LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration 
monitoring of digoxin is recommended when coadministered with LDV/SOF. 
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 (e.g., active cancer, 
transplantation) are not listed under this Concomitant Medication section and are disallowed in 
the study.


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Amendment 1.0
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6.
STUDY PROCEDURES
All subjects will complete screening, on-treatment, and post-treatment assessments. Screening 
assessments will be completed within 28 days of the Day 1 visit. The end of study will occur at 
the 24-week Post-Treatment visit. The schedule of assessments is described below. 
Information on the specific laboratory parameters to be measured and clinical assessments to be 
performed are provided in Section 6.6.
6.1.
Subject Enrollment 
Each candidate’s parent or legal guardian must sign an Informed Consent Form prior to the
conduct of any screening procedures. Each study candidate who has the ability to read and write
must sign an Assent Form, as required by IRB/IEC/local requirements, prior to the conduct of
any study procedures. Screening evaluations will be used to determine the eligibility of each 
candidate for study enrollment. Candidates who fail to meet eligibility criteria by screening 
evaluations may be re-screened once ≥ 30 days after the initial screen if there is a reasonable 
expectation that the candidate will be eligible after repeat screening.
6.2.
Screening Assessments
6.2.1.
Screening Visit (Day –28 to Day 0)
Subjects will complete all screening assessments within 28 days of the Day 1 visit. The screening 
window can be extended to 42 days for subjects requiring additional HCV GT testing or for 
extenuating circumstances.
The following procedures will be performed and documented:

Written informed consent from parent or legal guardian and assent from subject, if applicable 
(see above)

Medical history, including:
— Hepatitis C history
— Hepatitis C treatment history
— Family history, including height and weight of parents
— Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate) and body weight and height


LDV/SOF FDC
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Amendment 1.0
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
Obtain blood samples for tests as listed in Section 6.6.1:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Determination of HCV viral GT and subtype
— HCV antibody, HIV 1/2 antibody, and HBs antigen, HAV antibody
— HbA1c
— TSH
— IL28B
— Serum -hCG pregnancy test for females of childbearing potential only
— Alpha fetoprotein (AFP)
— Alpha-1 anti-trypsin (ATT)

Obtain urine sample for:
— Urinalysis
— Urine Drug Screen

Review of concomitant medications

Ask subject and/or parent/legal guardian if the subject is able to swallow and tolerate taking 
pills.

Review of all inclusion and exclusion criteria

Perform LDV/SOF FDC swallowability assessment 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the Day 1 visit assessments.


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
6.3. 
PK Lead-in: Treatment Assessments 
6.3.1. 
Day 1 Visit 
Final 
Amendment 1.0 
After confnmation of eligibility has been evaluated, the following tests and procedmes must be 
completed prior to emollment and dosing/dispensing on Day 1: 
• 
Perf01m complete physical examination 
• 
Tanner Pubertal Stage Assessment 
• 
Vital signs, including body weight and height measmements 
• 
A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pruiicipants (all subj ects ~ 12 yeru·s of age and subjects < 12 yeru·s of age at the discretion of 
the Investigator based on subject's pubertal status) 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (ru·chive) 
_ 
PD 
• 
Obtain mine samples for the following procedmes: 
-
Urinalysis 
-
~ -hCG pregnancy test for females of childberu·ing potential only 
• 
Subject completes quality of life smvey: Subject is to review questionnaire with a 
parent/guardian and write/mru·k answers directly onto the questionnaire. 
CONFIDENTIAL 
Page 38 
08 October 2014 


LDV/SOF FDC
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Amendment 1.0
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08 October 2014
6.3.1.1.
Drug Administration

Dispense study drug as directed by the IWRS

Instruct the subject on the packaging, storage and administration of study drug

Perform LDV/SOF FDC swallowability assessment (for subjects administered LDV/SOF 
FDC in tablet form only if not previously completed at screening).  Observe the subject 
taking the first dose of study drug (with or without food) and record the time of first dose

Subjects will be administered a dosing diary with instructions.
6.3.2.
Day 3
The following procedures/assessments are to be completed on Day 3:

Perform a symptom-directed physical examination as needed

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Review medication compliance with subject and/or subject’s parent/guardian

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 10 – Intensive PK 
The Day 10 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 10 Intensive PK visit may 
be performed within +3 days of the protocol-specified visit date (subjects will continue daily 
dosing through the Intensive PK Visit).
Subjects should come in a fasted state for the Day 10 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 10 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 10 dose of LDV/SOF FDC must not be taken 
until the evaluations listed below are completed. 


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 1.0
CONFIDENTIAL
Page 40
08 October 2014
If the subject has already dosed prior to the Day 10 clinic visit or is not in a fasted state, the 
Day 10 intensive PK assessments must not be completed. The subject and/or parents/guardians 
should be instructed to return in a fasted state within 3 days (Days 11, 12, or 13) for the intensive 
PK visit. 
If dosing non-compliance is identified as per subject dosing diary and pill count on or prior to the 
Day 10 visit, the Day 10 intensive PK assessments must not be completed. The subject and/or 
parents/guardians should be counseled regarding proper dosing and be scheduled to return for the 
Day 10 intensive PK visit no sooner than 3 days following compliant dosing and no later than 
Day 14 (i.e., return on Day 13 or Day 14).  If dosing non-compliance is due to an AE, 
consultation with the Gilead Medical Monitor is required regarding the potential of rescheduling 
the Day 10 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded not 
to take the LDV/SOF FDC prior to arriving at the clinic on the day of the re-scheduled intensive 
PK visit. All Day 10 intensive PK assessments listed below should be completed when the 
subject returns.
The following evaluations are to be completed at the Day 10 Intensive PK visit:

Perform a symptom-directed physical examination 

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Perform study drug accountability 

Review Subject Dosing Diary

Review medication compliance with subject and/or parent/guardian.

Obtain urine samples for the following procedures:
— Urinalysis
— Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test 
is positive, the Intensive PK sampling will not be completed. The positive result will be 
confirmed with a serum pregnancy test. 

Obtain blood samples for the following laboratory analyses:
— Hematology 
— Chemistry 
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)


LDV/SOF FDC
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Amendment 1.0
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
Perform intensive PK sampling: 
Blood samples will be collected at 0 (predose, ≤30 minutes prior to dosing). After 
collection of the predose sample, subjects will be provided a standardized meal. Within 
5 minutes after consuming the standardized meal, subjects will be dosed with LDV/SOF 
FDC per dosing requirements.
Post-dose blood samples will be collected as follows: 
■
For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 5, 8, and 12 hours post-dose (with predose also 
serving as t= 24).
■
For Cohort 3 only: 0.5, 2, 4, 8, and 12 hours post-dose (with predose also serving as 
t = 24).
Subjects will be restricted from food intake until after collection of the 4-hour post dose 
blood sample, except for subjects in Cohort 3. Please also refer to the PK manual for 
details about standardized meals and PK sample processing instructions.
After completing the Day 10 intensive PK visit subjects will then continue to the Week 2 visit in 
Treatment Phase (described in Section 6.4.2) with no interruption in dosing.
6.4.
Treatment Phase: Treatment Assessments 
6.4.1.
Day 1 Visit
After confirmation of eligibility has been evaluated, the following tests and procedures must be 
completed prior to enrollment and dosing/dispensing on Day 1:

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements 

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Review of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status). 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCV RNA 
-
Viral sequencing (archive) 
_ 
PD 
• 
Obtain urine sample for: 
-
Urinalysis 
-
~ -hCG pregnancy test for females of childbearing potential only 
Final 
Amendment 1.0 
• 
Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire 
• 
Perf01m LDV/SOF FDC swallowability assessment (for subjects administered LDV/SOF 
FDC in tablet fonn only if not previously completed at screening) 
6.4.1.1. 
Dmg Adminisu·ation 
• 
Dispense study dmg as directed by the IWRS 
• 
lnstiuct the subject on the packaging, storage, and adminisu·ation of study dmg 
• 
Observe the subject taking the first dose of study dmg (with or without food) and record the 
time of fust dose 
6.4.2. 
Weeks 1 and 2 (± 3 days) 
Subjects who participated in the PK Lead-in will start study visits in the Treatinent Phase at 
Week 2. The following procedures/assessments are to be completed at these visits: 
• 
Vital signs, including body weight and height measurements 
• 
Perf01m symptom-directed physical examination 
• 
Assessment of AEs and concomitant medications 
CONFIDENTIAL 
Page42 
08 October 2014 


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Gilead Sciences, Inc.
Amendment 1.0
CONFIDENTIAL
Page 43
08 October 2014

Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— Single PK 
6.4.3.
Weeks 4 and 8 (3 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— Single PK 

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drugs at these visits)

Dispense study drug as directed by the IWRS


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Gilead Sciences, Inc.
Amendment 1.0
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6.4.4.
Week 12 (3 days)

Perform complete physical examination

Tanner Pubertal Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— TSH
— Single PK 

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles of study drug at the Week 12 Visit
6.4.5.
Unscheduled Visit/Early Termination Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments are at the investigator’s discretion.
The Sponsor/CRO should be informed when a subject comes off treatment due to an adverse 
event. If a subject discontinues treatment then the assessments outlined below should be 
performed.


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 1.0
CONFIDENTIAL
Page 45
08 October 2014

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— TSH
— Single PK 

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles of study drug at the Early Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as described in 
Section 6.5.
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
experimental or approved anti-HCV therapy will be followed every 6 months for assessments of 
growth, quality of life, and long-term viral suppression (if applicable) in a separate protocol 
(GS-US-334-1113). This follow-up will continue for 5 years.


LDV/SOF FDC
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Gilead Sciences, Inc.
Amendment 1.0
CONFIDENTIAL
Page 46
08 October 2014
6.5.
Post-Treatment Assessments
6.5.1.
4-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for: 
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status) 
6.5.2.
12-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements

Perform symptom-directed physical examination

Assessment of SAEs

Perform Tanner Pubertal Stage assessment

Obtain blood samples for 
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 1.0
CONFIDENTIAL
Page 47
08 October 2014

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire
6.5.3.
24-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of SAEs

Tanner Pubertal Stage Assessment

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Obtain blood samples for 
— HCV RNA
— Viral sequencing (archive)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire.
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed every 6 months for 
assessments of growth, quality of life, and long-term viral suppression (if applicable) in a 
separate protocol (GS-US-334-1113). This follow-up will continue for 5 years.
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) 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
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Chemistry Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct Bilirubin), Glucose, 
Lipase, Potassium, Sodium, Gamma-glutamyl transferase (GGT), alpha fetoprotein (AFP), 
alpha-1 anti-trypsin, creatine kinase (CK) and amylase.
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® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System. 
HCV GT 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 
GT should the above assays become unavailable.
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 right to use alternate assays for 
IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum -hCG, Urine -hCG (if positive, requires immediate confirmation with 
Serum -hCG)
Additional Tests: Urine Drug Screen (for amphetimines, cocaine, methadone, opiates), 
Hemoglobin A1c (HbA1c), TSH (reflex Free T4), Alfa fetoprotein (AFP), Alpha-1 anti-trypsin
(AAT).
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. Parental heights will be recorded at Day 1.
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.
Tanner Pubertal Stage Assessment
The Tanner Stage scale is available in Appendix 4.  All subjects will receive a baseline Tanner 
Pubertal Stage Assessment. If the assessment determines that the subject is at a Tanner 5 at 
Day 1, no further Tanner Pubertal Stage Assessments are to be completed. Date of first menses 
will be documented. 


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6.6.5.
Height & Weight Measurement
Height and weight measurement will be collected at each study visit. The difference in body 
weight and height measurements between Day 1 and End of Treatment, post-treatment Week 12, 
and post-treatment Week 24 will be calculated.  
6.6.6.
Bone Age Assessment
A single X-ray of the left wrist, hand, and fingers will be performed at Day 1 Visit and 
post-treatment Week 24.  Local radiologist to determine bone age from x-ray.
6.6.7.
Swallowability Assessment
A LDV/SOF FDC swallowability assessment will be performed at screening up to Day 1.  
Subjects who have indicated that they can take pills will be observed taking a placebo to match 
the 90 mg/ 400 mg LDV/SOF FDC tablet. This will confirm the swallowability of the 90 mg/
400 mg tablet size. If a subject is unable to swallow the 90 mg/ 400 mg LDV/SOF FDC tablet 
size, he/she will repeat the assessment with a placebo for the 22.5 mg/ 100 mg LDV/SOF FDC 
tablet. If unable to swallow the 22.5 mg/ 100 mg LDV/SOF FDC tablet, enrollment of the 
subject will be deferred until the granule formulation is available.
6.6.8.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.6.9.
Estimated Glomerular Filtration Rate (GFR)
Estimated Glomerular Filtration Rate (GFR) using Schwartz Formula (mL/min/1.73m2) = 
k L/Scr [(k is a proportionality constant, for adolescent females ≥12 years old is 0.55; and for 
adolescent males ≥12 years old is 0.70); L is height in centimeters (cm); and Scr is serum 
creatinine (mg/dL)]
6.6.10.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
Unused samples may be archived.


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6.6.11.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every 4 weeks during the 
dosing period and for a minimum of 30 days following the last dose of LDV/SOF FDC. If 
required by local regulations, additional pregnancy tests beyond 30 days may be added. In the 
event of a positive urine pregnancy result, subjects will be instructed to stop study drugs 
immediately (if applicable) and return to the clinic as soon as possible for a serum pregnancy 
test.
6.6.12.
Quality of Life Survey (PedsQL™)
The PedsQL ™ Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be completed 
in Treatment Phase of the study at Day 1, End of Treatment, Early Termination (if applicable), 
12-Week Post-Treatment, and 24-Week Post-Treatment visits.  
The PedsQL ™  has separate survey instruments administered by age group, including the Teen 
Report (ages 13-18), Child Report (ages 8-12), Young Child Report (ages 5-7), and Toddlers 
(ages 2-4).  Each survey will be administered to the subject for the current age group at the time 
of survey administration.  


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7.
TOXICITY MANAGEMENT
7.1.
Subject Stopping Rules for LDV/SOF FDC
The Gilead Medical Monitor should be consulted prior to dose discontinuation of LDV/SOF 
FDC unless the investigator believes that immediate action is warranted to ensure the continued 
safety of the subject.
Administration of LDV/SOF FDC may be discontinued due to a clinical or laboratory event. 
There is no option for LDV/SOF FDC dose reduction. If LDV/SOF FDC is stopped for toxicity, 
it should not be restarted.
Subjects who meet any of the following laboratory criteria must stop treatment with LDV/SOF 
FDC:

Elevation of ALT and/or AST >5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT >3x Day 1 and total bilirubin >2 x ULN, confirmed by 
immediate repeat testing

Confirmed elevation of ALT >15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with LDV/SOF FDC


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8.
ADVERSE EVENTS MANAGEMENT
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
8.1.1.
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-mandated procedures, 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 8.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history CRF
8.1.2.
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

Persistent or significant disability/incapacity


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
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.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
8.2.1.
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 investigational 
medicinal product. For SAEs, an alternative causality must be provided (e.g., 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 AE reporting.


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The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures (eg., venipuncture)
8.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4 weeks after last administration of study drug 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 protocol defined follow up 
period.
Serious Adverse Events
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 24-week 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
after informed consent is signed 
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. Investigators are not 
obligated to actively seek SAEs after the 24 week post-treatment follow-up period.  However, if 


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the investigator leam s of any SAEs that occur after study prui icipation has concluded and the 
event is deemed relevant to the use of IMP, he/she should promptly document and rep01i the 
event directly to Gilead DSPH. 
• 
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Rep01iing Process 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infonnation 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 infonnation electr·onically, ie, the eCRF 
database is not ftmctioning, record the SAE on the paper serious adverse event rep01i ing 
f01m and submit within 24 hours to: 
Gilead Sciences, Dmg 
Fax: 
+ 1 650 522-5477 
Safety and Public 
E-mail: 
Safety _FC@gilead.com 
Health: 
PRA Intemational 
Fax: 
+1 888 772 6919 (N01ih America); 
Phrumacovigilance 
+49 621 8782 181 (Rest of World) 
Representative: 
E-mail: 
CHOSafety@praintl.com 
Gilead Sciences, 
Name: 
Bittoo Kanwar, MD 
Medical Monitor: 
Phone: 
PPD 
Mobile: 
PPD 
Fax: 
PPD 
E-mail: 
t-'t-'U 
I 
• 
As soon as it is possible to do so, any SAE rep01i ed via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been rep01ied via a paper fonn because the eCRF database has been locked, no 
ftnther action is necessruy. 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
• 
For fatal or life-threatening events, copies of hospital case rep01is, autopsy rep01is, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the tr·aceability of a document to the subject identifiers. 
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
Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
report form.
8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
8.5.
Special Situations Reports
8.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 


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question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging or distribution of the medicinal product.  
8.5.2.
Instructions for Reporting Special Situations
8.5.2.1.
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-treatment follow-up period, to Gilead DSPH using the pregnancy report form within 
24 hours of becoming aware of the pregnancy.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 8.1 and 8.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported directly to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 or Fax: +1 (650) 522-5477.
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy report form and pregnancy outcome report forms within 24 hours. Monitoring of the 
partner pregnancy 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 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.


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8.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management and outcome will be reported, when available.


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Objectives and Endpoints 
9.1.1. 
Analysis Objectives 
The prima1y objective ofPK Lead-in Phase of this study is: 
Final 
Amendment 1.0 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose ofLDV/SOF FDC 
in chronic HCV-infected pediatric subjects 
The secondruy objective ofPK Lead-in Phase of this study is: 
• 
To evaluate the safety, tolerability, and viral activity of 10 days of dosing ofLDV/SOF FDC 
in chronic HCV-infected pediatric subjects 
The primru·y objective of Treatment Phase of this study is: 
• 
To evaluate the safety and tolerability ofLDV/SOF FDC for 12 weeks in chronic 
HCV -infected pediatric subjects 
The secondruy objectives of Treatment Phase of this study ru·e: 
• 
To dete1mine the antiviral efficacy of 12 weeks ofLDV/SOF FDC treatment in chronic 
HCV-infected subjects, as assessed by the prop01iion of subjects with SVR 12 weeks after 
completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of 12 weeks ofLDV/SOF FDC treatment in chronic 
HCV-infected subjects (including the impact ofHCV genotype, IL28 genotype and prior 
treatment experience), as assessed by the proportion of subjects with SVR 4 and 24 weeks 
after completion of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment 
• 
To evaluate the effect of growth and development on pediatric subjects during and after 
treatment 
The explorat01y objective ofthis study is: 
• 
PD 
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9.1.2.
Primary Endpoints
For the PK Lead-in Phase, AUCtau of GS-331007 and LDV are considered the primary PK 
parameters for determining the appropriate LDV/SOF FDC dose.
For the Treatment Phase, the primary safety endpoint is any AE leading to permanent 
discontinuation of study drug (s). The primary efficacy endpoint is SVR12.
9.1.3.
Secondary Endpoints
For the PK Lead-in Phase, the secondary PK endpoints will include early viral kinetics and the 
following PK endpoints: AUCtau, Cmax, AUClast, Tmax, Clast, Tlast, Ctau and t1/2 for 
GS-331007, SOF, and LDV as appropriate. AEs leading to permanent discontinuation of study 
drug(s) will be evaluated as a secondary safety endpoint.
For the Treatment Phase, secondary efficacy endpoints include SVR4, SVR24, breakthrough and 
relapse. Additional efficacy evaluations may include HCV RNA change from Day 1; ALT 
normalization; and viral kinetic parameters. Secondary safety endpoints of growth and 
development measurements will be assessed (e.g. height, weight, and Tanner Stage Assessment).
9.2.
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).
9.2.1.
Analysis Sets 
9.2.1.1.
Pharmacokinetics (PK) Analysis Sets
Intensive PK Analysis Set 
The intensive PK analysis set will include all PK Lead-in subjects who received at least one dose 
of study drug and for whom at least one non-missing PK concentration data, during the intensive 
sampling period, reported by PK lab. The PK analysis set will be used for detailed 
pharmacokinetic analysis of LDV, SOF, and metabolites.  
Sparse PK Analysis Set 
The PK analysis set will include all enrolled subjects who received at least one dose of study 
drug and for whom at least one observed concentration data of LDV, SOF, or GS-331007 are 
available. The PK analysis set will be used for analysis of general PK and single sample plasma
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9.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses will include subjects who were enrolled and have 
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 last dose of study drug plus 30 days.
9.2.1.3.
Efficacy Analysis Set
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which includes 
HCV-infected subjects who were enrolled and have received at least one dose of study drug.
9.2.2.
Data Handling Conventions
Natural logarithm transformation for key PK parameters, such as Cmax and AUCtau, will be 
applied for pharmacokinetic analysis.
The PK concentration values below the limit of quantitation (BLQ) will be treated as zero for the 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing and will be excluded in any calculation of geometric 
means or ratios. For the presentation of summary and order statistics, if at least 1 subject has a 
concentration value BLQ for the time point, then the minimum value will be displayed as 
“BLQ”. If more than 50% of the subjects have a concentration data value BLQ for the time 
point, then the minimum and median values will be displayed as “BLQ”. If all subjects have 
concentration data values BLQ for the time point, then all order statistics (minimum, first 
quartile [Q1], median, third quartile [Q3], maximum) will be displayed as “BLQ”.
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, 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 
preceded and followed in time by values that are deem 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 medication will be 
considered a failure at the time points subsequent to 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.


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
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).
9.2.3.
Interim Analysis
No formal interim analyses are planned for this study.
9.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by age group and overall for PK Lead-in and Treatment Phase respectively. 
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight, height, body mass index, HCV RNA level 
(log10 IU/mL), HCV GT, prior treatment experience, and additional endpoints as necessary.
9.4.
Pharmacokinetic Analysis
PK analysis will be performed for PK Lead-in using the intensive PK analysis set. The 
concentration data of LDV, SOF, and metabolites (GS-566500 and GS-331007) over sampling 
time will be listed and summarized by nominal time and cohort. Pharmacokinetic parameters 
(e.g., AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½) will be listed and 
summarized for LDV, SOF,  and metabolites (as applicable) using descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean and its 95% confidence interval, coefficient 
of variation %, standard deviation, median, Q1, Q3, minimum, and maximum) by cohort and 
overall. Plasma concentrations over time will be plotted in semilogarithmic and linear formats as 
mean ± standard deviation and median (Q1, Q3).


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To evaluate if the exposures of LDV and GS-331007 achieved in pediatric subjects of this study 
are similar to the exposures observed in adult subjects (Table 9-1). The LDV and GS-331007
exposure data from this study will be compared to the integrated adult data. The primary 
endpoint of this analysis will be evaluated by carrying out an analysis of variance (ANOVA) for 
log-transformed GS-331007 AUCtau and LDV AUCtau. The secondary endpoints of this analysis 
will be the Cmax of LDV and GS-331007 and Ctau of LDV. The 90% confidence intervals will be 
constructed for the ratio of geometric means of each PK parameters. The equivalence boundary 
is set as 50% to 200%.  
Given that dose ranging studies for SOF established that a dose of 200 mg results in suboptimal 
exposure compared to the 400 mg dose, and the lack of clinically significant exposure-safety 
relationships observed across a broad range of GS-331007 exposure, bounds of 50% to 200% for 
GS-331007 AUCtau will allow identification of a clinically relevant difference in exposure in the 
pediatric population.
A phase 2 study evaluating LDV doses of 30 or 90 mg LDV in combination with DAAs 
VDV+TGV+RBV suggested LDV exposure may be suboptimal at the 30 mg dose based on the 
incidence of virologic breakthrough being approximately half in the 90 mg arm; as such the 
90 mg dose was selected for further development.  In the 90 mg LDV arm of this study, the LDV 
AUCtau at the 25 percentile was 3230 hr*ng/mL.  While this value is 62% lower than the mean 
LDV AUCtau (8530 hr*ng/mL) observed in adult HCV-infected subjects in the LDV/SOF FDC 
Phase 2/3 population, it provides ~99.8% of maximal viral load reduction (exposure-response 
model established in the monotherapy proof of concept study).  In the Phase 2/3 population when 
administered the LDV/SOF FDC, there was a lack of clinically significant exposure-efficacy or 
safety relationships observed across the broad range of LDV exposure.  Taken together these 
data support the utility of bounds of 50% to 200% for LDV AUCtau to identify a clinically 
relevant difference in LDV exposure in the pediatric population.      
In all pediatric age groups, the targeted exposures for GS-331007 and LDV are the adult 
equivalent for which safety and efficacy has been established.  In the absence of any pediatric 
PK information (ie., variability and exposure of GS-331007 or LDV is unknown) assuming a 
2-fold higher  variability, or a 30 % difference in GS-331007 or LDV AUCtau in the pediatric 
population compared to adults, the predicted 90% CIs of the geometric mean ratio (GMR) will 
be contained within the bounds of 50% to 200%.
Individual patient management will be performed by maintaining exposures comparable to 
adults.  In the event more than one subject in each cohort exhibits LDV (AUCtau) or GS-331007 
(AUCtau) exposures less than the 2.5th percentile of adult values, a dose assessment may be 
require for the cohort as appropriate.
The effect of age and LDV/SOF FDC dose on PK (LDV, SOF and GS-331007) will be assessed.


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Table 9-1.
SOF, GS-331007, and LDV PK Parameters after Once-Daily 
Administration of SOF/LDV in HCV-Infected Adults Subjects 
(Population PK Analysis from Phase 2 and 3 Studies) 
Mean (%CV) PK Parametera
GS-331007 (N=2113)
LDV (N=2113)
AUCtau (ng•h/mL)
12,500 (29.2)
8530 (60.8)
Cmax (ng/mL)
736 (28.2)
364 (51.4)
Ctau (ng/mL)
N/A
247 (59.2)
a
Pharmacokinetic parameters are presented as mean (%CV) and are shown to 3 significant digits.
9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in and overall study Treatment Phase
respectively. Safety data will be summarized by age group, by GT, by overall and by age group 
and GT.
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements, and by the documentation of AEs.
All safety data collected while on or after the first dose of study drug administration up to 
30 days after the last dose of study drug will be summarized by cohort according to the study 
drug received.
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.
9.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the CRF. Exposure data will be summarized.
9.5.2.
Adverse Events
Clinical and laboratory AEs 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 study drug up to the date of last dose of study drug plus 30 days. 


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Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC 
and preferred term) will be provided by cohort:

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,

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.
9.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled visits will be summarized. Graded laboratory 
abnormalities will be defined using the grading scheme in Grading of Laboratory Abnormalities 
provided in Appendix 3. 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 
and including the date of last dose of study drug plus 30 days, will be summarized by age group 
and overall. If baseline data are missing, then any graded abnormality (i.e., at least a Grade 1) 
will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
9.5.4.
Other Safety Evaluations
9.5.4.1.
Tanner Pubertal Stage Assessment
Tanner Stages (Appendix 4) will be summarized by baseline Tanner Stage using frequency and 
percentage. Age of first menses will be summarized descriptively.


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Vital Signs (including Body Weight and Height) 
Final 
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Vital signs including body weight and height and change from baseline will be summarized at 
each visit by age group, by GT, by overall and by age group and GT. 
9.6. 
Efficacy Analysis 
Efficacy will be evaluated using scheduled assessments of HCV RNA perf01m ed using CO BAS® 
TaqMan® HCV Test, v2.0 for use with the High Pure System. 
Efficacy analysis will be perf01m ed by age group, by GT, by overall, and by age group and GT 
for Treatment Phase. 
All continuous endpoints will be summarized using an 8-number summruy (n, mean, standru·d 
deviation, median, Ql , Q3, minimum, maximum). All categorical endpoints will be summru·ized 
by number and percentage of subjects who meet the endpoint definition. 
9.6.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
treatment) in the F AS population. Point estimate and its 95% confidence interval will be 
provided. 
9.6.2. 
Secondary Efficacy Analysis 
For the PK Lead-in Phase, senun HCV RNA actual values and change from baseline will be 
summarized at each visit. 
For the Treatment Phase, the proportion of subjects with HCV RNA below LLOQ over time 
(including SVR endpoints SVR4 and SVR24) will be presented in tabulru· and graphical f01m . In 
addition, descriptive summaries and listings will be provided for additional efficacy evaluations 
including senun HCV RNA actual values and change from baseline, prop01iion of subjects with 
virologic failures, and other endpoints of interest including AL T n01m alization. 
PD 
9.6.3. 
Subgroup Analysis 
Subgroup analysis on SVR12 will be perf01m ed by treatment experience (treatment-naive vs. 
treatment experienced), by IL28 genotype, by GT, and by u·eatment experience and GT. Other 
clinically relevant subgroup analyses may be conducted as appropriate (i.e., assuming that 
adequate munbers of subjects in these subsets ru·e available for analysis). 
Details on efficacy analyses will be described in the statistical analysis plan. 
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9.7.
Quality of Life Analysis
The data from PedsQL ™ Pediatric Quality of Life survey will be summarized by visit and age 
group and overall.
9.8.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety and provide recommendation to Gilead about 
whether the nature, frequency, and severity of adverse effects associated with study treatment 
warrant the early termination of the study in the best interests of the participants, whether the 
study should continue as planned, or the study should continue with modifications. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
9.9.
Sample Size
With approximately 100 subjects enrolled into each age group of Treatment Phase, a two-sided 
95.0% confidence interval of the SVR12 rate will extend at most 5.9% in both directions from 
the observed SVR12 rate, assuming the expected SVR12 rate is 90%.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
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. For studies conducted under a United States IND, the investigator 
will ensure that 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, are adhered to.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that investigators and all subinvestigators must provide documentation of their financial 
interest or arrangements with Gilead Sciences, or proprietary interests in the drug being studied. 
This documentation must be provided before participation of the investigator and any 
subinvestigator. The investigator and subinvestigator agree to notify Gilead Sciences of any 
change to reportable interests during the study and for one year following completion of the 
study. Study completion is defined as the date that the last subject has completed 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.”
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
This protocol 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/assent) will be submitted by the investigator to an IRB (for studies conducted in the 
United States) or IEC (for studies conducted outside of the United States). Approval from the 
IRB or IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation.


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10.1.3.
Informed Consent/Assent
The investigator is responsible for obtaining written informed consent from the parent/legal 
guardian of the subject participating in this study after adequate explanation to the parent/legal 
guardian and subject of the aims, methods, objectives, and potential hazards of the study and 
before undertaking any study-related procedures. Written assent should be obtained from the 
subject as required by IRB/IEC/local requirements for this age population.  The investigator must 
utilize an IRB- or IEC-approved consent/assent form for documenting written informed 
consent/assent. Each informed consent/assent will be appropriately signed and dated by the 
subject or the subject’s parent/legally authorized representative and the person obtaining 
consent/assent.
10.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, and an 
identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the Sponsor, IRB or IEC, or laboratory. The investigator must keep a screening log 
showing codes, names, and addresses for all subjects screened and for all subjects enrolled in the 
trial.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational new drug, and any 
other study information, remain the sole and exclusive property of Gilead Sciences during the 
conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Gilead Sciences. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data are listed in the Source Data verification Plan, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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
Participation in trial (including trial number);

Trial 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 trial medication (preferably drug dispensing 
and return should be documented as well);

Record of all AEs and other safety parameters (start and end date, and preferably including 
causality and intensity);

Concomitant medication (including start and end date, dose if relevant; dose changes should 
be motivated);

Date of trial completion and reason for early discontinuation, if applicable.
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) 
and until there are no pending or contemplated 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 required by applicable regulatory requirements, by local 
regulations, or by an agreement with Gilead Sciences. The investigator must notify 
Gilead Sciences 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 Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences 
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period up to 15 years for purposes of this study.
10.1.6.
Case Report Forms
For each subject enrolled, a CRF (or eCRF) must be completed and signed by the principal 
investigator or subinvestigator (as appropriate) within a reasonable time period after data 
collection. This also applies to records for those subjects who fail to complete the study 
(even during a prerandomization screening period if a CRF was initiated). If a subject withdraws 


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from the study, the reason must be noted on the CRF. If a subject is withdrawn from the study 
because of a treatment-limiting adverse event, thorough efforts should be made to clearly 
document the outcome.
10.1.7.
Drug Accountability
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product, and comparators. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), subject 
dispensing records, and returned or destroyed study product. Dispensing records will document 
quantities received from Gilead Sciences and quantities dispensed to subjects, including lot 
number, date dispensed, subject identifier number, subject initials, and the initials of the person 
dispensing the medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRBs or IECs, 
or to regulatory authority or health authority inspectors.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB, IEC, or 
competent authorities in accordance with local requirements. Approval must be obtained before 
changes can be implemented.


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10.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies). 
Gilead Sciences 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.
After conclusion of the study and without prior written approval from Gilead Sciences, 
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 Sciences in an abstract, manuscript, or presentation form; or

the study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).
The investigator will submit 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. The investigator will comply with Gilead Sciences’ 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.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the CRFs for consistency.
The monitor is responsible for routine review of the CRFs 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 CRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences 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 Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.


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10.3.3.
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 Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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11.
REFERENCES
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Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
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Hu J, Doucette K, Hartling L, Tjosvold L, Robinson J. Treatment of hepatitis C in 
children: a systematic review. PLoS ONE 2010;5 (7):e11542.
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Mohan N, Gonzalez-Peralta RP, Fujisawa T, Chang MH, Heller S, Jara P, et al. 
Chronic hepatitis C virus infection in children. J Pediatr Gastroenterol Nutr 
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Bortolotti F, Verucchi G, Camma C, Cabibbo G, Zancan L, Indolfi G, et al. Long-
term course of chronic hepatitis C in children: from viral clearance to end-stage 
liver disease. Gastroenterology 2008;134 (7):1900-7.
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Serranti D, Buonsenso D, Ceccarelli M, Gargiullo L, Ranno O, Valentini P. 
Pediatric hepatitis C infection: to treat or not to treat...what's the best for the 
child? European review for medical and pharmacological sciences 2011;15 
(9):1057-67.
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Wirth S. Current treatment options and response rates in children with chronic 
hepatitis C. World J Gastroenterol 2012;18 (2):99-104.
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Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti F, Zancan L, Jara P, et al. 
High sustained virologic response rates in children with chronic hepatitis C 
receiving peginterferon alfa-2b plus ribavirin. J Hepatol 2010;52 (4):501-7.
28583
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and 
sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370 
(20):1889-98.
28585
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. 
Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N 
Engl J Med 2014;370 (16):1483-93.
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Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. 
Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N 
Engl J Med 2014;370 (20):1879-88.
29292
Gane E, Hyland RH, An D, Pang PS, Symonds WT, McHutchison JG, et al. 
Ledipasvir/Sofosbuvir Fixed-Dose Combination Is Safe and Effective in Difficult-
to-Treat Populations Including GT 3 Patients, Decompensated GT 1 Patients, and 
GT 1 Patients With Prior Sofosbuvir Experience [Oral Presentation 6]. 49th 
Annual Meeting of The European Association for the Study of the Liver (EASL); 
2014 April 9-13; London, UK. 


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CONFIDENTIAL
Page 75
08 October 2014
12.
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.
Tanner Stages
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


LDV/SOF FDC 
Protocol GS-US-337-1116 
Final 
Gilead Sciences, Inc. 
Amendment 1.0 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-Label, Multicenter, Muti-cohort Study to Investigate the Safety and 
Efficacy of Ledipasvir/Sofosbuvir in Adolescents and Children with Chronic 
HCV -infection 
GS-US-337-1116, Original Protocol, 08 October 2014 
This protocol has been approved by Gilead Sciences, Inc. The fo llowing signature documents 
this approval. 
pp0..---------------. 
'1? 1\TOO 
Bittoo Kanwar, MD (Printed) 
Medical Monitor 
0~ Ocin\xr 
Date 
loll( 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 76 
08 October 2014 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 1.0
CONFIDENTIAL
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08 October 2014
Appendix 2.
Study Procedures Table
Appendix Table 1.
PK Lead-in: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X j
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Vital Signsa
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X
Subject Dosing Diary
X
X
X


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 78
08 October 2014
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
Viral Sequencing c
X
X
X
Serum or Urine Pregnancy Testinge
X
X
X
Urinalysis
X
X
X
Urine Drug Screen
X
Intensive PK
X d
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
Alpha fetoprotein
X
Alpha-1 anti-trypsin
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, body weight, and height
b
Day 1 assessments must be performed prior to dosing
c
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
d
For Cohorts 1 and 2, plasma samples will be collected for PK analyses following dosing of study drugs on Day 10 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5,
8, and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours post-dose.
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 79
08 October 2014
e
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test. 
f
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status). 
g
h
Swallowability can occur at Day 1 if not completed during screening.
i
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
j
Parental height will be collected with medical history at Screening (if available) as stated in Section 6.2.1
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 80
08 October 2014
Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
Early 
Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
Xi
Complete Physical Examination
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
Tanner Pubertal Stage Assessment
X
X
X
Vital Signsa
X
X
X
X
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling g
X
X
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey e
X
X
X
Review of Study Medication Compliance
X
X
X
X
Study Drug Dispensingb
X
X
X
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
X
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
X


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 81
08 October 2014
Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
Early 
Termination
Viral Sequencing d
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testing
X
X
X
X
X
X
Single PK
X
X
X
X
X
X
Urinalysis
X
X
Urine Drug Test
X
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs antigen, 
HAV antibody
X
HbA1c
X
TSH
X
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, and body weight and height
b
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
c
Subjects rolling over from PK Lead-in will not be required to repeat screening, Day 1 or Week 1 visits during the on Treatment Phase  
d
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
e
Quality of life survey will be completed at Day 1, Week 12, and Early Termination if a site is approved to use the survey. Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire.
f
g
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
h
Swallowability can occur at Day 1 if not completed during screening.
i
Parental height will be collected with medical history at Screening (if available) as stated in Section 6.2.1
PPD
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 82
08 October 2014
Appendix Table 3.
Treatment Phase: Post Treatment Visits Following Primary Study
4 Weeks Post Treatment
12 Weeks Post Treatment
24 Weeks Post Treatment
Clinical Assessments
Vital Signs, Body weight and Height
X
X
X
Symptom-directed Physical Exam
X
X
X
AEs
X
Xc
Xc
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counselingd
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Test
X
X
a
Quality of life survey will be completed by all subjects at 12-Week and 24-Week Post Treatment visits if a site is approved to use the survey.  Subject is to review 
questionnaire with a parent/guardian and write/mark answers directly onto the questionnaire.
b
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
c
At Post Treatment Week 12 and 24, only SAEs will be captured
d
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 83
08 October 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 84
08 October 2014
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 85
08 October 2014
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 86
08 October 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 87
08 October 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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 88
08 October 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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 89
08 October 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
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


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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


LDV/SOF FDC
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Gilead Sciences, Inc
Amendment 1.0
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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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Gilead Sciences, Inc
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SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or  
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


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


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Gilead Sciences, Inc
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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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Gilead Sciences, Inc
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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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Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
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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


LDV/SOF FDC
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Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
Page 105
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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


LDV/SOF FDC
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Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
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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


LDV/SOF FDC
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Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
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08 October 2014
Appendix 4.
Tanner Stages
1. Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2. Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of testes and scrotum and increased darkening 
of scrotal skin (13.5-15)
Tanner V 
Genitalia adult in size and shape
3. Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen 
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with 
surrounding breast 
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V 
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. 


LDV/SOF FDC
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Final
Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Background
Non-clinical toxicity studies of LDV/SOF FDC demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of LDV/SOF FDC 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)
For the purpose of this trial, all post-menarchal females will be considered to be of childbearing 
potential, unless there is documentation of irreversible ovarian failure or surgical sterilization.
Post-menarchal females must have a negative serum pregnancy test at Screening and a negative 
urine pregnancy test on the Day 1 visit prior to randomization. They must also agree to one of 
the following from 3 weeks prior to Day 1 until 30 days after last dose of LDV/SOF FDC:

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 the last dose of LDV/SOF FDC:
— 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
— implants of levonorgestrel
— injectable progesterone
— oral contraceptives (either combined or progesterone only)
— contraceptive vaginal ring 
— transdermal contraceptive patch


LDV/SOF FDC
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Gilead Sciences, Inc
Amendment 1.0
CONFIDENTIAL
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3. Contraceptive Requirements for Male Subjects (and their female partners)
All male study participants must agree to consistently and correctly use a condom from Day 1
until 90 days after the last dose of LDV/SOF FDC. If their female partner is of childbearing 
potential (as defined above), their female partner must use 1 of the methods of birth control listed 
above from the date of Screening until 90 days after last dose of LDV/SOF FDC.
Male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of 
LDV/SOF FDC.
4. Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days (90 days for partners of male subjects) of 
last LDV/SOF FDC 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 8.5.2.1.

SAP_007.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed 
Dose Combination ± Ribavirin in Adolescents and Children with 
Chronic HCV-Infection
Name of Test Drug:
Ledipasvir/Sofosbuvir Fixed Dose Combination
Study Number:
GS-US-337-1116
Protocol Version (Date):
Original:
10 July 2014
Amendment 1: 08 October 2014
Amendment 2: 08 December 2014
Amendment 3: 28 May 2015
Amendment 4: 15 March 2016
Amendment 5: 04 November 2016
Amendment 6: 08 June 2017
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
10 July 2018
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS AND DEFINITIONS ............................................................................7
1.
INTRODUCTION ................................................................................................................................................8
1.1.
Study Objectives ......................................................................................................................................8
1.2.
Study Design............................................................................................................................................9
1.2.1.
PK Lead-in Phase.................................................................................................................10
1.2.2.
Treatment Phase ...................................................................................................................10
1.2.3.
Study Duration .....................................................................................................................11
1.3.
Sample Size and Power..........................................................................................................................11
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................12
2.1.
DMC Analyses.......................................................................................................................................12
2.2.
Final Analysis ........................................................................................................................................12
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................13
3.1.
Analysis Sets..........................................................................................................................................13
3.1.1.
All Enrolled Analysis Set.....................................................................................................13
3.1.2.
Full Analysis Set ..................................................................................................................13
3.1.3.
Safety Analysis Set...............................................................................................................13
3.1.4.
Pharmacokinetic Analysis Set..............................................................................................13
3.2.
Subject Grouping ...................................................................................................................................14
3.3.
Strata and Covariates..............................................................................................................................15
3.4.
Examination of Subject Subsets.............................................................................................................15
3.5.
Missing Data and Outliers......................................................................................................................16
3.5.1.
Missing Data ........................................................................................................................16
3.5.2.
Outliers.................................................................................................................................17
3.6.
Data Handling Conventions and Transformations .................................................................................17
3.7.
Visit Windows........................................................................................................................................18
3.7.1.
Definition of Study Day .......................................................................................................18
3.7.2.
Analysis Windows................................................................................................................19
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis 
Window................................................................................................................................20
4.
SUBJECT DISPOSITION ..................................................................................................................................22
4.1.
Subject Enrollment and Disposition.......................................................................................................22
4.2.
Extent of Exposure.................................................................................................................................23
4.2.1.
Durations of Exposure to Study Regimen and Individual Study Drug.................................23
4.2.2.
Adherence to Study Drug.....................................................................................................23
4.3.
Protocol Deviations................................................................................................................................26
5.
BASELINE CHARACTERISTICS....................................................................................................................27
5.1.
Demographics ........................................................................................................................................27
5.2.
Other Baseline Characteristics ...............................................................................................................27
5.3.
Swallowability Assessment for LDV/SOF Placebo Tablets ..................................................................28
5.4.
Palatability of LDV/SOF Oral Granules ................................................................................................28
5.5.
Medical History......................................................................................................................................29


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GS-US-337-1116
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6.
EFFICACY ANALYSES ...................................................................................................................................30
6.1.
Key Efficacy Endpoint...........................................................................................................................30
6.1.1.
Definition of the Key Efficacy Endpoint..............................................................................30
6.1.2.
Analysis Methods for the Key Efficacy Endpoint................................................................30
6.1.3.
Subgroup Analysis of the Key Efficacy Endpoint................................................................30
6.2.
Secondary Efficacy Endpoints ...............................................................................................................30
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................30
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................31
6.3.
Exploratory Efficacy Endpoints.............................................................................................................32
6.3.1.
Definition of Exploratory Efficacy Endpoints......................................................................32
6.3.2.
Analysis Methods for Exploratory Efficacy Endpoints........................................................32
6.4.
Changes From Protocol-Specified Efficacy Analyses............................................................................33
7.
SAFETY ANALYSES........................................................................................................................................34
7.1.
Adverse Events and Deaths....................................................................................................................34
7.1.1.
Adverse Event Dictionary ....................................................................................................34
7.1.2.
Adverse Event Severity........................................................................................................34
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................34
7.1.4.
Serious Adverse Events........................................................................................................34
7.1.5.
Treatment-Emergent Adverse Events...................................................................................34
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................35
7.2.
Laboratory Evaluations ..........................................................................................................................37
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................37
7.2.2.
Graded Laboratory Values ...................................................................................................38
7.3.
Vital Signs..............................................................................................................................................39
7.4.
Body Weight, Height and BMI ..............................................................................................................39
7.5.
Mid-Parental Height Assessment...........................................................................................................40
7.6.
Bone Age Assessment............................................................................................................................40
7.7.
Tanner Pubertal Stage Assessment.........................................................................................................40
7.8.
Prior and Concomitant Medications.......................................................................................................41
7.9.
Other Safety Measures ...........................................................................................................................41
7.10.
Changes From Protocol-Specified Safety Analyses...............................................................................41
8.
PHARMACOKINETIC ANALYSES ................................................................................................................42
8.1.
PK Analysis in the PK Lead-in Phase (Intensive PK Analysis).............................................................42
8.2.
Population PK Analysis .........................................................................................................................42
9.
REFERENCES ...................................................................................................................................................43
10.
SOFTWARE.......................................................................................................................................................44
11.
SAP REVISION..................................................................................................................................................45
12.
APPENDICES ....................................................................................................................................................46
Appendix 1.
Study Procedures Table..........................................................................................................47
Appendix 2.
Tanner Stages* .......................................................................................................................54
Appendix 3.
PedsQL™ Score Calculation Algorithms...............................................................................55


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GS-US-337-1116
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LIST OF IN-TEXT TABLES
Table 1-1.
Subject Enrollment by HCV Genotype, Country, and Treatment Duration .............................9
Table 3-1.
Non-safety Treatment Groups* ..............................................................................................14
Table 3-2.
Safety Treatment Groups........................................................................................................15
Table 3-3.
Subgroups for Selected Analyses in 3 to < 6 years of Age.....................................................15
Table 3-4.
Analysis Windows for On-treatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................19
Table 3-5.
Analysis Windows for Posttreatment HCV RNA, Body Weight, Height, Vital Sign 
and Safety Laboratory Data....................................................................................................20


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GS-US-337-1116
Statistical Analysis Plan
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CONFIDENTIAL
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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CFR
Code of Federal Regulations
CI
confidence interval
eCRF
electronic case report form
CSR
clinical study report
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
FAS
Full Analysis Set
FDC
Fixed Dose Combination
Gilead
Gilead Sciences, Inc.
GT
genotype
Hb
hemoglobin
HCV
hepatitis C virus
HLT
high level term
HLGT
high level group term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
LDV
Ledipasvir
LLT
lower level term
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
PedsQLTM
Pediatric Quality of Life Inventory™
PK
pharmacokinetics
PT
preferred term
Q1
first quartile
Q3
third quartile
RBV
ribavirin
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SI (units)
International system of units
SOC
system organ class
SOF
Sofosbuvir 


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SVR
sustained virologic response
SVRx
sustained virologic response x weeks after stopping study drug
TEAE
treatment-emergent adverse events
TFLs
tables, figures, and listings
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS AND DEFINITIONS
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
phase of the log plasma/serum concentration versus time curve of the drug
AUC
area under the plasma/serum concentration versus time curve
AUCtau
area under the plasma/serum concentration versus time curve over the dosing interval
CL
systemic clearance of the drug after intravenous administration
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf, where “Dose” is the dose of the drug
Cmax
maximum observed plasma/serum concentration of drug
Ctau
observed drug concentration at the end of the dosing interval
Emax
maximum (pharmacodynamic) effect
t½
estimate of the terminal elimination half-life of the drug in serum/plasma, calculated by dividing 
the natural log of 2 by the terminal elimination rate constant (z)
Tmax
time (observed time point) of Cmax


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-337-1116. This SAP is based on the study Protocol Amendment 6 dated 
08 June 2017 and the electronic case report form (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR.
1.1.
Study Objectives
The primary objectives of this study are as follows:

The primary objective of the pharmacokinetics (PK) Lead-in Phase of this study is to 
evaluate the steady state PK and confirm the dose of Ledipasvir/Sofosbuvir Fixed Dose 
Combination (LDV/SOF FDC) in hepatitis C virus (HCV)-infected pediatric subjects. 

