A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Arm Study to Investigate the Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children With Genotype 2 or 3 Chronic HCV Infection
Phase: PHASE2
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences

Study Title: 
Sponsor: 
IND No.: 
EudraCT Number: 
Indication: 
Protocol ID: 
Gilead Sciences Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Aim 
Study to Investigate the Safety and Efficacy of 
Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106739 
TBD 
Hepatitis C Vims Infection 
GS-US-334-1112 
Name: 
Telephone: 
Mobile: 
Fax: 
E-mail: 
Original: 
Alnendment 1: 
Alnendment 2: 
Luisa Stamm, MD, PhD 
~:~ 
PD 
t-'U 
20 December 2013 
10 Febmmy 2014 
14 Mm·ch 2014 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmi iculm·ly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Institutional Review Board or Independent Ethics Committee. The inf01mation is 
only to be used by you in connection with authorized clinical studies of the investigational 
dmg described in the protocol. You will not disclose any of the infonnation to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessmy to obtain 
inf01med consent from those persons to whom the dmg may be administered. 

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TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................................................................2
LIST OF IN-TEXT TABLES.................................................................................................................................5
LIST OF IN-TEXT FIGURES ...............................................................................................................................5
PROTOCOL SYNOPSIS .......................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................16
1.
INTRODUCTION .......................................................................................................................................19
1.1.
Background.....................................................................................................................................19
1.2.
Sofosbuvir.......................................................................................................................................20
1.3.
Ribavirin (RBV)..............................................................................................................................20
1.4.
Rationale for the Current Study ......................................................................................................21
1.5.
Rationale for Dose Selection of SOF ..............................................................................................21
1.6.
Overall Risk/Benefit Assessment....................................................................................................22
2.
OBJECTIVES..............................................................................................................................................23
3.
STUDY DESIGN ........................................................................................................................................24
3.1.
Treatment Plan and Regimen..........................................................................................................24
3.1.1.
PK Lead-in ....................................................................................................................24
3.1.2.
Treatment Phase............................................................................................................24
3.2.
Visit Schedule .................................................................................................................................26
3.2.1.
PK Lead-in ....................................................................................................................26
3.2.2.
Treatment Phase............................................................................................................27
3.3.
Virologic Response-Based Stopping Criteria..................................................................................27
3.4.
Treatment Discontinuations Criteria...............................................................................................28
3.5.
Discontinuations .............................................................................................................................28
3.6.
Pharmacogenomic Substudy...........................................................................................................28
3.7.
Long-Term Follow-Up....................................................................................................................28
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.
Sofosbuvir.......................................................................................................................................33
5.2.1.
Description and Handling..............................................................................................33
5.2.2.
Storage and Handling....................................................................................................34
5.2.3.
Dosage and Administration of SOF ..............................................................................35
5.3.
Ribavirin .........................................................................................................................................35
5.3.1.
Description and Handling of RBV................................................................................35
5.3.2.
Dosage and Administration of RBV .............................................................................36
5.4.
Co-administration of SOF and RBV...............................................................................................37
5.5.
Study Drug Compliance..................................................................................................................37
5.6.
Prior and Concomitant Medications................................................................................................37
6.
STUDY PROCEDURES .............................................................................................................................39
6.1.
Subject Enrollment..........................................................................................................................39

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6.2.
Screening Assessments ...................................................................................................................39
6.2.1.
Screening Visit (Day –28 to Day 0)..............................................................................39
6.3.
PK Lead-in: Treatment Assessments ..............................................................................................41
6.3.1.
Day 1 Visit ....................................................................................................................41
6.3.2.
Day 3.............................................................................................................................42
6.3.3.
Day 7 – Intensive PK ....................................................................................................42
6.4.
Treatment Phase: Treatment Assessments ......................................................................................44
6.4.1.
Day 1 Visit ....................................................................................................................44
6.4.2.
Weeks 1 and 2 (3 days)..............................................................................................46
6.4.3.
Weeks 4 and 8 (3 days)..............................................................................................46
6.4.4.
Week 12 (3 days) .......................................................................................................47
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects only.........................................................48
6.4.6.
Week 24 (3 days) – GT-3 Subjects only ....................................................................48
6.4.7.
Unscheduled Visit/Early Termination Visit ..................................................................49
6.5.
Post-Treatment Assessments...........................................................................................................50
6.5.1.
4-Week Post-Treatment Visit (5 days).......................................................................50
6.5.2.
12-Week Post-Treatment Visit (5 days).....................................................................51
6.5.3.
24-Week Post-Treatment Visit (5 days).....................................................................52
6.6.
Procedures and Specifications.........................................................................................................52
6.6.1.
Clinical Laboratory Analytes ........................................................................................52
6.6.2.
Medical History.............................................................................................................53
6.6.3.
Complete Physical Examination ...................................................................................53
6.6.4.
Tanner Pubertal Stage Assessment................................................................................53
6.6.5.
Height & Weight Measurement with Percentiles..........................................................53
6.6.6.
Bone Age Assessment...................................................................................................53
6.6.7.
Swallowability Assessment...........................................................................................54
6.6.8.
Vital Signs.....................................................................................................................54
6.6.9.
Body Mass Index (BMI) ...............................................................................................54
6.6.10.
Estimated Glomerular Filtration Rate (GFR)................................................................54
6.6.11.
Viral Sequencing (Archive) ..........................................................................................54
6.6.12.
Pregnancy Testing.........................................................................................................54
6.6.13.
Quality of Life Survey (PedsQL™)................................................................................55
7.
TOXICITY MANAGEMENT.....................................................................................................................56
7.1.
Modification of Dose/Schedule Due to Toxicity ............................................................................56
7.2.
Subject Stopping Rules for SOF .....................................................................................................56
8.
ADVERSE EVENTS MANAGEMENT.....................................................................................................57
8.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events..........................57
8.1.1.
Adverse Events..............................................................................................................57
8.1.2.
Serious Adverse Events.................................................................................................57
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events..............................................................58
8.2.
Assessment of Adverse Events and Serious Adverse Events..........................................................58
8.2.1.
Assessment of Causality for Study Drugs and Procedures............................................58
8.2.2.
Assessment of Severity .................................................................................................59
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events ...............................................................................................................................59
8.4.
Gilead Reporting Requirements......................................................................................................61
8.5.
Special Situations Reports ..............................................................................................................61
8.5.1.
Definitions of Special Situations...................................................................................61
8.5.2.
Instructions for Reporting Special Situations................................................................62

