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
Phase: PHASE2
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences

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The information contained in this document, particularly unpublished data, is the property or under control of 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
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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
1.3.
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). 
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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 
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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.
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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 
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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 
summary statistics. For example,

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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 
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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
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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

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
Page 88
10 July 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
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
10 July 2014
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

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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
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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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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

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

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

LDV/SOF FDC
Protocol GS-US-337-1116
Final
Gilead Sciences, Inc
Original
CONFIDENTIAL
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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
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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.