The primary objective of the Treatment Phase of this study is to evaluate the safety and 
tolerability of LDV/SOF FDC ± ribavirin (RBV) for 12 or 24 weeks in HCV-infected 
pediatric subjects.
The secondary objectives of this study are as follows:

The secondary objective of the PK Lead-in Phase of this study is to evaluate the safety and 
tolerability of 10 days of dosing of LDV/SOF FDC in HCV-infected pediatric subjects.

The secondary objectives of the Treatment Phase of this study are:
To determine the antiviral efficacy of 12 or 24 weeks of LDV/SOF FDC ± RBV 
treatment in chronic HCV-infected subjects (including the impact of HCV genotype, 
IL28B genotype, and prior treatment experience), as assessed by the proportion of 
subjects with sustained viral response 12 weeks after discontinuation of therapy (SVR12)
To determine the antiviral efficacy of 12 or 24 weeks of LDV/SOF FDC ± RBV 
treatment in chronic HCV-infected subjects, as assessed by the proportion of subjects 
with sustained viral response 4 and 24 weeks after discontinuation of therapy (SVR4 and 
SVR24)
To evaluate the kinetics of circulating HCV RNA during treatment and after completion 
of treatment
To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment
To evaluate the acceptability assessed by swallowability of tablets and palatability of 
granules
To evaluate the effect of growth and development on pediatric subjects during and after 
treatment


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The exploratory objective of this study is as follows:

 
1.2.
Study Design
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and efficacy of 
LDV/SOF FDC ± RBV in chronic HCV-infected pediatric subjects.
The study will enroll both treatment-naive and treatment–experienced pediatric subjects with up 
to 40 subjects allowed to be treatment experienced. Approximately 220 total subjects will be 
enrolled as follows:

Approximately 100 adolescents aged 12 to < 18 years 

Approximately 120 children aged 3 to < 12 years
Subjects of 3 age groups will be enrolled in a sequential fashion: 12 to <18 years old, followed 
by 6 to <12 years old, and 3 to <6 years old.
Eligible subjects will receive the following treatment regimens based on HCV genotype, prior 
treatment experience, cirrhosis status and country of enrollment:
Table 1-1.
Subject Enrollment by HCV Genotype, Country, and Treatment 
Duration
GT1, GT4, GT5, & GT6
GT1
GT4, GT5, & 
GT6
GT3
Cirrhotic or 
Non-cirrhotic 
Subjects 
(TN)
Non - cirrhotic 
Subjects 
(TE)
Cirrhotic 
Subjects 
(TE)
Cirrhotic 
Subjects 
(TE)
Non-cirrhotic or 
Cirrhotic 
Subjects 
(TE)
United States, 
Australia, New 
Zealand
12 Weeks of 
treatment with 
LDV/SOF FDC
12 Weeks of 
treatment with 
LDV/SOF FDC
24 Weeks of 
treatment with 
LDV/SOF FDC
12 Weeks of 
treatment with 
LDV/SOF FDC
N/A
United 
Kingdom
24 Weeks of 
treatment with 
LDV/SOF FDC
24 Weeks of 
treatment with 
LDV/SOF FDC + 
RBV
TN = Treatment Naïve, TE = Treatment Experienced, N/A = Not Applicable
Therefore, subjects actually enrolled are grouped into the treatment groups according to their age 
groups, HCV genotype, prior treatment experience, cirrhosis status, and treatment duration, as 
specified in Section 3.2.
PPD


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The schedules of assessments for the study are provided as appendixes to the SAP (see Study 
Procedures Table, Appendix 1). 
1.2.1.
PK Lead-in Phase
The PK Lead-in Phase will evaluate and/or confirm the age appropriate LDV/SOF FDC dose by 
analyzing PK, safety, and antiviral activity of LDV/SOF FDC through 10 days of dosing.
At least 10 treatment-naïve subjects without history of cirrhosis will be sequentially enrolled into 
each of the following 3 cohorts:

Cohort 1: 12 to < 18 years old, weighing ≥ 45kg

Cohort 2: 6 to < 12 years old, weighing ≥ 17kg and < 45kg

Cohort 3: 3 to < 6 years old
At least 4 subjects weighing ≥17 kg
At least 4 subjects weighing < 17 kg
Intensive PK and safety results through Day 10 of each Cohort will be reviewed to confirm the 
appropriateness of the LDV/SOF FDC dose for that age group as well as to determine the age-
appropriate dose to be evaluated in the PK Lead-in Phase of the next age Cohort.
Subjects enrolled in the PK Lead-in Phase will immediately enroll in the Treatment Phase as 
they complete Day 10 of PK Lead-in. They will continue dosing with LDV/SOF FDC with no 
interruption of study drug administration until the appropriateness of the dose is confirmed by 
PK and safety data from the PK Lead-in Phase.
Cohort 1 subjects received LDV/SOF FDC (90 mg/ 400 mg adult tablet or 4 × 22.5 mg/100 mg 
tablets if determined necessary based on LDV/SOF FDC swallowability assessment) for 10 days 
with intensive PK conducted on Day 10. 
Cohort 2 subjects received LDV/SOF FDC 45 mg/ 200 mg (2 × 22.5 mg/ 100 mg tablets) for
10 days with intensive PK conducted on Day 10. 
Cohort 3 subjects weighing ≥17 kg received LDV/SOF FDC 45 mg/ 200 mg (4 × 11.25 mg/ 
50 mg packets containing granules) for 10 days with intensive PK conducted on Day 10. 
Cohort 3 subjects weighing <17 kg received LDV/SOF FDC 33.75 mg/ 150 mg (3 × 11.25 mg/ 
50 mg packets containing granules) for 10 days with intensive PK conducted on Day 10. 
1.2.2.
Treatment Phase
Additional HCV-infected children will be enrolled into the Treatment Phase upon confirmation 
of the appropriateness of the dose from the PK Lead-in Phase. The Treatment Phase will be
initiated sequentially by age group as defined in Cohorts 1, 2, and 3 of the PK Lead-in Phase. 


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Subjects who participated in the PK Lead-in Phase will immediately roll over into the Treatment 
Phase with no interruption of study drug administration until the appropriateness of the dose has
been confirmed by PK and safety results from the PK Lead-in Phase. The first visit in the 
Treatment Phase for these subjects will be the Week 2 visit. 
After dose confirmation in the PK Lead-in Phase of each age group, the identical dose was used 
in subjects of the corresponding age group enrolled in the Treatment Phase.
1.2.3.
Study Duration
The total time to complete all study visits is up to approximately 40 weeks for subjects treated 
with 12 weeks of therapy and 52 weeks for subjects treated for 24 weeks of therapy including the 
following periods:

28-day (4-week) screening period

12 or 24 week treatment period

24-week posttreatment period
1.3.
Sample Size and Power
With approximately 100 subjects enrolled into the 12 to <18 years of age group, a two-sided 
95.0% confidence interval of the SVR12 rate will extend at most 5.9% in both directions from 
the observed SVR12 rate, assuming the expected SVR12 rate is 90%.
With approximately 120 subjects enrolled into the 3 to < 12 years of age group, a two-sided 
95.0% confidence interval of the SVR12 rate will extend at most 5.4% in both directions from 
the observed SVR12 rate, assuming the expected SVR12 rate is 90%.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
DMC Analyses
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data and provide recommendation to Gilead about 
whether the nature, frequency, and severity of adverse effects associated with study treatment 
warrant the early termination of the study in the best interests of the participants, whether the 
study should continue as planned, or the study should continue with modifications.
Specific activities of the DMC will be defined by a mutually agreed charter, which will define 
DMC membership, conduct and meeting schedule.
2.2.
Final Analysis
After all subjects have completed through the post-treatment week 24 visit or have prematurely 
discontinued from the study, outstanding data queries have been resolved, and the database has 
been cleaned and finalized, the final analysis of the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects [n], mean, standard deviation [SD] or standard error [SE], median, first 
quartile [Q1], third quartile [Q3], minimum, and maximum will be presented.
Data collected in the study will be presented in by-subject listings for all subjects in the Safety 
Analysis Set, unless otherwise specified. All by-subject listings will be presented by subject 
identification (ID) number in ascending order, unless otherwise specified.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The number of subjects eligible for each analysis set will be 
provided. Subjects who were excluded from Safety and Full Analysis Sets will be provided in a 
by-subject listing with reasons for exclusion. 
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all subjects enrolled in the study after screening. All analyses 
based on the All Enrolled Analysis Set will be performed according to the treatment group to 
which subjects were enrolled.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes HCV infected subjects who were enrolled into the study 
and received at least one dose of study drug. The study drugs in this study include LDV/SOF 
FDC and RBV. Subjects are grouped within the FAS by the treatment group to which they were 
enrolled.
This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug (ie,
LDV/SOF FDC ± RBV). Subjects will be grouped according to the treatment they actually 
received. 
This is the primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic Analysis Set
PK Lead-in Phase Intensive PK Analysis Set
The PK Lead-in Phase Intensive PK Analysis Set includes all PK Lead-in Phase subjects who 
received at least one dose of study drug and for whom at least one non-missing PK concentration 


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data value is available from the PK Lead-in Phase intensive sampling. This is the primary 
analysis set for PK Lead-in Phase intensive PK analysis.
Population PK Analysis Set
The Population PK Analysis Set includes all enrolled subjects who received at least one dose of 
study drug and for whom at least one non-missing PK concentration data value is available from 
the PK sampling. This is the primary analysis set for the Population PK modeling and PK 
exposure analyses.
The PK Analysis Set is equivalent to the Population PK Analysis Set.
3.2.
Subject Grouping
For analyses based on the All Enrolled Analysis Set or FAS, subjects will be grouped according 
to the treatment to which they were enrolled. For analyses based on the Safety Analysis Set, 
subjects will be grouped according to the actual treatment received. The actual treatment 
received is defined as the enrolled treatment except for subjects who received treatment that 
differs from the enrolled treatment for the entire treatment duration. In this case, the actual 
treatment received is defined as the treatment received for the entire treatment duration.
Generally, subjects are analyzed, except for the safety analysis, by treatment groups based on age 
group, HCV genotype, prior treatment experience, cirrhosis status, and treatment duration:
Table 3-1.
Non-safety Treatment Groups*
12 to < 18 Years Old
3 to < 12 Years Old
LDV/SOF  
(90/400 mg)              
12 Weeks
LDV/SOF  
(45/200 mg or 33.75/150 mg)          
12 Weeks  
LDV/SOF 
(45/200 mg)     
24 Weeks
LDV/SOF+RBV
(45/200 mg)     
24 Weeks
GT1
TN
w/ or w/o 
cirrhosis
(N = )
GT1
TE 
without 
cirrhosis
(N = )
GT1, GT4
TN
w/ or w/o 
cirrhosis
(N = )
GT1 
TE  
without      
cirrhosis
(N = )
GT1
TE
with        
cirrhosis
(N = )
GT3
TE              
w/ or w/o
cirrhosis
(N = )
6 to < 12 Years Old
3 to < 6 Years Old
LDV/SOF
(45/200 mg)                 
12 Weeks
LDV/SOF 
(45/200 mg)     
24 Weeks
LDV/SOF+RBV
(45/200 mg) 
24Weeks
LDV/SOF
(45/200 mg or 33.75/150 mg)         
12 Weeks
GT1, GT4 
TN           
w/ or w/o 
cirrhosis
(N = )
GT1
TE       
without 
cirrhosis
(N = )
GT1
TE              
with        
cirrhosis
(N = )
GT3
TE                
w/ or w/o           
cirrhosis
(N = )
GT1, GT4  
TN  
w/ or w/o 
cirrhosis
(N = )
GT = genotype, TN = Treatment Naïve, TE = Treatment Experienced, w/ = with, w/o = without
*Treatment Groups reflect the subjects actually enrolled.


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For the safety analysis, subjects will be analyzed by the following groups based on age group,
treatment regimen and duration:
Table 3-2.
Safety Treatment Groups
12 to < 18 Years Old
3 to < 12 Years Old
LDV/SOF 
(90/400 mg)              
12 Weeks 
(N = )
LDV/SOF                 
(45/200 mg or 33.75/150 mg)  
12 Weeks 
(N = )
LDV/SOF        
(45/200 mg)         
24 Weeks 
(N = )
LDV/SOF+RBV          
(45/200 mg)                
24 Weeks 
(N = )
6 to < 12 Years Old
3 to < 6 Years Old
LDV/SOF                
(45/200 mg)               
12 Weeks 
(N = )
LDV/SOF                 
(45/200 mg)                
24 Weeks 
(N = )
LDV/SOF+RBV     
(45/200 mg)        
24 Weeks 
(N = )
LDV/SOF                   
(45/200 mg or 33.75/150 mg)  
12 Weeks 
(N = )
Subjects in the 3 to < 6 years of age group will have additional selected efficacy and safety
analyses performed according to baseline weight in the following subgroups:
Table 3-3.
Subgroups for Selected Analyses in 3 to < 6 years of Age
3 to < 6 Years Old
< 17 kg
LDV/SOF                                          
(33.75/150 mg)                                      
12 Weeks 
(N = )
≥17 kg
LDV/SOF                                    
(45/200 mg)                                  
12 Weeks                                    
(N = )
3.3.
Strata and Covariates
This study does not use a stratified randomization schedule for enrolling subjects. No covariates 
will be included in efficacy and safety analyses.
3.4.
Examination of Subject Subsets
The efficacy endpoint SVR12 will be analyzed for the following subsets:

sex (male, female)

race (black, non-black)

ethnicity (Hispanic or Latino, non-Hispanic or Latino)

baseline weight (≤ median, > median)


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
IL28B (CC, non-CC [further broken down to CT, TT])

baseline HCV RNA (< 800,000 IU/mL, ≥ 800,000 IU/mL)

baseline ALT (≤1.5 × ULN, > 1.5 × ULN)

Interferon (IFN) eligibility (IFN-eligible, IFN-ineligible)

most recent response to prior HCV treatment (non-response, relapse/breakthrough, 
IFN-intolerant) for treatment experienced subjects

study treatment status (completed study treatment, discontinued study treatment)

adherence to study regimen (< 80%, ≥ 80%).
3.5.
Missing Data and Outliers
3.5.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
For missing last dosing date of study drug, imputation rules are described in Section 3.7.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in 
Section 7.1.5.2, and for prior and concomitant medications in Section 7.8.
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed up to 
the time of the last dose (for on-treatment displays). If the study day associated with the last 
dosing date is greater than or equal to the lower bound of a visit window, and the value at the 
visit is missing, the value will be imputed. If the study day associated with the last dosing date is 
less than the lower bound of a visit window then the on-treatment value at that visit will remain 
missing. 
If a data point is missing and is preceded and followed in time by values that are “< LLOQ target 
not detected (TND)”, then the missing data point will be set to “< LLOQ TND”. If a data point is 
missing and preceded and followed by values that are “< LLOQ detected”, or preceded by 
“< LLOQ detected” and followed by “< LLOQ TND”, or preceded by “< LLOQ TND” and 
followed by “< LLOQ detected”, then the missing value will be set to “< LLOQ detected”. In 
these situations the data point will be termed a bracketed success; otherwise, the data point will 
be termed a bracketed failure (ie, ≥LLOQ detected). If a data point is missing and is not 
bracketed, the missing data point will also be termed a failure (ie, ≥LLOQ detected) except for 
SVR24, which will be imputed according to SVR12 status. Success for SVR12 who have no 
further HCV RNA measurements collected will be counted as a success for SVR24 due to the 
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For the analyses of continuous HCV RNA efficacy data, when and only when a missing HCV 
RNA value is imputed as < LLOQ TND or < LLOQ detected according to the imputation rule 
described above, the corresponding continuous value will be imputed to LLOQ - 1 IU/mL. No 
other imputation will be performed for continuous HCV RNA data.
In the analysis of the PedsQL™Pediatric Quality of Life Inventory V4.0 Short Form (SF15) 
questionnaire, missing data at on-treatment visits and posttreatment follow-up Week 12 (FU-12) 
visit will not be imputed. Last posttreatment observation carried forward will be used for 
imputation of missing data at posttreatment follow-up Week 24 visit.
3.5.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.6.
Data Handling Conventions and Transformations
By-subject listings will be presented for all subjects in the Safety Analysis Set and sorted by 
subject ID number, visit date, and time (if applicable) unless otherwise specified. Data collected 
on log forms, such as AEs, will be presented in chronological order within subject. 
Age (in years) on the date of the first dose of study drug and sex at birth will be used for analyses 
and presentation in listings.
If a subject was not dosed with study drug at all, then the date the informed consent was signed 
will be used instead of the first dose date of study drug. For some countries, only birth year is 
collected on the eCRF. In those cases, “01 January” will be used for the unknown birth day and 
month for the purpose of age calculation, unless age is captured on the eCRF. 
Non-PK data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed as follows:

A value that is one unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “x” (where x is considered the
limit of quantitation). For example, if the values are reported as < 50 and < 5.0, values of 
49 and 4.9, respectively, will be used for calculation of summary statistics. An exception for 
this rule is any value reported < 1. For the values reported as < 1 or < 0.1, value of 0.9 or 
0.09 will be used for calculation of summary statistics.

A value that is one unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “> x” (where x is considered the 
limit of quantitation). Values with decimal points will follow the same logic as above.

The limit of quantitation will be used for calculation of descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the limit of quantitation).


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The COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for use with the High Pure 
System was used to determine HCV RNA results in this study. The lower limit of quantitation 
(LLOQ) of the assay is 15 IU/mL.
When the calculated HCV RNA value is within the linear range of the assay, then the result will 
be reported as the “<< numeric value>> IU/mL”. This result will be referred to in this document 
as the numeric result or as “≥ LLOQ detected” for categorical result.
When HCV RNA is not detected, the result is reported as “No HCV RNA detected” or “target 
not detected”. This result will be referred to in this document as “< LLOQ target not detected” or 
“< LLOQ TND”.
When the HCV RNA IU/mL is less than LLOQ of the assay, the result is reported as 
“< 15 IU/mL HCV RNA detected”. This result will be referred to in this document as “< LLOQ 
detected”.
The overall category of HCV RNA < LLOQ includes “< LLOQ TND” and “< LLOQ detected.”
For numerical HCV RNA data, values below LLOQ will be set to the LLOQ – 1 IU/mL 
(ie, 14 HCV RNA IU/mL). HCV RNA values returned as “No HCV RNA detected” will also be 
set to 14 IU/mL.
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data (eg, log10 scale) or nonparametric analysis 
methods may be used, as appropriate.
Natural logarithm transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma concentration values that are below the lower limit of quantitation (BLQ) 
will be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated 
as 0 for determination of summary and order statistics and will be excluded in any calculation of 
geometric means or ratios.
For the presentation of summary and order statistics, if at least 1 subject has a concentration 
value of BLQ for the time point, then the minimum value will be displayed as “BLQ” If more 
than 25% of the subjects have a concentration data value of BLQ for a given time point, then the 
minimum and Q1 values will be displayed as “BLQ” If more than 50% of the subjects have a 
concentration data value of BLQ for a given time point, then the minimum, Q1, and median 
values will be displayed as “BLQ” If more than 75% of the subjects have a concentration data 
value of BLQ for a given time point, then the minimum, Q1, median, and Q3 values will be 
displayed as “BLQ” If all subjects have concentration data values of BLQ for a given time point, 
then all order statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ”.
3.7.
Visit Windows
3.7.1.
Definition of Study Day
Study day is the day relative to the date of the first dose of study drug. Study Day 1 will be 
defined as the day of first dose of study drug administration.


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Study day will be calculated from the date of first dose of study drug administration and derived 
as follows:

For postdose study days: Assessment Date – First Dose Date + 1

For days prior to the first dose: Assessment Date – First Dose Date
The last dose date for an individual study drug will be the end date on study drug administration 
eCRF for the record where the “subject permanently discontinued” flag is ‘Yes’. The last dose 
date will be defined as the maximum of the last dose dates of individual study drugs in a 
treatment group.
If there are subjects for whom the date of last study drug is unknown due to the reason that the 
subject was lost to follow-up and not able to be contacted, the date of last dose will be estimated 
using the maximum of nonmissing study drug start or stop dates, visit dates and laboratory 
collection dates (posttreatment visits and unscheduled visits are not included).
3.7.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
In general, the baseline value will be the last nonmissing value on or prior to the first dose date 
of study drug. 
HCV RNA, vital signs, and safety laboratory data collected up to the last dose date + 2 days are 
considered to be on-treatment data and HCV RNA, vital signs and safety laboratory data 
collected after the last dose date + 2 days are considered posttreatment data. The analysis 
windows for on-treatment HCV RNA, vital signs and safety laboratory data are provided in 
Table 3-4.
Table 3-4.
Analysis Windows for On-treatment HCV RNA, Vital Signs and 
Safety Laboratory Data
Nominal Visit
LDV/SOF FDC 12 Weeks 
LDV/SOF FDC ± RBV 24 Weeks
Nominal Day
Lower Limit
Upper Limit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
1
(none)
1
Week 1
7
2
11
7
2
11
Week 2
14
12
21
14
12
21
Week 4
28
22
42
28
22
42
Week 8
56
43
70
56
43
70
Week 12
84
71
≥ 85
84
71
98
Week 16
NA
112
99
126
Week 20
140
127
154
Week 24
168
155
≥ 169


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Subjects who participated in the PK Lead-in Phase will immediately roll over into the Treatment 
Phase with no interruption of study drug administration until the appropriateness of the dose is 
confirmed by PK and safety data from the PK-Lead-in Phase. These subjects will start at the 
Week 2 visit of the Treatment Phase. Week 1 records for these subjects will be chosen from 
Day 10 in the PK Lead-in Phase.
HCV RNA, vital sign, and safety laboratory data collected after the last dose date + 2 days will 
be assigned to the posttreatment follow-up (FU) visits. Visit windows will be calculated from the 
last dose date (ie, FU Day = collection date minus the last dose date) as shown in Table 3-5.
Table 3-5.
Analysis Windows for Posttreatment HCV RNA, Body Weight, 
Height, Vital Sign and Safety Laboratory Data
Nominal 
FUa Visit
HCV RNA, Body weight and Height
Vital Signs and Safety Laboratory Datab
Nominal FU Day
Lower Limit
Upper Limit
Nominal FU Day
Lower Limit
Upper Limit
FU-4
28
21
69
28
3
30
FU-12
84
70
146
NA
NA
NA
FU-24
168
147
210
NA
NA
NA
a
FU-x visit = posttreatment Week-x follow-up visit.
b
Vital signs (blood pressure, pulse, respiratory rate, and temperature) and safety labs will only be summarized for the FU-4
visit (up to 30 days after last dose).
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. 
If multiple valid nonmissing numeric observations exist in an analysis window, records will be 
chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, average (arithmetic mean) will be used for the baseline value. 

For postbaseline visits: 
The record closest to the nominal day for that visit will be selected except for HCV RNA 
posttreatment follow-up visits, for which the latest record in the analysis window will be 
selected. 
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.


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If multiple valid nonmissing categorical observations exist in a window, records will be selected
as follows:

For baseline, the last available record on or prior to the date of the first dose of study drug
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, the value with the lowest severity will be selected (eg, normal will be selected over 
abnormal).

For postbaseline visits, follow the same rules described above for postbaseline numeric 
observations, except that if there are multiple records on the same day, the most conservative 
value will be selected (eg, abnormal will be selected over normal).


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by treatment group for each country, 
investigator within a country, and overall. The summary will present the number and percentage 
of subjects in the Safety Analysis Set. For each column, the denominator for the percentage 
calculation will be the total number of subjects analyzed for that column. 
A summary of subject disposition will be provided by treatment group. This summary will 
present the number of subjects screened, the number of subjects enrolled, the number of subjects 
enrolled but never treated, and the number and percentage of subjects in each of the categories 
listed below. For the “Treated” category, the denominator for the percentage calculation will be 
the total number of subjects enrolled for each column. For all other categories, the denominator 
for the percentage calculation will be the total number of subjects in the Safety Analysis Set for 
each column. 

Treated (Safety Analysis Set) 

In FAS

In PK Analysis Set

Completed study treatment

Did not complete study treatment with reasons for premature discontinuation of study 
treatment

Completed the study

Did not complete the study with reason for premature discontinuation of study
Among subjects who completed study treatment and who discontinued study treatment, the 
number and percentage of subjects will be summarized for:

Who had no HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 and 
thereafter)

Who had HCV posttreatment Week 4 assessment but no HCV posttreatment Week 12 
assessment and thereafter (With HCV FU-4 but No FU-12 and thereafter)
If a subject did not have any HCV RNA assessment ≥ 21 days after the last dose of any study 
drug (ie, lower bound of FU-4 visit for HCV RNA data), the subject is categorized as having 
“No HCV FU-4 and thereafter”. If a subject had the HCV FU-4 assessment but did not have any 
HCV RNA assessment ≥ 70 days after the last dose of any study drug (ie, lower bound of FU-12 
visit for HCV RNA data), the subject is categorized as having “With HCV FU-4 but No FU-12 
and thereafter”.


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In addition, the total number of subjects who were enrolled, and the number of subjects in each 
of the disposition categories listed above will be displayed in a flowchart.
The following by-subject listings will be provided by subject ID number in ascending order to 
support the above summary tables:

Disposition of subjects who complete study treatment and study

Disposition of subjects who did not complete study treatment and/or study with reasons for 
premature discontinuation of study drug and/or study

Lot number and kit ID (if applicable)
4.2.
Extent of Exposure
Extent of exposure to study regimen and individual study drug will be examined by assessing the 
total durations of study regimen and individual study drug exposure and the level of adherence to 
any study drug and individual study drug specified in the protocol. 
4.2.1.
Durations of Exposure to Study Regimen and Individual Study Drug
Total duration of exposure to study regimen will be defined as last dose date of any study drug 
minus first dose date of any study drug plus 1, regardless of any temporary interruptions in study 
drug administration, and will be expressed in weeks using up to 1 decimal place (e.g. 4.5 weeks).
Total duration of exposure to individual study drug will be defined as last dose date of individual 
study drug minus first dose date of individual study drug plus 1, regardless of any temporary 
interruptions in study drug administration.
The total durations of exposure to study regimen and individual study drug will be summarized 
using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) and using 
the number (ie, cumulative counts) and percentage of subjects exposed through the following 
time periods: Baseline (Day 1), Week 1 (Day 7), Week 2 (Day 14), Week 4 (Day 28), Week 8 
(Day 56), and Week 12 (Day 84) for all subjects and additionally Week 16 (Day 112), Week 20 
(Day 140), and Week 24 (Day 168) for subjects receiving 24 weeks of treatment. A 3-day
window is applied to the last planned on-treatment visit to match with the protocol-specified visit 
window. Summaries will be provided by treatment group for the Safety Analysis Set. 
4.2.2.
Adherence to Study Drug
The level of adherence to individual study drug will be assessed separately based on the total 
amount of individual study drug administered relative to the total amount of individual study 
drug prescribed. In this study, LDV/SOF FDC 90/400 mg tablets, LDV/SOF FDC 22.5/100 mg
tablets, and LDV/SOF 11.25/50 mg packets containing granules have been used. For RBV, both 
REBETOL capsules and REBETOL RBV oral solution could be used. Each capsule contains 
200 mg RBV and the oral solution contains 40 mg RBV per mL.


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Given the fact that multiple formulations of the study drug have been used in this study, the 
adherence will be calculated based on the amount of LDV/SOF FDC (mg) or RBV (mg) by the 
following formula:
100
  
baseline
at 
Prescribed
Drug
Study 
of
Amount 
Total
  
ed
Administer
Drug
Study 
of
Amount 
Total
(%)
Adherence
of
Level








Where the presumed total amount of study drug (mg) administered to a subject will be 
determined by the data collected on the drug accountability eCRF using the following formula:







Returned
(mg)
Drug
Study 
  
of
Amount 
Total
Dispensed
(mg)
Drug
Study 
  
of
Amount 
Total
ed
Administer
(mg)
Drug
Study 
of
Amount 
Total
Note: If calculated adherence is greater than 100%, the result will be set to 100%.
The total amount of prescribed LDV/SOF FDC (mg) for 12 weeks and 24 weeks are as follows:
Age Group and 
Body Weight 
LDV/SOF Daily Dose
Total Amount of LDV/SOF
Prescribed for 12 Weeks
Total Amount of LDV/SOF
Prescribed for 24 Weeks
12 to <18 years
any weight
490 mg/day
41160 mg
N/A*
6 to <12 years
any weight
245 mg/day
20580 mg
41160 mg
3 to <6 years 
weighing ≥17 kg
245 mg/day
20580 mg
N/A*
3 to < 6 years 
weighing <17 kg
183.75 mg/day
15435 mg
N/A*
*Note: No subject 12 to <18 or 3 to <6 years old was assigned to 24 weeks of treatment.


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For subjects infected with HCV GT3, RBV was prescribed by weight at baseline. The total 
amount of RBV (mg) prescribed for 24 weeks is as follows:
Body Weight 
kg (lbs.)
RBV Daily Dose
RBV Number of Capsules
Total Amount of RBV 
Prescribed for 24 Weeks
<47 (<103)
15 mg/kg/day
Use Oral Solution. Divided dose in 
the morning and evening.
2,520 mg/kg
47-49
(103-108)
600 mg/day
1 200-mg capsules A.M.
2 200-mg capsules P.M.
504 capsules (100800 mg)  
50-65
(110 – 143)
800 mg/day
2 200-mg capsules A.M.
2 200-mg capsules P.M.
672 capsules (134400 mg)
66-80
(145 – 176)
1000 mg/day
2 200-mg capsules A.M.
3 200-mg capsules P.M.
840 capsules (168000 mg)
81-105 (178-
231)
1200 mg/day
3 200-mg capsules A.M.
3 200-mg capsules P.M.
1,008 capsules (201600 mg)
>105 (>231)
1400 mg/day
3 200-mg capsules A.M.
4 200-mg capsules P.M.
1,176 capsules (235200 mg)
Note: Subjects with a body weight greater than or equal to 47 kg may utilize the RBV oral solution if necessary.
Weight reported as a decimal number was rounded to the whole number to determine the 
prescribed RBV dosage. For example, a subject weighing 49.5 kg fell into the 50-65 kg category 
and received 800 mg/day.
Subjects who prematurely discontinue study drug for lack of efficacy (ie, virologic failure) will 
have the total amount of study drug prescribed calculated up to the first date when virologic 
failure criteria were met. For virologic failure confirmed by 2 consecutive measurements the date 
of the first measurement will be used. If there are study drug bottles dispensed on or after the 
subject first met virologic failure criteria, these bottles will not be included in the calculation of 
adherence. If a bottle is dispensed and the bottle is returned empty, then the number of tablets 
returned will be entered as zero. If a bottle is dispensed but not returned (missing), the number of 
tablets taken from that bottle will be counted as zero.
Descriptive statistics for the level of adherence (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) with the number and percentage of subjects belonging to adherence categories 
(e.g. < 80%, ≥ 80 to < 90%, ≥ 90%) will be provided by treatment group for the Safety Analysis 
Set. No inferential statistics will be provided for duration of exposure and adherence to study 
drug. Categorical displays will be provided for the number of subjects who are at least 80% 
adherent to individual study drug and study regimen (ie, adherence is ≥ 80% for each of the 
study drugs). No inferential statistics will be provided. 
A separate by-subject listing of study drug administration and drug accountability will be 
provided by subject ID number (in ascending order) and visit (in chronological order).


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4.3.
Protocol Deviations
A summary of important protocol deviations will be provided by the Clinical Operations group 
for subjects in the Safety Analysis Set.
Subjects who received study drug other than their enrolled treatment assignment will be listed 
with the start and stop dates that they received incorrect study treatment.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by treatment 
group and total in each age group using descriptive statistics (n, mean, SD, median, Q1, Q3, 
minimum, and maximum) for age, and using the numbers and percentages of subjects for sex, 
race, and ethnicity. Age is calculated in years at the date of initial study drug administration. If a 
subject did not receive study drug after enrollment, the subject’s age will be calculated from the 
date that the subject signed the informed consent form. The summary of demographic data will 
be provided for the Safety Analysis Set.
In addition, for subjects 3 to < 6 years of age, demographic variables (ie, age, sex, race, and 
ethnicity) will be summarized by treatment group as defined in Table 3-3 and total.
A by-subject demographic listing will be provided by subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include:

weight in kg

height in cm

body mass index (BMI; in kg/m2)

HCV genotype (genotype 1 [further broken down to 1a, 1b, and other], genotype 3, genotype 
4, and other as applicable)

cirrhosis (presence, absence, unknown)

IL28B (CC, CT, TT) 

baseline HCV RNA (log10 IU/mL) as a continuous variable and as categories 
(< 800,000 IU/mL, ≥ 800,000 IU/mL)

baseline ALT (U/L) as a continuous variable and as categories (≤1.5 × ULN, > 1.5 × ULN)

estimated glomerular filtration rate (eGFR) using Schwartz Formula (mL/min/1.73m2)

prior treatment experience (treatment naïve, treatment experienced)

IFN eligibility (IFN-eligible, IFN-ineligible)


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
most recent response to prior HCV treatment (non-response, relapse/breakthrough, 
IFN-intolerant) for treatment experienced subjects

mode of HCV Infection

bone age in years

Tanner Stage 
Estimated Glomerular Filtration Rate (GFR) will be calculated using Schwartz Formula 
(mL/min/1.73m2) = k L/Scr [(k is a proportionality constant, for adolescent females ≥12 years 
old is 0.55; for adolescent males ≥ 12 years old is 0.70, and for children 3- <12 years old is 0.55); 
L is height in centimeters (cm); and Scr is serum creatinine (mg/dL)]
These baseline characteristics will be summarized by treatment group and total in each age group
using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for 
continuous variables and using the numbers and percentages of subjects for categorical variables. 
The summary of baseline characteristics will be provided for the Safety Analysis Set.
In addition, for subjects 3 to < 6 years of age, baseline characteristics will be summarized by 
treatment group as defined in Table 3-3 and total.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Swallowability Assessment for LDV/SOF Placebo Tablets
For subjects in the 12 to <18 and 6 to <12 age groups, swallowability of LDV/SOF placebo
tablets will be summarized using the numbers and percentages of subjects in each swallowability 
category (ie, Able to Swallow, Unable to Swallow). 
A by-subject listing of Swallowability of LDV/SOF FDC tablets will be provided by subject ID 
number in ascending order.
5.4.
Palatability of LDV/SOF Oral Granules
For subjects in any age group, dosed with granules, palatability will be assessed by numeric 
response marked on line between numbers 0-100 (higher scores indicate better taste).


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Palatability of LDV/SOF oral granules will be summarized using the numbers and percentages of 
subjects by age group in the following palatability categories:

Did Not Taste the Study Drug

Tasted the Study Drug:

Taste score > 60 to 100

Taste score 40 to 60

Taste score 0 to < 40
A by-subject listing of Palatability of LDV/SOF oral granules will be provided by subject ID 
number in ascending order.
5.5.
Medical History
General medical history (ie, conditions not specific to the disease being studied) data will be 
collected at screening and listed only. General medical history data will not be coded. A 
by-subject listing of disease-specific medical history will be provided by subject ID number 
(in ascending order) and medical history of abnormalities (in chronological order).


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6.
EFFICACY ANALYSES
6.1.
Key Efficacy Endpoint
6.1.1.
Definition of the Key Efficacy Endpoint
The key efficacy endpoint is SVR12 defined as HCV RNA < LLOQ (ie, < 15 IU/mL) 12 weeks 
after discontinuation of all study drugs in the FAS. The COBAS® AmpliPrep/COBAS®
TaqMan® HCV Test, v2.0 for use with the High Pure System will be used to measure HCV 
RNA.
6.1.2.
Analysis Methods for the Key Efficacy Endpoint
No inferential statistics will be provided for efficacy endpoints. No statistical comparison will be 
conducted.
The point estimates of SVR12 rate and 2-sided 95% exact CI based on Clopper-Pearson method 
will be provided for the SVR12 rate by treatment group and total in each age group
{Clopper 1934}.
6.1.3.
Subgroup Analysis of the Key Efficacy Endpoint
The point estimates of SVR12 rate and 2-sided 95% exact CIs based on Clopper-Pearson method 
will be provided for each treatment group within each subgroup specified in Section 3.4
{Clopper 1934}. 
A Forest plot will graphically present estimates and 95% confidence intervals of SVR12 rates for 
each treatment group within each subgroup.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include the following:

The percentage of subjects who attain SVR at 4 and 24 weeks after stopping therapy, defined 
as HCV RNA < LLOQ (ie, < 15 IU/mL) 4 and 24 weeks after stopping treatment (SVR 4 and 
SVR 24)

The percentage of subjects with HCV RNA below LLOQ by study visit

HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) through end 
of treatment (EOT)

The percentage of subjects with virologic failure as the following:


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


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For the SVR12 endpoint analysis, a summary table of the number and percentage of subjects 
with SVR12, virologic failure (VF), and Other will be created. All subjects who achieve SVR12 
will be categorized as SVR12. Virologic failure will be descriptively summarized as 
“on-treatment virologic failure” and relapse (which will be broken down by study drug 
completed yes/no). Subjects who do not achieve SVR12 and do not meet criteria for VF will be 
categorized as Other. The denominator for relapse will be the number of subjects who had 
HCV RNA < LLOQ on their last observed on-treatment HCV RNA measurement; otherwise, the 
denominator will be the number of subjects in the FAS. Additional summary table will be 
provided by treatment group defined in Table 3-3 for 3 to < 6 years of age subjects.
A concordance table between SVR12 and SVR24 will be provided by treatment group and total 
in each age group. Subjects with both observed SVR12 and observed SVR24 data will be 
included for this analysis.
In addition, a summary table of the number and percentage of subjects with HCV RNA < LLOQ 
and ≥LLOQ at the posttreatment follow-up visit (observed and imputed, with reasons for 
imputed) will be provided for each posttreatment follow-up visit. 95% Clopper-Pearson exact 
CIs will be presented for the overall proportion of subjects with HCV RNA < LLOQ.
Tables for ALT normalization by visit will use similar methodology to the analyses of HCV 
RNA < LLOQ, but will use a missing = excluded analysis. Only those subjects with ALT greater 
than the ULN range at baseline (defined as the last ALT value collected prior to first dose of 
study drug) will be included in the analysis of ALT normalization.
Drug resistant substitutions will be analyzed as part of the Virology Study Report.
6.3.
Exploratory Efficacy Endpoints
 
 
 
 
 
 
 
 
 
PPD


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6.4.
Changes From Protocol-Specified Efficacy Analyses
There are no changes from protocol-specified efficacy analyses. 
PPD


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using 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 provided in the 
AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria 
specified in the protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings and the most 
severe will be considered (for sorting purpose only) in data presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE eCRF to the 
question of “Related to Study Treatment”. Events for which the investigator did not record 
relationships to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing from that captured on the 
CRF.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE specified in the study protocol. Serious adverse events captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead Pharmacovigilance and 
Epidemiology Department before database finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment Emergent
Treatment-emergent adverse events (TEAEs) are defined as one or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete, then the month and year (or year alone if month is not 
recorded) of onset determine whether an AE is treatment emergent, as long as the AE stop date is 
not prior to the first dose date of study drug. The event is considered treatment emergent if both
of the following 2 criteria are met:

The AE onset and end dates are the same as or after the month and year (or year) of the first 
dose date of study drug

The AE onset date is the same as or before the month and year (or year) of the 30th day after
the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dose date of study drug, will be considered to be treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
A brief high-level summary of TEAEs will be provided by treatment group and by the number 
and percentage of subjects who had the following: any AE; any AE of Grade 3 or above; any AE 
of Grade 2 or above; any treatment-related AE; any treatment-related AE of Grade 3 or above; 
any treatment-related AE of Grade 2 or above; any SAE; any treatment-related SAE; any AE that 
led to premature discontinuation of any study drug; any AE that led to premature discontinuation 
of all study drugs; any AE that led to premature discontinuation of LDV/SOF FDC; any AE that 
led to premature discontinuation of RBV; any AE that led to modification or interruption of any 
study drug; any AE that led to interruption of LDV/SOF FDC; any AE that led to modification or 
interruption of RBV. All deaths (including those that are treatment emergent and those that are 
not treatment emergent) observed during the study will also be summarized and included in this 
table. Additionally, for subjects 3 to < 6 years of age, a brief high-level summary of TEAEs will 
be provided by treatment group defined Table 3-3.
Adverse event summaries will provide the number and percentage of subjects with TEAEs by 
SOC and PT, by treatment group based on the Safety Analysis Set as follows:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs


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
All treatment-related SAEs 

AEs leading to premature discontinuation of any study drug

AEs leading to premature discontinuation of all study drugs

AEs leading to premature discontinuation of LDV/SOF FDC

AEs leading to premature discontinuation of RBV

AEs leading to modification or interruption of any study drug

AEs leading to interruption of LDV/SOF FDC

AEs leading to modification or interruption of RBV
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and then by PT in order of descending
incidence of the pooled treatment groups within each SOC. In summaries by severity grade, the 
most severe grade will be used for those AEs that occurred more than once in an individual 
subject during the study. 
In addition to the above summary tables, TEAEs will be summarized by PT only, in order of 
descending incidence within the pooled treatment groups for:

AEs that occurred in at least 5% of subjects within any treatment group

AEs of Grade 3 or above

All treatment-related AEs

All SAEs

AEs leading to premature discontinuation of any study drug

AEs leading to premature discontinuation of all study drugs

AEs leading to premature discontinuation of LDV/SOF FDC

AEs leading to premature discontinuation of RBV

AEs leading to modification or interruption of any study drug

AEs leading to interruption of LDV/SOF FDC

AEs leading to modification or interruption of RBV


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In addition to the by-treatment summaries described above, data listings will be provided for the 
following:

All AEs (with a variable indicating whether the event is treatment emergent)

AEs of Grade 3 or above

SAEs

Deaths

AEs leading to premature discontinuation of any study drug

AEs leading to modification or interruption of any study drug
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days
for subjects who have permanently discontinued study drug or all available data at the time of the 
database snapshot for subjects those who were ongoing at the time of an interim analysis. The 
analysis will be based on values reported in conventional units. When values are below the limit 
of quantitation, they will be listed as such, and the closest imputed value will be used for the 
purpose of calculating summary statistics. For example, if “< 0.2” was recorded, a value of 0.1 
will be used for the purpose of calculating summary statistics; if “< 0.1” was recorded, a value of 
0.09 will be used for the purpose of calculating summary statistics.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
flagged in the data listings, as appropriate.
No inferential statistics will be generated.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
by treatment group for ALT, AST, total bilirubin, alkaline phosphatase, hemoglobin, 
reticulocytes, white blood cell (WBC), neutrophils, lymphocytes, platelets, and INR as follows:

Baseline values

Values at each postbaseline analysis window

Change from baseline at each postbaseline analysis window


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A baseline laboratory value will be defined as the final assessment performed on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
will be displayed to the reported number of digits; SD to the reported number of digits plus 1.
Median (Q1, Q3) of the observed values for these laboratory parameters will be plotted using a 
line plot by treatment group and visit. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3 (Selection of Data in the Event of Multiple Records in a Window). 
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used for assigning toxicity grades to laboratory results for analysis as Grade 0, Grade 1, Grade 2, 
Grade 3, or Grade 4. Grade 0 includes all values that do not meet the criteria for an abnormality 
of at least Grade 1. Some laboratory tests have criteria for both increased and decreased levels; 
analyses for each direction (ie, increased, decreased) will be presented separately. 
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug, or all 
available data in the database snapshot for subjects who were still on treatment at the time of an 
interim analysis. If the relevant baseline laboratory value is missing, then any abnormality of at 
least Grade 1 will be considered treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by analyte and treatment group; subjects will be categorized 
according to the most severe postbaseline abnormality grade for a given analyte:

Graded laboratory abnormalities

Grade 3 or above laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dose for the laboratory parameter of 
interest.
A by-subject listing of treatment-emergent Grade 3 or above laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the analyte of interest, with all applicable 
severity grades or abnormal flags displayed.