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9.
STATISTICAL CONSIDERATIONS.........................................................................................................64
9.1.
Analysis Objectives and Endpoints.................................................................................................64
9.1.1.
Analysis Objectives.......................................................................................................64
9.1.2.
Primary Endpoints.........................................................................................................65
9.1.3.
Secondary Endpoints.....................................................................................................65
9.2.
Analysis Conventions .....................................................................................................................65
9.2.1.
Analysis Sets.................................................................................................................65
9.2.2.
Data Handling Conventions ..........................................................................................66
9.2.3.
Interim Analysis............................................................................................................67
9.3.
Demographic Data and Baseline Characteristics ............................................................................67
9.4.
Pharmacokinetic Analysis...............................................................................................................68
9.5.
Safety Analysis ...............................................................................................................................68
9.5.1.
Extent of Exposure........................................................................................................68
9.5.2.
Adverse Events..............................................................................................................69
9.5.3.
Laboratory Evaluations .................................................................................................69
9.5.4.
Other Safety Evaluations...............................................................................................70
9.6.
Efficacy Analysis............................................................................................................................70
9.6.1.
Primary Efficacy Analysis ............................................................................................70
9.6.2.
Secondary Efficacy Analysis ........................................................................................70
9.6.3.
Subgroup Analysis ........................................................................................................71
9.7.
Quality of Life Analysis..................................................................................................................71
9.8.
Data Monitoring Committee ...........................................................................................................71
9.9.
Sample Size.....................................................................................................................................71
10.
RESPONSIBILITIES ..................................................................................................................................72
10.1.
Investigator Responsibilities ...........................................................................................................72
10.1.1.
Good Clinical Practice ..................................................................................................72
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval..............................................................................................................72
10.1.3.
Informed Consent/Assent..............................................................................................73
10.1.4.
Confidentiality ..............................................................................................................73
10.1.5.
Study Files and Retention of Records...........................................................................73
10.1.6.
Case Report Forms........................................................................................................75
10.1.7.
Drug Accountability......................................................................................................75
10.1.8.
Inspections ....................................................................................................................75
10.1.9.
Protocol Compliance.....................................................................................................75
10.2.
Sponsor Responsibilities.................................................................................................................76
10.2.1.
Protocol Modifications..................................................................................................76
10.2.2.
Study Report and Publications ......................................................................................76
10.3.
Joint Investigator/Sponsor Responsibilities ....................................................................................76
10.3.1.
Access to Information for Monitoring...........................................................................76
10.3.2.
Access to Information for Auditing or Inspections .......................................................77
10.3.3.
Study Discontinuation...................................................................................................77
11.
REFERENCES ............................................................................................................................................78
12.
APPENDICES .............................................................................................................................................80
Appendix 1.
Investigator Signature Page...........................................................................................81
Appendix 2.
Study Procedures Table.................................................................................................82
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities .............................................................................................89
Appendix 4.
Tanner Stages..............................................................................................................112

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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements ................................................................113
LIST OF IN-TEXT TABLES
Table 7-1.
RBV Dose Reduction Guidelines..................................................................................56
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema................................................................................................................26

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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, Single-Arm 
Study to Investigate the Safety and Efficacy of 
Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection
IND Number:
EudraCT Number:
106739
TBD
Study Centers:
Approximately 50 sites in the United States, Europe, Russia, 
Australia, and New Zealand
Number of Subjects:
Approximately 100 subjects
Target Population:
Adolescents and children (aged 3 to < 18) with chronic hepatitis C 
virus (HCV) infection
Treatment Duration:
PK Lead-in – 7 days
Treatment Phase – 12 or 24 weeks
Objectives:
The primary objective of the PK Lead-in Phase of this study is:

To evaluate the steady state pharmacokinetics (PK) and 
confirm the dose of sofosbuvir (SOF) in HCV-infected 
pediatric subjects
The secondary objective of the PK Lead-in Phase of this study is:

To evaluate the safety and tolerability of 7 days of dosing of 
SOF + ribavirin (RBV) in HCV-infected pediatric subjects
The primary objectives of the Treatment Phase of this study are:

To evaluate the safety and tolerability of SOF + RBV for 12 or 
24 weeks in HCV-infected pediatric subjects with genotype
(GT) GT-2 or GT-3, respectively

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Study Design: 
CONFIDENTIAL 
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The seconda!y objectives of the Treatment Phase of this study are: 
• 
To detennine the antiviral efficacy of SOF + RBV u·eatment in 
GT-2 and GT-3 HCV-infected subjects separately, as assessed 
by the proportion of subjects with SVR 12 weeks after 
completion ofu·eatment (SVR12) 
• 
To detennine the antiviral efficacy of SOF + RBV u·eatment in 
GT-2 and GT-3 HCV-infected subjects separately, as assessed 
by the proportion of subjects with SVR 4 and 24 weeks after 
completion ofu·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of circulating HCV RNA dming 
u·eatment and after completion of u·eatment 
• 
To evaluate the emergence of viral resistance to SOF dming 
u·eatment and after completion of u·eatment 
The explorat01y objective of this study is: 
• 
PO 
Open-label, multi-cohort, two-part study evaluating the PK, safety, 
and antiviral activity ofSOF in chronic HCV-infected pediau·ic 
subjects. 
The study will be divided into 2 parts as follows: 
PK Lead-in: Will evaluate and/or confi1m age appropriate SOF 
doses by analyzing PK, safety, and antiviral activity of SOF 
administered in combination with RBV through 7 days of dosing 
for each of three coh01is. Children aged 3 < 6, children aged 6 to 
< 12 years and adolescents aged 12 to < 18 years with genotype 
GT-2 or GT-3 HCV infection and evidence of HCV RNA 
~ 1000 ID/mL at study enu·y will be evaluated. Subjects must be 
u·eatment naive to pruiicipate in the PK Lead-in Phase. 
Three coh01is of up to 10 subjects each will be sequentially 
emolled: 
• 
Cohort 1: 12 to < 18 yeru·s old weighing ~ 45kg 
• 
Coh01i 2: 6 to < 12 yeru·s old 
• 
Cohort 3: 3 to < 6 yeru·s old 
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The study will start with Cohort 1.  Subjects will receive SOF
(400 mg adult tablet or 4 x 100 mg tablets if determined necessary 
based on SOF swallowability assessment) + RBV for 7 days with 
intensive PK conducted on Day 7. 
PK Lead-in subjects in each cohort (Cohorts 1, 2 and 3) will 
immediately enroll in the Treatment Phase as they complete Day 7 
of the PK Lead-in Phase.  They will continue dosing with SOF +
RBV 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 will be reviewed to confirm 
the appropriateness of the evaluated SOF 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: Will be initiated sequentially by cohort after 
confirmation of age-appropriate SOF dosage levels. Subjects who 
participated in PK Lead-in Phase will immediately rollover into 
Treatment Phase with no interruption of study drug administration
until the appropriateness of the dose is confirmed by PK and safety 
data from the PK-Lead-in.  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 GT-2 or GT-3 infection and evidence of HCV 
RNA ≥1000 IU/mL at study entry (those who were dosed in the 
PK Lead-in Phase will have met this criteria prior to enrollment) 
will be evaluated. 
Subjects enrolled in the study will receive the following regimen:

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and 
treatment-experienced pediatric subjects, with up to 20 subjects 
allowed to be treatment experienced. Approximately 100 total 
subjects, including subjects that participate in the PK Lead-in
Phase, will be enrolled in Treatment Phase as follows

Group 1: Approximately 50 adolescent subjects (12 to 
< 18 years of age)

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Substudy and 
Long-Te1m 
Follow-Up Study: 
• 
Group 2: Approximately 50 pediau·ic subjects (3 to < 12 years 
of age) 
The following definitions will be used for u·eatment-experienced 
subjects: 
• 
Interferon intolerant: Subject who discontinued therapy 
(~ 12 weeks total) due to ~ 1 adverse event 
• 
Interferon non-responder: Subject who did not achieve 
lmdetectable HCV RNA levels while on u·eahnent 
• 
Relapse/breakthrough: Subject who achieved undetectable 
HCV RNA dming u·eahnent or within 4 weeks of the end of 
u·eahnent but did not achieve a sustained virologic response 
(SVR) 
The study schedule contains the following visits: Screening, Day 1, 
Weeks 1, 2, 4, 8, 12 (and Weeks 16, 20, and 24 for GT-3) dming 
the u·eatment phase followed by post-u·eahnent visits 4, 12 and 
24 weeks after discontinuation of therapy. 
All subjects who do not attain SVR or have viral relapse will be 
encomaged to discuss u·eatment with standard-of-care (SOC) 
therapy with their healthcare provider. 
Pharmacogenomics (PG) Substudy 
PO 
Long-Term Follow-up 
Subjects who attain SVR24 or those who do not attain SVR24 and 
do not initiate experimental or approved anti-HCV therapy will be 
followed eve1y 6 months for assessments of growth, quality of life, 
and long-te1m viral suppression (if applicable) in a separate 
protocol (GS-US-334-1113). This follow-up will continue for 
5 years. 
Diagnosis and Main Chronic HCV-infected, u·eahnent-na'ive and up to 20 subjects may 
Eligibility Criteria: 
be u·eahnent experienced, male and female subjects aged 3 to < 18. 
CONFIDENTIAL 
Inclusion Criteria: 
• 
Chronic HCV infection documented by either: 
a) a positive anti-HCV antibody test or positive HCV RNA or 
positive HCV genotyping test at least 6 months prior to the 
Day 1 visit, or 
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b) a liver biopsy performed prior to the Day 1 visit with 
evidence of chronic HCV infection