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7.2.2.3.
On-Treatment Liver-Related Laboratory Events
The following liver-related laboratory events will be summarized using data from all the 
on-treatment postbaseline visits (up to 2 days after the last dose of any study drug):

Aspartate aminotransferase (AST) or ALT > 3 × ULN and total bilirubin > 2 × ULN

ALT > 5 × ULN

Total bilirubin > 2 × ULN
For the composite criterion of AST or ALT and total bilirubin, AST or ALT and total bilirubin 
must meet the specified cut-offs at a given postbaseline time point; subjects will be counted once 
when the criterion is met. The denominator will be the number of subjects in the Safety Analysis 
Set with at least 1 postbaseline value of AST or ALT and total bilirubin at the same time point. 
For individual laboratory tests, subjects will be counted once based on the most severe 
postbaseline values when the criterion is met. The denominator will be the number of subjects in 
the Safety Analysis Set with at least 1 nonmissing postbaseline value for the test. A listing will 
be provided including ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, HCV 
RNA (log10) and yes/no flag for subjects meeting at least 1 of the 3 criteria. All the available data 
for the subjects will be listed.
7.3.
Vital Signs
Vital signs (systolic and diastolic blood pressure [mmHg], pulse [beats/min]) at each visit, and 
change from baseline at each visit will be summarized for the Safety Analysis Set using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) by treatment 
group. The baseline value will be defined as the last available value collected on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the postbaseline value minus the baseline value.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3 (Selection of Data in the Event of Multiple Records in a Window). No 
inferential statistics will be generated.
A by-subject listing of vital signs (systolic and diastolic blood pressure [mmHg], pulse 
[beats/min], respiration [breaths/min], and body temperature [°C]) will be provided by subject ID 
number and visit in chronological order. 
7.4.
Body Weight, Height and BMI
An age- and sex-specific percentile will be derived for each weight, height and BMI measurement 
according to the downloadable SAS program available on the Centers for Disease Control (CDC) 
website using the year 2000 growth charts. Methods and SAS program published on the following 
CDC website will be applied to calculate the percentile {Centers for Disease Control and 
Prevention (CDC) 2016a, Centers for Disease Control and Prevention (CDC) 2016b}.


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Body weight, height, BMI and percentiles for body weight, height, BMI at each visit, and change 
from baseline at each visit will be summarized for the Safety Analysis Set using descriptive 
statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) by treatment group. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3 (Selection of Data in the Event of Multiple Records in a Window). No 
inferential statistics will be generated.
A by-subject listing of body weight, weight percentile, height, height percentile, BMI and BMI 
percentile will be provided by subject ID number and visit in chronological order.
7.5.
Mid-Parental Height Assessment
The calculation of mid-parental height has been a standard procedure for assessing individual 
child’s future adult height since it was first described by Tanner {Tanner 1970}. Mid-parental 
height was calculated as the average of father's and mother's height. For boys, calculate the 
sex-adjusted mid-parental height by adding 2.5 inch or 6.5 cm from the mean of the parents' 
heights. For girls, subtract 2.5 inch or 6.5 cm from the mean of the parents' heights. If any one of 
parents’ heights is missing, the calculation will be excluded.
A by-subject listing of parents’ heights and derived mid-parental height will be provided by 
subject ID number in ascending order.
7.6.
Bone Age Assessment
A single X-ray of the left wrist, hand, and fingers will be performed at Day 1 Visit and
post-treatment Week 24. Local radiologist will determine the bone age from x-ray.
Bone age at baseline visit, FU-24 visit and change from baseline visit will be summarized for the 
Safety Analysis Set using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by treatment group. 
A by-subject listing of bone age will be provided by subject ID number in ascending order and 
visit in chronological order.
7.7.
Tanner Pubertal Stage Assessment
The Tanner stages will be used to evaluate the onset and progression of pubertal changes. 
Females will be rated for pubic hair growth and breast development, and males will be rated for 
pubic hair growth and genitalia development. If the subject is at a Tanner 5 at Day 1, no further 
Tanner Pubertal Stage Assessments are to be completed. The Tanner stages (Pubic Hair and 
Breasts for female; Pubic Hair and Genitalia for male) at EOT, FU-12 and FU-24 visit will be 
summarized by baseline Tanner stages using frequency count and percentage by sex overall and 
by sex within each treatment group.


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7.8.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version
of the World Health Organization (WHO) Drug dictionary. The medications will be categorized 
as prior or concomitant using the following definitions:

Prior medications: any medications taken and stopped prior to or on the date of first study 
drug administration

Concomitant medications: any medications taken after the date of first study drug 
administration and up to the last dosing date of study drug
Concomitant medications will be summarized by preferred name using the number and 
percentage of subjects for each treatment group. A subject reporting the same medication more 
than once will be counted only once when calculating the number and percentage of subjects 
who received that medication. The summary of concomitant medications will be ordered by 
preferred term in descending frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
Summaries will be based on the Safety Analysis Set. No inferential statistics will be generated. 
For purposes of analysis, any medication with a stop date that is on or prior to the initial study 
drug dosing date or a start date that is after the last study drug dosing date will be excluded from 
a concomitant medication summary. If a partial stop date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) prior to the initial 
study drug dosing date will be excluded from the concomitant medication summary. If a partial 
start date is entered, then any medication with the month and year (if day is missing) or year (if 
day and month are missing) after the study drug stop date will be excluded from the concomitant 
medication summary. Medications with completely missing dates will be included in the 
concomitant medication summary.
A summary of prior medications will not be provided.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.9.
Other Safety Measures
A data listing will be provided for subjects who become pregnant during the study.
7.10.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
8.1.
PK Analysis in the PK Lead-in Phase (Intensive PK Analysis)
Intensive PK Analysis will be performed using the PK Lead-in Phase Intensive PK Analysis Set.
Concentrations of SOF, GS-331007 and LDV from subjects in the PK lead-in Phase over 
sampling time will be listed and summarized using descriptive statistics (n, arithmetic mean, 
geometric mean and its 95% confidence interval, coefficient of variation [%CV], SD, median, 
Q1, Q3, minimum, and maximum) by nominal time and cohort. For Cohorts 1 and 2, plasma 
samples will be collected for PK analyses following dosing of study drugs on Day 10 at the 
following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, and 12 hours postdose. For Cohort 3, 
plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 
2, 4, 8, and 12 hours postdose. PK parameters from subjects in the PK lead-in Phase will be 
summarized (e.g; AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau, T1/2, volume of distribution and 
clearance, as appropriate) by cohort.
To confirm the appropriateness of LDV/SOF FDC dose for each age group, PK parameters for 
SOF, GS-331007 and LDV will be compared between each age group from this study and the 
LDV/SOF FDC NDA patient population (which includes population-PK derived PK exposure 
data from adult Phase 2 and 3 studies) by carrying out an analysis of variance (ANOVA) for log-
transformed AUCtau of GS-331007 and LDV as the primary endpoint and Cmax of GS-331007 
and LDV as a secondary endpoint. Geometric Mean Ratio and its 90% confidence interval will 
be provided.
8.2.
Population PK Analysis
Population PK modeling will be applied on the combined data from both intensive PK samples 
collected in PK Lead-in Phase and sparse PK samples collected in the Treatment Phase to 
characterize the pharmacokinetics of SOF, GS-331007 and LDV using mixed-effect modeling 
techniques. Estimated PK parameters using the population PK model will be presented in a 
separate Population PK report.


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9.
REFERENCES
Centers for Disease Control and Prevention (CDC). Division of Nutrition, Physicial Activity, and 
Obesity> Nutrition: Growth Chart Training: A SAS Program for the 2000 CDC 
Growth Charts (ages 0 to <20 years). Available at: 
http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm.  2016a.
Centers for Disease Control and Prevention (CDC). Division of Nutrition, Physicial Activity, and 
Obesity> Nutrition: Growth Chart Training: Other Growth Chart Resources. 
Available at: 
http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/index.htm.  2016b.
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Dec. Biometrika 1934;26 (4):pp. 404-13.
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of disease 
in childhood 1969;44 (235):291-303.
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of 
disease in childhood 1970;45 (239):13-23.
Tanner JM, Goldstein H, Whitehouse RH. Standards for Children's Height at Ages 2-9 Years 
Allowing for Height of Parents. Archives of disease in childhood 1970;45:755-62.


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


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


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12.
APPENDICES
Appendix 1.
Study Procedures Table
Appendix 2.
Tanner Stages*
Appendix 3.
PedsQL™ Score Calculation Algorithms


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Appendix 1.
Study Procedures Table
Appendix Table 1.
PK Lead-in Phase: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X j
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Vital Signsa
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study Medication Compliance
X
X
Study Drug Dispensingb
X
Subject Dosing Diary
X
X
X


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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
Viral Sequencing c
X
X
X
Serum or Urine Pregnancy Testinge
X
X
X
Urinalysis
X
X
X
Urine Drug Screen
X
Intensive PK
X d
HCV Genotyping, IL28B
X
HCV antibody, HIV antibody, HBs antigen, HBs 
antibody, HBc antibody, and HAV antibody
X
HbA1c
X
TSH
X
Alpha fetoprotein
X
Alpha-1 anti-trypsin
X
HBV DNAk
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, body weight, and height
b
Day 1 assessments must be performed prior to dosing 
c
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
d
For Cohorts 1 and 2, plasma samples will be collected for PK analyses following dosing of study drug on Day 10 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours post-dose.
PPD


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e
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test. 
f
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status). 
g
h
Swallowability, for subjects on tablet formulation, can occur at Day 1 if not completed during screening.
i
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
j
Parental height will be collected (if available)
k
Only subjects HBcAb positive at Screening
PPD


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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
Xi
Complete Physical Examination
X
X
Xj
X
X
Symptom-Directed Physical Examination
X
X
X
X
Xk
X
X
Tanner Pubertal Stage Assessment
X
Xj
X
X
Vital Signsa
X
X
X
X
X
X
X
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling g
X
Xj
X
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey e
X
Xj
X
X
Review of Study Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xk
X
X
Palatability Assessment of Oral Granules as 
applicable
X
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
X
X
X
X
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
X
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X


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Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early Termination
Serum or Urine Pregnancy Testingl
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Urine Drug Test
X
HCV Genotyping, IL28B
X
HCV antibody, HIV antibody, HBs antigen, 
HBs antibody, HBc antibody, and HAV antibody
X
HbA1c
X
TSH
X
Xj
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
HBV DNAm
X
X
X
X
X
X
X
X
Single PK collected at any time point
X
X
X
X
X
X
X
Single PK Sample collected between 15 minutes 
to 4 hours post-dosen
X
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, and body weight and height
b
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
c
Subjects rolling over from PK Lead-in phase will not be required to repeat screening, Day 1 or Week 1 visits during the on Treatment Phase  
d
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
e
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
f
g
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
h
Swallowability, for subjects on tablet formulation, can occur at Day 1 if not completed during screening.
i
Parental height will be collected (if available) 
PPD
PPD
PPD


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j
Subjects on 12 Week Treatment regimen only
k
Subjects on 24 Week Treatment regimen only
l
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test
m
Only subjects with positive HBcAb at Screening
n
A single PK sample will be collected at Weeks 4 and 8 between 15 minutes to 4 hours post dose as applicable, 
 
 
o
 
PPD
PPD


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Appendix Table 3.
Treatment Phase: Post Treatment Visits Following Primary Study
4 Weeks Post Treatment
12 Weeks Post Treatment
24 Weeks Post Treatment
Clinical Assessments
Vital Signs, Body weight and Height
X
X
X
Symptom-directed Physical Exam
X
X
X
AEs
X
Xc
Xc
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counselingd
X
Xf
Xf
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Test
X
Xe
Xe
HBV DNAg
X
X
X
a
Quality of life survey will be completed by all subjects at 12-Week and 24-Week Post Treatment visits if a site is approved to use the survey.  Subject is to review 
questionnaire with a parent/guardian and write/mark answers directly onto the questionnaire.
b
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
c
At Post Treatment Week 12 and 24, only SAEs will be captured
d
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
e
GT-3 subjects only: Female subjects of childbearing potential should be provided with Urine Pregnancy Test Kits, instructed on their use and requested to continue to 
self-monitor for pregnancy for 6 months after their last dose of RBV. If required by regulations, additional pregnancy tests beyond 6 months may be added. The subject 
should be contacted every 4 weeks and asked to report results of the urine pregnancy tests. If a positive urine pregnancy test is reported, the subject should return to the clinic 
for a serum pregnancy test. 
f
GT-3 subjects only
g
Only subjects HBcAb positive at Screening


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Appendix 2.
Tanner Stages*
1. Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2. Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of testes and scrotum and increased darkening of 
scrotal skin (13.5-15)
Tanner V
Genitalia adult in size and shape
3. Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen 
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with 
surrounding breast 
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V 
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. 
*
Chart referenced from Marshall WA, Tanner JM, variations in the pattern of pubertal changes in boys and girls {Marshall 1969, Marshall 1970}


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Appendix 3.
PedsQL™Score Calculation Algorithms
The Parent Report for Toddlers (ages 2-4) and the Child & Parent Reports for Young 
Children (ages 5-7), Children (ages 8-12) and Teens (ages 13-18) of the PedsQL™4.0 SF15 
Generic Core Scales are composed of 15 items comprising 4 dimensions.
DESCRIPTION OF THE SF15 QUESTIONNAIRE:
Dimensions
Number of Items
Cluster of Items
Reversed Scoring
Direction of Dimensions
Physical Functioning
5
1-5
1-5
Higher scores indicate 
better HRQOL
Emotional Functioning
4
1-4
1-4
Social Functioning
3
1-3
1-3
School Functioning
3
1-3
1-3
SCORING OF DIMENSIONS:
Item Scaling
5-point Likert scale from 0 (Never) to 4 (Almost always)
3-point scales: 0 (Not at all), 2 (Sometimes) and 4 (A lot) for the Young Child 
self-report
Weighting of Items
No
Extension of the Scoring 
Scale
Scores are transformed on a scale from 0 to 100
Scoring Procedure
Step 1: Transform Score
Items are reversed scored and linearly transformed to a 0-100 scale as follows:
0=100, 1=75, 2=50, 3=25, 4=0.
Step 2: Calculate Scores
Score by Dimensions:

If more than 50% of the items in the scale are missing, the scale scores should 
not be computed,

Mean score = Sum of the items over the number of items answered.
Psychosocial Health Summary Score = Sum of the items over the number of items 
answered in the Emotional, Social, and School Functioning Scales.
Physical Health Summary Score = Physical Functioning Scale Score
Total Score: Sum of all the items over the number of items answered on all the Scales.
Interpretation and 
Analysis of Missing Data
If more than 50% of the items in the scale are missing, the Scale Scores should not 
be computed.

Prot_006.pdf: 
Study Title: 
Sponsor: 
IND No.: 
EudraCT Number: 
Indication: 
Protocol ID: 
Gilead Sciences 
Medical Monitor and 
Study Director: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-coh01i Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed 
Dose Combination+/- Ribavirin in Adolescents and Children with 
Chronic HCV-Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
115268 
2014-003578-17 
Hepatitis C Vims Infection 
GS-US-337-1116 
Name: 
Benedetta Massetto, MD 
rpo 
rpo 
I"'U 
Telephone: 
Fax: 
E-mail: 
Original: 
10 July 2014 
Amendment 1.0: 08 October 2014 
Amendment 2.0: 08 December 2014 
Amendment 2.1: 09 Janmuy 2015 (United Kingdom Only) 
Amendment 2.2: 01 April 2015 (United Kingdom Only) 
Amendment 3.0: 28 May 2015 
Amendment 4.0: 15 March 2016 
Amendment 5.0: 04 November 2016 
Amendment 6.0: 08 Jlme 2017 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmiicularly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Bom·d or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 2
08 June 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................19
1.
INTRODUCTION ..............................................................................................................................................22
1.1.
Background ............................................................................................................................................22
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................23
1.2.1.
Summary of Additional Clinical Experience with Ledipasvir/Sofosbuvir 
Fixed-Dose Combination .....................................................................................................23
1.3.
Ribavirin (RBV).....................................................................................................................................30
1.4.
Rationale for the Current Study .............................................................................................................30
1.5.
Rationale for Dose Selection of LDV/SOF FDC ...................................................................................31
1.6.
Overall Risk/Benefit Assessment...........................................................................................................34
2.
OBJECTIVES.....................................................................................................................................................35
3.
STUDY DESIGN................................................................................................................................................36
3.1.
Treatment Plan and Regimen .................................................................................................................36
3.1.1.
PK Lead-in Phase.................................................................................................................36
3.1.2.
Treatment Phase ...................................................................................................................37
3.2.
Visit Schedule ........................................................................................................................................39
3.2.1.
PK Lead-in ...........................................................................................................................39
3.2.2.
Treatment Phase ...................................................................................................................40
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................40
3.4.
Treatment Discontinuations Criteria ......................................................................................................41
3.5.
Discontinuations.....................................................................................................................................41
3.6.
Optional Intensive Pharmacokinetics Substudy.....................................................................................41
3.7.
Pharmacogenomics Substudy.................................................................................................................41
3.8.
Long-Term Follow-Up...........................................................................................................................42
3.9.
Breakthrough Futility Assessment .........................................................................................................42
3.10.
Reconsent...............................................................................................................................................42
4.
SUBJECT POPULATION..................................................................................................................................43
4.1.
Number of Subjects and Subject Selection ............................................................................................43
4.2.
Inclusion Criteria....................................................................................................................................43
4.3.
Exclusion Criteria...................................................................................................................................44
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................46
5.1.
Randomization and Blinding..................................................................................................................46
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................46
5.2.1.
Description and Handling.....................................................................................................46
5.2.2.
Storage and Handling...........................................................................................................48
5.2.3.
Dosage and Administration of LDV/SOF FDC ...................................................................48
5.3.
Ribavirin (GT-3 Subjects Only).............................................................................................................49
5.3.1.
Description and Handling of RBV .......................................................................................49
5.3.2.
Dosage and Administration of RBV (GT-3 Subjects Only).................................................50
5.4.
Co-administration of LDV/SOF FDC and RBV (GT-3 Subjects Only).................................................50
5.5.
Study Drug Compliance.........................................................................................................................51


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5.6.
Prior and Concomitant Medications.......................................................................................................51
6.
STUDY PROCEDURES ....................................................................................................................................53
6.1.
Subject Enrollment.................................................................................................................................53
6.2.
Screening Assessments ..........................................................................................................................53
6.2.1.
Screening Visit (Day –28 to Day 0) .....................................................................................53
6.3.
PK Lead-in: Treatment Assessments .....................................................................................................55
6.3.1.
Day 1 ....................................................................................................................................55
6.3.2.
Day 3 ....................................................................................................................................56
6.3.3.
Day 10 – Intensive PK..........................................................................................................56
6.4.
Treatment Phase: Treatment Assessments .............................................................................................58
6.4.1.
Day 1 ....................................................................................................................................58
6.4.2.
Weeks 1 and 2 (± 3 days) .....................................................................................................60
6.4.3.
Weeks 4 and 8 (± 3 days) .....................................................................................................60
6.4.4.
Week 12 (± 3 days) - Subjects on 12 Week Treatment Regimen Only................................61
6.4.5.
Week 12 (± 3 days) - Subjects on 24 Week Treatment Regimen Only................................62
6.4.6.
Week 16 and 20 (± 3 days) – Subjects on 24 Week Treatment Regimen 
Only......................................................................................................................................63
6.4.7.
Week 24 (± 3 days) – Subjects on 24 Week Treatment Regimen Only ...............................63
6.4.8.
Optional Intensive Pharmacokinetics (PK) Substudy...........................................................64
6.4.9.
Unscheduled Visit/Early Termination Visit .........................................................................66
6.5.
Post-Treatment Assessments..................................................................................................................67
6.5.1.
4-Week Post-Treatment Visit (± 5 days)..............................................................................67
6.5.2.
12-Week Post-Treatment Visit (± 5 days)............................................................................68
6.5.3.
24-Week Post-Treatment Visit (± 5 days)............................................................................69
6.6.
Procedures and Specifications................................................................................................................69
6.6.1.
Clinical Laboratory Analytes ...............................................................................................69
6.6.2.
Medical History....................................................................................................................70
6.6.3.
Complete Physical Examination...........................................................................................70
6.6.4.
Tanner Pubertal Stage Assessment.......................................................................................70
6.6.5.
Height & Weight Measurement............................................................................................71
6.6.6.
Bone Age Assessment..........................................................................................................71
6.6.7.
Acceptability Assessment.....................................................................................................71
6.6.8.
Vital Signs............................................................................................................................71
6.6.9.
Estimated Glomerular Filtration Rate (GFR) .......................................................................71
6.6.10.
Viral Sequencing (Archive)..................................................................................................72
6.6.11.
Pregnancy Testing................................................................................................................72
6.6.12.
Quality of Life Survey (PedsQL™) .....................................................................................72
7.
TOXICITY MANAGEMENT............................................................................................................................73
7.1.
Modification of Dose/Schedule Due to Toxicity....................................................................................73
7.2.
Subject Stopping Rules for LDV/SOF FDC and RBV...........................................................................73
8.
ADVERSE EVENTS MANAGEMENT ............................................................................................................74
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................74
8.1.1.
Adverse Events.....................................................................................................................74
8.1.2.
Serious Adverse Events........................................................................................................74
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................75
8.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................75
8.2.1.
Assessment of Causality for Study Drug and Procedures ....................................................75
8.2.2.
Assessment of Severity ........................................................................................................76
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................76


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8.4.
Gilead Reporting Requirements.............................................................................................................78
8.5.
Special Situations Reports......................................................................................................................78
8.5.1.
Definitions of Special Situations..........................................................................................78
8.5.2.
Instructions for Reporting Special Situations.......................................................................79
9.
STATISTICAL CONSIDERATIONS................................................................................................................81
9.1.
Analysis Objectives and Endpoints........................................................................................................81
9.1.1.
Analysis Objectives..............................................................................................................81
9.1.2.
Primary Endpoints................................................................................................................82
9.1.3.
Secondary Endpoints............................................................................................................82
9.2.
Analysis Conventions.............................................................................................................................82
9.2.1.
Analysis Sets ........................................................................................................................82
9.2.2.
Data Handling Conventions .................................................................................................83
9.2.3.
Interim Analysis ...................................................................................................................84
9.3.
Demographic Data and Baseline Characteristics ...................................................................................84
9.4.
Pharmacokinetic Analysis......................................................................................................................85
9.5.
Safety Analysis.......................................................................................................................................86
9.5.1.
Extent of Exposure...............................................................................................................86
9.5.2.
Adverse Events.....................................................................................................................87
9.5.3.
Laboratory Evaluations ........................................................................................................88
9.5.4.
Other Safety Evaluations......................................................................................................88
9.6.
Efficacy Analysis ...................................................................................................................................88
9.6.1.
Key Efficacy Analysis..........................................................................................................88
9.6.2.
Secondary Efficacy Analysis................................................................................................88
9.6.3.
Subgroup Analysis ...............................................................................................................89
9.7.
Quality of Life Analysis.........................................................................................................................89
9.8.
Acceptability ..........................................................................................................................................89
9.9.
Data Monitoring Committee ..................................................................................................................89
9.10.
Sample Size............................................................................................................................................90
10.
RESPONSIBILITIES..........................................................................................................................................91
10.1.
Investigator Responsibilities ..................................................................................................................91
10.1.1.
Good Clinical Practice..........................................................................................................91
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................91
10.1.3.
Informed Consent/Assent.....................................................................................................92
10.1.4.
Confidentiality......................................................................................................................92
10.1.5.
Study Files and Retention of Records ..................................................................................92
10.1.6.
Case Report Forms...............................................................................................................94
10.1.7.
Drug Accountability.............................................................................................................94
10.1.8.
Inspections............................................................................................................................94
10.1.9.
Protocol Compliance............................................................................................................94
10.2.
Sponsor Responsibilities ........................................................................................................................95
10.2.1.
Protocol Modifications.........................................................................................................95
10.2.2.
Study Report and Publications .............................................................................................95
10.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................95
10.3.1.
Access to Information for Monitoring..................................................................................95
10.3.2.
Access to Information for Auditing or Inspections ..............................................................96
10.3.3.
Study Discontinuation..........................................................................................................96
11.
REFERENCES ...................................................................................................................................................97
12.
APPENDICES ..................................................................................................................................................100


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Appendix 1.
Investigator Signature Page..................................................................................................101
Appendix 2.
Study Procedures Table........................................................................................................102
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............108
Appendix 4.
Tanner Stages* .....................................................................................................................130
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................131
LIST OF IN-TEXT TABLES
Table 1-1.
Statistical Comparison of Pharmacokinetic Parameters for Formulation Comparison 
- Test versus Reference Treatments (Primary PK analysis Set) .............................................26
Table 1-2.
Statistical Comparison of Pharmacokinetic Parameters for Food Effect Comparison 
- Test versus Reference Treatments (Primary PK analysis Set) .............................................27
Table 1-3.
Steady-state PK and Statistical Comparisons of LDV, SOF and GS-331007 PK in 
Adolescent Subjects (PK Lead-in) and Adult Subjects (Phase 2/3 Population PK 
Analysis).................................................................................................................................29
Table 1-4.
Steady-state PK and Statistical Comparisons of LDV, SOF and GS-331007 PK in 
Pediatric Cohort 2 Subjects (6 to <12 years old; PK Lead-in) and Adult Subjects 
(Phase 2/3 Population PK Analysis).......................................................................................29
Table 3-1.
Subject Enrollment by HCV Genotype, Country, and Treatment Duration ...........................38
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................52
Table 7-1.
RBV Dose Reduction Guidelines...........................................................................................73
Table 9-1.
GS-331007, SOF, and LDV PK Parameters after Once-Daily Administration of 
LDV/SOF FDC in HCV-Infected Adults Subjects (Population PK Analysis from 
Phase 2 and 3 Studies)............................................................................................................86
LIST OF IN-TEXT FIGURES
Figure 1-1.
Predicted LDV, SOF, and GS-331007 AUCtau following administration of 
LDV/SOF FDC 45 mg/ 200 mg or LDV/SOF FDC 33.75 mg/ 150 mg (3 to < 6 
years of age) ...........................................................................................................................33
Figure 3-1.
PK Lead-in Phase Study Schema ...........................................................................................37


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc. 
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed 
Dose Combination +/- Ribavirin in Adolescents and Children with 
Chronic HCV Infection
IND Number:
EudraCT Number:
115268
2014-003578-17
Study Centers:
Approximately 30 sites in the United States, Europe, Australia, and 
New Zealand
Number of Subjects:
Approximately 220 subjects
Target Population:
Adolescents and children (aged 3 to < 18 years) chronic hepatitis C 
virus (HCV) infection
Treatment Duration:
PK Lead-in – 10 days
Treatment Phase – 12 or 24 weeks
Objectives:
The primary objective of the PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm 
the dose of LDV/SOF FDC in chronic HCV-infected pediatric 
subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 
10 days of dosing of LDV/SOF FDC in chronic HCV infected 
pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV 
for 12 or 24 weeks in chronic HCV -infected pediatric subjects. 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
Final 
Amendment 6.0 
The seconda!y objectives of the Treatment Phase ofthis study are: 
• 
To detennine the antiviral efficacy of 12 or 24 weeks of 
LDV/SOF FDC +/- RBV u·eatment in chronic HCV infected 
subjects (including the impact of HCV genotype, IL28B 
genotype, and prior u·eatment experience), as assessed by the 
prop01iion of subjects with sustained virological response (SVR) 
12 weeks after completion ofu·eatment (SVR12) 
• 
To determine the antiviral efficacy of 12 or 24 weeks of 
LDV/SOF FDC +/- RBV u·eatment in chronic HCV -infected 
subjects, as assessed by the prop01iion of subjects with SVR 4 and 
24 weeks after completion ofu·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during 
u·eatment and after completion of u·eatment 
• 
To evaluate acceptability assessed by swallowability of tablets 
and palatability of granules 
• 
To evaluate the emergence of viral resistance to LDV and SOF 
during u·eatlnent and after completion of u·eatment 
• 
To evaluate the effect of growth and development on pediau·ic 
subjects during and after u·eatment 
The explorat01y objective of this study is: 
• 
PD 
Open-label, multi-coh01i, two-patt study evaluating the PK, safety, 
and antiviral activity ofLDV/SOF FDC +/- RBV in chronic 
HCV -infected pediau·ic subjects. 
The study commenced with GT-1 , -3 and -4 HCV-infected pediau·ic 
subjects. Subjects with GT-5 and -6 are cunently eligible for 
inclusion into actively emolling groups/coh01is following the 
demonsu·ation ofbenefit:risk in the adult population. Subjects with 
GT-2 will be included once adult data m·e available, if appropriate. 
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Gilead Sciences, Inc.
Amendment 6.0
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PK Lead-in Phase: PK Lead-in will evaluate and/or confirm age 
appropriate LDV/SOF FDC doses by analyzing PK, safety, and 
antiviral activity of LDV/SOF FDC through 10 days of dosing for 
each of the three cohorts. Children aged 3 to < 6, children aged 
6 to < 12 years, and adolescents aged 12 to < 18 years with evidence 
of chronic HCV and HCV RNA ≥1000 IU/mL at study entry will be 
evaluated. Subjects must be treatment naïve without history of 
cirrhosis to participate in the PK Lead-in Phase.
Three cohorts of at least 10 subjects each will be sequentially 
enrolled: 

Cohort 1: 12 to < 18 years old, weighing ≥ 45kg

Cohort 2: 6 to < 12 years old, weighing ≥ 17 kg and < 45 kg

Cohort 3: 3 to < 6 years old 
At least 4 subjects weighing ≥ 17 kg 
At least 4 subjects weighing < 17 kg
The study will start with Cohort 1. Subjects will receive LDV/SOF 
FDC (90 mg/ 400 mg fixed dose combination tablet or 
4 x 22.5 mg/ 100 mg based on LDV/SOF FDC swallowability 
assessment) for 10 days with intensive PK conducted on Day 10.
Once Cohort 1 data is analyzed and a Cohort 2 dose is determined, 
Cohort 2 will open for screening. Cohort 2 subjects will receive 
45 mg/ 200 mg LDV/SOF FDC (2 × 22.5 mg/ 100 mg tablets) for 
10 days with intensive PK conducted on Day 10. Cohort 3 subjects 
will receive LDV/SOF FDC oral granules formulation; subjects 
weighing ≥17 kg will receive 45 mg/ 200 mg LDV/SOF FDC
(4 × 11.25 mg/ 50 mg packets) and subjects weighing <17 kg will 
receive 33.75 mg/ 150 mg LDV/SOF FDC (3 × 11.25 mg/ 50 mg 
packets) for 10 days with intensive PK conducted on Day 10. 
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 10
of the PK Lead-in Phase. They will continue dosing with LDV/SOF 
FDC with no interruption of study drug administration. Subjects 
rolling over from the PK Lead-in will not be required to perform 
Treatment Phase Screening, Day 1, or Week 1 visits in the Treatment 
Phase. 
Following completion of study treatment in the PK Lead-in of each 
Cohort, intensive PK and safety results of study treatment will be 
reviewed to confirm the appropriateness of the evaluated LDV/SOF 
FDC dose for the Treatment Phase of that Cohort as well as to 
determine the age-appropriate dose to be evaluated in the PK Lead-in 
of the next Cohort.


LDV/SOF FDC
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Gilead Sciences, Inc.
Amendment 6.0
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Treatment Phase: Treatment Phase will be initiated sequentially by 
cohort after confirmation of age-appropriate LDV/SOF FDC dosage 
levels. Subjects who participate in PK Lead-in Phase will 
immediately rollover into Treatment Phase, with no interruption of 
study drug administration, until the appropriateness of the dose is 
confirmed by PK and safety data from the PK Lead-In Phase. These 
subjects will start at the Week 2 visit of the Treatment Phase. 
Additional subjects will be enrolled in the Treatment Phase after 
completion of each Cohort and upon confirmation of the appropriate 
dose.
Children aged 3 to < 12 years and adolescents aged 12 to < 18 years 
with chronic HCV infection and a HCV RNA ≥1000 IU/mL at study 
entry (those who were dosed in the PK Lead-in Phase will have met 
these criteria prior to enrollment) will be evaluated. The study 
commenced with GT-1, -3 and -4 HCV-infected pediatric subjects. 
Subjects with GT-5 and -6 are currently eligible for inclusion into 
actively enrolling groups/cohorts following the demonstration of 
benefit:risk in the adult population. Subjects with GT-2 will be 
included once adult data are available, if appropriate.
Subjects enrolled in the study will receive the following regimen:

United Kingdom:
GT-1, GT-4, GT-5, and GT-6 treatment-naïve with or without 
cirrhosis: LDV/SOF FDC for 12 weeks
GT-1, GT-4, GT-5, and GT-6 treatment-experienced without 
cirrhosis: LDV/SOF FDC for 12 weeks
GT-1, GT-4, GT-5, and GT-6 treatment-experienced with 
cirrhosis: LDV/SOF FDC for 24 weeks
GT-3 treatment-experienced with or without cirrhosis: 
LDV/SOF FDC + RBV for 24 weeks

United States/Australia/New Zealand:
GT-1 treatment-naïve with or without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1 treatment-experienced without cirrhosis: LDV/SOF 
FDC for 12 weeks
GT-1 treatment-experienced with cirrhosis: LDV/SOF FDC 
for 24 weeks
GT-4, GT-5, and GT-6 treatment-naïve or 
treatment-experienced with or without cirrhosis: LDV/SOF 
FDC for 12 weeks


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Substudies and 
Long-Te1m 
Follow-Up Study: 
CONFIDENTIAL 
Final 
Amendment 6.0 
The study will enroll both treatment-naive and treatment-experienced 
pediatric subjects, with up to 40 subjects allowed to be treatment 
experienced. Approximately 220 subjects, including subjects that 
prui icipated in the PK Lead-in Phase, will be enrolled in the 
Treatment Phase as follows: 
• 
Group 1: Approximately 100 adolescent subjects (12 to < 18 yeru·s 
of age) 
• 
Group 2: Approximately 120 pediatric subjects (3 to < 12 yeru·s of 
age) 
The following defmitions will be used for treatment-experienced 
subjects: 
• 
Interferon intolerant: Subject who discontinued therapy 
(:::; 12 weeks total) due to:=::: 1 adverse event 
• 
Interferon non-responder: Subject who did not achieve 
undetectable HCV RNA levels while on treatment 
• 
Relapse/breakthrough: Subject who achieved undetectable HCV 
RNA dming treatment or within 4 weeks of the end of treatment 
but did not achieve a sustained virologic response (SVR) 
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, and 12 (and Weeks 16, 20, and 24 for subjects 
requiring 24 weeks of treatment) dm'ing the treatment phase followed 
by post-treatment visits 4, 12, and 24 weeks after discontinuation of 
therapy. 
All subjects who do not attain SVR or have viral relapse will be 
encomaged to discuss treatment with standard-of-care (SOC) therapy 
with their healthcru·e provider. 
Optional Intensive Pharmacokinetics (PK) Substudy: 
PD 
Pharmacogenomics (PG) Substudy 
PD 
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08 Jnne 2017 


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Amendment 6.0
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Long-Term Follow-up
Subjects who attain SVR24 or those who do not attain SVR24 and do 
not initiate other experimental or approved anti-HCV therapy will be 
followed every 6 months for the first 2 years followed by every 
12 months for assessments of growth, quality of life, and long-term 
viral suppression (if applicable) in a separate protocol 
(GS-US-334-1113). This follow-up will continue for 5 years.
Diagnosis and Main 
Eligibility Criteria: 
Chronic HCV-infected, treatment-naïve and treatment experienced
(up to 40 subjects); male and female subjects aged 3 to < 18 as 
determined at Day 1. The study commenced with GT-1, -3, and -4
HCV -infected pediatric subjects. Subjects with GT-5 and -6 are 
currently eligible for inclusion into actively enrolling groups/cohorts 
following the demonstration of benefit:risk in the adult population. 
Subjects with GT-2 will be included once adult data are available, if 
appropriate. 
Inclusion Criteria:

Chronic HCV infection documented by either:
A) positive anti-HCV antibody test or positive HCV RNA or 
positive HCV genotyping test at least 6 months prior to the 
Day 1 visit, or
B) liver biopsy performed prior to the Day 1 visit with evidence 
of chronic HCV- infection

HCV RNA ≥ 1000 IU/mL at Screening 

PK Lead-in Only: subjects in Cohort 1 (age 12 to < 18 years of 
age) must weigh ≥ 45 kg

PK Lead-in Only: subjects in Cohort 2 (age 6 to < 12 years of 
age) must weigh ≥ 17 kg and < 45 kg

Females of childbearing potential (as defined in Appendix 5) must 
have a negative pregnancy test at Screening and Day 1.

Hematologic or biochemical parameters at screening within the 
protocol-specified requirements
Exclusion Criteria:

HIV, acute hepatitis A virus (HAV) or chronic HBV infection

History of or current decompensated liver disease

Hepatocellular carcinoma or other malignancy (with exception of 
certain resolved skin cancers)


LDV/SOF FDC
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Amendment 6.0
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
Chronic liver disease of a non-HCV etiology 
(e.g., hemochromatosis, Wilson’s disease, alpha-1 antitrypsin 
deficiency)

Systemic corticosteroid use for > 2 weeks (pulmonary/nasal 
administration is permitted)

Active or recent history (≤ 1 year) of drug or alcohol abuse

History or current evidence of any condition, therapy, laboratory
abnormality or other circumstance that might confound the results 
of the study, or interfere with the subject’s participation for the 
full duration of the study, such that it is not in the best interest of 
the subject to participate.

Sexually active subjects who are not willing to use 2 forms of an 
effective method of contraception, as referenced in Appendix 5
See Sections 4.2 and 4.3 of the protocol for full eligibility criteria.
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the Day 1 
visit. 
Screening assessments will include: informed consent, medical 
history (including parental height, if available), complete physical 
examination, vital signs (including body height and weight), 
concomitant medications, LDV/SOF FDC Swallowability 
Assessment, as applicable (may be performed at screening up to 
Day 1), hematology, safety laboratory tests, coagulation tests, HCV 
RNA, serum β-human chorionic gonadotropin (hCG - females of 
childbearing potential only), urinalysis, urine drug screen, IL28B 
genotyping, serology (HIV, HAV, HCV, and HBV, HCV 
genotyping), HbA1c, thyroid stimulating hormone (TSH), alpha 
fetoprotein, alpha-1 anti-trypsin.
For subjects continuing from PK Lead-in into the Treatment Phase, a 
screening visit for the Treatment Phase will not be required.
PK Lead-in Phase: 
Study Visits will occur at Day 1, Day 3, and Day 10.
On-Treatment assessments include physical examination, Tanner 
Pubertal Stage Assessment (Day 1 only), vital signs (including body 
height and weight), bone age assessment (Day 1 only), adverse events 
(AEs), concomitant medications, pregnancy prevention counseling 
(Day 1 only; all subjects ≥ 12 years of age and subjects 
< 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status), quality of life survey (Day 1 only), safety 
laboratory tests, HCV RNA, viral sequencing sampling and 


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Amendment 6.0
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urinalysis. Coagulation testing and urine pregnancy tests (females of 
child bearing potential only) will be performed at Day 1 and Day 10 
only. LDV/SOF FDC swallowability assessment as applicable with 
placebo will be performed (if not performed at Screening) on Day 1 
to assess a subject’s ability to swallow the 90 mg/ 400 mg or 22.5 mg/ 
100 mg tablet, as applicable (only subjects administered LDV/SOF 
FDC in tablet form). 
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in 
Phase will participate in an intensive PK evaluation on Day 10. 
Following completion of the Day 10 intensive PK visit, subjects will 
then return for scheduled study visits outlined in the Treatment Phase 
and will continue dosing with LDV/SOF FDC with no interruption of 
study drug administration. Subjects will be administered a dosing 
diary with instructions. 
Treatment Phase: 
Study visits will occur at Day 1, and at the end of Weeks 1, 2, 4, 8, 
and 12 (and Weeks 16, 20, and 24 for subjects requiring 24 weeks of 
treatment). All Treatment Phase subjects will then return for 
follow-up visits at 4, 12, and 24 weeks after discontinuation of 
therapy. 
On-treatment assessments will include physical examination, vital 
signs (including body height and weight), AEs, concomitant 
medications, pregnancy prevention counseling (all subjects 
≥12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status), safety laboratory
tests, coagulation tests, HCV RNA, HBV DNA for HBcAb positive 
subjects, viral sequencing, urine pregnancy tests (females of 
childbearing potential only), a quality of life survey, and urinalysis. 
Tanner Pubertal Stage assessment will be performed at Day 1 and end 
of treatment visits; parental heights will be recorded at Day 1 as 
available. The Bone Age Assessment will be performed at the Day 1 
visit. LDV/SOF FDC swallowability assessment as applicable will be 
performed (if not performed at Screening) on Day 1 to assess a 
subject’s ability to swallow a placebo to match the 90 mg/ 400 mg or 
22.5 mg/ 100 mg LDV/SOF FDC tablet, as applicable (only subjects 
administered LDV/SOF FDC in tablet form). For subjects continuing 
from the PK Lead-in, the screening, Day 1, and Week 1 visits of the 
Treatment Phase will not be required. Samples for viral RNA 
sequencing/phenotyping will be collected at Day 1 and every visit 
thereafter. Palatability of LDV/SOF FDC oral granules will be 
assessed at Day 1 in subjects from 3 to <6 years of age, as applicable. 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
CONFIDENTIAL 
PD 
Final 
Amendment 6.0 
For all subjects in the Treatment Group 2, the following single PK 
sampling timepoints will be collected as applicable: 
• 
For subjects receiving 12 weeks of treatment: a PK sample will be 
collected at any time point at the following visits: Weeks 1, 2, 12 
and Unscheduled or Early T ennination. 
• 
For subjects receiving 24 weeks of treatment: a PK sample will be 
collected at any time point at the following visits: Weeks 1, 2, 12, 
16, 20, 24 and Unscheduled or Early Tennination. 
Post-treatment assessments will include vital signs (including body 
weight and height), symptom-directed physical examination, AEs 
(only SAEs will be captured at post-treatment Week 12 and 
post-treatment Week 24), concomitant medications (only 
post-treatment Week 4), safety laborat01y tests, HCV RNA, HBV 
DNA for HBcAb positive subjects, Tanner Pube1ial Stage assessment 
(only post-treatment Week 12 and post-treatment Week 24), Bone 
Age Assessment (only post-treatment Week 24) and urine pregnancy 
tests (as defmed in Appendix 5). 
PD 
Page 14 
08 Jnne 2017 


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 15
08 June 2017
Test Product, Dose, 
and Mode of 
Administration:
PK Lead-in: 
(Cohort 1) LDV/SOF FDC is manufactured as a tablet, consisting of 
400 mg SOF and 90 mg LDV, for oral administration. LDV/SOF 
FDC tablets will be administered once daily. Subjects unable to 
swallow the LDV/SOF FDC 90 mg/ 400 mg adult tablet (as 
determined by LDV/SOF FDC Swallowability Assessment at 
Screening or at Day 1) will be re-assigned to 4 × 22.5 mg/ 100 mg 
LDV/SOF FDC tablets daily.
(Cohort 2) LDV/SOF FDC 45 mg/ 200 mg (2 × 22.5 mg/ 100 mg) 
will be administered once daily.
(Cohort 3) LDV/SOF FDC oral granules will be administered once 
daily for 10 days. Subjects who weigh ≥17kg will receive 45 mg/ 
200 mg LDV/SOF FDC (4 × 11.25 mg/ 50 mg packets) and subjects 
who weigh <17kg will receive 33.75 mg/ 150 mg LDV/SOF FDC 
(3 × 11.25 mg/ 50 mg packets).
Intensive PK and safety results from the PK Lead-in of each Cohort 
will be reviewed to confirm the appropriateness of the evaluated 
LDV/SOF FDC dose for the Treatment Phase of that Cohort as well 
as to determine the age-appropriate dose to be evaluated in the PK 
Lead-in of the next Cohort.
Treatment Phase: 
Subjects who participated in PK Lead-in of each Cohort will continue 
in the Treatment Phase with no interruption of study drug 
administration until the appropriateness of the dose is confirmed by 
PK and safety data from the PK-Lead-in. Additional subjects will be 
enrolled in the Treatment Phase of each Cohort upon confirmation of 
the appropriateness of the dose.