Infection with HCV GT-2 or GT-3 as determined at Screening

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 ≥ 45kg

Agree to use 2 forms of highly effective contraception, as 
referenced in Appendix 5, for the duration of the study and for 
6 months (for female subjects) or 7 months (for male subjects)
after the last dose of study medication if age, cultural, and 
sexual activity status appropriate (eg: if sexually active; does 
not pertain to pre-pubertal subjects). 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)

Chronic use of systemic immunosuppressive agents or
immunomodulatory agents

Active or recent history (≤ 1 year) of drug or alcohol abuse

History or current evidence of any condition, therapy, 
laboratory abnormality or other circumstance that might 
confound the results of the study, or interfere with the subject’s 
participation for the full duration of  the study, such that it is 
not in the best interest of the subject to participate.

See Sections 4.2 and 4.3 of the protocol for full eligibility 
criteria.

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Study Procedures/
Frequency:
PK Lead-in Phase: 
Screening assessments will be completed within 28 days of the 
Day 1 visit. 
Screening assessments will include: physical examination, vital 
signs (including height and weight), Tanner Pubertal Stage 
assessment, concomitant medications, safety laboratory tests, 
coagulation tests, HCV RNA, serology (HIV, HAV, HCV, HBV), 
alpha-1 anti-trypsin, serum β-human chorionic gonadotropin hCG 
(females of childbearing potential only), thyroid stimulating 
hormone, HbA1c, IL28B genotyping, alpha fetoprotein, urinalysis, 
and urine drug screen.
Study Visits will occur at Screening, Day 1, Day 3, and Day 7.
On-Treatment assessments include adverse events (AEs), 
concomitant medications, physical examination, bone age 
assessment, vital signs, height, weight, safety laboratory tests, 
HCV RNA, viral sequencing sampling, urine pregnancy tests 
(females of child bearing potential only), and urinalysis. 
Coagulation will be performed at Day 1 and Day 7. SOF
swallowability assessment with placebo will be performed at 
screening up to Day 1 to assess a subject’s ability to swallow the 
400 mg or 100 mg SOF tablet (only subjects administered SOF in 
tablet form).
Subjects (up to 10 subjects) enrolled in the PK Lead-in Phase will 
participate in an intensive PK evaluation on Day 7. Following 
completion of the Day 7 intensive PK visit, subjects will then 
return for scheduled study visits outlined in the Treatment Phase
and continue dosing with SOF + RBV with no interruption of 
study drug administration.  Subjects will be administered a dosing 
diary with instructions.
Treatment Phase: 
Screening assessments will be completed within 28 days of the 
Day 1 visit. For subjects continuing from the PK Lead-in, 
screening for Treatment Phase will not be required.
Screening assessments will include physical examination, vital 
signs, concomitant medications, safety laboratory tests, HCV 
RNA, serology (HIV, HAV, HCV, HBV), alpha-1 anti-trypsin 
serum β-human chorionic gonadotropin hCG (females of 
childbearing potential only), thyroid stimulating hormone, IL28B 
genotyping, urinalysis, and urine drug screen.