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 16
08 June 2017
RBV Weight-Based Dosing (GT-3 Subjects only):
The RBV dose is:
Body Weight kg
(lbs.)
RBV Daily 
Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution. Divided dose in the 
morning and evening.
47-49 (103-108)
600 mg/day
1 × 200-mg capsules A.M.
2 × 200-mg capsules P.M.
50-65 (110 – 143)
800 mg/day
2 × 200-mg capsules A.M.
2 × 200-mg capsules P.M.
66-80 (145 – 176)
1000 mg/day
2 × 200-mg capsules A.M.
3 × 200-mg capsules P.M.
81-105 (178-231)
1200 mg/day
3 × 200-mg capsules A.M.
3 × 200-mg capsules P.M.
>105 (>231)
1400 mg/day
3 × 200-mg capsules A.M.
4 × 200-mg capsules P.M.
*
Note: Subjects with a body weight greater than or equal to 47 kg may utilize the RBV 
oral solution if necessary.
The morning dose of RBV will be taken with food and a weight 
and/or age-appropriate dose of LDV/SOF FDC. The evening dose of 
RBV will be taken with food.
Reference Therapy:
None
Evaluation Criteria:
Safety:
AEs, laboratory tests, physical examinations, and vital sign 
measurements will be collected throughout the study. 
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV RNA 
performed using COBAS® AmpliPrep/COBAS® TaqMan® HCV 
Test.
PK:
For subjects in the PK Lead-in, the steady-state PK of LDV, SOF,
and its major metabolites (GS-331007 and GS-566500) will be 
assessed at Day 10. For Cohorts 1 and 2, plasma samples will be 
collected for PK analyses following dosing of study drug on Day 10
at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, and 
12 hours postdose (with predose also serving as t= 24). For Cohort 3, 
plasma samples for PK analyses will be collected at the following 
time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours postdose (with 
predose also serving as t = 24).


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Statistical Methods: 
CONFIDENTIAL 
Final 
Amendment 6.0 
Plasma PK parameters such as Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, and 
t112 will be estimated. 
PD 
For Treatment Group 2 subjects, a PK blood sample will be collected 
at all visits while on u·eatment: a PK sample will be collected between 
15 minutes to 4 hours post-dose at Weeks 4 and 8 as applicable. A PK 
sample will be collected at any timepoint at all remaining visits, as 
applicable. The PK of GS-331 007, SOF and LDV will be assessed. 
The effect of age and LDV/SOF FDC dose on PK (GS-331007, SOF, 
and LDV) will be explored. 
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, Ctau, 
AUCtau, AUClast, and t112 will be estimated. The PK parameters will be 
summarized by cohort. The effect of age and LDV/SOF FDC dose on 
PK (GS-331007, SOF, and LDV) will be explored. 
For the Treatment Phase, the primruy safety endpoint is any AE 
leading to pennanent discontinuation of study. The key efficacy 
endpoint is SVR12 in all emolled and u·eated subjects. Point estimate 
of SVR12 rate and its 95% confidence interval will be provided for 
each age group. 
Acceptability of the study u·eatments will be summru·ized using 
descriptive statistics by assessing swallowability of tablets and 
palatability of granules as applicable. Clinically relevant subgroup 
analysis on SVR12 may be conducted as appropriate (i.e., assuming 
that adequate numbers of patients in the subsets are available for 
analysis). 
All continuous endpoints will be summarized using an 8-number 
surmnruy (n, mean, standru·d deviation, median, Q1, Q3, minimum, 
and maximum). All categorical endpoints will be sUIIllnru·ized 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 abn01m alities for categorical values or 
8-number summruy (n, mean, standru·d deviation, median, Q1, Q3, 
minimum, maximum) for continuous data. 
Page 17 
08 Jnne 2017 


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 18
08 June 2017
With approximately 100 subjects enrolled into 12 to <18 years 
(Group 1) of the Treatment Phase, a two-sided 95.0% confidence 
interval of the SVR12 rate will extend at most 5.9% in both directions 
from the observed SVR12 rate, assuming the expected SVR12 rate is 
90%.
With approximately 120 subjects enrolled into the 3 to < 12 years 
(Group 2) of the Treatment Phase, a two-sided 95.0% confidence 
interval of the SVR12 rate will extend at most 5.4% in both directions 
from the observed SVR12 rate, assuming the expected SVR12 rate is 
90%.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 19
08 June 2017
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
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)
BLQ
below the lower limit of quantification
BMI
body mass index
CK
creatine kinase
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
dL
Deciliter
DNA
deoxyribonucleic acid
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
EMA
European Medicines Agency
ESA
Erythropoiesis stimulating agent
ESPGHAN
European Society for Paediatric Gastroenterology
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed-Dose Combination
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 20
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GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
HAV
Hepatitis A Virus
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HBsAb
Hepatitis B surface antibody
HBcAb
Hepatitis B core antibody
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
peginterferon alfa-2a
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
QD
once daily (use only in tables)


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 21
08 June 2017
RBC
Red blood cell count
RBV
ribavirin
RNA
ribonucleic acid
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard-of-Care
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TSH
Thyroid stimulating hormone
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count


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Amendment 6.0
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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease worldwide 
and accounts for 70% of cases of chronic hepatitis in industrialized countries. The global 
prevalence of chronic hepatitis C is estimated to average 3% {Esteban 2008}. 
The natural history of chronic HCV-infection in children differs from that in adults since 
HCV-infection in children is relatively benign. Most children chronically infected with HCV are 
asymptomatic or have mild nonspecific symptoms. Clinical symptoms are present in 
approximately 20% of children in the first 4 years of life, with hepatomegaly being the most 
frequent sign (10%). Many, but not all, perinatally infected children will have intermittently or 
persistently abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
levels, particularly in the first 2 years of life. In children with vertical HCV-infection who have 
undergone liver biopsy, the histological spectrum is usually mild, although severe liver disease is 
encountered {Mohan 2010}. Despite the overall more favorable prognosis compared to adults, 
approximately 4% to 6% of children with chronic HCV-infection have evidence of advanced 
fibrosis or cirrhosis and some children eventually require liver transplantation for end-stage liver 
disease as a consequence of HCV-infection {Hu 2010}.
The goal of HCV treatment in both pediatric and adult populations is eradication of the virus, 
thereby preventing hepatic inflammation, hepatic fibrosis, cirrhosis, and liver failure resulting in 
either death or need for liver transplantation. This goal, however, is limited by the nature of the 
disease and the fact that not all patients are suitable candidates for currently approved treatments. 
In addition, pediatric treatment is controversial as the current treatment options are limited and 
severe side effects and tolerability can significantly limit or preclude their use. Despite 
well-established guidelines for the treatment of HCV in adults, there is no universal consensus 
on when or if to treat chronic HCV-infection in children. In 2010, the European Society for 
Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) issued guidance for clinical 
trial development for chronic HCV-infection in children {Wirth 2010}. In the guideline, the 
ESPGHAN suggested that the primary goal of treatment in children is to eradicate the infection 
to prevent late complications. Hence, the goal is not the treatment of an ongoing liver disease, 
but rather the prevention of a future one.
PEG and weight-based RBV are currently considered the SOC for the treatment of 
HCV-infection in children. Current recommendations are that patients with GT-2 or GT-3 be 
treated with PEG+RBV for 24 weeks and those with GT-1 or GT-4 should receive 48 weeks of 
therapy. Successful treatment of GT-1, however, has proved very difficult to achieve in spite of 
additional therapy or increased duration of treatment. A number of pediatric studies have 
reported that despite 48 weeks of treatment, sustained virologic response (SVR24) was observed 
in only 36% to 53% of subjects with GT-1, while response rates were > 80% in subjects with 
GT-2 or GT-3 {Wirth 2012}. Safety and efficacy data in pediatric patients with GT-5 or GT-6 
are limited.


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Amendment 6.0
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Most children treated with PEG+RBV experience at least 1 adverse event due to treatment 
{Wirth 2012}. Although most of these events are mild to moderate in severity, many of them 
result in dose reductions of 1 or both of the drugs. The most common adverse events have 
consisted of influenza-like illness (91%), headache (62%), and injection site reactions (45%), 
often leading to poor compliance and/or discontinuation from treatment.
Additionally, the concern for growth and development in this age group and the role that both 
PEG and RBV potentially play in reducing growth rates has initiated significant debate among 
pediatric hepatologists as to whether these treatments should even be considered in the pediatric 
population {Serranti 2011}. Many pediatricians currently advocate delay of treatment past 
adolescence or even into adulthood when options with DAAs are possible {Serranti 2011}. 
Unfortunately, in the 25% of pediatric patients who do meet the criteria for treatment (elevated 
transaminases and viral loads), the option of PEG+RBV therapy remains inadequate in regard to 
both efficacy in GT-1 and safety due to the many risks associated with this treatment.
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
Ledipasvir/Sofosbuvir fixed-dose combination (LDV/SOF FDC) combines two HCV specific 
direct acting antiviral (DAA) agents into a single tablet for the treatment of chronic 
HCV-infection. SOF is a nucleotide analog that is a potent and selective inhibitor of 
NS5B-directed HCV replication with demonstrated activity against GT 1-6 HCV-infection. 
Ledipasvir (LDV) is a novel HCV NS5A inhibitor that has demonstrated potent anti-HCV 
activity, with the highest activity against GT-1 HCV-infection. 
Harvoni® (LDV/SOF FDC) is approved in the United States (US) by the Food and Drug 
Administration (FDA) and in the European Union by the European Medicines Agency (EMA) 
for treatment of GT-1, GT-4, GT-5, and GT-6 HCV infection in both treatment-naïve and 
treatment-experienced adult patients with or without cirrhosis. Additionally, LDV/SOF FDC + 
RBV is approved for treatment of GT-3 HCV infection in treatment-experienced adult patients 
with or without cirrhosis. The recommended treatment regimens depend on HCV genotype, 
presence or absence of cirrhosis, and prior treatment experience. 
1.2.1.
Summary of Additional Clinical Experience with Ledipasvir/Sofosbuvir 
Fixed-Dose Combination
The LDV/SOF FDC phase 3 program consisted of 3 clinical studies: GS-US-337-0102 {Afdhal 
2014b}, GS-US-337-0109 {Afdhal 2014a}, and GS-US-337-0108 {Kowdley 2014}. Studies 
GS-US-337-0102 and GS-US-337-0109 evaluated treatment with LDV/SOF FDC ± RBV for 
12 or 24 weeks in treatment-naïve and treatment-experienced subjects, respectively, infected 
with GT-1 HCV. Both studies enrolled up to 20% of HCV-infected subjects who had 
documented compensated cirrhosis. GS-US-337-0108 evaluated LDV/SOF FDC ± RBV 
treatment for 8 weeks and LDV/SOF FDC treatment for 12 weeks in non-cirrhotic 
treatment-naïve subjects with GT-1 HCV-infection. Across these 3 clinical studies, LDV/SOF 
FDC demonstrated a high degree of efficacy (> 93%) for treatment-naïve and treatment
experienced subjects with GT-1 HCV-infection in subjects with and without cirrhosis and
achieved their primary efficacy endpoints {Afdhal 2014a, Afdhal 2014b, Kowdley 2014}. 
Additionally, treatment with LDV/SOF FDC ± RBV was safe and well tolerated in the Phase 3 


LDV/SOF FDC
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Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 24
08 June 2017
studies {Afdhal 2014a, Afdhal 2014b, Kowdley 2014}. The inclusion of RBV to the treatment 
regimen was associated with an increase in the total incidence of adverse events and in graded 
laboratory abnormalities of anemia and increased bilirubin. 
LDV/SOF FDC indication in GT-3 HCV infection is supported by the Phase 2 Study 
GS-US-337-0122 (ELECTRON-2). In this Phase 2 open-label study, the safety and efficacy of 
LDV/SOF FDC were evaluated with or without RBV in 51 treatment-naïve patients with GT-3 
HCV infection, with or without cirrhosis. Subjects were treated with LDV/SOF FDC (n = 25) or 
LDV/SOF FDC + RBV (n = 26) for 12 weeks. SVR12 rates were 64% (16/25) and 100% (26/26) 
in the LDV/SOF FDC and LDV/SOF FDC + RBV treatment groups, respectively. The relative 
efficacy of a 12-week regimen consisting of LDV/SOF FDC + RBV, compared to a 24-week 
regimen of SOF + RBV has not been investigated. Therefore, 24 weeks of therapy is advised in 
all treatment-experienced GT-3 patients and those treatment-naïve GT-3 patients with cirrhosis 
to maximize therapeutic benefit to achieve SVR.
Both nonclinical and clinical data support the inclusion of GT-4 HCV-infected subjects in the 
Study GS-US-337-1116. LDV displays potent antiviral activity against GT-4. In the replicon 
system the EC50 value of LDV for GT-4d HCV was 0.60 nM and 0.39 nM for GT-4a HCV. For 
reference, the EC50 values of LDV for GT-1a and GT-1b is 0.031 nM and 0.004 nM, 
respectively.
In the Phase 3 Study GS-US-337-0102 (ION-1), 2 subjects with GT-4d HCV infection were 
inadvertently randomized in violation of the protocol inclusion/exclusion criteria. Both subjects 
achieved SVR12. Subject 
 was treated for 12 weeks with LDV/SOF FDC and 
Subject 
 was treated for 24 weeks with LDV/SOF FDC + RBV.
Data from Study GS-US-337-1119 support the inclusion of GT-4 as well as GT-5 HCV-infected 
subjects within the current study. Study GS-US-337-1119 was a European study that investigated
the efficacy and safety of LDV/SOF FDC in treatment-naive and treatment-experienced subjects 
with chronic GT-4 or GT-5 HCV infection. A total of 44 subjects with GT-4 HCV infection, of 
whom 10 (23%) had cirrhosis and 22 (50%) were treatment experienced, were enrolled to 
receive LDV/SOF FDC for 12 weeks. SVR12 was achieved by 41 (93%) of the GT-4 HCV
infection subjects including 21 (96%) who were treatment-naïve and 20 (91%) who were 
treatment-experienced subjects. In addition, a total of 41 subjects with GT-5 HCV infection were 
enrolled, of whom 9 (22%) had cirrhosis and 20 (49%) were treatment-experienced, and received 
LDV/SOF FDC for 12 weeks. SVR12 was achieved by 39 (95%) including 19 (95%) who were 
treatment-experienced and 8 (89%) with cirrhosis.
In addition, data are available from the NIAID/NIH collaborative Study CO-US-337-0117. In 
this study, 21 subjects with GT-4 HCV infection received 12 weeks of LDV/SOF FDC 
treatment. SVR12 was achieved by 20 of 21 subjects including 6 subjects with cirrhosis.
Inclusion of subjects with GT-6 HCV in the current study is supported by data from the 
ELECTRON-2 study (GS-US-337-0122). In ELECTRON-2, treatment-naïve or 
treatment-experienced adult subjects with GT-6 HCV infection with or without cirrhosis (n = 25) 
received LDV/SOF FDC for 12 weeks. In this study, 96% (24/25) of patients achieved SVR12.
PPD
PPD


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
1.2.1.1. 
GS-US-337-2091 
Final 
Amendment 6.0 
Study GS-US-337-2091 was a single dose, randomized, 3-period crossover Phase 1 study in 
healthy adult subjects conducted to evaluate relative bioavailability and the effect of food on 
LDV/SOF FDC oral granules. Subjects were administered the following treatments in a 
randomized order with a 9 day washout between doses: 1 x 90 mg/ 400 mg LDV/SOF FDC 
tablet (adult fonnulation) in the fasted state (Treatment A), 90 mg/ 400 mg LDV/SOF FDC oral 
granules (8 x 11.25 mg/ 50 mg packets) in a fasted state (Treatment B), and 90 mg/ 400 mg 
LDV /SOF oral granules (8 x 11.25 mg/ 50 mg packets) after a standardized high-fat meal 
(Treatment C). F01iy-two healthy subjects were emolled and completed all u·eatments. Overall, 
both LDV/SOF FDC f01mulations were well tolerated. No subjects experienced a serious 
adverse event (SAE) or a Grade 3/4 u·eatment emergent adverse event (AE), and no subjects 
required u·eatment discontinuation for an AE. Grade 3/4laboratOiy abn01m alities were seen in 
1 subject who had a u·ansient Grade 4 lipase elevation (481 UIL) prior to the 3rd dose, followed 
by progressive decrease through 3 weeks after the dose. The subject was asymptomatic and had a 
medical hist01y notable for isolated lipase elevation. 
In accordance with the FDA and EU guidance for Bioavailability and Bioequivalence studies the 
primaty PK analysis set consisted of subjects with pre-dose concenu·ations < 5% of Cmax for each 
period (Guidance for Industry: Bioavailability and Bioequivalence Studies Submitted in NDAs 
or INDs - General Considerations [FDA], Guideline on the Investigation of Bioequivalence EU] 
{Emopean Medicines Agency (EMEA) 2010, U.S. Depm·tment of Health and Human Services 
2014}). A sensitivity analysis including PK data from all subjects was also conducted. 
1.2.1.1.1. 
GS-US-337-2091 F01mulation Comparison 
Statistical compat·isons of the primaty PK paratneters AUCinf, AUC1ast> Cmax for LDV, and 
GS-331 007 (the primruy circulating metabolite of SOF) are presented below following 
adminisu·ation of90 mg/ 400 mg LDV/SOF FDC oral granules (8 x 11.25 mg/ 50 mg) fasted 
(Treatment B; Test) relative to 90 rng/ 400 mg LDV/SOF FDC tablets (1 x 90 mg/ 400 mg). 
fasted Treatment A; Reference . PO 
CONFIDENTIAL 
Page 25 
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LDVISOFFDC 
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Gilead Sciences, Inc. 
Amendment 6.0 
Table 1-1. 
Statistical Comparison of Pharmacokinetic Parameters for 
Formulation Comparison- Test versus Reference Treatments 
(Primary PK analysis Set) 
Mean (%CV) 
% GLSM Ratio (90% CI) 
LDV/SOF 
LDV/SOF FDC 
FDC Tablet 
Oral Granules 
LDV /SOF FDC Oral Granules 
90 mg/400 mg 
Sx 11.25 mg/50 mg 
VS 
PK Parameter 
(Reference) 
(Test) 
LDV/SOF FDC Tablet 
LDV (N=42 reference/N=39 test) 
AUC~as~ (h*ng/mL) 
7362.3 (48.3) 
6242.5 (40.7) 
87.76 (77.94, 98.82) 
AUCinf (h *ng/mL) 
8467.5 (54.4) 
7088.4 (46.3) 
88.36 (78.43, 99.54) 
Cmax (ng/mL) 
261.3 (43.5) 
214.8 (38.2) 
84.59 (74.69, 95.81) 
GS-331007 (N=42 reference/N=42 test) 
AUC~as~ (h*ng/mL) 
11146.3 (26.9) 
11525.8 (26.3) 
103.14 (96.71, 110.00) 
AUCinf (h *ng/mL) 
11720.0 (26.1) 
12095.0 (24.4) 
103.64 (98.48, 109.07) 
Cmax (ng/mL) 
833.9 (23.6) 
951.9 (27.0) 
112.81 (104.12, 122.22) 
SOF (N=42 reference/N=42 test) 
AUC~as~ (h*ng/mL) 
1559.8 (40.5) 
1676.9 (43.7) 
102.13 (87.16, 119.67) 
AUCinf (h *ng/mL) 
1580.8 (40.2) 
1684.1 (43.5) 
101.60 (86.67, 119.10) 
Cmax (ng/mL) 
1221.0 (38.5) 
1266.7 (46.6) 
95.98 (78.00, 118.11) 
GS-566500 (N=42 reference/N=42 test) 
AUC~as~ (h*ng/mL) 
1846.6 (31.4) 
1952.9 (33.5) 
100.59 (88.89, 113.83) 
AUCinf (h *ng/mL) 
1894.9 (30.8) 
2009.7 (33.0) 
101.37 (90.17, 113.96) 
Cmax (ng/mL) 
475.1 (33.9) 
511.3 (34.9) 
103.04 (91.06, 116.60) 
* 
Primary PK analysis set excluded subjects with pre-dose concentrations> 5% of Cmax for each period 
Data from the primruy analysis demonstrated modestly lower LDV exposure (~ 1 2%) in the 
LDV /SOF FDC oral granules as compru·ed with the LDV /SOF FDC tablet, with the lower 
bounds of the 90% CI being approximately 75-78%. A slightly larger (20%) reduction in LDV 
was observed using sensitivity analysis that included data from all subjects. These modest 
decreases in exposure are not considered to be clinically relevant based on the established 
exposure/efficacy relationship for LDV and LDV/SOF. 
GS-331007 exposure in the LDV/SOF FDC oral granules was bioequivalent to the LDV/SOF 
FDC tablets. PO 
CONFIDENTIAL 
Page 26 
08 June 2017 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
1.2.1.1.2. 
GS-US-337-2091 - Food Effect Evaluation 
Final 
Amendment 6.0 
Statistical comparisons of the primmy PK parameters AUCinf and AUC1ast for LDV, and 
GS-331 007 (the primmy circulating metabolite of SOF) are presented below following 
administration ofLDV/SOF oral granules (8 x 11.25 mg/ 50 mg packets in fed state 
Treatment C; Test relative to a fasted state Treatment B; Reference . PD 
Table 1-2. 
Statistical Comparison of Pharmacokinetic Parameters for Food 
Effect Comparison - Test versus Reference Treatments 
(Primary PK analysis Set) 
Mean (OfoCV) 
OfoGLSM Ratio (90% CI) 
LDV/SOF FDC 
LDV/SOFFDC 
LDV/SOFFDC 
Oral Granules 
Oral Granules 
Oral Granules + 
High-Fat Meal 
Fasted 
High-Fat Meal 
VS 
PK Parameter 
(Reference) 
(Test) 
Fasted 
LDV(N=39 reference/N=40 test) 
AUC~as~ (h*ng/mL) 
6242.5 (40.7) 
5149.6 (26.2) 
87.62 (79.65, 96.39) 
AUCinf (h *ng/mL) 
7088.4 (46.3) 
5748.3 (29.0) 
87.06 (78.95, 96.00) 
Cmax (ng/mL) 
214.8 (38.2) 
159.8 (28.9) 
78.15 (71.26, 85.71) 
GS-331007 (N=42 reference/N=42 test) 
AUC~as~ (h*ng/mL) 
11525.8 (26.3) 
11653.6 (18.9) 
103.12 (97.61, 108.94) 
AUCinf (h *ng/mL) 
12095.0 (24.4) 
12220.6 (18.3) 
102.26 (98.18, 106.52) 
cmax (ng/mL) 
951.9 (27.0) 
583.1 (24.2) 
62.01 (56.90, 67.59) 
SOF (N=42 reference/N=42 test) 
AUC1as1 (h*ng/mL) 
1676.9 (43.7) 
2577.2 (33.1) 
166.11 (145.00, 190.30) 
AUCinf (h *ng/mL) 
1684. 1 (43.5) 
2597.7 (32.9) 
166.18 (145.56, 189.71) 
Cmax (ng/mL) 
1266.7 (46.6) 
1236.3 (49.0) 
100.32 (84.83, 118.65) 
GS-566500 (N=42 reference/N=42 test) 
AUC~as~ (h*ng/mL) 
1952.9 (33.5) 
2931.7 (19.1) 
163.23 (144.62, 184.23) 
AUCinf (h *ng/mL) 
2009.7 (33.0) 
2988.8 (18.7) 
160.65 (143.40, 179.99) 
Cmax (ng/mL) 
511.3 (34. 9) 
593.9 (31.0) 
122.12 (108.28, 137.73) 
* 
Primary PK analysis set excluded subjects with pre-dose concentrations > 5% of Cmax for each period 
CONFIDENTIAL 
Page 27 
08 Jnne 2017 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Final 
Amendment 6.0 
With regards to food effect, the primruy and sensitivity analyses demonsu·ated that the 
prespecified equivalence criteria for LDV (70-143%) and GS-331007 (80-125%) AUC!ast and 
AUCinrafter adminisu·ation ofLDV/SOF FDC oral granules with a high-fat/hi h-calorie meal 
comj)ru·ed with fasted adminisu·ation were met. PD 
1.2.1.2. 
GS-US-337-1116 
Preliminruy data are available for the cunent study in adolescent subjects Coh01i 1 
(12 to < 18 yeru·s of age; N=10) and pediau·ic subjects Cohort 2 (6 to <12 yeru·s of age; N=12) 
who emolled in the PK Lead-in Phase and received an adult clinical dose ofLDV/SOF FDC 90 
mg/ 400 mg or a reduced dose ofLDV/SOF FDC 45 mg/200 mg, respectively. Of note, 2 out of 
12 subjects (subject PO 
and PPD 
in Coh01i 2 enoneously received a dose of 90 mg/ 
400 mg LDV/SOF FDC during the PK Lead-in Phase: Subjecg~;D received 90 mg/ 400 mg 
from Day 1 through Day 10 and Subject PD 
received 90 m 
400 mg from Day 1 through 
Day 4 followed by the con ect dose of 45 mg/ 200 mg for the remainder of the PK Lead-in Phase 
(Day 5 through Day 10). 
Evaluation ofPK in Coh01i 2 subjects was conducted using data from all12 subjects; observed 
LDV, SOF, and GS-331007 (primruy SOF metabolite) exposures on Day 10 were used for 
Subject PD 
and exposures were scaled to 45 mg/ 200 mg for SubjectPPD 
(Table 1-4). Mean 
exposures ofLDV, SOF, and GS-331007 in Coh01i 1 and 2 subjects were comparable to 
observed exposures in the adult subjects in the Phase 2/3 LDV/SOF FDC clinical progrrun; 
thereby confirming the appropriateness of the adult dose (90 mg/ 400 mg) in the adolescent 
population (12 to < 18 yeru·s of age) and 45 mg/ 200 mg in pediau·ic patients (6 to < 12 yeru·s of 
age) Table 1-3 and Table 1-4. The appropriateness of the 90 mg/ 400 mg LDV/SOF FDC dose in 
adolescents and 45 mg/ 200 mg LDV /SOF FDC dose in the pediau·ic patients is fmiher 
supported by available safety and efficacy data in the treatment phases of the study. 
CONFIDENTIAL 
Page 28 
08 Jnne 2017 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 29
08 June 2017
Table 1-3.
Steady-state PK and Statistical Comparisons of LDV, SOF and 
GS-331007 PK in Adolescent Subjects (PK Lead-in) and Adult 
Subjects (Phase 2/3 Population PK Analysis)
Mean (%CV)
Adolescents (N=10)
Phase 2/3 (N=2113)
GMR% (90% CI)
LDV
AUCtau (ng*hr/ml)
10200 (50.9)
8530 (60.8)
127 (94.9, 170)
Cmax (ng/ml)
564 (41.2)
364 (51.4)
162 (125, 209)
Ctau (ng/ml)
319 (71.5)
247 (59.2)
128 (95.2, 172)
SOF*
AUCtau (ng*hr/ml)
2180 (26.6)
1380 (34.0)
160 (138, 185)
Cmax (ng/ml)
1140 (57.2)
659 (34.0)
156 (127, 190)
GS-331007
AUCtau (ng*hr/ml)
12700 (13.7)
12500 (29.2)
105 (90.6, 122)
Cmax (ng/ml)
1010 (21.5)
736 (28.2)
139 (120, 161)
Data reported to 3 significant figures; *N=1542
Table 1-4.
Steady-state PK and Statistical Comparisons of LDV, SOF and 
GS-331007 PK in Pediatric Cohort 2 Subjects (6 to <12 years old; PK 
Lead-in) and Adult Subjects (Phase 2/3 Population PK Analysis)
Mean (%CV)
Pediatrics (N=12)**
Phase 2/3 (N=2113)
GMR% (90% CI)
LDV
AUCtau (ng*hr/ml)
7520 (58.0)
8530 (60.8)
86.9 (66.5, 114)
Cmax (ng/ml)
432 (51.3)
364 (51.4)
116 (92.1, 147)
Ctau (ng/ml)
248 (67.5)
247 (59.2)
91.1 (69.5, 120)
SOF*
AUCtau (ng*hr/ml)
1600 (29.7)
1380 (34.0)
116 (101, 133)
Cmax (ng/ml)
906 (36.0)
659 (34.0)
139 (116, 167)
GS-331007
AUCtau (ng*hr/ml)
8140 (31.6)
12500 (29.2)
65.2 (56.9, 74.7)
Cmax (ng/ml)
772 (24.4)
736 (28.2)
106 (92.8, 122)
Data reported to 3 significant figures; *N=1542 (Phase 2/3), ** Similar results were observed following exclusion of subjects 
 and 
 who received LDV/SOF 90 mg/400 mg during the PK-Lead-in
PPD
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 30
08 June 2017
Please refer to the Investigator’s Brochure (IB) for additional information on the LDV/SOF FDC 
including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA 
and DNA viruses {Roche Laboratories Inc. 2010, Roche Products Limited 2010}. Ribavirin 
monotherapy has little or no effect on the replication of HCV but can result in normalization of 
serum ALT activity and improvement in liver histology. When combined with interferon or PEG 
therapy, RBV decreases substantially the relapse rate seen after cessation of interferon therapy 
{McHutchison 1998, Poynard 1998}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to accumulate 
intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, extreme care 
must be taken to avoid pregnancy during RBV therapy and for up to 7 months following 
completion of treatment. A comprehensive review of RBV is contained in the package 
insert/SmPC.
1.4.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy, pharmacokinetics, and safety of treatment 
with LDV/SOF FDC +/- RBV for adolescents and children with chronic HCV-infection. 
Currently PEG and weight-based RBV are considered the SOC for the treatment of 
HCV-infection in children. Therefore, there is a need for new treatments for HCV in the 
pediatric population that combine potent and sustained efficacy with improved tolerability and 
safety. The primary aim for new treatments of pediatric patients with HCV is to eliminate the 
need to use PEG. In this way, pediatric patients would be able to avoid the necessity of weekly 
injections which can be traumatic and burdensome, and significantly reduce the serious adverse 
events seen with PEG administration. The secondary aim is to eliminate RBV and the adverse 
events seen with its administration within HCV infected subjects.
Harvoni® (LDV/SOF FDC) is approved in the US and EU for the treatment of adults with 
chronic HCV infection. LDV/SOF FDC +/- RBV would provide an all-oral, IFN-free regimen 
with a shorter treatment duration (12 or 24 weeks of LDV/SOF FDC +/- RBV treatment versus 
standard-of-care 24 to 48 weeks of treatment) for GT-1, -3, -4, -5, and -6 HCV infected patients
and would offer another important option in the treatment of HCV infection in the pediatric 
population.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 31
08 June 2017
In vitro viral replicon assay has data demonstrating LDV has potent, antiviral activity against all 
HCV genotypes. In the LDV/SOF FDC phase 3 program, LDV/SOF FDC without RBV has been 
shown to have good efficacy and safety in adults infected with GT-1 HCV infection. In the 
GS-US-337-0102 (ION-1), GS-US-337-1119, and CO-US-337-0117 studies, LDV/SOF FDC 
without RBV has been shown to have good efficacy and safety in adults infected with GT-4
HCV-infection. In study GS-US-337-0122, a phase 2 open-label study of GT-3 treatment-naïve
adult subjects with and without cirrhosis, LDV/SOF FDC for 12 weeks resulted in an SVR12 of 
64% whereas LDV/SOF + RBV for 12 weeks resulted in an SVR of 100% {Gane 2014}. The 
clinical data to support the use of Harvoni® in patients infected with HCV GT-3 are limited. As a 
result, the current study includes a 24-week RBV treatment regimen for only 
treatment-experienced pediatric subjects with GT-3 HCV-infection.
Considering that SOF has pan-genotypic activity and LDV has in vitro, picomolar to nanomolar 
antiviral activity against certain subtypes within GT 4-6 and sub-micromolar antiviral activity 
against certain subtypes within GT-2, studies in patients with GT-5 and GT-6 HCV have been 
completed and used to support treatment recommendations for the use of LDV/SOF FDC in 
adults infected with GT-5 and GT-6 HCV in both the US and EU. In studies GS-US-337-1119 
and GS-US-337-0122, LDV/SOF FDC for 12 weeks resulted in SVR12 rates of 93% and 96% in 
GT-5 and GT-6 HCV, respectively. Based on these clinical data pediatric subjects with GT-5 and 
GT-6 infection are eligible for enrollment into this clinical study.
If emerging LDV/SOF FDC data in GT-2 HCV infected subjects support treatment in adults,
pediatric subjects with GT-2, will be enrolled in the current study. Of note, there is an ongoing 
study enrolling GT-2 (and GT-3) pediatric patients, GS-US-334-1112, for treatment with 
SOF + RBV for 12 and 24 weeks, respectively.
1.5.
Rationale for Dose Selection of LDV/SOF FDC
Ledipasvir /Sofosbuvir (90 mg/ 400 mg) fixed-dose combination tablet +/- RBV has 
demonstrated favorable safety and efficacy profiles in over 3000 HCV-infected subjects across 
different patient populations in Phase 2 and 3 clinical trials. These doses represent the marketed 
dose of a ledipasvir/sofosbuvir fixed-dose combination tablet for the treatment of HCV-infection
in adults.
Selection of doses of LDV/SOF FDC +/- RBV for adolescents and younger age groups will 
target systemic exposures similar to those observed in adults at the proposed marketed dose. 
LDV and SOF are substrates for efflux drug transporters P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP). LDV is also a subject to slow oxidative metabolism via an unknown 
mechanism. SOF is extensively metabolized to the pharmacologically active nucleoside analog 
phosphate. The activation pathway involves hydrolysis by intestinal and hepatically expressed 
carboxylesterase (CES1) and Cathepsin A (CatA) enzymes {Yang 2009, Zhu 2009}. SOF is also 
converted to GS-331007, an inactive circulating metabolite, which is eliminated renally by active 
tubular secretion and glomerular filtration. Available data suggest comparable hepatic expression 
of CES1 in adolescents and adults with modestly decreased expression in children. However, 
little is known about the developmental regulation of Pgp, CES, and CatA. When adjusted for 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 32
08 June 2017
BSA, the processes of active secretion and glomerular filtration approximate adult activity by 
6 to 12 months of age {Kearns 2003}. 
The adult clinical dose of LDV/SOF FDC (90 mg/ 400 mg) was evaluated in adolescent subjects 
(12 to <18 years old) while a lower LDV/SOF FDC (45 mg/ 200 mg) is being evaluated in 
children (6 to <12 years old), respectively. The appropriateness of these doses are supported by 
data from the Cohort 1 and Cohort 2 PK Lead-in Phase which demonstrated comparable LDV, 
SOF, and GS-331007 exposures in adolescent subjects who received LDV/SOF FDC (90 mg/
400 mg) or children who received LDV/SOF FDC (45 mg/ 200 mg) compared to adult subjects 
in Phase 2/3 population PK analyses.
In Cohort 3 (3 to < 6 years of age), a dose of LDV/SOF FDC (45 mg/ 200 mg) administered as 
granules is proposed for evaluation in children weighing ≥ 17 kg, whereas a lower LDV/SOF
FDC granules dose (33.75 mg/ 150 mg) is proposed for evaluation in children weighing < 17 kg. 
These proposed doses are supported by scaling of adult exposures based on correlations between 
body weight and clearance capacity (liver volume/size for LDV and SOF, and renal capacity for 
GS-331007) for the expected body weight range in children (3 to < 6 years of age), and the 
results of the relative bioavailability Phase 1 evaluation of LDV/SOF FDC oral granules 
(GS-US-337-2091), as presented in Figure 1-1 {Fanta 2007, Kearns 2003}. Based on this scaling 
approach, doses of LDV/SOF FDC oral granules (45 mg/ 200 mg) in children ≥17 kg and 
LDV/SOF FDC granules (33.75 mg/ 150 mg) in children < 17 kg are expected to achieve mean 
systemic exposures of LDV, SOF, and GS-331007 within the range of those observed in the 
Phase 2/3 population (Figure 1-1). Safety and PK data in children (3 to < 6 years of age) who 
enroll in the PK-Lead-in Phase will be evaluated to confirm the appropriateness of the dose for 
this age group.


LDVISOFFDC 
Protocol GS-US-337-1116 
Final 
Gilead Sciences, Inc. 
Amendment 6.0 
Figure 1-1. 
Predicted LDV, SOF, and GS-331007 AUCtau following 
administration ofLDV/SOF FDC 45 mg/ 200 mg or LDV/SOF FDC 
33.75 mg/ 150 mg (3 to< 6 years of age) 
~ 
Cl> 
iii 
u 
~ 
-!!!.e 
"1:: 
S.c: 
g •CI 
<(.S 
u. 
0 
5000 
150 mg SOF 
Predicted SOF exposure 
200 mg SOF 
(<17kg) 
(~17kg) 
•••••••••·t•·•••••••••••••••••••••••••••••••••••••••••• max 
I 
I 
95th%ile 
Q3 
median 
C/) 
1000 
Q1 
5th%ile 
500 
min 
20000 
10 12 14 161718 20 22 24 26 28 30 32 34 36 38 40 42 44 
weight (kg) 
o 
5th percentile 
o 
01 "' median 
v 
03 o 
95th percentile 
150 mg SOF 
Predicted GS-331007 exposure 
200 mg SOF 
• (-:=-J ?. ~9) .•................. ,(;::::,1.~ l<W •..•.........••.••• max 
95th %ile 
"=- 10000 
~ E 
Oo:: 
Q3 
median 
Q1 
::I.e 
<( • 
,... Cl 
o.S 
0 
5th %ile 
5000 
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 
nlin 
10 12 14 161718 20 22 24 26 28 30 32 34 36 38 40 42 44 
weight (kg) 
o 
5th percentile 
o 
Q1 
6 
median 
v 
03 o 
95th percentile 
r-O-o 
~::r 
CJ)A> 
Olll 
"TIC!> 
CD~ 
0-o 
3 0 
ce-o 
-
c: 
~­
oA> 
oe. 
3 g 
cc 
CONFIDENTIAL 
Page 33 
08 Jtme 2017 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
1.6. 
50000 
:0 '* 
10000 
(J ~ 
~"E 
:>1:: 
S.r:. 
gc, 
<.s 
Ei 
..J 
1000 
Predicted LDV exposure 
33.75 mg LDV 
45 mg LDV 
(<1 7 kg) 
(?!:17 kg) 
................ "'!"····· .•..........................................•............... 
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 
weight (kg) 
o 
5th percentile 
o 
Q1 
" 
Q2 
v 
Q3 
<> 
95th percentile 
Overall Risk/Benefit Assessment 
max 
95th %lie 
Q3 
Q2 
Q1 
5th %lie 
min 
Final 
Amendment 6.0 
r-
O-o 
~:r 
C/)1» 
o"' 
.,co 
~~ 
CD W 
0"'0 
3 0 
(Q"O 
-
c 
..,._ 
Ol» 
0~ 
3 g 
e 
Although the majority of pediatric patients infected with HCV exhibit minimal hepatic sequelae 
despite active viral replication and inflammation, a subset of children and adolescents will 
require treatment. Studies suggest that 3 major categories of disease can occur within 10 years 
after putative HCV exposure: (1) undetectable viremia and n01mal ALT, (2) persistent yet 
uncomplicated mild liver disease, and (3) progression to end-stage liver disease {Bortolotti 
2008}. It is the last two groups of children in whom therapy may be indicated to prevent 
end-stage disease, either during childhood/adolescence or in early adulthood. 
Given that the cmTent SOC for the treatment of children infected with HCV is PEG and RBV 
and these regimens are long in duration, relatively toxic, and not well tolerated, there continues 
to be a need for new treatments for HCV that combine potent and sustained efficacy with 
improved tolerability and safety. 
The combination ofLDV plus SOF is anticipated to offer greater antiviral efficacy which could 
result in a sho1ter treatment duration and/or lead to a regimen without RBV or interferon. These 
in tum could result in reduction in adverse events. LDV /SOF FDC could also potentially be of 
benefit in patients who have failed prior treatment with SOF+/-RBV+/- PEG. 
If high rates of SVR can be obtained with sh01t, well-tolerated regimens, the anticipated 
improvements in safety and tolerability would offer a favorable risk-benefit dete1mination for 
individuals with chronic HCV-infection. 
CONFIDENTIAL 
Page 34 
08 Jtme 2017 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
2. 
OBJECTIVES 
The prima1y objective of the PK Lead-in Phase of this study is: 
Final 
Amendment 6.0 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose ofLDV/SOF FDC 
in chronic HCV-infected pediatric subjects 
The secondruy objective of the PK Lead-in Phase of this study is: 
• 
To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing ofLDV/SOF 
FDC in chronic HCV -infected pediatric subjects 
The primary objective of the Treatment Phase of this study is: 
• 
To evaluate the safety and tolerability ofLDV/SOF FDC +/- RBV for 12 or 24 weeks in 
chronic HCV -infected pediatric subjects 
The secondruy objectives of the Treatment Phase of this study ru·e: 
• 
To dete1mine the antiviral efficacy of 12 or 24 weeks ofLDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects (including the impact of HCV genotype, IL28B genotype, 
and prior treatment experience), as assessed by the prop01iion of subjects with SVR 
12 weeks after completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of 12 or 24 weeks ofLDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment 
• 
To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment 
• 
To evaluate acceptability 
• 
assessed by swallowability of tablets and palatability of granules. 
• 
To evaluate the effect of growth and development on pediatric subjects during and after 
treatment 
The explorat01y objective of this study is: 
• 
PD 
CONFIDENTIAL 
Page 35 
08 Jnne 2017 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 36
08 June 2017
3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and antiviral 
activity of LDV/SOF FDC +/- RBV in chronic HCV-infected pediatric subjects.
3.1.1.
PK Lead-in Phase
The PK Lead-in Phase will evaluate and/or confirm the age appropriate LDV/SOF FDC dose by 
analyzing PK, safety, and antiviral activity of LDV/SOF FDC through 10 days of dosing for each 
cohort. Children aged 3 to < 6 years, children aged 6 to < 12 years, and adolescents 
aged 12 to < 18 years with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry 
will be evaluated. Subjects must be treatment naïve without history of cirrhosis to participate in 
the PK Lead-in Phase. Three cohorts of at least 10 subjects each will be sequentially enrolled: 

Cohort 1: 12 to < 18 years old, weighing ≥45kg

Cohort 2: 6 to < 12 years old, weighing ≥ 17 kg and < 45 kg

Cohort 3: 3 to < 6 years old 
At least 4 subjects weighing ≥ 17 kg 
At least 4 subjects weighing < 17 kg
The study will start with Cohort 1. Subjects will receive LDV/SOF FDC (90 mg/ 400 mg 
adult tablet or 4 × 22.5 mg/100 mg tablets if determined necessary based on LDV/SOF FDC
swallowability assessment) for 10 days with intensive PK conducted on Day 10. 
Cohort 2: Subjects will receive LDV/SOF FDC 45 mg/ 200 mg (2 × 22.5 mg/ 100 mg tablets) for 
10 days with intensive PK conducted on Day 10.
Cohort 3: Subjects will receive LDV/SOF FDC oral granules; subjects weighing ≥17 kg will 
receive LDV/SOF FDC 45 mg/ 200 mg (4 × 11.25 mg/ 50 mg packets) and subjects weighing 
<17 kg will receive LDV/SOF FDC 33.75 mg/ 150 mg (3 × 11.25 mg/ 50 mg packets) for 
10 days with intensive PK assessments conducted on Day 10.
Subjects enrolled in the PK Lead-in Phase of each cohort (Cohorts 1, 2, and 3) will immediately 
enroll in the Treatment Phase as they complete Day 10 of PK Lead-in Phase. They will continue 
dosing with LDV/SOF FDC with no interruption of study drug administration. Subjects rolling 
over from the PK Lead-in Phase will not be required to perform the screening, Day 1, or Week 1 
visit of the Treatment Phase.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 37
08 June 2017
Figure 3-1.
PK Lead-in Phase Study Schema
3.1.2.
Treatment Phase
The Treatment Phase will be initiated sequentially by age group as defined in Cohort 1, 2, and 3 
of the PK Lead-in. Subjects who participated in PK Lead-in phase will immediately rollover into 
Treatment Phase with no interruption of study drug administration until the appropriateness of 
the dose has been confirmed by PK and safety results from the PK Lead-in. The first visit in the 
Treatment Phase for these subjects will be the Week 2 visit. Additional subjects will be enrolled 
in the Treatment Phase of each Cohort upon confirmation of the appropriateness of the dose from 
the PK Lead-in.
Children aged 3 to < 12 years (Group 2) and adolescents aged 12 to < 18 years (Group 1) with 
chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry (those who were dosed in 
the PK Lead-in phase will have met this criteria prior to enrollment) will be evaluated.
Subjects enrolled in the Treatment Phase will receive the following regimen:
a) United Kingdom:

GT-1, GT-4, GT-5, & GT-6 treatment-naïve subjects with or without cirrhosis: LDV/SOF 
FDC for 12 weeks

GT-1, GT-4, GT-5, & GT-6 treatment-experienced subjects without cirrhosis: LDV/SOF 
FDC for 12 weeks

GT-1, GT-4, GT-5, & GT-6 treatment-experienced subjects with cirrhosis: LDV/SOF 
FDC for 24 weeks

GT-3 treatment-experienced subjects with or without cirrhosis: LDV/SOF FDC + RBV 
for 24 weeks


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b) United States/Australia/New Zealand:

GT-1 treatment-naïve subjects with or without cirrhosis: LDV/SOF FDC for 12 weeks

GT-1 treatment-experienced subjects without cirrhosis: LDV/SOF FDC for 12 weeks

GT-1 treatment-experienced subjects with cirrhosis: LDV/SOF FDC for 24 weeks

GT-4, GT-5, & GT-6 treatment-naïve or treatment-experienced subjects with or without 
cirrhosis: LDV/SOF FDC for 12 weeks
Table 3-1.
Subject Enrollment by HCV Genotype, Country, and Treatment 
Duration
GT-1
GT-3
GT-4, GT-5, & GT-6
Cirrhotic or 
Non-cirrhotic 
Subjects 
(TN)
Non-cirrhotic 
Subjects 
(TE)
Cirrhotic 
Subjects 
(TE)
Non-cirrhotic 
or Cirrhotic 
Subjects 
(TE)
Cirrhotic or 
Non-cirrhotic 
Subjects 
(TN)
Non-cirrhotic 
Subjects 
(TE)
Cirrhotic 
Subjects 
(TE)
United 
States
12 Weeks of 
treatment with 
LDV/SOF 
FDC
12 Weeks of 
treatment with 
LDV/SOF 
FDC
24 Weeks 
of treatment 
with 
LDV/SOF 
FDC
N/A
12 Weeks of 
treatment with 
LDV/SOF 
FDC
12 Weeks of 
treatment with 
LDV/SOF 
FDC
12 Weeks 
of treatment 
with 
LDV/SOF 
FDC
Australia
12 Weeks of 
treatment with 
LDV/SOF 
FDC
12 Weeks of 
treatment with 
LDV/SOF 
FDC
24 Weeks 
of treatment 
with 
LDV/SOF 
FDC
N/A
12 Weeks of 
treatment with 
LDV/SOF 
FDC
12 Weeks of 
treatment with 
LDV/SOF 
FDC
12 Weeks 
of treatment 
with 
LDV/SOF 
FDC
New 
Zealand
12 Weeks of 
treatment with 
LDV/SOF 
FDC
12 Weeks of 
treatment with 
LDV/SOF 
FDC
24 Weeks 
of treatment 
with 
LDV/SOF 
FDC
N/A
12 Weeks of 
treatment with 
LDV/SOF 
FDC
12 Weeks of 
treatment with 
LDV/SOF 
FDC
12 Weeks 
of treatment 
with 
LDV/SOF 
FDC
United 
Kingdom
12 Weeks of 
treatment with 
LDV/SOF 
FDC
12 Weeks of 
treatment with 
LDV/SOF 
FDC
24 Weeks 
of treatment 
with 
LDV/SOF 
FDC
24 Weeks of 
treatment with 
LDV/SOF 
FDC + RBV
12 Weeks of 
treatment with 
LDV/SOF 
FDC
12 Weeks of 
treatment with 
LDV/SOF 
FDC
24 Weeks 
of treatment 
with 
LDV/SOF 
FDC
TN = Treatment Naïve, TE = Treatment Experienced, N/A = Not Applicable
Subjects with GT -1, -3, and -4 were enrolled initially. GT-5 and GT-6 subjects will be included 
in those groups/cohorts actively enrolling subjects given confirmation of benefit:risk in adult 
patients has been obtained. If emerging LDV/SOF FDC data in GT-2 support treatment in adults,
pediatric subjects with GT-2 will be subsequently enrolled. 