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Test Product, Dose, 
and Mode of 
Administration: 
CONFIDENTIAL 
• 
GT-2 Subjects: Study visits for GT-2 subjects will occur at 
screening, Day 1, and the end of Weeks 1, 2, 4, 8, and 12. 
• 
GT-3 Subjects: Study visits for GT-3 subjects will occur at 
screening, Day 1, and the end of Weeks 1, 2, 4, 8, 12, 16, 20, 
and 24. 
All Treatment Phase subjects will then retum for follow-up visits 
at 4, 12 and 24 weeks after discontinuation of therapy. 
On-u·eatment assessments will include adverse events, concomitant 
medications, physical examination, vital signs (including height 
and weight), safety laborat01y tests, coagulation tests, HCV RNA, 
PK samples, and urine pregnancy tests (females of childbearing 
potential only). Height and weight measurements (with percentiles) 
and Tanner Pubertal Stage assessment will be perfonned at Day 1, 
end ofu·eahnent, post-u·eatment Week 12 and post-u·eahnent 
24-week; parental heights will be recorded at Day 1. The Bone 
Age Assessment will be perfonned at Day 1 and post-u·eatment 
Week 24 visit. If available, results from liver biopsies will be 
collected at screening. SOF swallowability assessment with 
placebo will be perf01med at screening up to Day 1 to assess a 
subject's ability to swallow a 400 mg or 100 mg SOF tablet (all 
subjects administered SOF in tablet f01m). For subjects continuing 
from the PK Lead-in, the screening, Day 1 and Week 1 visits of the 
Treatment Phase will not be required. Post-u·eatment assessments 
will include adverse events, concomitant medications, vital signs, 
safety laborat01y tests, HCV RNA, and urine pregnancy tests 
(females of childbearing potential only). Samples for viral RNA 
sequencing/phenotyping will be collected at Day 1 and eve1y visit 
thereafter. 
PO 
PKLead-in: 
(Coh01t 1) SOF 400 mg tablets will be administered once daily 
along with RBV weight-based dosing. Subjects dete1mined unable 
to swallow the placebo for 400 mg SOF tablet (by SOF Placebo 
swallowability assessment at Screening or at any time during the 
study) will be re-assigned to 4 x 100 mg tablets daily. 
Intensive PK and safety results from the PK Lead-In of each 
Cohort will be reviewed to confnm the appropriateness of the 
evaluated SOF dose for the Treatment Phase of that Coh01t as well 
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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.
RBV Weight-Based Dosing (All age groups):
The RBV dose is:
Body Weight kg
(lbs)
RBV Daily Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution
47-49 (103-108)
600 mg/day
1 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
50-65 (110 – 143)
800 mg/day
2 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
65-80 (143 – 176)
1000 mg/day
2 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
81-105 (178-231)
1200 mg/day
3 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
>105 (>231)
1400 mg/day
3 x 200-mg capsules A.M.
4 x 200-mg capsules P.M.
The morning dose of RBV will be taken with food with an age-
appropriate dose of SOF. The evening dose of RBV will be taken 
with food.
Reference Therapy:
None
Evaluation Criteria:
Safety:
AEs, laboratory tests, and Tanner Pubertal Stage assessments 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.

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PK:
For subjects in the PK Lead-in, steady-state PK of SOF and its 
major metabolites GS-566500 and GS-331007 will be assessed at
Day 7. For Cohorts 1 and 2, plasma samples will be collected for 
PK analyses following dosing of study drugs on Day 7 at the 
following time points: 0 (predose), 0.5, 1, 2, 3, 4, 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), 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/or ribavirin will be assessed.
The effect of age and SOF dose on PK (SOF and GS-331007) 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 SOF dose on PK 
(SOF and GS-331007) 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 genotype, by overall and by age 
group and GT.  Point estimate and its 95% confidence interval will 
be provided.  
In addition, SVR12 will be compared with historical SVR12 rate of 
80% from pegylated interferon + ribavirin for pediatric GT-2 and 
GT-3 subjects {20280}, using two-sided exact one-sample binomial 
test at the 0.05 significance level.  
Secondary efficacy endpoints are SVR4, SVR24, breakthrough and 
relapse.
Subgroup analysis on SVR12 will be performed by treatment 
experience (treatment-naive vs. experienced) 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). 
All continuous endpoints will be summarized using an 8-number 

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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.
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 50 subjects enrolled into each age group of 
Treatment Phase, a two-sided 95.0% confidence interval of the 
SVR12 rate will extend at most 11.1% in both directions from the 
observed SVR12 rate, assuming the expected SVR12 rate is 80%. 
In addition, a sample size of 100 subjects will provide over 80% 
power to detect a 11% improvement in SVR12 rate from 80% to 
91% using two-sided one-sample binomial test at significance level 
of 0.05.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval 
(tau)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
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)
CMH
Cochran-Mantel-Haenszel
COPD
Chronic obstructive pulmonary disease
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
Emax
maximal effect
EU
European Union
EVR
Early virologic response
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GCSF
Granulocyte colony stimulating factor
GFR
glomerular filtration rate

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
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
IV
Intravenous
IWRS
interactive web response system
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LLN
lower limit of the normal range
LLOD
Lower limit of detection
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

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’ formula
RBC
Red blood cell count 
RBV
Ribavirin
RDRP
RNA-dependent RNA polymerase
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction
SAE
serious adverse event
SD
Standard deviation
SOC
Standard of Care
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
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 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 standard of care 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.
Sofosbuvir
Sovaldi™(Sofosbuvir) is a potent nucleotide analogue that inhibits HCV RNA replication in 
vitro and has demonstrated high rates of sustained viral response (SVR) when given with 
RBV +/- PEG to subjects with chronic GT- 1, 2, 3 or 4 HCV infection {27503}, {23275}, 
{24713}, {24715}.  Sovaldi™has been approved in the United States by the Food and Drug 
Administration (FDA) for the treatment of HCV infection GT- 1, 2, 3 and 4 including 
treatment naïve and experienced patients and HIV/HCV co-infected patients.  Sovaldi™is
also approved in EU, Canada and Turkey.
For further information on the clinical pharmacology, virology, safety and efficacy of SOF, 
please refer to the current version of the Investigator’s Brochure and the local prescribing 
information.  
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of 
RNA and DNA viruses {15572}, {15668}. Ribavirin monotherapy has little or no effect on the 
replication of HCV but can result in normalization of serum ALT activity and improvement 
in liver histology. When combined with interferon or PEG therapy, RBV decreases 
substantially the relapse rate seen after cessation of interferon therapy {12557}, {12558}.
Ribavirin is a known teratogen (FDA category X).  Furthermore, RBV is known to 
accumulate intracellularly where it is cleared slowly, and is also excreted in semen. 
Therefore, extreme care must be taken to avoid pregnancy during RBV therapy and for up to 
7 months following completion of treatment.  A comprehensive review of RBV is contained 
in the package insert/SmPC.

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1.4.
Rationale for the Current Study
This clinical study is designed to evaluate the efficacy and safety of treatment with SOF +
RBV for adolescents and children with GT-2 and GT-3 chronic HCV infection. 
Currently PEG and weight-based RBV are considered the standard of care for the treatment 
of HCV infection in children. However, this PEG and RBV regimen is long in duration, 
relatively toxic, and not well tolerated. Thus, there continues to be a need for new treatments 
for HCV that combine potent and sustained efficacy with improved tolerability and safety. 
Therapy that provides shorter duration and improved efficacy with an all-oral regimen would 
be a significant advancement over current options in pediatric patients.
The main aim for the treatment of pediatric patients with HCV is to eliminate the need to use 
PEG regimens. In this way, pediatric patients are able to avoid the necessity of weekly 
injections, which can be traumatic and burdensome, and also to significantly reduce the 
serious adverse events seen on administration of PEG regimens. 
SOF is a promising candidate to combine with RBV based on its acceptable safety profile 
and its antiviral activity.  Clinical trials from adult studies have demonstrated the antiviral 
efficacy, potency, and safety of SOF in subjects with HCV infection. SOF in combination 
with RBV would provide an all-oral, IFN-free regimen with a shorter treatment duration 
(12 - 24 weeks of SOF treatment versus standard-of-care 24 to 48 weeks of treatment) and 
would offer another important option in the treatment of HCV infection in the pediatric 
population.
While emerging Phase 3 data demonstrate high SVR12 rates in subjects with GT-2 HCV 
infection, these studies suggest that patients with GT-3 infection may benefit from a longer 
treatment duration with SOF + RBV. Optimal duration of SOF + RBV, for GT-3 subjects,
was established in FISSION and VALENCE.  Increasing treatment duration from 12 to 
24 weeks increased SVR12 from 61 to 93% in non-cirrhotics and from 34 to 92% in 
cirrhotics.
1.5.
Rationale for Dose Selection of SOF
SOF 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and favorable safety profile in over 
3300 HCV-infected adult subjects across multiple patient populations in Phase 2 and 3 trials. 
This dose is the marketed dose of SOF for the treatment of HCV-infection in adults.
Selection of doses of SOF for adolescents and younger age groups will target systemic 
exposures similar to those observed in adults at the marketed dose, taking into account body 
weight/body surface area, the potential ontogenic changes in hepatically expressed 
carboxylesterase 1 (CES1) and Cathepsin A (CatA) enzymes, and the results obtained in 
older age groups.  Available data suggest comparable hepatic expression of CES1 in 
adolescents and adults, with modestly decreased expression in children.  As such, the adult 
clinical dose, 400mg, will be evaluated in adolescents (12 to <18 years old) {20288}.  Safety 
and PK data in the adolescent group (Cohort 1) in the PK Lead-in, will inform dose selection 
for the younger age groups in addition to body weight/body surface area. 

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Age-appropriate formulations of SOF (a smaller, 100 mg strength tablet and a non-tablet 
formulation currently in 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 solid-dose formulation.
1.6.
Overall Risk/Benefit Assessment
Although the majority of pediatric patients infected with HCV exhibit minimal hepatic
sequelae despite active viral replication and inflammation, a subset of children and
adolescents will require treatment. Studies suggest that 3 major categories of disease can
occur within 10 years after putative HCV exposure: (1) undetectable viremia and normal
ALT, (2) persistent yet uncomplicated mild liver disease, and (3) progression to end-stage
liver disease {20273}. It is the last two groups of children in whom therapy may be indicated 
to prevent end-stage disease, either during childhood/adolescence or in early adulthood.
Given that the current standard of care 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. 
SOF has demonstrated efficient inhibition of viral replication in in vitro and in vivo studies. 
Available clinical data indicate SOF has a favorable safety profile and is well tolerated. SOF 
in combination with RBV is likely to provide significant therapeutic benefit in the treatment 
of HCV infection in pediatric patients compared to currently available therapies in the 
following areas:

Expected improved efficacy in a pediatric population compared to the current standard of 
care

Expected improvement in safety and tolerability in relation to either adverse reactions or 
potential medication errors in the pediatric population compared to the current standard 
of care

Improved dosing scheme or method of administration (oral compared to subcutaneously 
administration and reduced treatment duration) leading to improved safety, efficacy,
tolerability, and compliance

Expected availability of a clinically relevant age-appropriate formulation

Different mechanism of action with potential advantage for the pediatric population in 
terms of improved efficacy and safety

Expected improvement in quality of life (eg, minimized duration of therapy and
avoidance of IFN-related adverse events that affect patient quality of life such as flulike
syndrome and depression)
Additionally, the study sponsor will perform an ongoing review of safety data during the 
conduct of the study.