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The study will enroll both treatment naïve and treatment experienced pediatric subjects with up 
to 40 subjects allowed to be treatment experienced. Approximately 220 subjects, including 
subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as follows:

Group 1: Approximately 100 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 120 pediatric subjects (3 to < 12 years of age)
The following definitions will be used for treatment experienced subjects:

Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to ≥1 adverse 
event

Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels while 
on treatment

Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment or 
within 4 weeks of the end of treatment but did not achieve a sustained virologic response 
(SVR)
All subjects who do not attain SVR or have viral relapse will be encouraged to discuss treatment 
with SOC therapy with their healthcare provider.
3.2.
Visit Schedule
3.2.1.
PK Lead-in
Screening assessments will be completed within 28 days of the Day 1 visit. 
Study Visits will occur at Screening, Day 1, Day 3, and Day 10.
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in Phase will participate in an 
intensive PK evaluation on Day 10. Subjects will be administered a dosing diary with 
instructions. 
Following completion of the Day 10 intensive PK visit, subjects will then return for scheduled 
study visits outlined in the Treatment Phase and continue dosing with LDV/SOF FDC with no 
interruption of study drug administration. Subjects rolling over from the PK Lead-in Phase will 
not be required to perform the screening, Day 1, or Week 1 visits of the Treatment Phase.


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Amendment 6.0
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3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. Subjects continuing 
from the PK Lead-in Phase will not be required to complete Screening, Day 1, and Week 1 visits 
of the Treatment Phase.

Subjects requiring 12 weeks of treatment: Study visits will occur at Screening, Day 1, and 
the end of weeks 1, 2, 4, 8, and 12.

Subjects requiring 24 weeks of treatment: Study visits will occur at Screening, Day 1, and 
the end of weeks 1, 2, 4, 8, 12, 16, 20, and 24.
All subjects will then return for follow-up visits at 4, 12, and 24 weeks after discontinuation of
therapy.
The total time to complete all study visits is approximately 40 or 52 weeks including:

28 day (4 week) screening period

12 or 24 week treatment period

24 week post-treatment period
The assessments performed at each visit are described in Section 6.
3.3.
Virologic Response-Based Stopping Criteria
HCV RNA will be unblinded to the Investigator and Sponsor.
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 from nadir 

HCV RNA ≥LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination of 
initial observation. Subjects that meet the virologic response-based stopping criteria above will 
be notified of their eligibility to participate in the Long-Term Follow-Up Study 
(GS-US-334-1113).


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Gilead Sciences, Inc. 
3.4. 
Treatment Discontinuations Criteria 
Final 
Amendment 6.0 
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances: 
• 
Unacceptable toxicity (as defmed in Section 7) 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 or female partner of male subject. 
• 
Efficacy failure as defmed in Section 3.3. 
• 
Significant protocol violation including non-compliance with study assessments. 
• 
Subject request to discontinue for any reason; it is imp01tant to detennine 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, regulat01y agency, or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). 
3.5. 
Discontinuations 
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Tennination visit as described in the Section 6.4.9. 
Subjects who pennanently discontinue the study dmg for any reason including safety and/or 
tolerability concems prior to completion of the assigned dosing period will be followed 
according to the post-u·eatment study assessments described in Section 6.5. 
3.6. 
Optional Intensive Pharmacokinetics Substudy 
PD 
3.7. 
Pharmacogenomics Substudy 
CONFIDENTIAL 
Page41 
08 Jnne 2017 


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3.8.
Long-Term Follow-Up
All subjects (those who do or do not attain SVR24) who do not initiate other experimental or 
approved anti-HCV therapy will be followed every 6 months for the first 2 years followed by 
every 12 months for assessments of growth, quality of life, and long-term viral suppression (if 
applicable) in a separate protocol (GS-US-334-1113). This follow-up study will continue for 5 
years.
3.9.
Breakthrough Futility Assessment
A futility assessment will be performed after the first 10 subjects complete Week 8 on study or 
have viral breakthrough at or prior to Week 8. If 3 or more of the first 10 subjects enrolled have 
viral breakthrough at or prior to Week 8 or are non-responders (HCV RNA > LLOQ through 
8 weeks of treatment) then further enrollment of subjects will be suspended. Virologic 
breakthrough is defined as confirmed HCV RNA > LLOQ while on treatment after 
two consecutive visits with HCV RNA < LLOQ.
If a holding rule has been met and following an internal safety review it is deemed appropriate to 
restart enrollment, a request to restart enrollment with pertinent data will be submitted to the 
appropriate regulatory agencies. Enrollment will only resume after review by the appropriate 
regulatory agencies. Any subject on treatment when a holding rule has been met will be allowed 
to continue to treatment.
Subjects with known or suspected study drug non-adherence will not be considered to meet the 
definition of virologic breakthrough, relapse, or non-responder. 
3.10.
Reconsent
When a subject reaches the age of consent in their country/region, they will be invited to consent 
as an adult to allow them to continue participating in the clinical trial.


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Amendment 6.0
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 220 subjects will be enrolled in this study.
In order to manage the total study enrollment, Gilead Sciences, Inc. at its sole discretion, may 
suspend screening and/or discontinue the enrollment at any site at any time (upon written notice 
to the site). Discontinuation of the enrollment phase may result in the immediate ineligibility of 
all subjects screened but not yet enrolled, regardless of the progress or outcome of the screening 
assessments performed.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Parent or legal guardian able to provide written informed consent prior to any screening 
evaluations and willing to comply with study requirements. Subjects will provide assent if 
possible.
2) 3 years to < 18 years of age as determined at Day 1 (consent of parent or legal guardian 
required)
3) PK Lead-in phase only: subjects in Cohort 1 (age 12 to <18 years of age) must weigh 45 kg
4) PK Lead-in phase only: subjects in Cohort 2 (age 6 to <12 years of age) must weigh 17 kg
and < 45 kg
5) PK Lead-in phase only: all subjects must be treatment naïve: no prior exposure to any IFN, 
RBV, or other approved or experimental HCV-specific DAA agent
6) Treatment experienced subjects: prior treatment failure to a regimen including interferon 
either with or without RBV that was completed at least 8 weeks prior to Day 1.
i)
Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to 
≥1 adverse event
ii) Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels 
while on treatment
iii) Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment 
or within 4 weeks of the end of treatment but did not achieve a sustained virologic 
response (SVR)


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7) 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 Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV-infection
8) Infection with HCV as determined at Screening:
a) United Kingdom Only: As of Protocol Amendment 4.0, the study is enrolling GT-1, -3, 
-4, -5, and -6 HCV-infected pediatric subjects and will subsequently enroll subjects with 
GT-2 once adult data is available, if appropriate.
b) United States/ Australia/ New Zealand Only: As of Protocol Amendment 4.0, the study is 
enrolling GT-1, -4, -5, and -6 HCV-infected pediatric subjects and will subsequently 
enroll subjects with GT-2 once adult data is available, if appropriate.
9) HCV RNA ≥1000 IU/mL at Screening
10) Adequate hematologic function (absolute neutrophil count 1,500/mm3; 
hemoglobin 11 g/dL or 12 g/dL for GT-3 males only).
11) Negative serum -HCG pregnancy test (for females of childbearing potential only, as defined 
in Appendix 5)
12) Subject able to provide written assent, if they have the ability to read and write, as 
determined by IRB/IEC/local requirements and Investigator’s discretion
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Pregnant or lactating subjects
2) Sexually-active males or females of childbearing potential who are not willing to use an 
effective method of contraception during the study (see Appendix 5 for further details)
3) Treatment-naïve subjects with GT-3 HCV infection as determined at Screening. Treatment 
naïve is define by no prior exposure to any IFN, RBV, or other approved or experimental 
HCV-specific DAA agent
4) Decompensated liver disease defined as INR 1.2 ULN, platelets 50,000/mm3, serum 
albumin 3.5 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, 
jaundice, encephalopathy, variceal hemorrhage)
5) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)


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6) -fetoprotein 50 ng/mL
7) Serum creatinine > 1.5 mg/dL
8) Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula
9) Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of 
certain resolved skin cancers)
10) Co-infection with HIV, acute HAV, or HBV (i.e. Hepatitis B Surface Ag positive at 
screening)
11) Significant cardiovascular, pulmonary, or neurological disease
12) Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications
13) History of solid organ or bone marrow transplantation
14) Chronic daily non-steroidal anti-inflammatory drug therapy
15) Systemic corticosteroid use for > 2 weeks (pulmonary/nasal administration is permitted)
16) Investigational agents taken within the past 28 days (except with the expressed approval of 
the Sponsor)
17) Clinically-relevant alcohol or drug abuse within 12 months of screening. A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator
18) Known hypersensitivity to the study drug, the metabolites, or formulation excipients
19) Any other condition (including alcohol or substance abuse) or prior therapy that, in the 
opinion of the Investigator, would make the subject unsuitable for the study or unable to 
comply with dosing requirements
20) Use of any prohibited concomitant medications as described in Section 5.6
21) PK Lead-in phase only: subjects with history of cirrhosis (as determined by liver biopsy)
22) 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 enrollment or has not required medication in the last 12 months may be 
included.


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Amendment 6.0
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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
5.2.1.
Description and Handling 
5.2.1.1.
Formulations
5.2.1.1.1.
LDV/SOF FDC 90 mg/ 400 mg tablets
LDV/SOF FDC 90 mg/400 mg tablets are orange, diamond-shaped, film-coated tablets 
containing 90 mg of LDV and 400 mg of SOF. The tablets are debossed with “GSI” on one side 
and “7985” on the other side. The LDV/SOF 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.
Placebo to match LDV/SOF FDC 90 mg/ 400 mg tablets for the Swallowability Assessment are 
orange, diamond-shaped, film-coated tablets debossed with “GSI” on one side and “7985” on the 
other side. The tablets contain lactose monohydrate, copovidone, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, 
polyethylene glycol, FD&C yellow # 6 /sunset yellow FCF aluminum lake.
5.2.1.1.2.
LDV/SOF FDC 22.5 mg/ 100 mg tablets 
Age-appropriate formulations of LDV/SOF FDC have been developed for subjects who are 
unable to swallow the LDV/SOF FDC 90 mg/ 400 mg tablets which include a lower dose 
strength tablet (LDV/SOF FDC 22.5 mg/100 mg) formulation. LDV/SOF FDC lower dose 
strength tablets are round, plain-faced, white film-coated tablets containing 22.5 mg of LDV and 
100 mg of SOF. The LDV/SOF FDC lower dose strength tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc,
and polyethylene glycol.
Placebo to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for the Swallowability Assessment 
are round, plain-faced, white film-coated tablets. The placebo tablets contain the following 
inactive ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc and 
polyethylene glycol.


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Amendment 6.0
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5.2.1.1.3.
LDV/SOF FDC Oral Granules
The LDV/SOF FDC oral granules 11.25 mg/ 50 mg are orange, round, film-coated granules. The 
LDV/SOF FDC oral granules contain the following inactive ingredients: lactose monohydrate, 
copovidone, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, hypromellose, talc, polyethylene glycol, titanium dioxide, iron oxide 
yellow, iron oxide red, and amino methacrylate copolymer.
5.2.1.2.
Packaging and Labeling
5.2.1.2.1.
LDV/SOF FDC 90 mg/ 400 mg tablets
LDV/ SOF FDC 90 mg/ 400 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 or 30 tablets, a silica gel desiccant, and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child resistant screw 
cap with an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 90 mg/ 400 mg tablets for the Swallowability 
Assessment are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 30 tablets, a silica gel desiccant and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child resistant screw cap with an induction-sealed, aluminum 
faced liner.
5.2.1.2.2.
LDV/SOF FDC 22.5 mg/ 100 mg tablets
LDV/SOF FDC 22.5 mg/ 100 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets, a silica gel desiccant, and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child resistant screw cap with 
an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets, 
a silica gel desiccant and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child resistant screw cap with an induction-sealed, aluminum faced liner.
5.2.1.2.3.
LDV/SOF FDC oral granules
The LDV/SOF FDC 11.25 mg/ 50 mg oral granules are packaged in aluminum foil packets. A 
prespecified number of packets will be packaged into cartons for dispensation to subjects at 
clinical sites.
All LDV/SOF FDC tablets, oral granules, and placebo to match LDV/SOF FDC bottles to be 
distributed in the US, EU, and the rest of the countries shall be labeled to meet all applicable 
requirements of the US Food and Drug Administration (FDA), Annex 13 of Good Manufacturing 
Practices: Manufacture of investigational medicinal products (February 2010), and/or other local 
regulations as applicable.


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Amendment 6.0
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5.2.2.
Storage and Handling
LDV/ SOF FDC 90 mg/ 400 mg tablets, 22.5 mg/ 100 mg tablets, and 11.25 mg/ 50 mg packets
should be stored at controlled room temperature until required for administration. Controlled 
room temperature is defined as 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C 
(59 °F to 86 °F).
Placebo to match LDV/SOF FDC tablets, 90 mg/ 400 mg, and 22.5 mg/ 100 mg, for the 
Swallowability Assessment should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25 °C (77 °F); excursions are 
permitted between 15 °C and 30 °C (59 °F to 86 °F). 
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the 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 
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 
LDV/SOF FDC.
Sufficient quantities of LDV/SOF FDC tablets, oral granule packets, and placebo tablets will be 
shipped to the investigator or qualified designee from Gilead Sciences (or its designee).
5.2.3.
Dosage and Administration of LDV/SOF FDC
PK Lead-in Phase: 
Cohort 1: LDV/SOF FDC 90 mg/ 400 mg tablets will be administered once daily with or without 
food. Subjects determined unable to swallow the placebo to match the 90 mg/ 400 mg LDV/SOF 
FDC tablet (via LDV/SOF FDC Placebo Swallowability Assessment at Screening up to Day 1) 
will be re-assigned to 4 × 22.5 mg/ 100 mg tablets daily. Subjects who weigh < 45 kg will be 
excluded.
Cohort 2: LDV/SOF FDC 2 × 22.5 mg/ 100 mg tablets will be administered once daily with or 
without food. Subjects must weigh ≥ 17 kg and < 45 kg.
Cohort 3: LDV/SOF FDC oral granules 45 mg/ 200 mg (4 × 11.25 mg/ 50 mg packets) will be 
administered once daily with or without food for subjects weighing ≥17kg. LDV/SOF FDC oral
granules 33.75 mg/ 150 mg (3 x 11.25 mg/ 50 mg packets) will be administered once daily with 
or without food for subjects weighing <17 kg.
Intensive PK and safety results from the PK Lead-in Phase of each cohort will be reviewed to 
confirm the appropriateness of the evaluated LDV/SOF FDC dose for the Treatment Phase of 
that cohort as well as to determine the age-appropriate dose to be evaluated in the PK Lead-in
phase of the next cohort.


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Amendment 6.0
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Treatment Phase: Subjects who participated in the PK Lead-in Phase of each cohort will continue 
in the Treatment Phase with no interruption of study drug administration until the 
appropriateness of the dose is confirmed by PK and safety data from the PK-Lead-in Phase. 
Additional subjects will be enrolled in the Treatment Phase of each cohort upon confirmation of 
the appropriateness of the dose. 
Subjects should be instructed that if vomiting occurs within 5 hours of dosing an additional tablet 
should be taken. If vomiting occurs more than 5 hours after dosing, no further dose is needed.
If a dose is missed and it is within 18 hours of the normal time, subjects should be instructed to 
take the tablet as soon as possible and then subjects should take the next dose at the usual time. If 
it is after 18 hours then subjects should be instructed to wait and take the next dose at the usual 
time. Subjects should be instructed not to take a double dose.
5.3.
Ribavirin (GT-3 Subjects Only)
5.3.1.
Description and Handling of RBV
5.3.1.1.
Formulation
REBETOL capsules consist of a white powder in a white, opaque, gelatin capsule. Each capsule 
contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose, lactose 
monohydrate (40 mg), croscarmellose sodium, and magnesium stearate. The capsule shell 
contains gelatin, titanium dioxide. The capsule shell imprint contains shellac, propylene glycol, 
ammonium hydroxide, coloring agent (E 132).The hard capsule is imprinted with blue ink.
REBETOL RBV Oral Solution 40 mg per mL is a clear, colorless to pale or light yellow bubble 
gum-flavored liquid. In addition to the active ingredient, RBV oral solution contains the 
following inactive ingredients: sucrose, glycerin, sorbitol, propylene glycol, sodium citrate, citric 
acid, sodium benzoate, natural and artificial flavor for bubble gum #15864, and water.
5.3.1.2.
Packaging and Labeling
The RBV capsules are packaged in blisters. Each blister card contains 20 capsules and seven 
cards (140 capsules) per carton.
The RBV oral solution is packaged in 4-oz amber glass bottles (100 mL/bottle) with 
child-resistant closures.
RBV capsules and oral solution to be distributed to centers in the US, EU and the rest of the 
countries shall be labeled to meet all applicable requirements of the US Food and Drug 
Administration (FDA) and Annex 13 of Good Manufacturing Practices: Manufacture of 
investigational medicinal products (February 2010) and/or other local regulations as applicable.
5.3.1.3.
Storage and Handling
RBV capsules should not be stored above 30C (86 F).
RBV oral solution should not be stored above 30°C (86°F).


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Amendment 6.0
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5.3.2.
Dosage and Administration of RBV (GT-3 Subjects Only)
RBV dose will be administered by weight as follows:
Body Weight kg (lbs.)
RBV Daily Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution. Divided dose in the morning and evening.
47-49 (103-108)
600 mg/day
1 × 200-mg capsules A.M.
2 × 200-mg capsules P.M.
50-65  (110 – 143)
800 mg/day
2 × 200-mg capsules A.M.
2 × 200-mg capsules P.M.
66-80 (145 – 176)
1000 mg/day
2 × 200-mg capsules A.M.
3 × 200-mg capsules P.M.
81-105 (178-231)
1200 mg/day
3 × 200-mg capsules A.M.
3 × 200-mg capsules P.M.
>105 (>231)
1400 mg/day
3 × 200-mg capsules A.M.
4 × 200-mg capsules P.M.
*
Note: Subjects with a body weight greater than or equal to 47 kg may utilize the RBV oral solution if necessary.
The morning dose of RBV will be taken with food and LDV/SOF FDC. The evening dose of 
RBV will be taken with food.
RBV will be supplied by Gilead Sciences for all subjects.
5.4.
Co-administration of LDV/SOF FDC and RBV (GT-3 Subjects Only)
In the Treatment Phase of the study, each subject will be given instructions to maintain 
approximately the same daily dosing interval between study drug doses.
For morning doses, subjects will be instructed to take study drugs as follows:

LDV/SOF FDC

Weight-based RBV (as per Section 5.3.2).
For evening doses, subjects will be instructed to take study drug as follows:

Weight-based RBV (as per Section 5.3.2).
If a subject forgets to take the study medication at the correct time, it may be taken later in the 
day; however, no more than the protocol specified dose of LDV/SOF FDC should be taken on 
any calendar day. The subject should resume the standing dosing schedule on the next day. Study 
medications should not be cut or split. 


LDV/SOF FDC
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Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
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08 June 2017
5.5.
Study Drug Compliance
Subjects will be instructed to return any unused LDV/SOF FDC and/or RBV in the original 
container on Day 3 (PK Lead-in), Day 10 (PK Lead-in), and/or at study treatment visits every 
4 weeks (Treatment Phase). 
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.6.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 30 days 
after the last dose of study drug, need to be recorded in the source documents and electronic case 
report form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment:

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

Drugs disallowed per prescribing information of REBETOL® for GT-3 subjects only
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters i.e., P-gp) with study drug(s) may result in PK interactions resulting in 
increases or decreases in exposure of study drug(s). Examples of representative medications 
which are prohibited from 21 days prior to Day 1 through the end of treatment are listed 
below (Table 5-1). In addition, the use of amiodarone is prohibited from 60 days prior to 
Baseline/Day 1 through the end of treatment.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 52
08 June 2017
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton- Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsc
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Cardiac Medications
Amiodaronee
Digoxinb, Dabigatranb
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinacea, Milk thistle 
(i.e., 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 LDV/SOF FDC administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF FDC at a dose that does not exceed doses comparable to
famotidine 40 mg twice daily. Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with LDV/SOF FDC or up to 2 hours after taking LDV/SOF FDC. Proton-pump inhibitors should not be 
taken before LDV/SOF FDC. 
b
May result in an increase in the concentration of study drug and/or concomitant medications. Co-administration of 
LDV/SOF FDC with digoxin or dabigatran may increase the concentration of digoxin or dabigatran. Caution is warranted 
and therapeutic concentration monitoring of digoxin or clinical monitoring of dabigatran is recommended when 
co-administered with LDV/SOF FDC. 
c
May result in a decrease in the concentrations of study drug.
d
Use with study drug 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.
e
May result in symptomatic bradycardia. Mechanism is not currently known. The use of amiodarone is prohibited from 
60 days prior to Baseline/Day 1 through the end of treatment.
Medications for disease conditions excluded from the protocol (e.g., active cancer, 
transplantation) are not listed under this Concomitant Medication section and are disallowed in 
the study.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 53
08 June 2017
6.
STUDY PROCEDURES
All subjects will complete screening, on-treatment, and post-treatment assessments. Screening 
assessments will be completed within 28 days of the Day 1 visit. The end of study will occur at 
the 24-week Post-Treatment visit. The schedule of assessments is described below. 
Information on the specific laboratory parameters to be measured and clinical assessments to be 
performed are provided in Section 6.6.
6.1.
Subject Enrollment 
Each candidate’s parent or legal guardian must sign an Informed Consent Form prior to the
conduct of any screening procedures. Each study candidate who has the ability to read and write
must sign an Assent Form, as required by IRB/IEC/local requirements, prior to the conduct of 
any study procedures. Screening evaluations will be used to determine the eligibility of each 
candidate for study enrollment. Candidates who fail to meet eligibility criteria by screening 
evaluations may be re-screened once ≥ 30 days after the initial screen if there is a reasonable 
expectation that the candidate will be eligible after repeat screening.
6.2.
Screening Assessments
6.2.1.
Screening Visit (Day –28 to Day 0)
Subjects will complete all screening assessments within 28 days of the Day 1 visit. The screening 
window can be extended to 42 days for subjects requiring additional HCV GT testing or for 
extenuating circumstances.
The following procedures will be performed and documented:

Written informed consent from parent or legal guardian and assent from subject, if applicable 
(see above)

Medical history, including:
Hepatitis C history
Hepatitis C treatment history
Family history (including height of parents, if known)
Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate) and body weight and height


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 54
08 June 2017

Obtain blood samples for tests as listed in Section 6.6.1:
Hematology
Chemistry
Coagulation tests
HCV RNA
Determination of HCV viral GT and subtype
HCV antibody, HIV 1/2 antibody, HBV surface antigen (HBsAg), HBV surface antibody 
(HBsAb), HBV core antibody (HBcAb), and HAV antibody
HbA1c
TSH
IL28B
Serum -hCG pregnancy test for females of childbearing potential only
Alpha fetoprotein (AFP)
Alpha-1 anti-trypsin (ATT)

Obtain urine sample for:
Urinalysis
Urine Drug Screen

Review of concomitant medications

Ask subject and/or parent/legal guardian if the subject is able to swallow and tolerate taking 
pills.

Review of all inclusion and exclusion criteria

Perform LDV/SOF FDC swallowability assessment, as applicable 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the Day 1 visit assessments.


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
6.3. 
PK Lead-in: Treatment Assessments 
6.3.1. 
Day l 
Final 
Amendment 6.0 
After confnmation of eligibility has been evaluated, the following tests and procedmes must be 
completed prior to emollment and dosing/dispensing on Day 1: 
• 
Perf01m complete physical examination 
• 
Tanner Pubertal Stage Assessment 
• 
Vital signs, including body weight and height measmements 
• 
A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pruiicipants (all subj ects ~ 12 yeru·s of age and subjects < 12 yeru·s of age at the discretion of 
the Investigator based on subject's pube1ial status) 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (ru·chive) 
-
HBV DNA testing for subjects HBcAb positive at Screening 
_ 
PD 
• 
Obtain mine samples for the following procedmes: 
-
Urinalysis 
-
~-hCG pregnancy test for females of childberu·ing potential only 
• 
Subject completes quality of life smvey: Subject is to review questionnaire with a 
pru·ent/guru·dian and write/mru·k answers directly onto the questionnaire. 
CONFIDENTIAL 
Page 55 
08 Jnne 2017 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 56
08 June 2017
6.3.1.1.
Drug Administration

Dispense study drug(s) as directed by the IWRS

Instruct the subject on the packaging, storage and administration of study drug

Perform LDV/SOF FDC swallowability assessment (for subjects administered LDV/SOF 
FDC in tablet form only if not previously completed at screening). Observe the subject taking 
the first dose of study drug (with or without food) and record the time of first dose

Subjects will be administered a dosing diary with instructions.
6.3.2.
Day 3
The following procedures/assessments are to be completed on Day 3:

Perform a symptom-directed physical examination as needed

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Review medication compliance with subject and/or subject’s parent/guardian

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 10 – Intensive PK
The Day 10 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 10 Intensive PK visit may 
be performed within +3 days of the protocol-specified visit date (subjects will continue 
daily dosing through the Intensive PK Visit).
Subjects should come in a fasted state for the Day 10 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 10 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 10 dose of LDV/SOF FDC must not be taken 
until the evaluations listed below are completed. 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 57
08 June 2017
If the subject has already dosed prior to the Day 10 clinic visit or is not in a fasted state, the 
Day 10 intensive PK assessments must not be completed. The subject and/or parents/guardians 
should be instructed to return in a fasted state within 3 days (Days 11, 12, or 13) for the intensive 
PK visit. 
If dosing non-compliance is identified as per subject dosing diary and study drug count on or 
prior to the Day 10 visit, the Day 10 intensive PK assessments must not be completed. The 
subject and/or parents/guardians should be counseled regarding proper dosing and be scheduled 
to return for the Day 10 intensive PK visit no sooner than 3 days following compliant dosing and 
no later than Day 14 (i.e., return on Day 13 or Day 14). If dosing non-compliance is due to an 
AE, consultation with the Gilead Medical Monitor is required regarding the potential of 
rescheduling the Day 10 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded not 
to take the LDV/SOF FDC prior to arriving at the clinic on the day of the re-scheduled intensive 
PK visit. All Day 10 intensive PK assessments listed below should be completed when the 
subject returns.
The following evaluations are to be completed at the Day 10 Intensive PK visit:

Perform a symptom-directed physical examination 

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Perform study drug accountability 

Review Subject Dosing Diary

Review medication compliance with subject and/or parent/guardian.

Obtain urine samples for the following procedures:
Urinalysis
Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test 
is positive, the Intensive PK sampling will not be completed. The positive result will be 
confirmed with a serum pregnancy test. 

Obtain blood samples for the following laboratory analyses:
Hematology 
Chemistry 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 58
08 June 2017
Coagulation tests
HCV RNA
Viral sequencing (archive)

Perform intensive PK sampling: 
Blood samples will be collected at 0 (predose, ≤30 minutes prior to dosing). After 
collection of the predose sample, subjects will be provided a standardized meal. Within 
5 minutes after consuming the standardized meal, subjects will be dosed with 
LDV/SOF FDC per dosing requirements.
Post-dose blood samples will be collected as follows: 
■
For Cohorts 1 and 2: 0.5, 1, 2, 3, 4, 5, 8, and 12 hours post-dose (with predose also 
serving as t= 24).
■
For Cohort 3 only: 0.5, 2, 4, 8, and 12 hours post-dose (with predose also serving as 
t = 24).
Subjects will be restricted from food intake until after collection of the 4-hour post dose 
blood sample, except for subjects in Cohort 3. Please also refer to the PK manual for 
details about standardized meals and PK sample processing instructions.
After completing the Day 10 intensive PK visit subjects will then continue to the Week 2 visit in 
Treatment Phase (described in Section 6.4.2) with no interruption in dosing.
6.4.
Treatment Phase: Treatment Assessments 
6.4.1.
Day 1
After confirmation of eligibility has been evaluated, the following tests and procedures must be 
completed prior to enrollment and dosing/dispensing on Day 1:

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements 

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Review of AEs and concomitant medications


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Final 
Amendment 6.0 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pmiicipants (all subj ects ~ 12 years of age and subjects < 12 yem·s of age at the discretion of 
the Investigator based on subject's pubertal status). 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (m·chive) 
-
HBV DNA testing for subjects HBcAb positive at Screening 
_ 
PD 
• 
Obtain urine sample for: 
-
Urinalysis 
-
~ -hCG pregnancy test for females of childbem·ing potential only 
• 
Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mm·k answers directly onto the questionnaire 
• 
Perf01m LDV/SOF FDC swallowability assessment (for subjects administered 
LDV /SOF FDC in tablet f01m only if not previously completed at screening) 
• 
Perf01m LDV/SOF FDC oral granules palatability assessment, for Treatinent Group 2 
subjects from 3 to < 6 years of age, as applicable. 
6.4.1.1. 
Dmg Adminisu·ation 
• 
Dispense study dmg as directed by the IWRS 
• 
GT-3 subjects only: Instiuct the subject on the appropriate RBV dose after weight-based 
dosage is calculated using Day 1 weight 
• 
Instiuct the subject on the packaging, storage, and adminisu·ation of study dmg 
• 
Observe the subject taking the first dose of study dmg (with or without food) and record the 
time of fust dose 
CONFIDENTIAL 
Page 59 
08 Jnne 2017 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
6.4.2. 
Weeks 1 and 2 (± 3 days) 
Final 
Amendment 6.0 
Subjects who patticipated in the PK Lead-in phase will strut study visits in the Treatment Phase 
at Week 2. The following procedures/assessments are to be completed at these visits: 
• 
Vital signs, including body weight and height measurements 
• 
Perf01m symptom-directed physical examination 
• 
Assessment of AEs and concomitant medications 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (m·chive) 
-
Single PK collected at any time point 
6.4.3. 
Weeks 4 and 8 (± 3 days) 
• 
PD 
• Vital signs, including body weight and height measurements 
• Perf01m symptom-directed physical examination 
• Assessment of AEs and concomitant medications 
• Obtain blood samples for 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
CONFIDENTIAL 
Page 60 
08 Jnne 2017 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 61
08 June 2017
Viral sequencing (archive)
A single PK sample will be collected between 15 minutes to 4 hours post-dose, as 
applicable 
HBV DNA testing for subjects HBcAb positive at Screening

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS
6.4.4.
Week 12 (± 3 days) - Subjects on 12 Week Treatment Regimen Only

Perform complete physical examination

Tanner Pubertal Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single PK collected at any time point


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 62
08 June 2017
HBV DNA testing for subjects HBcAb positive at Screening

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles of study drug at the Week 12 Visit
6.4.5.
Week 12 (± 3 days) - Subjects on 24 Week Treatment Regimen Only

Perform symptom-directed physical examination

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK collected at any time point
HBV DNA testing for subjects HBcAb positive at Screening

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 63
08 June 2017
6.4.6.
Week 16 and 20 (± 3 days) – Subjects on 24 Week Treatment Regimen Only

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single PK collected at any time point
HBV DNA testing for subjects HBcAb positive at Screening

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should return all 
study drug at these visits)

Dispense study drug as directed by the IWRS
6.4.7.
Week 24 (± 3 days) – Subjects on 24 Week Treatment Regimen Only

Perform complete physical examination

Tanner Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject’s pubertal status)


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (archive) 
-TSH 
-
Single PK collected at any time point 
-
HBV DNA testing for subjects HBcAb positive at Screening 
• 
Obtain urine sample for: 
-
~-hCG pregnancy test for females of childbearing potential only 
Final 
Amendment 6.0 
• 
Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire 
• 
Review medication compliance with subject and/or parent/guardian. 
• 
Subjects should retum all bottles and blister cards (if applicable) of study dmg at the 
Week 24 Visit 
6.4.8. 
Optional Intensive Pharmacokinetics (PK) Substudy 
PPD 
I 
I 
CONFIDENTIAL 
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08 Jnne 2017 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
PD 
I 
I 
I 
I 
I 
I 
I 
I ·-
• 
·-
·-
• ·-
• 
CONFIDENTIAL 
Page 65 
Final 
Amendment 6.0 
08 Jnne 2017 


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
• PD 
I 
I 
I 
6.4.9. 
Unscheduled Visit/Early Termination Visit 
Final 
Amendment 6.0 
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments are at the investigator's discretion. 
The Sponsor/CRO should be inf01med when a subject comes off u·eatment due to an adverse 
event. If a subject discontinues u·eatment then the assessments outlined below should be 
perfonned. 
• 
Perf01m complete physical examination 
• 
Tanner Pube1ial Stage Assessment 
• 
Vital signs, including body weight and height measurements 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pruiicipants (all subj ects ~ 12 yeru·s of age and subjects < 12 yeru·s of age at the discretion of 
the Investigator based on subject's pube1ial status) 
• 
Obtain blood srunples for: 
-
Hematology 
-
Chemistry 
-
Coagulation tests 
CONFIDENTIAL 
Page 66 
08 Jnne 2017 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 67
08 June 2017
HCV RNA
Viral sequencing (archive)
TSH
Single PK collected at any time
HBV DNA testing for subjects HBcAb positive at Screening

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles and/or blister cards (if applicable) of study drug at the Early 
Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as described in 
Section 6.5.
6.5.
Post-Treatment Assessments
6.5.1.
4-Week Post-Treatment Visit (± 5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for: 
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)
HBV DNA testing for subjects HBcAb positive at Screening


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 68
08 June 2017

Obtain urine sample for:
-hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status) 
Female subjects of childbearing potential on treatment with LDV/SOF FDC + RBV should be 
provided with Urine Pregnancy Test-Kits, instructed on their use, and requested to continue to 
self-monitor for pregnancy for 6-months after their last dose of RBV. If required by local 
regulations, additional pregnancy tests beyond 6 months may be added. The subject should be 
contacted every 4 weeks and asked to report results of the urine pregnancy tests. If a positive 
urine pregnancy test is reported, the subject should return to the clinic for a serum pregnancy 
test.
6.5.2.
12-Week Post-Treatment Visit (± 5 days)

Vital signs, including body weight and height measurements

Perform symptom-directed physical examination

Assessment of SAEs

Perform Tanner Pubertal Stage assessment

Obtain blood samples for 
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)
HBV DNA testing for subjects HBcAb positive at Screening

GT-3 subjects only: Obtain urine sample for -hCG pregnancy test for females of 
childbearing potential only

GT-3 subjects only: Pregnancy prevention counseling including partner pregnancy
prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age 
at the discretion of the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire


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6.5.3.
24-Week Post-Treatment Visit (± 5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of SAEs

Tanner Pubertal Stage Assessment

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Obtain blood samples for 
HCV RNA
Viral sequencing (archive)
HBV DNA testing for subjects HBcAb positive at Screening

GT-3 subjects only: Obtain urine sample for -hCG pregnancy test for females of 
childbearing potential only

GT-3 subjects only: Pregnancy prevention counseling including partner pregnancy 
prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age 
at the discretion of the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire.
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed every 6 months for the first 
2 years followed by every 12 months for assessments of growth, quality of life, and long-term 
viral suppression (if applicable) in a separate protocol (GS-US-334-1113). This follow-up will 
continue for 5 years.
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) 


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Chemistry Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct Bilirubin), Glucose, 
Lipase, Potassium, Sodium, Gamma-glutamyl transferase (GGT), alpha fetoprotein (AFP), 
alpha-1 anti-trypsin, creatine kinase (CK) and amylase.
Urinalysis: Appearance, Blood, Color, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV and HBV (HBsAg, HBsAb, HBcAb) and HAV; serology 
for HIV (including reflex testing as necessary). HCV RNA will be measured using the COBAS®
AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System. HCV GT
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 GT should the 
above assays become unavailable.
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 alternate assays 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum -hCG, Urine -hCG (if positive, requires immediate confirmation with 
Serum -hCG)
Additional Tests: Urine Drug Screen (for amphetimines, cocaine, methadone, opiates), 
Hemoglobin A1c (HbA1c), TSH (reflex Free T4), Alfa fetoprotein (AFP), Alpha-1 anti-trypsin
(AAT).
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. Parental heights will be recorded at Screening.
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; and neurological. 
6.6.4.
Tanner Pubertal Stage Assessment
The Tanner Stage scale is available in Appendix 4. All subjects will receive a baseline Tanner 
Pubertal Stage Assessment. If the assessment determines that the subject is at a Tanner 5 at 
Day 1, no further Tanner Pubertal Stage Assessments are to be completed. 


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6.6.5.
Height & Weight Measurement
Height and weight measurement will be collected at each study visit. The difference in body 
weight and height measurements between Day 1 and End of Treatment, post-treatment Week 12, 
and post-treatment Week 24 will be calculated. 
6.6.6.
Bone Age Assessment
A single X-ray of the left wrist, hand, and fingers will be performed at Day 1 Visit and 
post-treatment Week 24. Local radiologist will determine bone age from x-ray.
6.6.7.
Acceptability Assessment
A LDV/SOF FDC swallowability assessment as applicable will be performed at screening up to 
Day 1. Subjects who have indicated that they can take tablets will be observed taking a placebo 
to match the 90 mg/ 400 mg LDV/SOF FDC tablet. This will confirm the swallowability of the 
90 mg/ 400 mg tablet size. If a subject is unable to swallow the 90 mg/ 400 mg LDV/SOF FDC 
tablet size, he/she will repeat the assessment with a placebo for the 22.5 mg/ 100 mg 
LDV/SOF FDC tablet. If unable to swallow the 22.5 mg/ 100 mg LDV/SOF FDC tablet, the 
subject will be dosed with the oral granule formulation.
Palatability of LDV/SOF FDC oral granules will be assessed in subjects 3 to <6 years of age, at 
Day 1, as applicable. 
6.6.8.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for ≥5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.
6.6.9.
Estimated Glomerular Filtration Rate (GFR)
Estimated Glomerular Filtration Rate (GFR) using Schwartz Formula (mL/min/1.73m2) = 
k × L/Scr [(k is a proportionality constant, for adolescent females ≥12 years old is 0.55; for 
adolescent males ≥12 years old is 0.70; and for female and male children 3 to < 12 years old is 
0.55); L is height in centimeters (cm); and Scr is serum creatinine (mg/dL)]


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6.6.10.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
Unused samples may be archived.
6.6.11.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every 4 weeks during the 
dosing period and for a minimum of 6 months following the last dose of RBV or for a minimum 
of 30 days following the last dose of LDV/SOF FDC if not taking RBV. If required by local 
regulations, additional pregnancy tests beyond 6 months for RBV or 30 days for subjects not 
taking RBV may be added. In the event of a positive urine pregnancy result, subjects will be 
instructed to stop study drug immediately (if applicable) and return to the clinic as soon as 
possible for a serum pregnancy test.
GT-3 subjects only: Pregnancy test kits will be dispensed to female subjects of child bearing 
potential at the 4 Week Post-Treatment visit. The subject will be contacted by telephone monthly 
to confirm that urine pregnancy testing has been performed post-treatment and to record the 
outcome. Alternatively, if required by local regulations or preferred by the investigator or 
subject, the subject may return to the clinic for urine pregnancy tests.
6.6.12.
Quality of Life Survey (PedsQL™)
The PedsQL™Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be completed at 
Day 1, End of Treatment, Early Termination (if applicable), 12-Week Post-Treatment, and 
24-Week Post-Treatment visits.
The PedsQL™has separate survey instruments administered by age group, including the
Teen Report (ages 13-18), Child Report (ages 8-12), Young Child Report (ages 5-7), and 
Toddlers (ages 2-4). Each survey accompanied by the respective parent proxy survey will be 
administered to the subject and their parent/legal guardian (with the exception of the Toddlers 
Report which will only be completed by the parent/legal guardian) for the current age group at 
the time of survey administration.


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7.
TOXICITY MANAGEMENT
7.1.
Modification of Dose/Schedule Due to Toxicity
Dose reduction of RBV (GT-3 subjects only) due to toxicity should be performed according to 
the product label. Information is provided in Table 7-1.
Table 7-1.
RBV Dose Reduction Guidelines
Laboratory Values
Reduce RBV Dose by 200 mg/daya if:
Discontinue RBV if:
Hemoglobin in subjects with no 
cardiac disease
<10 g/dL
<8.5 g/dL
Hemoglobin in subjects with 
history of stable cardiac disease
≥2 g/dL decrease in hemoglobin during any 
4 week period treatment
<12 g/dL despite 4 weeks at 
reduced dose
a
Dose reduction in pediatric patients taking the oral solution is accomplished by modifying the recommended RBV dose 
from original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed.
7.2.
Subject Stopping Rules for LDV/SOF FDC and RBV
The Gilead Medical Monitor should be consulted prior to dose discontinuation of LDV/SOF 
FDC unless the investigator believes that immediate action is warranted to ensure the continued 
safety of the subject.
Administration of LDV/SOF FDC may be discontinued due to a clinical or laboratory event. 
There is no option for LDV/SOF FDC dose reduction. If LDV/SOF FDC is stopped for toxicity, 
it should not be restarted, RBV should be stopped (GT-3 subjects only), and the subject should 
complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria must stop treatment with LDV/SOF 
FDC:

Elevation of ALT and/or AST >5× Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT >3× Day 1 and total bilirubin >2 × ULN, confirmed by 
immediate repeat testing

Confirmed elevation of ALT >15 × ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with LDV/SOF FDC


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8.
ADVERSE EVENTS MANAGEMENT
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
8.1.1.
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-mandated procedures, 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 8.5.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history CRF
8.1.2.
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.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., 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 (e.g., 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 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
8.2.
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.
8.2.1.
Assessment of Causality for Study Drug and Procedures
The investigator or qualified sub-investigator 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 investigational 
medicinal product. For SAEs, an alternative causality must be provided (e.g., pre-existing 
condition, underlying disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures (e.g.., venipuncture)
8.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4 weeks after last administration of study drug 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 protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of causal relationship, that occurs after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required 24-week 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
after informed consent is signed.