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2. 
OBJECTIVES 
The prima1y objective of the PK Lead-in of this study is: 
Final 
Amendment2 
• 
To evaluate the steady state phrumacokinetics (PK) and confmn the dose of SOF in 
HCV -infected pediatric subjects 
The secondruy objective of the PK Lead-in of this study is: 
• 
To evaluate the safety and tolerability of 7 days of dosing of SOF + RBV in 
HCV -infected pediatric subjects 
The primary objectives of the Treatment Phase of this study are: 
• 
To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in HCV 
infected pediatric subjects with GT-2 or GT-3, respectively 
The secondruy objectives of the Treatment Phase of this study ru·e: 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects sepru·ately, as assessed by the proportion of subjects with SVR 
12 weeks after completion of treatment (SVR12) 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects separately, as assessed by the prop01tion 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 SOF during treatment and after 
completion of treatment 
The explorat01y objective ofthis study is: 
• 
PD 
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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and antiviral 
activity of SOF + RBV in chronic HCV-infected pediatric subjects.
3.1.1.
PK Lead-in
The PK Lead-in Phase will evaluate and/or confirm the age appropriate SOF dose by 
analyzing PK, safety, and antiviral activity of SOF + RBV through 7 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 GT-2 or GT-3 HCV infection and evidence of 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 up to 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 SOF (400 mg adult tablet or 
4 x 100 mg tablets if determined necessary based on SOF swallowability assessment) + RBV 
for 7 days with intensive PK conducted on Day 7. 
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 7 of PK Lead-in.  They will continue 
dosing with SOF + RBV with no interruption of study drug administration.  Subjects rolling 
over from the PK Lead-in Phase will not be required to perform the screening, Day 1 or 
Week 1 visit of the Treatment Phase.
3.1.2.
Treatment Phase
The Treatment Phase will be initiated sequentially by age group as defined in Cohort 1, 2 and 
3 of the PK Lead-in. Subjects who participated in PK Lead-in will immediately rollover into 
Treatment Phase with no interruption of study drug administration until the appropriateness 
of the dose has been confirmed by PK and safety results from the PK Lead-in.  The first visit 
in the Treatment Phase for these subjects will be the Week 2 visit.  Additional subjects will 

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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 GT-2 or GT-3 infection and evidence of HCV RNA ≥1000 IU/mL at study entry (those 
who were dosed in the PK Lead-in will have met this criteria prior to enrollment) will be 
evaluated.
Subjects enrolled in the Treatment Phase will receive the following regimen:

GT-2 subjects: SOF + RBV for 12 weeks

GT-3 subjects: SOF + RBV for 24 weeks
The study will enroll both treatment-naïve and treatment–experienced pediatric subjects, with 
up to 20 subjects allowed to be treatment experienced. Approximately 100 total subjects, 
including subjects from the PK Lead-in Phase, will be enrolled in the Treatment Phase as 
follows:

Group 1: Approximately 50 adolescent subjects (12 to < 18 years of age)

Group 2: Approximately 50 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 standard-of-care (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 7.
Subjects (up to 10 subjects) enrolled in the PK Lead-in Phase will participate in an intensive 
PK evaluation on Day 7. Subjects will be administered a dosing diary with instructions.  
Following completion of the Day 7 intensive PK visit, subjects will then return for scheduled 
study visits outlined in the Treatment Phase and continue dosing with SOF + RBV 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 
Treatment Phase.

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3.2.2.
Treatment Phase
Screening assessments will be completed within 28 days of the Day 1 visit. For subjects 
continuing from the PK Lead-in Phase, screening, Day 1 and Week 1 of the Treatment Phase
will not be required.

GT-2 Subjects: Study visits for GT-2 subjects will occur at screening, Day 1, and the 
end of weeks 1, 2, 4, 8, and 12. 

GT-3 Subjects: Study visits for GT-3 subjects will occur at screening, Day 1, and the 
end of weeks 1, 2, 4, 8, 12, 16, 20, and 24. 
All Treatment Phase subjects will then return for follow-up visits at 4, 12 and 24 weeks after 
discontinuation of therapy.
The total time to complete all study visits is approximately 40 or 52 weeks including:

28 day (4 week) screening period

12 or 24 week treatment period

24 week post-treatment period
The assessments performed at each visit are described in Section 6.
3.3.
Virologic Response-Based Stopping Criteria
HCV RNA will be unblinded to the Investigator and Sponsor.
The following on-treatment virologic response-based treatment stopping criteria will be 
utilized:

Confirmed HCV RNA ≥LLOQ after 2 consecutive HCV RNA <LLOQ

Confirmed >1 log10  increase from nadir 

HCV RNA ≥LLOQ through 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination 
of initial observation.  Subjects that meet the virologic response-based stopping criteria 
above will be notified of their eligibility to participate in the Long-Term Follow-Up Study 
(GS-US-334-1113).