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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. Investigators are not 
obligated to actively seek SAEs after the 24 week post-treatment follow-up period. However, if 
the investigator learns of any SAEs that occur after study participation has concluded and/or if 
patient is enrolled into the long term follow-up registry study (GS-US-334-1113), and/or eCRF 
database has been locked, and the event is deemed relevant to the use of IMP, he/she should 
promptly document on paper SAE form and report the event directly to Gilead DSPH within 
24 hours of awareness. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com; or
Fax: +1 (650) 522-5477
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, i.e., the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours to:
Gilead Sciences, Drug Safety and 
Public Health:
Fax:
E-mail:
+1 650 522-5477
Safety_FC@gilead.com

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.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
report form.


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8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
8.5.
Special Situations Reports
8.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE. 
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging or distribution of the medicinal product. 


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8.5.2.
Instructions for Reporting Special Situations
8.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (i.e., signs the informed consent) and throughout the study, including the 
post-treatment follow-up period, to Gilead DSPH using the pregnancy report form within 
24 hours of becoming aware of the pregnancy.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., 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 
Sections 8.1 and 8.3. Furthermore, any SAE occurring as an adverse pregnancy outcome 
post study must be reported directly to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 or Fax: +1 (650) 522-5477.
Pregnancies of female partners of male study subjects exposed to Gilead or other study drug
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy report form and pregnancy outcome report forms within 24 hours. Monitoring of the 
partner pregnancy 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. 
Clinical staff should also report any pregnancies to the Ribavirin Pregnancy Registry at 
1 800-593-2214 (see also http://www.ribavirinpregnancyregistry.com).
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
8.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 


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Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management and outcome will be reported, when available.


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9.
STATISTICAL CONSIDERATIONS
9.1.
Analysis Objectives and Endpoints
9.1.1.
Analysis Objectives
The primary objective of PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm the dose of LDV/SOF FDC
in chronic HCV-infected pediatric subjects
The secondary objective of PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing of 
LDV/SOF FDC in chronic HCV-infected pediatric subjects
The primary objective of Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC +/- RBV for 12 or 24 weeks in 
chronic HCV-infected pediatric subjects
The secondary objectives of Treatment Phase of this study are:

To determine the antiviral efficacy of 12 and 24 weeks of LDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects (including the impact of HCV genotype, IL28B genotype, 
and prior treatment experience), as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12)

To determine the antiviral efficacy of 12 and 24 weeks of LDV/SOF FDC +/- RBV treatment 
in chronic HCV-infected subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during treatment and after completion of 
treatment

To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment

To evaluate acceptability assessed by swallowability of tablets and palatability of granules

To evaluate the effect of growth and development on pediatric subjects during and after 
treatment


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
The explorat01y objective of this study is: 
• 
PD 
9.1.2. 
Primary Endpoints 
Final 
Amendment 6.0 
For the PK Lead-in Phase, the appropriateness of the LDV /SOF FDC dose will be assessed by 
evaluating the steady-state PK of the LDV/SOF FDC. The primruy endpoint for detennining 
steady state PK is AUCtau of GS-331 007, SOF, and LDV. Additional steady-state PK pru·ameters 
of GS-331007, SOF, and LDV (e.g., AUC!ast, Cmax, Tmax, Clast, Tlast, Ctau, 'Az, CLIF, VzJF and tv.) 
will be estimated and summru·ized as described in Section 9.4. 
For the Treatment Phase, the primruy safety endpoint is any AE leading to pennanent 
discontinuation of study dmg (s). 
9.1.3. 
Secondary Endpoints 
For the PK Lead-in Phase, the secondruy endpoint will include antiviral activity measmements, 
including assessment ofHCV RNA. AEs leading to pe1m anent discontinuation of study dmg will 
be evaluated as a secondaty safety endpoint. 
For the Treatment Phase, the key efficacy endpoint is SVR12 and secondruy efficacy endpoints 
include SVR4, SVR24, breakthrough and relapse. Additional efficacy evaluations may include 
HCV RNA change from Day 1; AL T nonnalization; and viral kinetic pru·ameters. Secondaty 
safety endpoints of growth and development measmements will be assessed (e.g. height, weight, 
and Tanner Stage Assessment). Other seconda1y endpoints include acceptability assessed by 
swallowability of tablets and palatability of granules. 
9.2. 
Analysis Conventions 
All individual subject data will be listed as measmed. All statistical summru'ies and analyses will 
be perfonned using SAS® software (SAS Institute, Cruy, North Cru·olina, USA). 
9.2.1. 
Analysis Sets 
9.2.1.1. 
Phrum acokinetics (PK) Analysis Sets 
Intensive PK Analysis Set 
The intensive PK Lead-in analysis set will include all PK Lead-in phase subjects who received at 
least one dose of study dmg and for whom at least one non-missing PK concentration data, 
dming the intensive sampling period, rep01ted by PK lab. The PK analysis set will be used for 
detailed phrum acokinetic analysis ofLDV, SOF, and metabolites. 
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Sparse PK Analysis Set 
Final 
Amendment 6.0 
The PK analysis set will include all enrolled subjects who received at least one dose of study 
dmg and for whom at least one observed concentration data of LDV, SOF, or GS-331 007 are 
available. The PK analysis set will be used for analysis of general PK and single sample plasma 
concentrations. 
9.2.1.2. 
Safety Analysis Set 
The prima1y analysis set for safety analyses will include subjects who have received at least one 
dose of study dmg. 
Treatment-emergent data will be analyzed and defmed as data collected from the first dose of 
study dmg through the date of last dose of study dmg plus 30 days. 
9.2.1.3. 
Efficacy Analysis Set 
The analysis set for antiviral activity analyses will be the Full Analysis Set (F AS) which includes 
HCV -infected subjects who were enrolled and have received at least one dose of study dmg. 
9.2.2. 
Data Handling Conventions 
Natural logarithm transf01m ation for key PK parameters, such as Cmax and AUCtau, will be 
applied for phannacokinetic analysis. 
The PK concentration values below the limit of quantitation (BLQ) will be treated as zero for the 
dete1mination of suminaty and order statistics. Individual values that m·e BLQ will be presented 
as "BLQ" in the concentration data listing and will be excluded in any calculation of geometric 
means or ratios. For the presentation of summmy and order statistics, if at least 1 subject has a 
concentration value BLQ for the time point, then the minimum value will be displayed as 
"BLQ". If more than 50% of the subjects have a concentration data value BLQ for the time 
point, then the minimum and median values will be displayed as "BLQ". If all subjects have 
concentration data values BLQ for the time point, then all order statistics (minimum, first 
qumi ile [Q1], median, third qumtile [Q3], maximum) will be displayed as "BLQ". 
Missing data can have an impact upon the inte1pretation of the trial data. Other than the 
endpoints discussed below, 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 
preceded and followed in time by values that m·e deem successes, then the missing data point 
will be tenned a success; othe1w ise the data point will be tenned a failure. 
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Any subject with missing data due to premature discontinuation of the study medication will be 
considered a failure at the time points subsequent to 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).
9.2.3.
Interim Analysis
Interim analyses may be performed to provide treatment regimen and duration recommendations
for adolescent subjects (12 to < 18 years of age).
There will be no changes to the study design, study conduct, or the sample size as a result of the 
interim analysis.
9.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by age group and overall for PK Lead-in phase and for Treatment Phase, respectively.
Demographic data will include sex, self-identified race/ethnicity, and age.


LDVISOFFDC 
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Final 
Amendment 6.0 
Baseline characteristic data will include body weight, height, body mass index, HCV RNA level 
(log10 ID/mL), HCV genotype, prior treatment experience, and additional endpoints as necessmy. 
9.4. 
Pharmacokinetic Analysis 
erfonned for PK Lead-in phase using the intensive PK Lead-in analysis set. 
The concentration data 
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and summm·ized by nominal time and coh01t. Phmmacokinetic pm·ameters (e.g., AUC~au, AUC1ast, 
Cmax, Tma.x, Clast, Tlast' Ctau' 'Az, CLIF, Vz/F and tv,) will be listed and summm·ized for LDV, SOF, 
and metabolites (as applicable) using descriptive statistics (e.g., sample size, arithmetic mean, 
geometric mean and its 95% confidence interval, coefficient of vm·iation %, standai·d deviation, 
median, Q1, Q3, minimum, and maximum) by coh01t and overall. Plasma concentrations over 
time will be plotted in seinilogarithmic and linear fonnats as mean ± standai·d deviation and 
median (Q1, Q3). 
To evaluate if the steady-state PK of GS-331007, SOF, and LDV achieved in pediatric subjects 
ofthis study m·e siinilm· to the exposmes observed in adult subjects (Table 9-1), the GS-331007, 
SOF, and LDV exposme data. from this study will be compared to the integrated adult data .. The 
primmy endpoint of this analysis will be evaluated by cm1ying out an analysis of variance 
(ANOVA) for log-transf01med GS-331007, SOF, and LDV AUCtau· The 90% confidence 
intervals will be constmcted for the ratio of geometric means of each PK pm·ameters. The 
equivalence boundmy is set as 50% to 200%. 
Given that dose ranging studies for SOF established that a dose of 200 mg results in suboptimal 
exposme compared to the 400 mg dose, and the lack of clinically significant exposme-safety 
relationships observed across a broad range of GS-331007 and SOF exposme, bounds of 50% to 
200% for GS-331007 and SOF AUCtau will allow identification of a clinically relevant difference 
in exposme in the pediatric population. 
A phase 2 study evaluating LDV doses of 30 or 90 mg LDV in combination with DAAs 
VDV+TGV+RBV suggested LDV exposme may be suboptimal at the 30 mg dose based on the 
incidence of virologic breakthrough being approximately half in the 90 mg mm; as such the 
90 mg dose was selected for fmther development. In the 90 mg LDV mm of this study, the LDV 
AUCtau at the 25 percentile was 3230 hr*ng/mL. While this value is 62% lower than the mean 
LDV AUCtau (8530 hr*ng/mL) observed in adult HCV-infected subjects in the LDV/SOF FDC 
Phase 2/3 population, it provides - 99.8% of maximal viral load reduction ( exposme-response 
model established in the monotherapy proof of concept study). In the Phase 2/3 population when 
administered the LDV/SOF FDC, there was a lack of clinically significant exposure-efficacy or 
safety relationships observed across the broad range of LDV exposme. Taken together these data 
supp01t the utility ofbmmds of 50% to 200% for LDV AUCrnu to identify a clinically relevant 
difference in LDV exposme in the pediatric population. 
In all pediatric age groups, the tm·geted exposmes for GS-331007, SOF, and LDV are the adult 
equivalent for which safety and efficacy has been established. In the absence of any pediatric PK 
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information (i.e., variability and exposure of GS-331007, SOF, or LDV is unknown) assuming a 
2-fold higher variability, or a 30 % difference in GS-331007, SOF, or LDV AUCtau in the 
pediatric population compared to adults, the predicted 90% CIs of the geometric mean ratio 
(GMR) will be contained within the bounds of 50% to 200%.
Individual patient management will be performed by maintaining exposures comparable to 
adults. In the event more than one subject in each cohort exhibits GS-331007, SOF, or LDV 
exposures (AUCtau) less than the 2.5th percentile of adult values, a dose assessment may be 
require for the cohort as appropriate.
The effect of age and LDV/SOF FDC dose on PK (LDV, SOF and GS-331007) will be assessed.
Table 9-1.
GS-331007, SOF, and LDV PK Parameters after Once-Daily 
Administration of LDV/SOF FDC in HCV-Infected Adults Subjects 
(Population PK Analysis from Phase 2 and 3 Studies)
Mean (%CV) PK Parametera
GS-331007 (N=2113)
SOF (N=1542)
LDV (N=2113)
AUCtau (ng•h/mL)
12,500 (29.2)
1380 (34.0)
8530 (60.8)
Cmax (ng/mL)
736 (28.2)
659 (34.0)
364 (51.4)
Ctau (ng/mL)
N/A
N/A
247 (59.2)
a
Pharmacokinetic parameters are presented as mean (%CV) and are shown to 3 significant digits.
9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in Phase and for Treatment Phase respectively. 
Safety data will be summarized by age group and overall for PK Lead-in Phase and by treatment
regimen for each age group for the Treatment Phase.
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital 
signs measurements, and by the documentation of AEs.
All safety data collected while on or after the first dose of study drug administration up to 
30 days after the last dose of study drug will be summarized according to the study drug 
received.
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.
9.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the CRF. Exposure data will be summarized.


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9.5.2.
Adverse Events
Clinical and laboratory AEs 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 adverse event with an onset date on or after the study drug 
start date and no later than 30 days after permanent discontinuation of the study drug or any 
adverse event leading to premature discontinuation of the study drug. 
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC 
and preferred term) will be provided by cohort:

All AEs,

All treatment-related AEs,

Combined Grade 2, 3 and 4 AEs,

Combined Grade 3 and 4 AEs,

Combined Grade 2, 3 and 4 treatment-related AEs,

Combined Grade 3 and 4 treatment-related AEs,

All AEs that caused permanent discontinuation from study drug,

All AEs that caused change in dose or temporary interruption of study drug,

All SAEs,

All treatment-related SAEs
All AEs collected during the course of the study will be presented in data listings.


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9.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled visits will be summarized. Graded laboratory 
abnormalities will be defined using the grading scheme in Grading of Laboratory Abnormalities 
provided in Appendix 3. 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 
and including the date of last dose of study drug plus 30 days, will be summarized by age group 
and overall. If baseline data are missing, then any graded abnormality (i.e., at least a Grade 1) 
will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
9.5.4.
Other Safety Evaluations
9.5.4.1.
Tanner Pubertal Stage Assessment
Tanner Stages (Appendix 4) will be summarized by baseline Tanner Stage using frequency and 
percentage. 
9.5.4.2.
Vital Signs (including Body Weight and Height)
Vital signs including body weight and height and change from baseline will be summarized at 
each visit.
9.6.
Efficacy Analysis
Efficacy will be evaluated using scheduled assessments of HCV RNA performed using COBAS®
TaqMan® HCV Test, v2.0 for use with the High Pure System.
Efficacy analysis will be performed by treatment regimen for each age group for Treatment 
Phase.
All continuous endpoints will be summarized using an 8-number summary (n, mean, standard 
deviation, median, Q1, Q3, minimum, maximum). All categorical endpoints will be summarized 
by number and percentage of subjects who meet the endpoint definition.
9.6.1.
Key Efficacy Analysis
The key efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
treatment) in the FAS population. Point estimate and its 95% confidence interval will be 
provided. 
9.6.2.
Secondary Efficacy Analysis
For the PK Lead-in Phase, serum HCV RNA actual values and change from baseline will be
summarized at each visit.


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Amendment 6.0 
For the Treatment Phase, the proportion of subjects with HCV RNA below LLOQ over time 
(including SVR endpoints SVR4 and SVR24) will be presented in tabular and graphical f01m. In 
addition, descriptive summaries and listings will be provided for additional efficacy evaluations 
including senun HCV RNA actual values and change from baseline, prop01iion of subjects with 
virologic failmes, and other endpoints of interest including AL T n01malization. 
PD 
9.6.3. 
Subgroup Analysis 
Subgroup analysis on SVR12 will be perf01m ed by treatment experience and cinhosis status, by 
IL28B genotype, and by HCV genotype. Other clinically relevant subgroup analyses may be 
conducted as appropriate (i.e., assuming that adequate numbers of subjects in these subsets are 
available for analysis). 
Details on efficacy analyses will be described in the statistical analysis plan. 
9.7. 
Quality of Life Analysis 
The data from PedsQL TM Pediau·ic Quality of Life survey will be summarized by visit and 
age group and overall. 
9.8. 
Acceptability 
Acceptability of the study u·eatments will be sUIIllnarized using descriptive statistics by assessing 
swallowability of the solid dosage tablet f01mulations (if subject is able to swallow the tablet) 
and evaluating palatability of the granules f01mulation as applicable. 
9.9. 
Data Monitoring Committee 
An extemal multidisciplinruy data monitoring committee (DMC) will review the progress of the 
study and perf01m interim reviews of safety and provide recommendation to Gilead about 
whether the nature, frequency, and severity of adverse effects associated with study u·eatment 
wruTant the eru·ly te1mination of the study in the best interests of the pruiicipants, whether the 
study should continue as planned, or the study should continue with modifications. 
The DMC's specific activities will be defmed by a mutually agreed chruier, which will define the 
DMC's membership, conduct and meeting schedule. 
While the DMC will be asked to advise Gilead regarding futme conduct of the study, including 
possible eru·ly study tennination, Gilead retains fmal decision-making authority on all aspects of 
the study. 
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9.10.
Sample Size
With approximately 100 subjects enrolled into 12 to <18 years (Group 1) of the Treatment Phase, 
a two-sided 95.0% confidence interval of the SVR12 rate will extend at most 5.9% in both 
directions from the observed SVR12 rate, assuming the expected SVR12 rate is 90%.
With approximately 120 subjects enrolled into the 3 to < 12 years (Group 2) of the Treatment 
Phase, a two-sided 95.0% confidence interval of the SVR12 rate will extend at most 5.4% in 
both directions from the observed SVR12 rate, assuming the expected SVR12 rate is 90%.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
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 Harmonization (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. For studies conducted under a United States IND, the investigator 
will ensure that 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, are adhered to.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Gilead Sciences, or proprietary interests in the drug being studied. 
This documentation must be provided before participation of the investigator and any 
sub-investigator. The investigator and sub-investigator agree to notify Gilead Sciences of any 
change to reportable interests during the study and for one year following completion of the 
study. Study completion is defined as the date that the last subject has completed 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.”
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
This protocol 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/assent) will be submitted by the investigator to an IRB (for studies conducted in the
United States) or IEC (for studies conducted outside of the United States). Approval from the 
IRB or IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. Additionally, modifications 
should be submitted to competent authorities, as necessary.


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10.1.3.
Informed Consent/Assent
The investigator is responsible for obtaining written informed consent from the parent/legal 
guardian of the subject participating in this study after adequate explanation to the parent/legal 
guardian and subject of the aims, methods, objectives, and potential hazards of the study and 
before undertaking any study-related procedures. Written assent should be obtained from the 
subject as required by IRB/IEC/local requirements for this age population. The investigator must 
utilize an IRB- or IEC-approved consent/assent form for documenting written informed 
consent/assent. Each informed consent/assent will be appropriately signed and dated by the 
subject or the subject’s parent/legally authorized representative and the person obtaining 
consent/assent.
10.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, and an 
identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the Sponsor, IRB or IEC, or laboratory. The investigator must keep a screening log 
showing codes, names, and addresses for all subjects screened and for all subjects enrolled in the 
trial.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational new drug, and any 
other study information, remain the sole and exclusive property of Gilead Sciences during the 
conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Gilead Sciences. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data are listed in the Source Data verification Plan, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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
Participation in trial (including trial number);

Trial 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 trial medication (preferably drug dispensing 
and return should be documented as well);

Record of all AEs and other safety parameters (start and end date, and preferably including 
causality and intensity);

Concomitant medication (including start and end date, dose if relevant; dose changes should 
be motivated);

Date of trial completion and reason for early discontinuation, if applicable.
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) 
and until there are no pending or contemplated 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 required by applicable regulatory requirements, by local 
regulations, or by an agreement with Gilead Sciences. The investigator must notify 
Gilead Sciences 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 Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences 
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period up to 15 years for purposes of this study.


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10.1.6.
Case Report Forms
For each subject enrolled, a CRF (or eCRF) must be completed and signed by the principal 
investigator or sub-investigator (as appropriate) within a reasonable time period after data 
collection. This also applies to records for those subjects who fail to complete the study 
(even during a pre-randomization screening period if a CRF was initiated). If a subject 
withdraws from the study, the reason must be noted on the CRF. If a subject is withdrawn from 
the study because of a treatment-limiting adverse event, thorough efforts should be made to
clearly document the outcome.
10.1.7.
Drug Accountability
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product, and comparators. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), subject 
dispensing records, and returned or destroyed study product. Dispensing records will document 
quantities received from Gilead Sciences and quantities dispensed to subjects, including lot 
number, date dispensed, subject identifier number, subject initials, and the initials of the person 
dispensing the medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRBs or IECs, 
or to regulatory authority or health authority inspectors.
10.1.9.
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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10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB, IEC, or 
competent authorities in accordance with local requirements. Approval must be obtained before 
changes can be implemented.
10.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency (ies). 
Gilead Sciences 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.
After conclusion of the study and without prior written approval from Gilead Sciences, 
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 Sciences in an abstract, manuscript, or presentation form; or

the study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).
The investigator will submit 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. The investigator will comply with Gilead Sciences’ 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.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the CRFs for consistency.
The monitor is responsible for routine review of the CRFs 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 CRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.


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10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences 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 Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
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 Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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Amendment 6.0
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11.
REFERENCES
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and 
sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 
2014a;370 (16):1483-93.
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for 
untreated HCV genotype 1 infection. N Engl J Med 2014b;370 (20):1889-98.
Bortolotti F, Verucchi G, Camma C, Cabibbo G, Zancan L, Indolfi G, et al. Long-term course of 
chronic hepatitis C in children: from viral clearance to end-stage liver disease. 
Gastroenterology 2008;134 (7):1900-7.
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus infection in 
Europe. J Hepatol 2008;48 (1):148-62.
European Medicines Agency (EMEA). Committee for Medicinal Products for Human Use 
(CHMP). Guideline on the Investigation of Bioequivalence. 2010.
Fanta S, Jonsson S, Backman JT, Karlsson MO, Hoppu K. Developmental pharmacokinetics of 
ciclosporin--a population pharmacokinetic study in paediatric renal transplant 
candidates. Br J Clin Pharmacol 2007;64 (6):772-84.
Gane E, Hyland RH, An D, Pang PS, Symonds WT, McHutchison JG, et al. 
Ledipasvir/Sofosbuvir Fixed-Dose Combination Is Safe and Effective in Difficult-
to-Treat Populations Including GT 3 Patients, Decompensated GT 1 Patients, and 
GT 1 Patients With Prior Sofosbuvir Experience [Oral Presentation 6]. 49th 
Annual Meeting of The European Association for the Study of the Liver (EASL); 
2014 April 9-13; London, UK. 
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. U.S. 
Prescribing Information. Foster City, CA.  Revised June.  2016:
Gilead Sciences International Ltd. HARVONI (ledipasvir/sofosbuvir) 90 mg/400 mg Film-
Coated Tablets. Summary of Product Characteristics. Cambridge, UK. Revised 
April.  2016:
Hu J, Doucette K, Hartling L, Tjosvold L, Robinson J. Treatment of hepatitis C in children: a 
systematic review. PLoS ONE 2010;5 (7):e11542.
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. 
Developmental pharmacology--drug disposition, action, and therapy in infants 
and children. N Engl J Med 2003;349 (12):1157-67.


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Amendment 6.0
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Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and 
sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 
2014;370 (20):1879-88.
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of disease 
in childhood 1969;44 (235):291-303.
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of 
disease in childhood 1970;45 (239):13-23.
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon 
alfa-2b alone or in combination with ribavirin as initial treatment for chronic 
hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339 
(21):1485-92.
Mohan N, Gonzalez-Peralta RP, Fujisawa T, Chang MH, Heller S, Jara P, et al. Chronic hepatitis 
C virus infection in children. J Pediatr Gastroenterol Nutr 2010;50 (2):123-31.
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of 
interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon 
alpha2b plus placebo for 48 weeks for treatment of chronic infection with 
hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). 
Lancet 1998;352 (9138):1426-32.
Roche Laboratories Inc. COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. 
Nutley, NJ. Revised: January 2010.
Roche Products Limited. Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Welwyn Garden City, United Kingdom. Revised: March 2010.
Serranti D, Buonsenso D, Ceccarelli M, Gargiullo L, Ranno O, Valentini P. Pediatric hepatitis C 
infection: to treat or not to treat...what's the best for the child? European review 
for medical and pharmacological sciences 2011;15 (9):1057-67.
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Guidance for Industry. Bioavailability 
and Bioequivalence Studies Submitted in NDAs or INDs — General 
Considerations [Draft Guidance].  March, 2014.
Wirth S. Current treatment options and response rates in children with chronic hepatitis C. World 
J Gastroenterol 2012;18 (2):99-104.
Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti F, Zancan L, Jara P, et al. High sustained 
virologic response rates in children with chronic hepatitis C receiving 
peginterferon alfa-2b plus ribavirin. J Hepatol 2010;52 (4):501-7.


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Yang D, Pearce RE, Wang X, Gaedigk R, Wan YJ, Yan B. Human carboxylesterases HCE1 and 
HCE2: ontogenic expression, inter-individual variability and differential 
hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem 
Pharmacol 2009;77 (2):238-47.
Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and sex-related expression and activity of 
carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos 2009;37 
(9):1819-25.


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12.
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.
Tanner Stages*
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


LDV/SOFFDC 
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Gilead Sciences, Inc. 
Amendment 6.0 
Appendix 1. 
Investigator Signature Page 
GIT..EAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety and Efficacy 
ofLedipasvir/Sofosbuvir Fixed Dose Combination+/- Ribavirin in Adolescents and Children 
with Chronic HCV -infection 
GS-US-337-1116, Protocol Amendment 6.0, 08 June 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Benedetta Massetto, MD (Printed) 
Medical Monitor 
PD 
Signature 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 101 
08 June 2017 


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Appendix 2.
Study Procedures Table
Appendix Table 1.
PK Lead-in: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X j
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Vital Signsa
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study Medication Compliance
X
X
Study Drug Dispensingb
X
Subject Dosing Diary
X
X
X


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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
Viral Sequencing c
X
X
X
Serum or Urine Pregnancy Testinge
X
X
X
Urinalysis
X
X
X
Urine Drug Screen
X
Intensive PK
X d
HCV Genotyping, IL28B
X
HCV antibody, HIV antibody, HBs antigen, HBs 
antibody, HBc antibody, and HAV antibody
X
HbA1c
X
TSH
X
Alpha fetoprotein
X
Alpha-1 anti-trypsin
X
HBV DNAk
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, body weight, and height
b
Day 1 assessments must be performed prior to dosing
c
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
d
For Cohorts 1 and 2, plasma samples will be collected for PK analyses following dosing of study drug on Day 10 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours post-dose.
e
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test. 
PPD


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f
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status). 
g
h
Swallowability, for subjects on tablet formulation, can occur at Day 1 if not completed during screening.
i
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
j
Parental height will be collected (if available)
k
Only subjects HBcAb positive at Screening
PPD


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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
16k
20k
24k
Early Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
Xi
Complete Physical Examination
X
X
Xj
X
X
Symptom-Directed Physical Examination
X
X
X
X
Xk
X
X
Tanner Pubertal Stage Assessment
X
Xj
X
X
Vital Signsa
X
X
X
X
X
X
X
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling g
X
Xj
X
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey e
X
Xj
X
X
Review of Study Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xk
X
X
Palatability Assessment of Oral Granules as 
applicable
X
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
X
X
X
X
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
X
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testingl
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
PPD


LDVISOFFDC 
Protocol GS-US-337-1116 
Gilead Sciences, Inc. 
Final 
Amendment 6.0 
Screening< 
Visit identified by on-treatment study week 
(-28 days) 
Day 1< 
l c 
2 
4 
Urine Drug Test 
X 
HCV Genotyping, IL28B 
X 
HCV antibody, HIV antibody, HBs antigen, 
X 
HBs antibody, HBc antibody, and HA V antibody 
HbAlc 
X 
TSH 
X 
Alpha fetoprotein, Alpha-! anti-trypsin 
X 
HBV DNAm 
X 
X 
Single PK collected at any time point 
X 
X 
Single PK Sample collected between 15 minutes 
X 
to 4 homs post-dosen 
rpo 
a 
b 
Vital signs include blood pressm·e, pulse, respiratory rate and temperature, and body weight and height 
The IWRS will provide dit·ection on the specifics of each subject's study drug dispensing. 
8 
12 
16k 
20k 
24k 
xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
c 
d 
Subjects rolling over from PK Lead-in phase will not be required to repeat screening, Day 1 or Week 1 visits dtumg the on Treatment Phase 
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies 
Early Termination 
X 
X 
X 
e 
Quality of life stuvey will be completed by all subjects if a site is approved to use the stuvey. Subject is to review questionnait·e with a parent/guardian and \¥rite/mark 
f 
g 
h 
J 
k 
1 
m 
n 
0 
answers directly onto the questionnaire. 
PPD 
'Iiic!Ud·m
~~g~p~a~r~
tne~r~p~re~gn=a~n~cy=p~re~v~e~n..-h~on~for male patttctpants (aJlSUbjeCtS ~ f2 years of age and SUbjeCtS< f2 years of age at tlie'Citscrehon on lie Ifiveshgator based on 
subject's pubertal status). 
Swallowability, for subjects on tablet f01mulation, can occm· at Day 1 if not completed dtumg screening. 
Parental height will be collected (if available) 
Subjects on 12 Week Treatment regitnen only 
Subjects on 24 Week Treatment regitnen only 
Females of childbeatmg potential only. Serum pregnancy test petfonued at screening and for confumation of positive tume pregnancy test 
Only subjects with positive HBcAb at Screening 
A sin ale PK sam2le will be collected at Weeks 4 and 8 between 15 minutes to 4 hotu-s post dose as applicable, P O 
~--------------------------------~ 
1-'U 
CONFIDENTIAL 
Page 106 
08 June 2017 
I 


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Appendix Table 3.
Treatment Phase: Post Treatment Visits Following Primary Study
4 Weeks Post Treatment
12 Weeks Post Treatment
24 Weeks Post Treatment
Clinical Assessments
Vital Signs, Body weight and Height
X
X
X
Symptom-directed Physical Exam
X
X
X
AEs
X
Xc
Xc
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counselingd
X
Xf
Xf
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Test
X
Xe
Xe
HBV DNAg
X
X
X
a
Quality of life survey will be completed by all subjects at 12-Week and 24-Week Post Treatment visits if a site is approved to use the survey.  Subject is to review 
questionnaire with a parent/guardian and write/mark answers directly onto the questionnaire.
b
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
c
At Post Treatment Week 12 and 24, only SAEs will be captured
d
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
e
GT-3 subjects only: Female subjects of childbearing potential should be provided with Urine Pregnancy Test Kits, instructed on their use and requested to continue to 
self-monitor for pregnancy for 6 months after their last dose of RBV. If required by regulations, additional pregnancy tests beyond 6 months may be added. The subject 
should be contacted every 4 weeks and asked to report results of the urine pregnancy tests. If a positive urine pregnancy test is reported, the subject should return to the clinic 
for a serum pregnancy test.
f
GT-3 subjects only
g
Only subjects HBcAb positive at Screening


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


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Amendment 6.0
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.  


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 110
08 June 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant  <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 to <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 111
08 June 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                          
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL                      
1.51 to < 1.74 mmolL
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 112
08 June 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days 
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 113
08 June 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/L to <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
** An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 114
08 June 2017
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 115
08 June 2017
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.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 116
08 June 2017
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
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08 June 2017
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
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08 June 2017
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)


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 119
08 June 2017
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
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08 June 2017
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


LDV/SOF FDC
Protocol GS-US-337-1116
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Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
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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)


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 122
08 June 2017
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (eg, 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (eg, 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 123
08 June 2017
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social &
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 124
08 June 2017
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 125
08 June 2017
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 126
08 June 2017
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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Final
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Amendment 6.0
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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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 128
08 June 2017
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 129
08 June 2017
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.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 130
08 June 2017
Appendix 4.
Tanner Stages*
1. Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2. Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of testes and scrotum and increased darkening 
of scrotal skin (13.5-15)
Tanner V 
Genitalia adult in size and shape
3. Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen 
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with 
surrounding breast 
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V 
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. 
*
Chart referenced from Marshall WA, Tanner JM, variations in the pattern of pubertal changes in boys and girls {Marshall 1969, Marshall 1970}


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Amendment 6.0
CONFIDENTIAL
Page 131
08 June 2017
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Background
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Pregnancy must be excluded before the start of 
treatment with study drugs and prevented thereafter by reliable contraceptive methods. 
Pregnancy tests will be performed regularly throughout this study. Furthermore, RBV is known 
to accumulate intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, 
extreme care must be taken to avoid pregnancy during RBV therapy and for up to 6 months 
following completion of treatment (7 months for males). Please refer to the latest version of the 
product insert for additional information.
Non-clinical toxicity studies of LDV/SOF FDC demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of LDV/SOF FDC 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)
For the purpose of this trial, all post-menarchal females will be considered to be of childbearing 
potential, unless there is documentation of irreversible ovarian failure or surgical sterilization.
Post-menarchal females must have a negative serum pregnancy test at Screening and a negative 
urine pregnancy test on the Day 1 visit prior to dosing. They must also agree to one of the 
following from 3 weeks prior to Day 1 until 6 months after last dose of RBV or 30 days after last 
dose of LDV/SOF FDC if not taking RBV:

Complete abstinence from intercourse. Abstinence is acceptable method of contraception 
only when it is in line with the subject’s preferred and usual lifestyle. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
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 
6 months after last dose of RBV or 30 days  after the last dose of LDV/SOF FDC if not 
taking RBV:
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization


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Amendment 6.0
CONFIDENTIAL
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vasectomy in male partner
implants of levonorgestrel
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 Day 1
until 7 months after last dose of RBV or 90 days after the last dose of LDV/SOF FDC if not 
taking RBV. If their female partner is of childbearing potential (as defined above), their female 
partner must use 1 of the methods of birth control listed above from the date of Screening until 
7 months after last dose of RBV or 90 days after last dose of LDV/SOF FDC if not taking RBV.
Male subjects must agree to refrain from sperm donation for at least 7 months after last dose of 
RBV or 90 days after the last dose of LDV/SOF FDC if not taking RBV.
4) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 6 months (7 months for partners of male subjects) of 
last RBV dose or 30 days (90 days for partners of male subjects) of last LDV/SOF FDC dose if 
not taking RBV. 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 8.5.2.1.

Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir 
Fixed Dose Combination in Adolescents and Children with 
Chronic HCV-Infection
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive 
Foster City, CA 94404, USA
IND No.:
EudraCT Number:
115268
TBD
Indication:
Hepatitis C Virus Infection 
Protocol ID:
GS-US-337-1116
Gilead Sciences Medical 
Monitor:
Name:
Luisa Stamm, MD, PhD
Telephone:
Mobile:
Fax:
E-mail:
Protocol Version/Date:
Original:
10 July 2014
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or under control of 
Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an applicable Institutional Review Board or Independent Ethics 
Committee. The information is only to be used by you in connection with authorized clinical studies of the 
investigational drug described in the protocol. You will not disclose any of the information to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from 
those persons to whom the drug may be administered.
PPD
PPD
PPD
PPD


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 2
10 July 2014
TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................................................................2
LIST OF IN-TEXT TABLES.................................................................................................................................5
LIST OF IN-TEXT FIGURES ...............................................................................................................................5
PROTOCOL SYNOPSIS .......................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................16
1.
INTRODUCTION .......................................................................................................................................19
1.1.
Background.....................................................................................................................................19
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination............................................................................20
1.3.
Rationale for the Current Study ......................................................................................................21
1.4.
Rationale for Dose Selection of LDV/SOF FDC ............................................................................22
1.5.
Overall Risk/Benefit Assessment....................................................................................................22
2.
OBJECTIVES..............................................................................................................................................24
3.
STUDY DESIGN ........................................................................................................................................25
3.1.
Treatment Plan and Regimen..........................................................................................................25
3.1.1.
PK Lead-in ....................................................................................................................25
3.1.2.
Treatment Phase............................................................................................................25
3.2.
Visit Schedule .................................................................................................................................27
3.2.1.
PK Lead-in ....................................................................................................................27
3.2.2.
Treatment Phase............................................................................................................28
3.3.
Virologic Response-Based Stopping Criteria..................................................................................28
3.4.
Treatment Discontinuations Criteria...............................................................................................28
3.5.
Discontinuations .............................................................................................................................29
3.6.
Pharmacogenomic Substudy...........................................................................................................29
3.7.
Long-Term Follow-Up....................................................................................................................29
3.8.
Breakthrough Futility Assessment ..................................................................................................29
4.
SUBJECT POPULATION...........................................................................................................................30
4.1.
Number of Subjects and Subject Selection .....................................................................................30
4.2.
Inclusion Criteria ............................................................................................................................30
4.3.
Exclusion Criteria ...........................................................................................................................31
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ....................................................................................33
5.1.
Randomization and Blinding...........................................................................................................33
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination............................................................................33
5.2.1.
Description and Handling..............................................................................................33
5.2.2.
Storage and Handling....................................................................................................34
5.2.3.
Dosage and Administration of LDV/SOF FDC ............................................................35
5.3.
Study Drug Compliance..................................................................................................................36
5.4.
Prior and Concomitant Medications................................................................................................36
6.
STUDY PROCEDURES .............................................................................................................................38
6.1.
Subject Enrollment..........................................................................................................................38
6.2.
Screening Assessments ...................................................................................................................38
6.2.1.
Screening Visit (Day –28 to Day 0)..............................................................................38
6.3.
PK Lead-in: Treatment Assessments ..............................................................................................40
6.3.1.
Day 1 Visit ....................................................................................................................40
6.3.2.
Day 3.............................................................................................................................41


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6.3.3.
Day 10 – Intensive PK ..................................................................................................41
6.4.
Treatment Phase: Treatment Assessments ......................................................................................43
6.4.1.
Day 1 Visit ....................................................................................................................43
6.4.2.
Weeks 1 and 2 (3 days)..............................................................................................44
6.4.3.
Weeks 4 and 8 (3 days)..............................................................................................45
6.4.4.
Week 12 (3 days) .......................................................................................................46
6.4.5.
Unscheduled Visit/Early Termination Visit ..................................................................46
6.5.
Post-Treatment Assessments...........................................................................................................48
6.5.1.
4-Week Post-Treatment Visit (5 days).......................................................................48
6.5.2.
12-Week Post-Treatment Visit (5 days).....................................................................48
6.5.3.
24-Week Post-Treatment Visit (5 days).....................................................................49
6.6.
Procedures and Specifications.........................................................................................................49
6.6.1.
Clinical Laboratory Analytes ........................................................................................49
6.6.2.
Medical History.............................................................................................................50
6.6.3.
Complete Physical Examination ...................................................................................50
6.6.4.
Tanner Pubertal Stage Assessment................................................................................50
6.6.5.
Height & Weight Measurement ....................................................................................51
6.6.6.
Bone Age Assessment...................................................................................................51
6.6.7.
Swallowability Assessment...........................................................................................51
6.6.8.
Vital Signs.....................................................................................................................51
6.6.9.
Estimated Glomerular Filtration Rate (GFR)................................................................51
6.6.10.
Viral Sequencing (Archive) ..........................................................................................51
6.6.11.
Pregnancy Testing.........................................................................................................52
6.6.12.
Quality of Life Survey (PedsQL™)................................................................................52
7.
TOXICITY MANAGEMENT.....................................................................................................................53
7.1.
Subject Stopping Rules for LDV/SOF FDC ...................................................................................53
8.
ADVERSE EVENTS MANAGEMENT.....................................................................................................54
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events..........................54
8.1.1.
Adverse Events..............................................................................................................54
8.1.2.
Serious Adverse Events.................................................................................................54
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events..............................................................55
8.2.
Assessment of Adverse Events and Serious Adverse Events..........................................................55
8.2.1.
Assessment of Causality for Study Drugs and Procedures............................................55
8.2.2.
Assessment of Severity .................................................................................................56
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO ..................................................................................................56
8.4.
Gilead Reporting Requirements......................................................................................................58
8.5.
Special Situations Reports ..............................................................................................................58
8.5.1.
Definitions of Special Situations...................................................................................58
8.5.2.
Instructions for Reporting Special Situations................................................................59
9.
STATISTICAL CONSIDERATIONS.........................................................................................................61
9.1.
Analysis Objectives and Endpoints.................................................................................................61
9.1.1.
Analysis Objectives.......................................................................................................61
9.1.2.
Primary Endpoints.........................................................................................................62
9.1.3.
Secondary Endpoints.....................................................................................................62
9.2.
Analysis Conventions .....................................................................................................................62
9.2.1.
Analysis Sets.................................................................................................................62
9.2.2.
Data Handling Conventions ..........................................................................................63
9.2.3.
Interim Analysis............................................................................................................64
9.3.
Demographic Data and Baseline Characteristics ............................................................................64


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9.4.
Pharmacokinetic Analysis...............................................................................................................64
9.5.
Safety Analysis ...............................................................................................................................66
9.5.1.
Extent of Exposure........................................................................................................66
9.5.2.
Adverse Events..............................................................................................................66
9.5.3.
Laboratory Evaluations .................................................................................................67
9.5.4.
Other Safety Evaluations...............................................................................................67
9.6.
Efficacy Analysis............................................................................................................................68
9.6.1.
Primary Efficacy Analysis ............................................................................................68
9.6.2.
Secondary Efficacy Analysis ........................................................................................68
9.6.3.
Subgroup Analysis ........................................................................................................68
9.7.
Quality of Life Analysis..................................................................................................................69
9.8.
Data Monitoring Committee ...........................................................................................................69
9.9.
Sample Size.....................................................................................................................................69
10.
RESPONSIBILITIES ..................................................................................................................................70
10.1.
Investigator Responsibilities ...........................................................................................................70
10.1.1.
Good Clinical Practice ..................................................................................................70
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval .............................................................................................................70
10.1.3.
Informed Consent/Assent..............................................................................................71
10.1.4.
Confidentiality ..............................................................................................................71
10.1.5.
Study Files and Retention of Records...........................................................................71
10.1.6.
Case Report Forms........................................................................................................73
10.1.7.
Drug Accountability......................................................................................................73
10.1.8.
Inspections ....................................................................................................................73
10.1.9.
Protocol Compliance.....................................................................................................73
10.2.
Sponsor Responsibilities.................................................................................................................74
10.2.1.
Protocol Modifications..................................................................................................74
10.2.2.
Study Report and Publications ......................................................................................74
10.3.
Joint Investigator/Sponsor Responsibilities ....................................................................................74
10.3.1.
Access to Information for Monitoring...........................................................................74
10.3.2.
Access to Information for Auditing or Inspections .......................................................75
10.3.3.
Study Discontinuation...................................................................................................75
11.
REFERENCES ............................................................................................................................................76
12.
APPENDICES .............................................................................................................................................77
Appendix 1.
Investigator Signature Page.............................................................................................78
Appendix 2.
Study Procedures Table...................................................................................................79
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities..................................................................................................................84
Appendix 4.
Tanner Stages ................................................................................................................107
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements .........................................................................................108


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LIST OF IN-TEXT TABLES
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution ..............................37
Table 9-1.
SOF, GS-331007, and LDV PK Parameters after Once-Daily Administration of 
SOF/LDV in HCV-Infected Adults Subjects (Population PK Analysis from 
Phase 2 and 3 Studies).....................................................................................................66
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema..................................................................................................................27


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed 
Dose Combination in Adolescents and Children with Chronic 
HCV-Infection
IND Number:
EudraCT Number:
115268
TBD
Study Centers:
Approximately 50 sites in the United States, Europe, Russia, 
Australia, and New Zealand
Number of Subjects:
Approximately 200 subjects
Target Population:
Adolescents and children (aged 3 to < 18) chronic hepatitis C virus 
(HCV) infection
Treatment Duration:
PK Lead-in – 10 days
Treatment Phase – 12 weeks
Objectives:
The primary objective of the PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and 
confirm the dose of LDV/SOF FDC in chronic HCV-infected 
pediatric subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 
10 days of dosing of LDV/SOF FDC in chronic HCV infected 
pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC for 
12 weeks in chronic HCV-infected pediatric subjects. 


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The secondary objectives of the Treatment Phase of this study are:

To determine the antiviral efficacy of 12 weeks of LDV/SOF 
FDC treatment in chronic HCV infected subjects (including the 
impact of HCV genotype, IL28 genotype, and prior treatment 
experience), as assessed by the proportion of subjects with 
sustained virological response (SVR) 12 weeks after 
completion of treatment (SVR12)

To determine the antiviral efficacy of 12 weeks of LDV/SOF 
FDC treatment in chronic HCV-infected subjects, as assessed 
by the proportion of subjects with SVR 4 and 24 weeks after 
completion of treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during 
treatment and after completion of treatment

To evaluate the emergence of viral resistance to LDV and SOF 
during treatment and after completion of treatment

To evaluate the effect of growth and development on pediatric 
subjects during and after treatment
The exploratory objective of this study is:

 
 
Study Design:
Open-label, multi-cohort, two-part study evaluating the PK, safety, 
and antiviral activity of LDV/SOF FDC in chronic HCV-infected 
pediatric subjects.
The study will be divided into 2 parts and will commence with 
GT-1 HCV-infected pediatric subjects as follows (subjects with 
GT-2, -4, -5, and -6 will be included once adult data is available, if 
appropriate):
PK Lead-in Phase: PK Lead-in will evaluate and/or confirm age 
appropriate LDV/SOF FDC doses by analyzing PK, safety, and 
antiviral activity of LDV/SOF FDC through 10 days of dosing for 
each of the three cohorts. Children aged 3 to < 6, children aged 
6 to < 12 years, and adolescents aged 12 to < 18 with years 
evidence of chronic HCV and HCV RNA ≥1000 IU/mL at study 
entry will be evaluated.  Subjects must be treatment naïve to 
participate in the PK Lead-in Phase.  
Three cohorts of at least 10 subjects each will be sequentially 
enrolled: 
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
Cohort 1: 12 to < 18 years, old weighing ≥ 45kg

Cohort 2: 6 to < 12 years old 

Cohort 3: 3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive 
LDV/SOF FDC (90 mg/ 400 mg fixed dose combination tablet or 
4 x 22.5 mg/ 100 mg based on LDV/SOF FDC swallowability 
assessment) for 10 days with intensive PK conducted on Day 10.
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete 
Day 10 of the PK Lead-in Phase. They will continue dosing with 
LDV/SOF FDC with no interruption of study drug administration. 
Subjects rolling over from the PK Lead-in will not be required to 
perform Treatment Phase Screening, Day 1, or Week 1 visits in the 
Treatment Phase.  
Following completion of study treatment in the PK Lead-in of each 
Cohort, intensive PK and safety results of study treatment will be 
reviewed to confirm the appropriateness of the evaluated 
LDV/SOF FDC dose for the Treatment Phase of that Cohort as 
well as to determine the age-appropriate dose to be evaluated in the 
PK Lead-in of the next Cohort. 
Treatment Phase: Treatment Phase will be initiated sequentially 
by cohort after confirmation of age-appropriate LDV/SOF FDC 
dosage levels. Subjects who participate in PK Lead-in Phase will 
immediately rollover into Treatment Phase, with no interruption of 
study drug administration, until the appropriateness of the dose is 
confirmed by PK and safety data from the PK Lead-In Phase.  
These subjects will start at the Week 2 visit of the Treatment 
Phase. Additional subjects will be enrolled in the Treatment Phase 
of each Cohort upon confirmation of the appropriateness of the 
dose.
Children aged 3 to < 12 years and adolescents aged 12 to 
< 18 years with chronic HCV-infection and a HCV RNA 
≥1000 IU/mL at study entry (those who were dosed in the PK 
Lead-in Phase will have met this criteria prior to enrollment) will 
be evaluated. The study will commence with GT-1 HCV infected 
pediatric subjects and will subsequently enroll subjects with GT-2, 
-4, -5, and -6 once adult data is available, if appropriate. 
All subjects enrolled in the study will receive the following 
regimen:

LDV/SOF FDC for 12 weeks


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The study will enroll both treatment-naïve and treatment
experienced pediatric subjects, with up to 40 subjects allowed to be 
treatment experienced. Approximately 200 total subjects, including 
subjects that participated in the PK Lead-in Phase, will be enrolled 
in Treatment Phase as follows:

Group 1: Approximately 100 adolescent subjects (12 to 
< 18 years of age)

Group 2: Approximately 100 pediatric subjects (3 to < 12 years 
of age)
The following definitions will be used for treatment experienced 
subjects: 

Interferon intolerant: Subject who discontinued therapy 
(≤12 weeks total) due to ≥ 1 adverse event 

Interferon non-responder: Subject who did not achieve 
undetectable HCV RNA levels while on treatment 

Relapse/breakthrough: Subject who achieved undetectable 
HCV RNA during treatment or within 4 weeks of the end of 
treatment but did not achieve a sustained virologic response 
(SVR)
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, and 12 during the treatment phase followed by 
post-treatment visits 4, 12 and 24 weeks after discontinuation of 
therapy.
All subjects who do not attain SVR or have viral relapse will be 
encouraged to discuss treatment with standard-of-care (SOC) 
therapy with their healthcare provider.
Substudy and 
Long-Term 
Follow-Up Study:
Pharmacogenomics (PG) Substudy
 
Long-Term Follow-up
Subjects who attain SVR24 or those who do not attain SVR24 and 
do not initiate experimental or approved anti-HCV therapy will be 
followed every 6 months for assessments of growth, quality of life, 
and long-term viral suppression (if applicable) in a separate 
protocol (GS-US-334-1113). This follow-up will continue for 
5 years.
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Diagnosis and Main 
Eligibility Criteria: 
Chronic HCV-infected, treatment-naïve and treatment experienced
(up to 40 subjects), male and female subjects aged 3 to < 18 as 
determined at Day 1. The study will commence with GT-1 
HCV-infected pediatric subjects and will subsequently enroll 
subjects with GT-2, -4, -5 and -6 once adult data is available, if 
appropriate. 
Inclusion Criteria:

Chronic HCVinfection 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 
Day 1 visit, or
B) a liver biopsy performed prior to the Day 1 visit with 
evidence of chronic HCV- infection

HCV RNA ≥ 1000 IU/mL at Screening

For the PK Lead-in Phase:  subjects in Cohort 1 (age 12 to 
< 18 years of age) must weigh ≥ 45 kg

Sexually active subjects must agree to use 2 forms of highly 
effective contraception, as referenced in Appendix 5, for the 
duration of the study and for 30 days (for female subjects) or 
90 days (for male subjects) after the last dose of study 
medication. Females of childbearing potential (as defined in 
Appendix 5) must have a negative pregnancy test at Screening 
and Day 1.
Exclusion Criteria:

Hematologic or biochemical parameters at screening outside 
the protocol-specified requirements

HIV, acute hepatitis A virus (HAV) or chronic HBV infection

History of or current decompensated liver disease

Hepatocellular carcinoma or other malignancy (with exception 
of certain resolved skin cancers)

Chronic liver disease of a non-HCV etiology 
(eg, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin 
deficiency)

Systemic corticosteroid use for 2 weeks (pulmonary/nasal 
administration is permitted)

Active or recent history (≤ 1 year) of drug or alcohol abuse

History or current evidence of any condition, therapy, 
laboratory abnormality or other circumstance that might 


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confound the results of the study, or interfere with the subject’s 
participation for the full duration of  the study, such that it is 
not in the best interest of the subject to participate.
See Sections 4.2 and 4.3 of the protocol for full eligibility criteria.
Study Procedures/
Frequency:
PK Lead-in Phase: 
Screening assessments will be completed within 28 days of the 
Day 1 visit. 
Screening assessments will include: complete physical 
examination, vital signs (including body height and weight), 
adverse events (AEs), concomitant medications, LDV/SOF FDC 
Swallowability Assessment (may be performed at screening up to 
Day 1), hematology, safety laboratory tests, coagulation tests, 
HCV RNA, serum β-human chorionic gonadotropin (hCG -
females of childbearing potential only), urinalysis, and urine drug 
screen, IL28B genotyping, serology (HIV, HAV, HCV, and HBV),
HbA1c, thyroid stimulating hormone (TSH), alpha fetoprotein,
alpha-1 anti-trypsin.
Study Visits will occur at Screening, Day 1, Day 3, and Day 10.
On-Treatment assessments include physical examination, Tanner 
Pubertal Stage Assessment (Day 1 only), vital signs (including 
body height and weight), bone age assessment (Day 1 only),
adverse events (AEs), concomitant medications, pregnancy 
prevention counseling (Day 1 only; all subjects ≥ 12 years of age
and subjects < 12 years of age at the discretion of the Investigator 
based on subject’s pubertal status), quality of life survey (Day 1 
only), safety laboratory tests, HCV RNA, viral sequencing 
sampling, and urinalysis.  Coagulation testing and urine pregnancy 
tests (females of child bearing potential only) will be performed at 
Day 1 and Day 10 only. LDV/SOF FDC swallowability assessment 
with placebo will be performed at Screening or up to Day 1 to 
assess a subject’s ability to swallow the 90 mg/ 400 mg or 22.5
mg/ 100 mg FDC tablet (only subjects administered LDV/SOF 
FDC in tablet form). 
Subjects (at least 10 subjects per cohort) enrolled in the PK 
Lead-in Phase will participate in an intensive PK evaluation on 
Day 10. Following completion of the Day 10 intensive PK visit, 
subjects will then return for scheduled study visits outlined in the 
Treatment Phase and will continue dosing with LDV/SOF FDC 
with no interruption of study drug administration. Subjects will be 
administered a dosing diary with instructions.


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Treatment Phase: 
Screening assessments will be completed within 28 days of the 
Day 1 visit. For subjects continuing from PK Lead-in, screening 
for Treatment Phase will not be required.
Screening assessments will include complete physical examination, 
vital signs (including body height and weight), AEs, concomitant 
medications, coagulation, safety laboratory tests, HCV RNA, 
serum β-human chorionic gonadotropin (hCG- females of 
childbearing potential only), urinalysis, urine drug screen, serology 
(HIV, HAV, HCV, HBV), IL28B genotyping, HbA1c, TSH, alpha 
fetoprotein, alpha-1 anti-trypsin. LDV/SOF FDC swallowability 
assessment with placebo will be performed at Screening or up to 
Day 1 to assess a subject’s ability to swallow the 90 mg/ 400 mg or 
22.5 mg/ 100 mg FDC tablet (only subjects administered 
LDV/SOF FDC in tablet form).
Study visits will occur at Screening, Day 1, and at the end of 
Weeks 1, 2, 4, 8, and 12. All Treatment Phase subjects will then 
return for follow-up visits at 4, 12 and 24 weeks after 
discontinuation of therapy. 
On-treatment assessments will include physical examination, vital 
signs (including body height and weight), AEs, concomitant 
medications, pregnancy prevention counseling (all subjects 
≥12 years of age and subjects < 12 years of age at the discretion of 
the Investigator based on subject’s pubertal status), safety 
laboratory tests, coagulation tests, HCV RNA, viral sequencing, 
urine pregnancy tests (females of childbearing potential only), PK 
samples, and urinalysis. Tanner Pubertal Stage assessment will be 
performed at Day 1, end of treatment, post-treatment Week 12, and 
post-treatment Week 24 visits; parental heights will be recorded at 
Day 1. The Bone Age Assessment will be performed at the Day 1 
and post-treatment Week 24 visits. If available, results from liver 
biopsies will be collected at screening. LDV/SOF FDC 
swallowability assessment will be performed at screening or up to 
Day 1 to assess a subject’s ability to swallow a placebo to match 
the 90 mg/ 400 mg or 22.5 mg/ 100 mg LDV/SOF FDC tablet
(only subjects administered LDV/SOF FDC in tablet form). For 
subjects continuing from the PK Lead-in, the screening, Day 1, and 
Week 1 visits of the Treatment Phase will not be required. Samples 
for viral RNA sequencing/phenotyping will be collected at Day 1 
and every visit thereafter.
Post-treatment assessments will include vital signs (including body 
weight and height), symptom-directed physical examination, AEs 
(only SAEs will be captured at post-treatment Week 12 and 


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post-treatment Week 24), concomitant medications (only 
post-treatment Week 4), safety laboratory tests, HCV RNA, and 
urine pregnancy tests (only females of childbearing potential at 
post-treatment Week 4 and post-treatment Week 12).  
 
 
Test Product, Dose, 
and Mode of 
Administration:
PK Lead-in: 
(Cohort 1) LDV/SOF FDC is manufactured as a tablet, consisting 
of 400 mg SOF and 90 mg LDV, for oral administration.  
LDV/SOF FDC tablets will be administered once daily. Subjects 
unable to swallow the LDV/SOF FDC 90 mg/ 400 mg adult tablets
(as determined by LDV/SOF FDC Placebo swallowability 
assessment at Screening or at any time during the study) will be 
re-assigned to 4 x 22.5 mg/ 100 mg LDV/SOF FDC tablets daily.
Intensive PK and safety results from the PK Lead-in of each 
Cohort will be reviewed to confirm the appropriateness of the 
evaluated LDV/SOF FDC dose for the Treatment Phase of that 
Cohort as well as to determine the age-appropriate dose to be 
evaluated in the PK Lead-in of the next Cohort.
Treatment Phase: 
Subjects who participated in PK Lead-in of each Cohort will 
continue in the Treatment Phase with no interruption of study drug 
administration until the appropriateness of the dose is confirmed by 
PK and safety data from the PK-Lead-in. Additional subjects will 
be enrolled in the Treatment Phase of each Cohort upon 
confirmation of the appropriateness of the dose.
Reference Therapy:
None
Evaluation Criteria:
Safety:
AEs, laboratory tests, physical examinations, and vital sign 
measurements will be collected throughout the study. 
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV 
RNA performed using COBAS® AmpliPrep/COBAS® TaqMan®
HCV Test.
PK:
For subjects in the PK Lead-in, a steady-state PK of LDV, SOF,
and its major metabolites (GS-566500 and GS-331007) will be 
assessed at Day 10. For Cohorts 1 and 2, plasma samples will be 
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collected for PK analyses following dosing of study drugs on 
Day 10 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 
8, and 12 hours postdose (with predose also serving as t= 24). For 
Cohort 3, plasma samples for PK analyses will be collected at the 
following time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours 
postdose (with predose also serving as t = 24).
Plasma PK parameters such as Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, 
and t1/2 will be estimated. 
For all subjects in the Treatment Phase, a single PK blood sample 
will be collected at all visits while on treatment. The PK of SOF, 
GS-566500 and GS-331007, and LDV will be assessed.
The effect of age and LDV/SOF FDC dose on PK (SOF, 
GS-331007, and LDV) will be explored.
Statistical Methods:
For the PK Lead-in, plasma PK parameters Cmax, Tmax, Clast, Tlast, 
Ctau, AUCtau, and t1/2 will be estimated. The PK parameters will be 
summarized by cohort. The effect of age and LDV/SOF FDC dose 
on PK (SOF, GS-331007, and LDV) will be explored.
For the Treatment Phase, the primary safety endpoint is any AE 
leading to permanent discontinuation of study drug and will be 
summarized by age group, by GT, and by overall. Primary efficacy 
endpoint is SVR12 in all enrolled and treated subjects and will be 
summarized by age group, by GT, by overall, and by age group 
and GT. Point estimate and its 95% confidence interval will be 
provided. 
Subgroup analysis on SVR12 will be performed by prior treatment 
experience (treatment-naïve vs. treatment experienced) and by GT. 
Other clinically relevant subgroup analyses may be conducted as 
appropriate (i.e., assuming that adequate numbers of patients in 
these subsets are available for analysis). 
All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation, median, Q1, Q3, minimum, 
and maximum). 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 by age group, by GT, by 
overall, and by age group and GT.
With approximately 100 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 


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SVR12 rate will extend at most 5.9% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 90%.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
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)
BLQ
below the lower limit of quantification
BMI
body mass index
CK
creatine kinase
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
dL
Deciliter
DNA
deoxyribonucleic acid
DMC
Data Monitoring Committee
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
ESA
Erythropoiesis stimulating agent
ESPGHAN
European Society for Paediatric Gastroenterology
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed-Dose Combination
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
HAV
Hepatitis A Virus
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
peginterferon alfa-2a
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
QD
once daily (use only in tables)
RBC
Red blood cell count
RBV
ribavirin
RNA
ribonucleic acid


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard-of-Care
SOF
Sofosbuvir
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TSH
Thyroid stimulating hormone
t½
An estimate of the terminal elimination half-life of the drug in 
serum/plasma/PBMC, calculated by dividing the natural log of 2 by the terminal 
elimination rate constant (λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count


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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease 
worldwide and accounts for 70% of cases of chronic hepatitis in industrialized countries. The 
global prevalence of chronic hepatitis C is estimated to average 3% {19705}. 
The natural history of chronic HCV-infection in children differs from that in adults since 
HCV-infection in children is relatively benign. Most children chronically infected with HCV 
are asymptomatic or have mild nonspecific symptoms. Clinical symptoms are present in 
approximately 20% of children in the first 4 years of life, with hepatomegaly being the most 
frequent sign (10%). Many, but not all, perinatally infected children will have intermittently 
or persistently abnormal alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) levels, particularly in the first 2 years of life. In children with vertical HCV-infection 
who have undergone liver biopsy, the histological spectrum is usually mild, although severe 
liver disease is encountered {19801}. Despite the overall more favorable prognosis compared 
to adults, approximately 4% to 6% of children with chronic HCV-infection have evidence of 
advanced fibrosis or cirrhosis and some children eventually require liver transplantation for 
end-stage liver disease as a consequence of HCV-infection {19799}.
The goal of HCV treatment in both pediatric and adult populations is eradication of the virus, 
thereby preventing hepatic inflammation, hepatic fibrosis, cirrhosis, and liver failure 
resulting in either death or need for liver transplantation. This goal, however, is limited by 
the nature of the disease and the fact that not all patients are suitable candidates for currently 
approved treatments. In addition, pediatric treatment is controversial as the current treatment 
options are limited and severe side effects and tolerability can significantly limit or preclude 
their use. Despite well-established guidelines for the treatment of HCV in adults, there is no 
universal consensus on when or if to treat chronic HCV-infection in children. In 2010, the 
European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 
issued guidance for clinical trial development for chronic HCV-infection in children {20286}.
In the guideline, the ESPGHAN suggested that the primary goal of treatment in children is to 
eradicate the infection to prevent late complications. Hence, the goal is not the treatment of 
an ongoing liver disease, but rather the prevention of a future one.
PEG and weight-based RBV are currently considered the SOC for the treatment of HCV-
infection in children. Current recommendations are that patients with GT-2 or GT-3 be 
treated with PEG+RBV for 24 weeks and those with GT-1 or GT-4 should receive 48 weeks 
of therapy. Successful treatment of GT-1, however, has proved very difficult to achieve in 
spite of additional therapy or increased duration of treatment. A number of pediatric studies 
have reported that despite 48 weeks of treatment, sustained virologic response (SVR24) was 
observed in only 36% to 53% of subjects with GT-1, while response rates were > 80% in 
subjects with GT-2 or GT-3 {20285}.


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Most children treated with PEG+RBV experience at least 1 adverse event due to treatment 
{20285}. Although most of these events are mild to moderate in severity, many of them result 
in dose reductions of 1 or both of the drugs. The most common adverse events have consisted 
of influenza-like illness (91%), headache (62%), and injection site reactions (45%), often 
leading to poor compliance and/or discontinuation from treatment.
Additionally, the concern for growth and development in this age group and the role that both 
PEG and RBV potentially play in reducing growth rates has initiated significant debate 
among pediatric hepatologists as to whether these treatments should even be considered in 
the pediatric population {20282}. Many pediatricians currently advocate delay of treatment 
past adolescence or even into adulthood when options with DAAs are possible {20282}. 
Unfortunately, in the 25% of pediatric patients who do meet the criteria for treatment 
(elevated transaminases and viral loads), the option of PEG+RBV therapy remains 
inadequate in regard to both efficacy in GT-1 and safety due to the many risks associated 
with this treatment.
1.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
Ledipasvir/Sofosbuvir fixed-dose combination (LDV/SOF FDC) combines two HCV specific 
direct acting antiviral (DAA) agents into a single tablet for the treatment of chronic HCV-
infection. SOF is a nucleotide analog that is a potent and selective inhibitor of NS5B-directed 
HCV replication with demonstrated activity against GT 1-6 HCV-infection. Ledipasvir 
(LDV) is a novel HCV NS5A inhibitor that has demonstrated potent anti-HCV activity, with 
the highest activity against GT1 HCV-infection.  
The LDV/SOF phase 3 program consisted of 3 clinical studies: GS-US-337-0102 {28583}, 
GS-US-337-0109 {28585}, and GS-US-337-0108 {28587}. Studies GS-US-337-0102 and 
GS-US-337-0109 evaluated treatment with LDV/SOF FDC RBV for 12 or 24 weeks in 
treatment-naïve and treatment experienced subjects, respectively, infected with GT-1 HCV. 
Both studies enrolled up to 20% of HCV-infected subjects who had documented 
compensated cirrhosis. GS-US-337-0108 evaluated LDV/SOF FDC ± RBV treatment for 
8 weeks and LDV/SOF FDC treatment for 12 weeks in non-cirrhotic treatment-naïve subjects 
with GT-1 HCV-infection. Across these 3 clinical studies, LDV/SOF FDC demonstrated a 
high degree of efficacy (> 93%) for treatment-naïve and treatment experienced subjects with 
GT-1 HCV-infection in subjects with and without cirrhosis and achieved their primary 
efficacy endpoints {28583}; {28585}; {28587}. Additionally, treatment with LDV/SOF FDC ± 
RBV was safe and well tolerated in the Phase 3 studies {28583}; {28585}; {28587}.  The 
inclusion of RBV to the treatment regimen was associated with an increase in the total 
incidence of adverse events and in graded laboratory abnormalities of anemia and increased 
bilirubin. 


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Please refer to the Investigator’s Brochure (IB) for additional information on the LDV/SOF 
FDC including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.3.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with 
LDV/SOF FDC for adolescents and children with chronic HCV-infection. 
Currently PEG and weight-based RBV are considered the SOC for the treatment of HCV-
infection in children. Therefore, there is a need for new treatments for HCV in the pediatric 
population that combine potent and sustained efficacy with improved tolerability and safety. 
The primary aim for new treatments of pediatric patients with HCV is to eliminate the need 
to use PEG. In this way, pediatric patients would be able to avoid the necessity of weekly 
injections which can be traumatic and burdensome and significantly reduce the serious 
adverse events seen with PEG administration. The secondary aim is to eliminate RBV and 
the adverse events seen with its administration. Consequently, LDV/SOF FDC has the 
potential to be a simple and highly effective all-oral treatment regimen for chronic HCV-
infection with treatment duration of 12 weeks without PEG or RBV for some GTs. 
In vitro viral replicon assay have data demonstrated that LDV has potent, picomolar antiviral 
activity against GT-1a and GT-1b HCV-infection. In the LDV/SOF FDC phase 3 program, 
LDV/SOF FDC without RBV has been shown to have good efficacy and safety in adults 
infected with GT-1 HCV-infection.  In study GS-US-337-0122, a phase 2 open-label study of 
GT-3 treatment-naïve adult subjects with and without cirrhosis, LDV/SOF FDC for 12 weeks 
resulted in an SVR12 of 64% whereas LDV/SOF + RBV for 12 weeks resulted in an SVR of 
100% {29292}.  As a result, the current study which does not include RBV in the treatment 
regimen will initially only enroll pediatric subjects with GT-1 HCV-infection and will not 
enroll subjects with GT-3.
Considering that SOF has pan-genotypic activity and LDV has in vitro, picomolar to 
nanomolar antiviral activity against certain subtypes within GT 4-6 and sub-micromolar 
antiviral activity against certain subtypes within GT-2, studies have been planned and/or
initiated with LDV/SOF FDC in adult subjects with GT-2, -4, -5, and -6.  If emerging 
LDV/SOF FDC data in these additional GTs support treatment in these genotypes in adults,
pediatric subjects with GT-2, -4, -5 and -6 will be enrolled in the current study.  Of note, 
there is an ongoing study enrolling GT-2 and -3 pediatric patients, GS-US-334-1112, for 
treatment with SOF + RBV for 12 and 24 weeks, respectively.


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1.4.
Rationale for Dose Selection of LDV/SOF FDC
Ledipasvir /Sofosbuvir (90 mg/400 mg) fixed-dose combination tablet, administered once 
daily, has demonstrated favorable safety and efficacy profiles in over 1952 HCV-infected 
subjects across different patient populations in phase 2 and 3 clinical trials. These doses are 
the proposed marketed dose of a ledipasvir/sofosbuvir fixed-dose combination tablet for the 
treatment of HCV-infection.
Selection of doses of LDV/SOF FDC for adolescents and younger age groups will target 
systemic exposures similar to those observed in adults at the proposed marketed dose and
taking into account body weight/body surface area, the potential ontogenic changes in 
intestinal and hepatically expressed carboxylesterase (CES1) and Cathepsin A (CatA) 
enzymes, the drug transporter p-glycoprotein (Pgp), and the results obtained in older age 
groups.  Available data suggests comparable hepatic expression of CES1 in adolescents and 
adults with modestly decreased expression in children.  However, little is known about the 
developmental regulation of Pgp, CES, and CatA.  As such, the adult clinical doses (90 mg /
400 mg) will be evaluated in adolescents (12 to <18 years old).  Safety and PK data in the 
adolescent group (Cohort 1) in the PK Lead-in, in addition to body weight/body surface area 
will inform dose selection for the younger age groups.
Age-appropriate formulations of LDV/SOF FDC (a smaller, 22.5 mg / 100 mg strength tablet 
and a non-tablet formulation currently under development) that offer an important option in 
the treatment of HCV-infection in the pediatric population are planned for evaluation in 
children below 12 years of age or children who are unable to swallow the adult dose tablet 
formulation.
1.5.
Overall Risk/Benefit Assessment
Although the majority of pediatric patients infected with HCV exhibit minimal hepatic
sequelae despite active viral replication and inflammation, a subset of children and
adolescents will require treatment. Studies suggest that 3 major categories of disease can
occur within 10 years after putative HCV exposure: (1) undetectable viremia and normal
ALT, (2) persistent yet uncomplicated mild liver disease, and (3) progression to end-stage
liver disease {20273}. It is the last two groups of children in whom therapy may be indicated 
to prevent end-stage disease, either during childhood/adolescence or in early adulthood.
Given that the current SOC for the treatment of children infected with HCV is PEG and RBV 
and these regimens are long in duration, relatively toxic, and not well tolerated, there 
continues to be a need for new treatments for HCV that combine potent and sustained 
efficacy with improved tolerability and safety. 


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The combination of LDV plus SOF is anticipated to offer greater antiviral efficacy which 
could result in a shorter treatment duration and/or lead to a regimen without RBV or 
interferon. These in turn could result in reduction in adverse events.  LDV/SOF FDC could 
also potentially be of benefit in patients who have failed prior treatment with SOF+/-RBV+/-
PEG.
If high rates of SVR can be obtained with short, well-tolerated regimens, the anticipated 
improvements in safety and tolerability would offer a favorable risk-benefit determination for 
individuals with chronic HCV-infection.


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2.
OBJECTIVES
The primary objective of the PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm the dose of LDV/SOF 
FDC in chronic HCV-infected pediatric subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and antiviral activity of 10 days of dosing of 
LDV/SOF FDC in chronic HCV-infected pediatric subjects
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC for 12 weeks in chronic 
HCV-infected pediatric subjects
The secondary objectives of the Treatment Phase of this study are:

To determine the antiviral efficacy of 12 weeks of LDV/SOF FDC treatment in chronic 
HCV-infected subjects (including the impact of HCV genotype, IL28 genotype, and prior 
treatment experience), as assessed by the proportion of subjects with SVR 12 weeks after 
completion of treatment (SVR12)

To determine the antiviral efficacy of 12 weeks of LDV/SOF FDC treatment in chronic
HCV-infected subjects, as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during treatment and after completion
of treatment

To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment

To evaluate the effect of growth and development on pediatric subjects during and after 
treatment
The exploratory objective of this study is:

 
 
PPD


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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and antiviral 
activity of LDV/SOF FDC in chronic HCV-infected pediatric subjects.
3.1.1.
PK Lead-in
The PK Lead-in Phase will evaluate and/or confirm the age appropriate LDV/SOF FDC dose 
by analyzing PK, safety, and antiviral activity of LDV/SOF FDC through 10 days of dosing
for each cohort. Children aged 3 to < 6 years, children aged 6 to < 12 years, and adolescents 
aged 12 to < 18 years with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study 
entry will be evaluated. Subjects must be treatment naïve to participate in the PK Lead-in
Phase. Three cohorts of at least 10 subjects each will be sequentially enrolled: 

Cohort 1:  12 to < 18 years old weighing ≥45kg

Cohort 2:  6 to < 12 years old 

Cohort 3:  3 to < 6 years old 
The study will start with Cohort 1.  Subjects will receive LDV/SOF FDC (90 mg/400 mg 
adult tablet or 4 x 22.5 mg/100 mg tablets if determined necessary based on LDV/SOF FDC
swallowability assessment) for 10 days with intensive PK conducted on Day 10. 
Following completion of study treatment in the PK Lead-in of Cohort 1 and pending PK and 
safety results, the PK Lead-in of Cohort 2 will initiate and receive study treatment (age 
appropriate dose and formulation). Following completion of study treatment in the PK 
Lead-in of Cohort 2 and pending PK and safety results, the PK Lead-in of Cohort 3 will 
initiate and receive study treatment (age-appropriate dose and formulation). 
Subjects enrolled in the PK Lead-in of each cohort (Cohorts 1, 2 and 3) will immediately 
enroll in the Treatment Phase as they complete Day 10 of PK Lead-in.  They will continue 
dosing with LDV/SOF FDC with no interruption of study drug administration.  Subjects 
rolling over from the PK Lead-in Phase will not be required to perform the screening, Day 1,
or Week 1 visit of the Treatment Phase.
3.1.2.
Treatment Phase
The Treatment Phase will be initiated sequentially by age group as defined in Cohort 1, 2,
and 3 of the PK Lead-in. Subjects who participated in PK Lead-in will immediately rollover 
into Treatment Phase with no interruption of study drug administration until the 
appropriateness of the dose has been confirmed by PK and safety results from the PK 
Lead-in.  The first visit in the Treatment Phase for these subjects will be the Week 2 visit.  


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Additional subjects will be enrolled in the Treatment Phase of each Cohort upon 
confirmation of the appropriateness of the dose from the PK Lead-in.
Children aged 3 to < 12 years (Group 2) and adolescents aged 12 to < 18 years (Group 1) 
with chronic HCV-infection and a HCV RNA ≥1000 IU/mL at study entry (those who were 
dosed in the PK Lead-in will have met this criteria prior to enrollment) will be evaluated.
Subjects enrolled in the Treatment Phase will receive the regimen of LDV/SOF FDC for 
12 weeks. Subjects with GT 1 will be enrolled first.  If emerging LDV/SOF FDC data in 
GT-2, -4, -5, and -6 support treatment in these GTs in adults, pediatric subjects with 
GT-2, -4, -5, and -6 will be subsequently enrolled.  
The study will enroll both treatment naïve and treatment experienced pediatric subjects with 
up to 40 subjects allowed to be treatment experienced. Approximately 200 total subjects, 
including subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as 
follows:

Group 1: Approximately 100 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 100 pediatric subjects (3 to < 12 years of age)
The following definitions will be used for treatment experienced subjects:

Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to 
≥1 adverse event

Interferon non-responder: Subject who did not achieve undetectable HCV RNA levels 
while on treatment

Relapse/breakthrough: Subject who achieved undetectable HCV RNA during treatment 
or within 4 weeks of the end of treatment but did not achieve a sustained virologic 
response (SVR)
All subjects who do not attain SVR or have viral relapse will be encouraged to discuss 
treatment with SOC therapy with their healthcare provider.


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Figure 3-1.
Study Schema
3.2.
Visit Schedule
3.2.1.
PK Lead-in
Screening assessments will be completed within 28 days of the Day 1 visit. 
Study Visits will occur at Screening, Day 1, Day 3, and Day 10.
Subjects (at least 10 subjects per cohort) enrolled in the PK Lead-in Phase will participate in 
an intensive PK evaluation on Day 10. Subjects will be administered a dosing diary with 
instructions.  
Following completion of the Day 10 intensive PK visit, subjects will then return for 
scheduled study visits outlined in the Treatment Phase and continue dosing with LDV/SOF 
FDC with no interruption of study drug administration.  Subjects rolling over from the PK 
Lead-in Phase will not be required to perform the Treatment Phase screening, Day 1, or 
Week 1 visits of the Treatment Phase.


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3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. Subjects 
continuing from the PK Lead-in Phase will not be required to complete Screening, Day 1,
and Week 1 visits of the Treatment Phase.
Study visits for all treatment phase subjects will occur at Screening, Day 1, and the end of
weeks 1, 2, 4, 8, and 12. All subjects will then return for follow-up visits at 4, 12, and 
24 weeks after discontinuation of therapy.
The total time to complete all study visits is approximately 40 weeks including:

28 day (4 week) screening period

12 week treatment period

24 week post-treatment period
The assessments performed at each visit are described in Section 6.
3.3.
Virologic Response-Based Stopping Criteria
HCV RNA will be unblinded to the Investigator and Sponsor.
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 from nadir 

HCV RNA ≥LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination 
of initial observation.  Subjects that meet the virologic response-based stopping criteria 
above will be notified of their eligibility to participate in the Long-Term Follow-Up Study 
(GS-US-334-1113).
3.4.
Treatment Discontinuations Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication 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 or female partner of male subject.

Efficacy failure as defined in Section 3.3.


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
Significant protocol violation including non-compliance with study assessments.

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).
3.5.
Discontinuations
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Termination visit as described in the Section 6.4.5.
Subjects who permanently discontinue the study drug for any reason including safety and/or 
tolerability concerns prior to completion of the assigned dosing period will be followed 
according to the post-treatment study assessments described in Section 6.5.
3.6.
Pharmacogenomic Substudy
 
 
3.7.
Long-Term Follow-Up
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed every 6 months for 
assessments of growth, quality of life, and long-term viral suppression (if applicable) in a 
separate protocol (GS-US-334-1113). This follow-up study will continue for 5 years.
3.8.
Breakthrough Futility Assessment
A futility assessment will be performed after the first 10 subjects complete Week 8 on study 
or have viral breakthrough at or prior to Week 8. If 5 or more of the first 10 subjects enrolled 
have viral breakthrough at or prior to Week 8 or are non-responders (HCV RNA > LLOQ 
through 8 weeks of treatment) then further enrollment of subjects will be 
suspended. Virologic breakthrough is defined as confirmed HCV RNA > LLOQ while on 
treatment after two consecutive visits with HCV RNA < LLOQ.
Subjects with known or suspected study drug non-adherence will not be considered to meet 
the definition of virologic breakthrough, relapse, or non-responder. 
PPD


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 200 subjects will be enrolled in this study.
In order to manage the total study enrollment, Gilead Sciences, Inc. at its sole discretion, may 
suspend screening and/or discontinue the enrollment at any site at any time (upon written 
notice to the site). Discontinuation of the enrollment phase may result in the immediate 
ineligibility of all subjects screened but not yet enrolled, regardless of the progress or 
outcome of the screening assessments performed.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study.
1. Parent or legal guardian able to provide written informed consent prior to any screening 
evaluations and willing to comply with study requirements.  Subjects will provide assent 
if possible.
2. 3 years to < 18 years of age as determined at Day 1 (consent of parent or legal guardian 
required)
3. PK Lead-in only: subjects in Cohort 1 (age 12 to <18 years of age) must weigh 45 kg
4. PK Lead-in only: all subjects must be treatment naïve: no prior exposure to any IFN, 
RBV, or other approved or experimental HCV-specific DAA agent
5. Treatment experienced subjects:  prior treatment failure to a regimen including interferon 
either with or without RBV that was completed at least 8 weeks prior to Day 1.
i.
Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to 
≥1 adverse event
ii.
Interferon non-responder: Subject who did not achieve undetectable HCV RNA 
levels while on treatment
iii.
Relapse/breakthrough: Subject who achieved undetectable HCV RNA during 
treatment or within 4 weeks of the end of treatment but did not achieve a 
sustained virologic response (SVR)


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6. 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 Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV-
infection
7. Infection with HCV as determined at Screening. The study will commence with GT-1 
HCV-infected pediatric subjects and will subsequently enroll subjects with GT-2, -4, -5 
and -6 once adult data is available, if appropriate. 
8. HCV RNA ≥1000 IU/mL at Screening
9. Adequate hematologic function (absolute neutrophil count 1,500/mm3; 
hemoglobin 11 g/dL).
10. Negative serum -HCG pregnancy test (for females of childbearing potential only, as 
defined in Appendix 5)
11. Subject able to provide written assent, if they have the ability to read and write, as 
determined by IRB/IEC/local requirements and Investigator’s discretion
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Pregnant or lactating subjects
2. Sexually-active males or females of childbearing potential who are not willing to use an 
effective method of contraception during the study (see Appendix 5 for further details)
3. Decompensated liver disease defined as INR 1.2 ULN, platelets 50,000/mm3,
serum albumin 3.5 g/dL, or prior history of clinical hepatic decompensation 
(e.g., ascites, jaundice, encephalopathy, variceal hemorrhage)
4. Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
5. -fetoprotein 50 ng/mL
6. Serum creatinine > 1.5 mg/dL
7. Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the Schwartz 
Formula
8. Evidence of hepatocellular carcinoma (HCC)


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9. Co-infection with HIV, acute HAV, or HBV
10. Significant cardiovascular, pulmonary, or neurological disease
11. Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption 
of orally administered medications
12. History of solid organ or bone marrow transplantation
13. Chronic daily non-steroidal anti-inflammatory drug therapy
14. Systemic corticosteroid use for 2 weeks (pulmonary/nasal administration is permitted)
15. Investigational agents taken within the past 28 days (except with the expressed approval 
of the Sponsor)
16. Clinically-relevant alcohol or drug abuse within 12 months of screening.  A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator
17. Known hypersensitivity to the study drugs, the metabolites, or formulation excipients
18. Any other condition (including alcohol or substance abuse) or prior therapy that, in the 
opinion of the Investigator, would make the subject unsuitable for the study or unable to 
comply with dosing requirements
19. Use of any prohibited concomitant medications as described in Section 5.4 within 
28 days of the Day 1 visit


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
5.2.1.
Description and Handling 
5.2.1.1.
Formulation
LDV/ SOF FDC tablets are orange, diamond-shaped, film-coated tablets containing 90 mg of 
LDV and 400 mg of SOF. The tablets are debossed with “GSI” on one side and “7985” on 
the other side. The LDV/SOF 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 aluminium lake.
Placebo to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment are 
orange, diamond-shaped, film-coated tablets debossed with “GSI” on one side and “7985” on 
the other side. The tablets contain 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 
aluminium lake.
Age-appropriate formulations of LDV/SOF FDC are currently under development which 
includes a lower dose strength tablet (LDV/SOF FDC 22.5 mg/ 100 mg) and a non-tablet 
formulation. The formulation and composition will be reflected in a protocol amendment 
which will be submitted for approval prior to dosing subjects who are unable to swallow the 
LDV/SOF FDC 90 mg/ 400 mg tablets.
Placebos to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment 
are currently under development. The formulation and composition will be available and 
reflected in a protocol amendment which will be submitted for approval prior to dosing 
subjects who are unable to swallow the LDV/SOF FDC 90 mg/ 400 mg tablets.
The non-tablet LDV/SOF FDC formulation will be based on the PK results obtained from 
cohorts 1 and/or 2 of this study. The formulation, composition, acceptability (including 
palatability) will be available and reflected in a protocol amendment which will be submitted 
for approval prior to dosing subjects who are unable to swallow tablets.


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5.2.1.2. 
Packaging and Labeling 
Final 
Original 
LDV I SOF FDC 90 mg/ 400 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 or 30 tablets, a silica gel desiccant, and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child resistant 
screw cap with an induction-sealed, aluminum faced liner. 
Placebo tablets to match LDV /SOF FDC 90 mg/ 400 mg tablets for Swallowability 
Assessment are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 30 tablets, a silica gel desiccant and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child resistant screw cap with an induction-sealed, 
aluminum faced liner. 
The packaging and labeling of LDV /SOF FDC 22.5 mg/1 00 mg tablets will be based on the 
chosen formulation. The packaging and labeling will be available and reflected in a protocol 
amendment which will be submitted for approval prior to dosing subjects who are unable to 
swallow the LDV /SOF FDC 90 mg/ 400 mg tablets. 
The packaging and labeling ofthe placebo to match LDV/SOF FDC 22.5 mg/100 mg will be 
based on the chosen formulation. The packaging and labeling will be available and reflected 
in a protocol amendment which will be submitted for approval prior to dosing subjects who 
are unable to swallow the LDV /SOF FDC 90 mg/ 400 mg tablets. 
The packaging and labeling ofthe non-tablet LDV/SOF FDC formulation will be based on 
the chosen formulation. The packaging and labeling will be available and reflected in a 
protocol amendment which will be submitted for approval prior to dosing subjects who are 
unable to swallow tablets. 
All LDV/SOF FDC and placebo to match LDV/SOF FDC bottles to be distributed in the US, 
EU, and the rest ofthe countries shall be labeled to meet all applicable requirements ofthe 
US Food and Drug Administration (FDA), Annex 13 of Good Manufacturing Practices: 
Manufacture of investigational medicinal products (February 20 10), and/or other local 
regulations as applicable. 
5.2.2. 
Storage and Handling 
LDV I SOF FDC tablets, 90 mg/ 400 mg, should be stored at controlled room temperature 
until required for administration. Controlled room temperature is defined as 25 oc (77 °F); 
excursions are permitted between 15 DC and 30 DC (59 °F to 86 °F). 
Placebo to match Ledipasvir (LDV)/Sofosbuvir (SOF) FDC tablets, 90 mg/ 400 mg, for 
Swallowability Assessment should be stored at controlled room temperature until required 
for administration. Controlled room temperature is defined as 25 DC (77 OF); excursions are 
permitted between 15 DC and 30 DC (59 OF to 86 OF). 
CONFIDENTIAL 
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10 July 2014 


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The storage and handling of the LDV/SOF FDC 22.5 mg/ 100 mg tablets and placebo to 
match LDV/SOF FDC will be based on the chosen formulation. The storage and handling 
will be available and reflected in a protocol amendment implemented prior to dosing subjects 
who are unable to swallow the LDV/SOF FDC 90 mg/ 400 mg tablets.
The storage and handling of the non-tablet LDV/SOF FDC formulation will be based on the 
chosen formulation. The storage and handling will be available and reflected in a protocol 
amendment implemented prior to dosing subjects who are unable to swallow tablets.
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 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 LDV/SOF FDC.
Sufficient quantities of LDV/SOF FDC tablets, non-tablet LDV/SOF FDC formulation, and 
placebo tablets will be shipped to the investigator or qualified designee from Gilead Sciences 
Materials & Logistics (or its designee).
5.2.3.
Dosage and Administration of LDV/SOF FDC
PK Lead-in: (Cohort 1) LDV/SOF FDC 90 mg/ 400 mg tablets will be administered once 
daily with or without food. Subjects determined unable to swallow the placebo to match the 
90 mg/ 400 mg LDV/SOF FDC tablet (by LDV/SOF FDC Placebo Swallowability 
Assessment at Screening up to Day 1) will be re-assigned to 4 x 22.5 mg/ 100 mg tablets 
daily.  Subjects who weigh < 45 kg will be excluded.
Intensive PK and safety results from the PK Lead-in of each Cohort will be reviewed to 
confirm the appropriateness of the evaluated LDV/SOF FDC dose for the Treatment Phase of 
that Cohort as well as to determine the age-appropriate dose to be evaluated in the PK 
Lead-in of the next Cohort.
Treatment Phase: Subjects who participated in the PK Lead-in of each Cohort will continue 
in the Treatment Phase with no interruption of study drug administration until the 
appropriateness of the dose is confirmed by PK and safety data from the PK-Lead-in.  
Additional subjects will be enrolled in the Treatment Phase of each Cohort upon 
confirmation of the appropriateness of the dose.  
An additional age-appropriate formulation for LDV/SOF FDC Oral Granulates is currently 
under development. The dose for this formulation will be dependent on the PK results 
obtained from Cohorts 1 and/or 2 of this study. The strength, composition, and dosing 
administration will be available and reflected in a protocol amendment which will be 
submitted for approval prior to dosing subjects who are unable to swallow tablets.


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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.
5.3.
Study Drug Compliance
Subjects will be instructed to return any unused LDV/SOF FDC in the original container on 
Day 10 (PK Lead-in) and/or at study treatment visits every 4 weeks (Treatment Phase).  
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.4.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 
30 days after the last dose of study drug, need to be recorded in the source documents and 
electronic case report form(s) (eCRFs).
The following medications are prohibited during the screening period and for a minimum of 
28 days prior to the Day 1 visit through the end of treatment:

Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents (ESAs); 
granulocyte colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics)

Chronic use of systemic immunosuppressants for reasons other than kidney graft 
maintenance 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(s) may result in PK interactions resulting in 
increases or decreases in exposure of study drug(s). Examples of representative 
medications which are prohibited from 21 days prior to Day 1 through the end of 
treatment are listed below:


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Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing 
Agentsa
Proton- Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Antiarrhythmics b
Quinidine
Anticonvulsantsc
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Cardiac Medications b
Digoxin, Valsartan, Olmesartan, 
Telmisartan, Ranolazine, Bosentan
Herbal/Natural 
Supplementsc
St. John’s Wort, Echinaccea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-
to (or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase 
Inhibitorsd
Rosuvastatin
Atorvastatin, Simvastatin, Pravastatin, 
Pitavastatin, Fluvastatin, Lovastatin
a
It is recommended to separate antacid and LDV/SOF administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF 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 LDV/SOF or up to 2 hours after taking LDV/SOF. Proton-pump inhibitors should not be taken 
before LDV/SOF. 
b
May result in an increase in the concentration of study drugs and/or concomitant medications. Coadministration of 
LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration 
monitoring of digoxin is recommended when coadministered with LDV/SOF. 
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 (e.g., active cancer, 
transplantation) are not listed under this Concomitant Medication section and are disallowed 
in the study.


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6.
STUDY PROCEDURES
All subjects will complete screening, on-treatment, and post-treatment assessments. 
Screening assessments will be completed within 28 days of the Day 1 visit. The end of study 
will occur at the 24-week Post-Treatment visit. The schedule of assessments is described 
below. 
Information on the specific laboratory parameters to be measured and clinical assessments to 
be performed are provided in Section 6.6.
6.1.
Subject Enrollment 
Each candidate’s parent or legal guardian must sign an Informed Consent Form prior to the
conduct of any screening procedures. Each study candidate who has the ability to read and 
write must sign an Assent Form, as required by IRB/IEC/local requirements, prior to the 
conduct of any study procedures. Screening evaluations will be used to determine the
eligibility of each candidate for study enrollment. Candidates who fail to meet eligibility
criteria by screening evaluations may be re-screened once ≥ 30 days after the initial screen if
there is a reasonable expectation that the candidate will be eligible after repeat screening.
6.2.
Screening Assessments
6.2.1.
Screening Visit (Day –28 to Day 0)
Subjects will complete all screening assessments within 28 days of the Day 1 visit. The 
screening window can be extended to 42 days for subjects requiring additional HCV GT
testing or for extenuating circumstances.
The following procedures will be performed and documented:

Written informed consent from parent or legal guardian and assent from subject, if
applicable (see above)

Medical history, including:
— Hepatitis C history
— Hepatitis C treatment history
— Family history, including height and weight of parents
— Liver biopsy results (if available)

Complete physical examination 


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
Vital signs (temperature, blood pressure, pulse, respiratory rate) and body weight and 
height

Obtain blood samples for tests as listed in Section 6.6.1:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Determination of HCV viral GT and subtype
— HCV antibody, HIV 1/2 antibody, and HBs antigen, HAV antibody
— HbA1c
— TSH
— IL28B
— Serum -hCG pregnancy test for females of childbearing potential only
— Alpha fetoprotein (AFP)
— Alpha-1 anti-trypsin (ATT)

Obtain urine sample for:
— Urinalysis
— Urine Drug Screen

Review of concomitant medications

Ask subject and/or parent/legal guardian if the subject is able to swallow and tolerate 
taking pills.

Review of all inclusion and exclusion criteria

Perform LDV/SOF FDC swallowability assessment 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to 
the clinic for the Day 1 visit assessments.


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6.3.
PK Lead-in: Treatment Assessments 
6.3.1.
Day 1 Visit
After confirmation of eligibility has been evaluated, the following tests and procedures must 
be completed prior to enrollment and dosing/dispensing on Day 1:

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject’s pubertal status)

Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
—
 
 

Obtain urine samples for the following procedures:
— Urinalysis
— -hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.
PPD


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6.3.1.1.
Drug Administration

Dispense study drug as directed by the IWRS

Instruct the subject on the packaging, storage and administration of study drug

Perform LDV/SOF FDC swallowability assessment (for subjects administered LDV/SOF 
FDC in tablet form only if not previously completed at screening).  Observe the subject 
taking the first dose of study drug (with or without food) and record the time of first dose

Subjects will be administered a dosing diary with instructions.
6.3.2.
Day 3
The following procedures/assessments are to be completed on Day 3:

Perform a symptom-directed physical examination as needed

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Review medication compliance with subject and/or subject’s parent/guardian

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 10 – Intensive PK 
The Day 10 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 10 Intensive PK visit may 
be performed within +3 days of the protocol-specified visit date (subjects will continue daily 
dosing through the Intensive PK Visit).
Subjects should come in a fasted state for the Day 10 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 10 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 10 dose of LDV/SOF FDC must not be 
taken until the evaluations listed below are completed. 


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If the subject has already dosed prior to the Day 10 clinic visit or is not in a fasted state, the 
Day 10 intensive PK assessments must not be completed. The subject and/or 
parents/guardians should be instructed to return in a fasted state within 3 days (Days 11, 12, 
or 13) for the intensive PK visit. 
If dosing non-compliance is identified as per subject dosing diary and pill count on or prior to 
the Day 10 visit, the Day 10 intensive PK assessments must not be completed. The subject 
and/or parents/guardians should be counseled regarding proper dosing and be scheduled to 
return for the Day 10 intensive PK visit no sooner than 3 days following compliant dosing 
and no later than Day 14 (i.e., return on Day 13 or Day 14).  If dosing non-compliance is due 
to an AE, consultation with the Gilead Medical Monitor is required regarding the potential of 
rescheduling the Day 10 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded 
not to take the LDV/SOF FDC prior to arriving at the clinic on the day of the re-scheduled 
intensive PK visit. All Day 10 intensive PK assessments listed below should be completed 
when the subject returns.
The following evaluations are to be completed at the Day 10 Intensive PK visit:

Perform a symptom-directed physical examination 

Vital signs, including body weight and height

Assessment of AEs and concomitant medications

Perform study drug accountability 

Review Subject Dosing Diary

Review medication compliance with subject and/or parent/guardian.

Obtain urine samples for the following procedures:
— Urinalysis
— Urine pregnancy test (females of childbearing potential only). If the urine pregnancy 
test is positive, the Intensive PK sampling will not be completed. The positive result 
will be confirmed with a serum pregnancy test. 

Obtain blood samples for the following laboratory analyses:
— Hematology 
— Chemistry 
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)


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
Perform intensive PK sampling: 
— Blood samples will be collected at 0 (predose, ≤30 minutes prior to dosing). After 
collection of the predose sample, subjects will be provided a standardized meal. 
Within 5 minutes after consuming the standardized meal, subjects will be dosed with 
LDV/SOF FDC per dosing requirements.
— Post-dose blood samples will be collected as follows: 

For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 5, 8, and 12 hours post-dose (with predose 
also serving as t= 24).

For Cohort 3 only: 0.5, 2, 4, 8, and 12 hours post-dose (with predose also serving 
as t = 24).
— Subjects will be restricted from food intake until after collection of the 4-hour post 
dose blood sample, except for subjects in Cohort 3. Please also refer to the PK 
manual for details about standardized meals and PK sample processing instructions.
After completing the Day 10 intensive PK visit subjects will then continue to the Week 2
visit in Treatment Phase (described in Section 6.4.2) with no interruption in dosing.
6.4.
Treatment Phase: Treatment Assessments 
6.4.1.
Day 1 Visit
After confirmation of eligibility has been evaluated, the following tests and procedures must 
be completed prior to enrollment and dosing/dispensing on Day 1:

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements 

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Review of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject’s pubertal status). 


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
Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
—
 
 

Obtain urine sample for:
— Urinalysis
— -hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire

Perform LDV/SOF FDC swallowability assessment (for subjects administered LDV/SOF 
FDC in tablet form only if not previously completed at screening) 
6.4.1.1.
Drug Administration

Dispense study drug as directed by the IWRS

Instruct the subject on the packaging, storage, and administration of study drug

Observe the subject taking the first dose of study drug (with or without food) and record 
the time of first dose
6.4.2.
Weeks 1 and 2 (3 days)
Subjects who participated in the PK Lead-in will start study visits in the Treatment Phase at 
Week 2.  The following procedures/assessments are to be completed at these visits:

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications
PPD


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
Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— Single PK 
6.4.3.
Weeks 4 and 8 (3 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— Single PK 

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should 
return all study drugs at these visits)

Dispense study drug as directed by the IWRS


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6.4.4.
Week 12 (3 days)

Perform complete physical examination

Tanner Pubertal Staging Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject’s pubertal status)

Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— TSH
— Single PK 

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles of study drug at the Week 12 Visit
6.4.5.
Unscheduled Visit/Early Termination Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. 
The assessments are at the investigator’s discretion.
The Sponsor/CRO should be informed when a subject comes off treatment due to an adverse 
event. If a subject discontinues treatment then the assessments outlined below should be 
performed.


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
Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject’s pubertal status)

Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— TSH
— Single PK 

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles of study drug at the Early Termination Visit
All subjects should complete Post-Treatment assessments after early termination, as 
described in Section 6.5.
Subjects who do not attain SVR24 and do not initiate experimental or approved anti-HCV 
therapy will be followed every 6 months for assessments of growth, quality of life, and 
long-term viral suppression (if applicable) in a separate protocol (GS-US-334-1113). This 
follow-up will continue for 5 years.


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6.5.
Post-Treatment Assessments
6.5.1.
4-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for: 
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject’s pubertal status) 
6.5.2.
12-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements

Perform symptom-directed physical examination

Assessment of SAEs

Perform Tanner Pubertal Stage assessment

Obtain blood samples for 
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)


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
Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion 
of the Investigator based on subject’s pubertal status)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire
6.5.3.
24-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of SAEs

Tanner Pubertal Stage Assessment

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Obtain blood samples for 
— HCV RNA
— Viral sequencing (archive)

Subject completes quality of life survey: Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire.
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed every 6 months for 
assessments of growth, quality of life, and long-term viral suppression (if applicable) in a 
separate protocol (GS-US-334-1113). This follow-up will continue for 5 years.
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) 


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Chemistry Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase 
(AST/SGOT), Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct 
Bilirubin), Glucose, Lipase, Potassium, Sodium, Gamma-glutamyl transferase (GGT), alpha 
fetoprotein (AFP), alpha-1 anti-trypsin, creatine kinase (CK) and amylase.
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® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure 
System. HCV GT 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 GT should the above assays become unavailable.
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 right to use alternate assays 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum -hCG, Urine -hCG (if positive, requires immediate confirmation 
with Serum -hCG)
Additional Tests: Urine Drug Screen (for amphetimines, cocaine, methadone, opiates), 
Hemoglobin A1c (HbA1c), TSH (reflex Free T4), Alfa fetoprotein (AFP), Alpha-1 
anti-trypsin (AAT).
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. Parental heights will be recorded at Day 1.
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.
Tanner Pubertal Stage Assessment
The Tanner Stage scale is available in Appendix 4.  All subjects will receive a baseline 
Tanner Pubertal Stage Assessment. If the assessment determines that the subject is at a 
Tanner 5 at Day 1, no further Tanner Pubertal Stage Assessments are to be completed. Date 
of first menses will be documented. 


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6.6.5.
Height & Weight Measurement
Height and weight measurement will be collected at each study visit. The difference in body 
weight and height measurements between Day 1 and End of Treatment, post-treatment 
Week 12, and post-treatment Week 24 will be calculated.  
6.6.6.
Bone Age Assessment
A single X-ray of the left wrist, hand, and fingers will be performed at Day 1 Visit and 
post-treatment Week 24.  Local radiologist to determine bone age from x-ray.
6.6.7.
Swallowability Assessment
A LDV/SOF FDC swallowability assessment will be performed at screening up to Day 1.  
Subjects who have indicated that they can take pills will be observed taking a placebo to 
match the 90 mg/ 400 mg LDV/SOF FDC tablet. This will confirm the swallowability of the 
90 mg/ 400 mg tablet size. If a subject is unable to swallow the 90 mg/ 400 mg LDV/SOF 
FDC tablet size, he/she will repeat the assessment with a placebo for the 22.5 mg/ 100 mg 
LDV/SOF FDC tablet. If unable to swallow the 22.5 mg/ 100 mg LDV/SOF FDC tablet, 
enrollment of the subject will be deferred until the granule formulation is available.
6.6.8.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, 
respiratory rate, and temperature.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm 
supported so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an 
appropriately sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or 
to the nearest whole number on an automatic device.
6.6.9.
Estimated Glomerular Filtration Rate (GFR)
Estimated Glomerular Filtration Rate (GFR) using Schwartz Formula (mL/min/1.73m2) = 
k L/Scr [(k is a proportionality constant, for adolescent females ≥12 years old is 0.55; and 
for adolescent males ≥12 years old is 0.70); L is height in centimeters (cm); and Scr is serum 
creatinine (mg/dL)]
6.6.10.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence 
analysis. Unused samples may be archived.


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6.6.11.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every 4 weeks during 
the dosing period and for a minimum of 30 days following the last dose of LDV/SOF FDC. If 
required by local regulations, additional pregnancy tests beyond 30 days may be added. In 
the event of a positive urine pregnancy result, subjects will be instructed to stop study drugs 
immediately (if applicable) and return to the clinic as soon as possible for a serum pregnancy 
test.
6.6.12.
Quality of Life Survey (PedsQL™)
The PedsQL ™ Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be 
completed in Treatment Phase of the study at Day 1, End of Treatment, Early Termination (if 
applicable), 12-Week Post-Treatment, and 24-Week Post-Treatment visits.  
The PedsQL ™  has separate survey instruments administered by age group, including the
Teen Report (ages 13-18), Child Report (ages 8-12), Young Child Report (ages 5-7), and 
Toddlers (ages 2-4).  Each survey will be administered to the subject for the current age 
group at the time of survey administration.  


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7.
TOXICITY MANAGEMENT
7.1.
Subject Stopping Rules for LDV/SOF FDC
The Gilead Medical Monitor should be consulted prior to dose discontinuation of LDV/SOF 
FDC unless the investigator believes that immediate action is warranted to ensure the 
continued safety of the subject.
Administration of LDV/SOF FDC may be discontinued due to a clinical or laboratory event. 
There is no option for LDV/SOF FDC dose reduction. If LDV/SOF FDC is stopped for 
toxicity, it should not be restarted.
Subjects who meet any of the following laboratory criteria should stop treatment with 
LDV/SOF FDC:

Elevation of ALT and/or AST >5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT >3x Day 1 and total bilirubin >2 x ULN, confirmed by 
immediate repeat testing

Confirmed elevation of ALT >15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with LDV/SOF
FDC


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8.
ADVERSE EVENTS MANAGEMENT
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
8.1.1.
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-mandated procedures, 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 8.5)

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
8.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the 
following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event that hypothetically might have caused death if it were more severe.)


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
In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is reportable 
under expedited reporting rules. Examples of medically important events include 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; and development of drug 
dependency or drug abuse. For the avoidance of doubt, infections resulting from 
contaminated medicinal product will be considered a medically important event and 
subject to expedited reporting requirements.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 8.1.1 and 8.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event
information and assessments.
8.2.1.
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 investigational 
medicinal product. For SAEs, an alternative causality must be provided (e.g., pre-existing 
condition, underlying disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally 
related in the context of AE reporting.
The relationship to study procedures (e.g., invasive procedures such as venipuncture or 
biopsy) should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures (eg., venipuncture)
8.2.2.
Assessment of Severity
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading 
Scale for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of 
the clinical severity in the context of the underlying conditions; this may or may not be in 
agreement with the grading of the laboratory abnormality.
8.3.
Investigator Requirements and Instructions for Reporting Adverse 
Events and Serious Adverse Events to Gilead or CRO
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of 
events should be reported on the case report form (CRF/eCRF): all SAEs and adverse events 
related to protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4 weeks after last administration of study drug 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 protocol defined 
follow up period.
Serious Adverse Events
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 24-week 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 after informed consent is signed 


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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of 
the last dose of study IMP, regardless of causality, should also be reported. Investigators are 
not obligated to actively seek SAEs after the 24 week post-treatment follow-up period.  
However, if the investigator learns of any SAEs that occur after study participation has 
concluded and the event is deemed relevant to the use of IMP, he/she should promptly 
document and report the event directly to Gilead DSPH.  

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in 
the eCRF completion guideline.
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead 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 to:
Gilead Sciences, 
Drug Safety and 
Public Health:
Fax:
E-mail:
+1 650 522-5477
Safety_FC@gilead.com
PRA International
Pharmacovigilance 
Representative:
Fax:
E-mail:
+1 888 772 6919 (North America);
+49 621 8782 181 (Rest of World)
CHOSafety@praintl.com
Gilead Sciences,
Medical Monitor:
Name:
Phone:
Mobile:
Fax:
E-mail:
Luisa Stamm, MD, PhD

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.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines 
outlined in the CRF/eCRF completion guideline.
PPD
PPD
PPD
PPD


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
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and 
other documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate 
safety reports.

Any medications necessary for treatment of the SAE must be recorded onto the 
concomitant medication section of the subject’s CRF/eCRF and the event description 
section of the SAE report form.
8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to 
expedite to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions 
(SADRs), or suspected unexpected serious adverse reactions (SUSARs). In accordance with 
the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify 
worldwide regulatory agencies and the relevant IEC in concerned Member States of 
applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports
associated with any study IMP. The investigator should notify the IRB or IEC of SUSAR 
reports as soon as is practical, where this is required by local regulatory agencies, and in 
accordance with the local institutional policy.
8.5.
Special Situations Reports
8.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, and 
pregnancy reports regardless of an associated AE.  
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.


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An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal product given per administration or cumulatively which is above the maximum 
recommended dose as per protocol or in the product labelling (as it applies to the daily dose 
of the subject in question). In cases of a discrepancy in drug accountability, overdose will be 
established only when it is clear that the subject has taken the excess dose(s). Overdose 
cannot be established when the subject cannot account for the discrepancy except in cases in 
which the investigator has reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging or distribution of the medicinal product.  
8.5.2.
Instructions for Reporting Special Situations
8.5.2.1.
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-treatment follow-up period, to Gilead DSPH using the pregnancy 
report form within 24 hours of becoming aware of the pregnancy.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate 
a pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as 
an SAE. The underlying medical reason for this procedure should be recorded as the AE
term.
A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Sections 8.1.1 and 8.3. Furthermore, any SAE occurring as an adverse pregnancy outcome 
post study must be reported directly to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH 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 or Fax: +1 (650) 522-5477.
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH using 
the pregnancy report form and pregnancy outcome report forms within 24 hours. Monitoring 
of the partner pregnancy should continue until the conclusion of the pregnancy. If the end of 
the pregnancy occurs after the study has been completed, the outcome should be reported 
directly to Gilead DSPH, fax number +1 (650) 522-5477 or email Safety_FC@gilead.com. 


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Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements.
8.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the 
situation. These reports must consist of situations that involve study IMP and/or Gilead 
concomitant medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be 
reported on the special situations report form; however, for special situations that result in 
AEs due to a non-Gilead concomitant medication, the AE should be reported on the AE 
form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or 
SAEs at the same time using the AE eCRF and/or the SAE report form. Details of the 
symptoms and signs, clinical management and outcome will be reported, when available.


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9.
STATISTICAL CONSIDERATIONS
9.1.
Analysis Objectives and Endpoints
9.1.1.
Analysis Objectives
The primary objective of PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and confirm the dose of LDV/SOF 
FDC in chronic HCV-infected pediatric subjects
The secondary objective of PK Lead-in Phase of this study is:

To evaluate the safety, tolerability, and viral activity of 10 days of dosing of LDV/SOF 
FDC in chronic HCV-infected pediatric subjects
The primary objective of Treatment Phase of this study is:

To evaluate the safety and tolerability of LDV/SOF FDC for 12 weeks in chronic 
HCV-infected pediatric subjects
The secondary objectives of Treatment Phase of this study are:

To determine the antiviral efficacy of 12 weeks of LDV/SOF FDC treatment in chronic 
HCV-infected subjects, as assessed by the proportion of subjects with SVR 12 weeks 
after completion of treatment (SVR12)

To determine the antiviral efficacy of 12 weeks of LDV/SOF FDC treatment in chronic 
HCV-infected subjects (including the impact of HCV genotype, IL28 genotype and prior 
treatment experience), as assessed by the proportion of subjects with SVR 4 and 
24 weeks after completion of treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during treatment and after completion
of treatment

To evaluate the emergence of viral resistance to LDV and SOF during treatment and after 
completion of treatment

To evaluate the effect of growth and development on pediatric subjects during and after 
treatment
The exploratory objective of this study is:

 
 
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9.1.2.
Primary Endpoints
For the PK Lead-in Phase, AUCtau of GS-331007 and LDV are considered the primary PK 
parameters for determining the appropriate LDV/SOF FDC dose.
For the Treatment Phase, the primary safety endpoint is any AE leading to permanent 
discontinuation of study drug (s). The primary efficacy endpoint is SVR12.
9.1.3.
Secondary Endpoints
For the PK Lead-in Phase, the secondary PK endpoints will include early viral kinetics and 
the following PK endpoints: AUCtau, Cmax, AUClast, Tmax, Clast, Tlast, Ctau and t1/2 for 
GS-331007, SOF, and LDV as appropriate. AEs leading to permanent discontinuation of 
study drug(s) will be evaluated as a secondary safety endpoint. Secondary safety endpoints of
growth and development measurements will be assessed (e.g. height, weight, and Tanner 
Stage Assessment).
For the Treatment Phase, secondary efficacy endpoints include SVR4, SVR24, breakthrough 
and relapse. Additional efficacy evaluations may include HCV RNA change from Day 1; 
ALT normalization; and viral kinetic parameters.
9.2.
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).
9.2.1.
Analysis Sets 
9.2.1.1.
Pharmacokinetics (PK) Analysis Sets
Intensive PK Analysis Set 
The intensive PK analysis set will include all PK Lead-in subjects who received at least one 
dose of study drug and for whom at least one non-missing PK concentration data, during the 
intensive sampling period, reported by PK lab. The PK analysis set will be used for detailed 
pharmacokinetic analysis of LDV, SOF, and metabolites.  
Sparse PK Analysis Set 
The PK analysis set will include all enrolled subjects who received at least one dose of study 
drug and for whom at least one observed concentration data of LDV, SOF, or GS-331007 are 
available. The PK analysis set will be used for analysis of general PK and single sample 
plasma concentrations.
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9.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses will include subjects who were enrolled and have 
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 last dose of study drug plus 30 days.
9.2.1.3.
Efficacy Analysis Set
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which 
includes HCV-infected subjects who were enrolled and have received at least one dose of 
study drug.
9.2.2.
Data Handling Conventions
Natural logarithm transformation for key PK parameters, such as Cmax and AUCtau, will be 
applied for pharmacokinetic analysis.
The PK concentration values below the limit of quantitation (BLQ) will be treated as zero for 
the determination of summary and order statistics. Individual values that are BLQ will be 
presented as “BLQ” in the concentration data listing and will be excluded in any calculation 
of geometric means or ratios. For the presentation of summary and order statistics, if at least 
1 subject has a concentration value BLQ for the time point, then the minimum value will be 
displayed as “BLQ”. If more than 50% of the subjects have a concentration data value BLQ 
for the time point, then the minimum and median values will be displayed as “BLQ”. If all 
subjects have concentration data values BLQ for the time point, then all order statistics 
(minimum, first quartile [Q1], median, third quartile [Q3], maximum) will be displayed as 
“BLQ”.
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, 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 preceded and followed in time by values that are deem 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 medication will 
be considered a failure at the time points subsequent to 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 
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
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).
9.2.3.
Interim Analysis
No formal interim analyses are planned for this study.
9.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by age group and overall for PK Lead-in and Treatment Phase respectively. 
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight, height, body mass index, HCV RNA 
level (log10 IU/mL), HCV GT, prior treatment experience, and additional endpoints as 
necessary.
9.4.
Pharmacokinetic Analysis
PK analysis will be performed for PK Lead-in using the intensive PK analysis set. The 
concentration data of LDV, SOF, and metabolites (GS-566500 and GS-331007) over 
sampling time will be listed and summarized by nominal time and cohort. Pharmacokinetic 
parameters (e.g., AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau, λz, CL/F, Vz/F and t½) will be 
listed and summarized for LDV, SOF,  and metabolites (as applicable) using descriptive 
statistics (e.g., sample size, arithmetic mean, geometric mean and its 95% confidence 


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interval, coefficient of variation %, standard deviation, median, Q1, Q3, minimum, and 
maximum) by cohort and overall. Plasma concentrations over time will be plotted in 
semilogarithmic and linear formats as mean ± standard deviation and median (Q1, Q3).
To evaluate if the exposures of LDV and GS-331007 achieved in pediatric subjects of this 
study are similar to the exposures observed in adult subjects (Table 9-1). The LDV and 
GS-331007 exposure data from this study will be compared to the integrated adult data. The 
primary endpoint of this analysis will be evaluated by carrying out an analysis of variance 
(ANOVA) for log-transformed GS-331007 AUCtau and LDV AUCtau. The secondary 
endpoints of this analysis will be the Cmax of LDV and GS-331007 and Ctau of LDV. The
90% confidence intervals will be constructed for the ratio of geometric means of each PK 
parameters. The equivalence boundary is set as 50% to 200%.  
Given that dose ranging studies for SOF established that a dose of 200 mg results in 
suboptimal exposure compared to the 400 mg dose, and the lack of clinically significant 
exposure-safety relationships observed across a broad range of GS-331007 exposure, bounds 
of 50% to 200% for GS-331007 AUCtau will allow identification of a clinically relevant 
difference in exposure in the pediatric population.
A phase 2 study evaluating LDV doses of 30 or 90 mg LDV in combination with DAAs 
VDV+TGV+RBV suggested LDV exposure may be suboptimal at the 30 mg dose based on 
the incidence of virologic breakthrough being approximately half in the 90 mg arm; as such 
the 90 mg dose was selected for further development.  In the 90 mg LDV arm of this study, 
the LDV AUCtau at the 25 percentile was 3230 hr*ng/mL.  While this value is 62% lower 
than the mean LDV AUCtau (8530 hr*ng/mL) observed in adult HCV-infected subjects in the 
LDV/SOF FDC Phase 2/3 population, it provides ~99.8% of maximal viral load reduction 
(exposure-response model established in the monotherapy proof of concept study).  In the 
Phase 2/3 population when administered the LDV/SOF FDC, there was a lack of clinically 
significant exposure-efficacy or safety relationships observed across the broad range of LDV 
exposure.  Taken together these data support the utility of bounds of 50% to 200% for LDV 
AUCtau to identify a clinically relevant difference in LDV exposure in the pediatric 
population.      
In all pediatric age groups, the targeted exposures for GS-331007 and LDV are the adult 
equivalent for which safety and efficacy has been established.  In the absence of any pediatric 
PK information (ie., variability and exposure of GS-331007 or LDV is unknown) assuming a 
2-fold higher  variability, or a 30 % difference in GS-331007 or LDV AUCtau in the pediatric 
population compared to adults, the predicted 90% CIs of the geometric mean ratio (GMR) 
will be contained within the bounds of 50% to 200%.
Individual patient management will be performed by maintaining exposures comparable to 
adults.  In the event more than one subject in each cohort exhibits LDV (AUCtau) or 
GS-331007 (AUCtau) exposures less than the 2.5th percentile of adult values, a dose
assessment may be require for the cohort as appropriate.


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The effect of age and LDV/SOF FDC dose on PK (LDV, SOF and GS-331007) will be 
assessed.
Table 9-1.
SOF, GS-331007, and LDV PK Parameters after Once-Daily 
Administration of SOF/LDV in HCV-Infected Adults Subjects 
(Population PK Analysis from Phase 2 and 3 Studies) 
Mean (%CV) PK Parametera
GS-331007 (N=2113)
LDV (N=2113)
AUCtau (ng•h/mL)
12,500 (29.2)
8530 (60.8)
Cmax (ng/mL)
736 (28.2)
364 (51.4)
Ctau (ng/mL)
N/A
247 (59.2)
a
Pharmacokinetic parameters are presented as mean (%CV) and are shown to 3 significant digits.
9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in and overall study Treatment Phase
respectively. Safety data will be summarized by age group, by GT, by overall and by age 
group and GT.
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, 
vital signs measurements, and by the documentation of AEs.
All safety data collected while on or after the first dose of study drug administration up to 
30 days after the last dose of study drug will be summarized by cohort according to the study 
drug received.
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.
9.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page of the CRF. Exposure data will be summarized.
9.5.2.
Adverse Events
Clinical and laboratory AEs 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 study drug up to the date of last dose of study drug 
plus 30 days. 


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Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC and preferred term) will be provided by cohort:

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,

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.
9.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled visits will be summarized. Graded laboratory 
abnormalities will be defined using the grading scheme in Grading of Laboratory 
Abnormalities provided in Appendix 3. 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 and including the date of last dose of study drug plus 30 days, 
will be summarized by age group and overall. If baseline data are missing, then any graded 
abnormality (i.e., at least a Grade 1) will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
9.5.4.
Other Safety Evaluations
9.5.4.1.
Tanner Pubertal Stage Assessment
Tanner Stages (Appendix 4) will be summarized by baseline Tanner Stage using frequency 
and percentage. Age of first menses will be summarized descriptively.


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9.5.4.2.
Vital Signs (including Body Weight and Height)
Vital signs including body weight and height and change from baseline will be summarized 
at each visit by age group, by GT, by overall and by age group and GT.
9.6.
Efficacy Analysis
Efficacy will be evaluated using scheduled assessments of HCV RNA performed using 
COBAS® TaqMan® HCV Test, v2.0 for use with the High Pure System.
Efficacy analysis will be performed by age group, by GT, by overall, and by age group and 
GT for Treatment Phase.
All continuous endpoints will be summarized using an 8-number summary (n, mean, 
standard deviation, median, Q1, Q3, minimum, maximum). All categorical endpoints will be 
summarized by number and percentage of subjects who meet the endpoint definition.
9.6.1.
Primary Efficacy Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
treatment) in the FAS population. Point estimate and its 95% confidence interval will be 
provided.  
9.6.2.
Secondary Efficacy Analysis
For the PK Lead-in Phase, serum HCV RNA actual values and change from baseline will be 
summarized at each visit.
For the Treatment Phase, the proportion of subjects with HCV RNA below LLOQ over time 
(including SVR endpoints SVR4 and SVR24) will be presented in tabular and graphical 
form. In addition, descriptive summaries and listings will be provided for additional efficacy 
evaluations including serum HCV RNA actual values and change from baseline, proportion 
of subjects with virologic failures, and other endpoints of interest including ALT 
normalization.
 
 
 
 
9.6.3.
Subgroup Analysis
Subgroup analysis on SVR12 will be performed by treatment experience (treatment-naïve vs. 
treatment experienced), by IL28 genotype, by GT, and by treatment experience and GT. 
Other clinically relevant subgroup analyses may be conducted as appropriate (i.e., assuming 
that adequate numbers of subjects in these subsets are available for analysis).
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Details on efficacy analyses will be described in the statistical analysis plan.
9.7.
Quality of Life Analysis
The data from PedsQL ™ Pediatric Quality of Life survey will be summarized by visit and 
age group and overall.
9.8.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of 
the study and perform interim reviews of safety and PK data and provide recommendation to 
Gilead about whether the nature, frequency, and severity of adverse effects associated with 
study treatment warrant the early termination of the study in the best interests of the 
participants, whether the study should continue as planned, or the study should continue with 
modifications. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define 
the DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, 
including possible early study termination, Gilead retains final decision-making authority on 
all aspects of the study.
9.9.
Sample Size
With approximately 100 subjects enrolled into each age group of Treatment Phase, a 
two-sided 95.0% confidence interval of the SVR12 rate will extend at most 5.9% in both 
directions from the observed SVR12 rate, assuming the expected SVR12 rate is 90%.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
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. For studies conducted under a United States IND, the 
investigator will ensure that 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, are adhered to.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, 
is adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted 
in a marketing application or reclassification petition subject to this part that the applicant or 
FDA relies on to establish that the product is effective (including studies that show 
equivalence to an effective product) or that make a significant contribution to the 
demonstration of safety.” This requires that investigators and all subinvestigators must 
provide documentation of their financial interest or arrangements with Gilead Sciences, or 
proprietary interests in the drug being studied. This documentation must be provided before 
participation of the investigator and any subinvestigator. The investigator and subinvestigator 
agree to notify Gilead Sciences of any change to reportable interests during the study and for 
one year following completion of the study. Study completion is defined as the date that the 
last subject has completed 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.”
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
This protocol 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/assent) will be submitted by the investigator to an IRB (for studies 
conducted in the United States) or IEC (for studies conducted outside of the United States). 
Approval from the IRB or IEC must be obtained before starting the study and should be 
documented in a letter to the investigator specifying the protocol number, protocol version, 
protocol date, documents reviewed, and date on which the committee met and granted the 
approval.
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation.


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10.1.3.
Informed Consent/Assent
The investigator is responsible for obtaining written informed consent from the parent/legal 
guardian of the subject participating in this study after adequate explanation to the 
parent/legal guardian and subject of the aims, methods, objectives, and potential hazards of 
the study and before undertaking any study-related procedures. Written assent should be 
obtained from the subject as required by IRB/IEC/local requirements for this age population.  
The investigator must utilize an IRB- or IEC-approved consent/assent form for documenting 
written informed consent/assent. Each informed consent/assent will be appropriately signed 
and dated by the subject or the subject’s parent/legally authorized representative and the 
person obtaining consent/assent.
10.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only subject initials, date of birth, 
and an identification code (i.e., not names) should be recorded on any form or biological 
sample submitted to the Sponsor, IRB or IEC, or laboratory. The investigator must keep a 
screening log showing codes, names, and addresses for all subjects screened and for all 
subjects enrolled in the trial.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational new drug, and 
any other study information, remain the sole and exclusive property of Gilead Sciences 
during the conduct of the study and thereafter. This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from Gilead Sciences. The investigator further 
agrees to take all reasonable precautions to prevent the disclosure by any employee or agent 
of the study site to any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following two categories: (1) investigator’s 
study file, and (2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB or IEC and governmental approval with correspondence, informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence.


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The required source data are listed in the Source Data verification Plan, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, i.e., history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria);

Participation in trial (including trial number);

Trial 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 trial medication (preferably drug 
dispensing and return should be documented as well);

Record of all AEs and other safety parameters (start and end date, and preferably 
including causality and intensity);

Concomitant medication (including start and end date, dose if relevant; dose changes 
should be motivated);

Date of trial completion and reason for early discontinuation, if applicable.
All clinical study documents must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (i.e., United States, Europe, or 
Japan) and until there are no pending or contemplated 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 required by applicable 
regulatory requirements, by local regulations, or by an agreement with Gilead Sciences. The 
investigator must notify Gilead Sciences 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 Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the investigator and 
Gilead Sciences to store these in sealed containers outside of the site so that they can be 
returned sealed to the investigator in case of a regulatory audit. When source documents are 
required for the continued care of the subject, appropriate copies should be made for storage 
outside of the site.


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Biological samples at the conclusion of this study may be retained in storage by the Sponsor 
for a period up to 15 years for purposes of this study.
10.1.6.
Case Report Forms
For each subject enrolled, a CRF (or eCRF) must be completed and signed by the principal 
investigator or subinvestigator (as appropriate) within a reasonable time period after data 
collection. This also applies to records for those subjects who fail to complete the study 
(even during a prerandomization screening period if a CRF was initiated). If a subject 
withdraws from the study, the reason must be noted on the CRF. If a subject is withdrawn 
from the study because of a treatment-limiting adverse event, thorough efforts should be 
made to clearly document the outcome.
10.1.7.
Drug Accountability
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate 
accountability of all used and unused investigational medicinal product, and comparators. 
This includes acknowledgment of receipt of each shipment of study product (quantity and 
condition), subject dispensing records, and returned or destroyed study product. Dispensing 
records will document quantities received from Gilead Sciences and quantities dispensed to 
subjects, including lot number, date dispensed, subject identifier number, subject initials, and 
the initials of the person dispensing the medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during 
the study if appropriate. At the end of the study, following final drug inventory reconciliation 
by the monitor, the study site will dispose of and/or destroy all unused investigational 
medicinal product supplies, including empty containers, according to these procedures. If the 
site cannot meet Gilead Sciences’ requirements for disposal, arrangements will be made 
between the site and Gilead Sciences or its representative for destruction or return of unused 
investigational medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by 
the study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from Gilead Sciences or its representatives, to 
IRBs or IECs, or to regulatory authority or health authority inspectors.
10.1.9.
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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10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Gilead Sciences. All protocol modifications must be submitted to the 
IRB or IEC in accordance with local requirements. Approval must be obtained before 
changes can be implemented.
10.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies). 
Gilead Sciences 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.
After conclusion of the study and without prior written approval from Gilead Sciences, 
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 Sciences in an abstract, manuscript, or presentation form; or

the study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead Sciences’ 
confidential information (see Section 10.1.4).
The investigator will submit 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. The investigator will comply with Gilead Sciences’ 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.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor 
must have direct access to the investigator’s source documentation in order to verify the data 
recorded in the CRFs for consistency.
The monitor is responsible for routine review of the CRFs 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 CRFs. The investigator agrees to cooperate with the 
monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved.


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10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences 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 Sciences medical monitor immediately. 
The investigator agrees to provide to representatives of a regulatory agency or 
Gilead Sciences access to records, facilities, and personnel for the effective conduct of any 
inspection or audit.
10.3.3.
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 Sciences and the investigator will assure that adequate consideration is given to the 
protection of the subjects’ interests.


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11.
REFERENCES
19705
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48 (1):148-62.
19799
Hu J, Doucette K, Hartling L, Tjosvold L, Robinson J. Treatment of hepatitis 
C in children: a systematic review. PLoS ONE 2010;5 (7):e11542.
19801
Mohan N, Gonzalez-Peralta RP, Fujisawa T, Chang MH, Heller S, Jara P, et 
al. Chronic hepatitis C virus infection in children. J Pediatr Gastroenterol Nutr 
2010;50 (2):123-31.
20273
Bortolotti F, Verucchi G, Camma C, Cabibbo G, Zancan L, Indolfi G, et al. 
Long-term course of chronic hepatitis C in children: from viral clearance to 
end-stage liver disease. Gastroenterology 2008;134 (7):1900-7.
20282
Serranti D, Buonsenso D, Ceccarelli M, Gargiullo L, Ranno O, Valentini P. 
Pediatric hepatitis C infection: to treat or not to treat...what's the best for the 
child? European review for medical and pharmacological sciences 2011;15 
(9):1057-67.
20285
Wirth S. Current treatment options and response rates in children with chronic 
hepatitis C. World J Gastroenterol 2012;18 (2):99-104.
20286
Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti F, Zancan L, Jara P, et 
al. High sustained virologic response rates in children with chronic hepatitis C 
receiving peginterferon alfa-2b plus ribavirin. J Hepatol 2010;52 (4):501-7.
28583
Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir 
and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 
2014;370 (20):1889-98.
28585
Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. 
Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N 
Engl J Med 2014;370 (16):1483-93.
28587
Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et 
al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without 
cirrhosis. N Engl J Med 2014;370 (20):1879-88.
29292
Gane E, Hyland RH, An D, Pang PS, Symonds WT, McHutchison JG, et al. 
Ledipasvir/Sofosbuvir Fixed-Dose Combination Is Safe and Effective in 
Difficult-to-Treat Populations Including GT 3 Patients, Decompensated GT 1 
Patients, and GT 1 Patients With Prior Sofosbuvir Experience [Oral 
Presentation 6]. 49th Annual Meeting of The European Association for the 
Study of the Liver (EASL); 2014 April 9-13; London, UK. 


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12.
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.
Tanner Stages
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


PPD
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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-Label, Multicenter, Muti-cohort Study to Investigate the Safety and 
Efficacy of Ledipasvir/Sofosbuvir in Adolescents and Children with Chronic HCV-
infection 
GS-US-337-1116, Original Protocol, 10 July 2014 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Luisa Stamm, MD, PhD (Printed) 
Medical Monitor 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to 
all information provided by Gilead Sciences, Inc. I will discuss this material with them to 
ensure that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 78 
10 July 2014 


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Appendix 2.
Study Procedures Table
Table 1.
PK Lead-in: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X j
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Vital Signsa
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X
Subject Dosing Diary
X
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X


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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 10
(+ 3 days)
HCV RNA
X
X
X
X
Viral Sequencing c
X
X
X
Serum or Urine Pregnancy Testinge
X
X
X
Urinalysis
X
X
X
Urine Drug Screen
X
Intensive PK
X d
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs 
antigen, HAV antibody
X
HbA1c
X
TSH
X
Alpha fetoprotein
X
Alpha-1 anti-trypsin
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, body weight, and height
b
Day 1 assessments must be performed prior to dosing
c
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
d
For Cohorts 1 and 2, plasma samples will be collected for PK analyses following dosing of study drugs on Day 10 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5,
8, and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 2, 4, 8, and 12 hours post-dose.
e
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test. 
f
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status). 
g
h
Swallowability can occur at Day 1 if not completed during screening.
i
Quality of life survey will be completed by all subjects if a site is approved to use the survey. Subject is to review questionnaire with a parent/guardian and write/mark 
answers directly onto the questionnaire.
j
Parental height will be collected with medical history at Screening (if available) as stated in Section 6.2.1
PPD
PPD


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Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
Early 
Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
Xi
Complete Physical Examination
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
Tanner Pubertal Stage Assessment
X
X
X
Vital Signsa
X
X
X
X
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
X
Pregnancy Prevention Counseling g
X
X
X
LDV/SOF FDC Swallowability Assessment
X
Xh
Quality of Life Survey e
X
X
X
Review of Study Medication Compliance
X
X
X
X
Study Drug Dispensingb
X
X
X


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Screeningc
(-28 days)
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12
Early 
Termination
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
X
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
Viral Sequencing d
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testing
X
X
X
X
X
X
Single PK
X
X
X
X
X
X
Urinalysis
X
X
Urine Drug Test
X
HCV Genotyping, IL28B
X
HCV antibody, HIV 1/2 antibody, HBs antigen, 
HAV antibody
X
HbA1c
X
TSH
X
X
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, and body weight and height
b
The IWRS will provide direction on the specifics of each subject’s study drug dispensing.
c
Subjects rolling over from PK Lead-in will not be required to repeat screening, Day 1 or Week 1 visits during the on Treatment Phase  
d
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
e
Quality of life survey will be completed at Day 1, Week 12, and Early Termination if a site is approved to use the survey. Subject is to review questionnaire with a 
parent/guardian and write/mark answers directly onto the questionnaire.
f
g
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).
h
Swallowability can occur at Day 1 if not completed during screening.
i
Parental height will be collected with medical history at Screening (if available) as stated in Section 6.2.1
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Table 3.
Treatment Phase: Post Treatment Visits Following Primary Study
4 Weeks Post Treatment
12 Weeks Post Treatment
24 Weeks Post Treatment
Clinical Assessments
Vital Signs, Body weight and Height
X
X
X
Symptom-directed Physical Exam
X
X
X
AEs
X
Xc
Xc
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Bone Age Assessment
X
Pregnancy Prevention Counselingd
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Test
X
X
a
Quality of life survey will be completed by all subjects at 12-Week and 24-Week Post Treatment visits if a site is approved to use the survey.  Subject is to review 
questionnaire with a parent/guardian and write/mark answers directly onto the questionnaire.
b
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
c
At Post Treatment Week 12 and 24, only SAEs will be captured
d
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of the Investigator based on 
subject’s pubertal status).


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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
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


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 


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


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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 89
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
>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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 90
10 July 2014
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 91
10 July 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 92
10 July 2014
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 
Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to Dipstick 
Hematuria.
With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for the 
AE.


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 93
10 July 2014
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 


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Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 94
10 July 2014
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


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Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 95
10 July 2014
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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Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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10 July 2014
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by 
study participant or  
caregiver (for disabled 
adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized 
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater than 
minimal interference with 
usual social & functional 
activities
Itching causing inability to 
perform usual social & 
functional activities 
NA


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 98
10 July 2014
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)


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


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Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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10 July 2014
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social &
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)


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Protocol GS-US-337-1116
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CONFIDENTIAL
Page 101
10 July 2014
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 102
10 July 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 103
10 July 2014
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]


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 104
10 July 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 105
10 July 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 106
10 July 2014
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


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 107
10 July 2014
Appendix 4.
Tanner Stages
1. Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2. Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of testes and scrotum and increased darkening 
of scrotal skin (13.5-15)
Tanner V 
Genitalia adult in size and shape
3. Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen 
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with 
surrounding breast 
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V 
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. 


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 108
10 July 2014
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Background
Non-clinical toxicity studies of LDV/SOF FDC demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of LDV/SOF FDC 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)
For the purpose of this trial, all post-menarchal females will be considered to be of 
childbearing potential, unless there is documentation of irreversible ovarian failure or 
surgical sterilization.
Post-menarchal females must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on the Day 1 visit prior to randomization. They must also agree 
to one of the following from 3 weeks prior to Day 1 until 30 days after last dose of LDV/SOF 
FDC:

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 the last dose of LDV/SOF FDC:
— 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
— implants of levonorgestrel
— injectable progesterone
— oral contraceptives (either combined or progesterone only)
— contraceptive vaginal ring 
— transdermal contraceptive patch


LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 109
10 July 2014
3. Contraceptive Requirements for Male Subjects (and their female partners)
All male study participants must agree to consistently and correctly use a condom from 
Day 1 until 90 days after the last dose of LDV/SOF FDC. If their female partner is of 
childbearing potential (as defined above), their female partner must use 1 of the methods of 
birth control listed above from the date of Screening until 90 days after last dose of 
LDV/SOF FDC.
Male subjects must agree to refrain from sperm donation for at least 90 days after the last 
dose of LDV/SOF FDC.
4. Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time 
during the study, or if they become pregnant within 90 days of last LDV/SOF FDC 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 8.5.2.1.