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3.4. 
Treatment Discontinuations Criteria 
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The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances: 
• 
Unacceptable toxicity, as defmed in Section 7 of the protocol, or toxicity that, in the 
judgment of the investigator, compromises the ability to continue study-specific 
procedures or is considered to not be in the subject's best interest. 
• 
Pregnancy of female subject or female partner of male subject. 
• 
Efficacy failure as defined in Section 3.3. 
• 
Significant protocol violation including non-compliance with study assessments. 
• 
Subject request to discontinue for any reason; it is imp01tant to detennine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy or other reason. 
• 
Discontinuation of the study at the request of Gilead, regulat01y agency or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). 
3.5. 
Discontinuations 
Subjects discontinuing treatment prior to completion of the assigned dosing period should 
complete an Early Tennination visit as described in the Section 6.4.7. 
Subjects who pennanently discontinue all study dmgs for any reason including safety and/or 
tolerability concems prior to completion of the assigned dosing period will be followed 
according to the post-u·eatment study assessments described in Section 6.5. 
3.6. 
Pharmacogenomic Substudy 
PD 
3.7. 
Long-Term Follow-Up 
All subjects (those who attain SVR24 or those who do not attain SVR24) who do not initiate 
other experimental or approved anti-HCV therapy will be followed eve1y 6 months for 
assessments of growth, quality of life, and long-te1m viral suppression (if applicable) in a 
separate protocol (GS-US-334-1113). This follow-up will continue for 5 years. 
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3.8.
Breakthrough Futility Assessment
A futility assessment will be performed after the first 10 subjects complete Week 8 on study 
or have viral breakthrough at or prior to Week 8. If 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. 

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 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 (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 
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 Baseline/Day 1.
6. Chronic HCV infection documented by either:
c) 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
d) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV 
infection
7. Infection with HCV GT-2 or GT-3 as determined at Screening
8. HCV RNA ≥1000 IU/mL at Screening
9. Adequate hematologic function (absolute neutrophil count 1,500/mm3; hemoglobin 
12 g/dL for males and 11g/dL for females.)

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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)
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 5 days (pulmonary/nasal administration is permitted)
15. Investigational agents taken within the past 30 days (except with the expressed approval 
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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 5.6 within 
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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
Not applicable.
5.2.
Sofosbuvir
5.2.1.
Description and Handling
5.2.1.1.
Formulation:
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. In addition to the active ingredient, SOF tablets 
contain the following inactive ingredients: mannitol, microcrystalline cellulose, 
croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, 
titanium dioxide, macrogol, talc, and yellow iron oxide.
Placebo tablets for Swallowability Assessment, 400 mg, are yellow, capsule-shaped, film-
coated tablets debossed with “GSI” on one side and “7977” on the other side. The tablets 
contain mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon 
dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow 
iron oxide.
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. In addition to the 
active ingredient, SOF tablets contain the following inactive ingredients: mannitol, 
microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium 
stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
Placebo tablets for Swallowability Assessment, 100 mg, are yellow, round, film-coated, 
plain-faced tablets. The tablets contain lactose, monohydrate, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, 
talc, and yellow iron oxide.
The formulation of SOF Oral Granules will be based on the PK results obtained from cohorts 
1 and/or 2 of this study. The formulation strength 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 tablets.
5.2.1.2.
Packaging and Labeling
SOF 400 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 30 tablets and a silica gel desiccant canister or sachet and polyester packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant screw cap 
with an induction-sealed, aluminum-faced liner.

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Placebo tablets for Swallowability Assessment, 400 mg, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 30 tablets and a silica gel desiccant 
canister or sachet and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child-resistant screw cap with an induction-sealed, aluminum-faced liner.
SOF 100 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and a 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 for Swallowability Assessment, 100 mg, are packaged in white, high density 
polyethylene (HDPE) bottles. Each bottle contains 10 tablets 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 SOF Oral Granules 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.
SOF bottles to be distributed to centers in the US, EU and the rest of the countries will be 
labeled to meet all applicable requirements of the US Food and Drug Administration (FDA) 
and Annex 13 of Good Manufacturing Practices: Manufacture of investigational medicinal 
products (February 2010) and/or other local regulations as applicable.
Placebo tablets for Swallowability Assessment, 100 mg and 400 mg, bottles to be distributed 
to centers in the US, EU and the rest of the countries shall be labeled to meet all applicable 
requirements of the US Food and Drug Administration (FDA) and Annex 13 of Good 
Manufacturing Practices: Manufacture of investigational medicinal products (February 2010) 
and/or other local regulations as applicable.
5.2.2.
Storage and Handling
SOF tablets, 100 mg and 400 mg, should be stored at controlled room temperature until 
required for administration. Controlled room temperature is defined as 25 C (77 F); 
excursions are permitted between 15 C and 30 C (59 F to 86 F).
Placebo tablets for Swallowability Assessment, 100 mg and 400 mg, should be stored at 
controlled room temperature until required for administration. Controlled room temperature 
is defined as 25 C (77 F); excursions are permitted between 15 C and 30 C (59 F to 
86 F).  
The storage and handling of the SOF Oral Granules 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 study drug and to ensure proper product 

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identification, the drug product should not be stored in a container other than the container in 
which they are supplied. Consideration should be given to handling, preparation, and 
disposal through measures that minimize drug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure through inhalation 
when handling SOF.
Sufficient quantities of SOF tablets, SOF Oral Granules 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 SOF
PK Lead-in: (Cohort 1) SOF 400 mg tablets will be administered once daily along with RBV 
weight-based dosing. Subjects determined unable to swallow the placebo for the 400 mg SOF 
tablet (by SOF Placebo swallowability assessment at Screening up to Day 1) will be 
re-assigned to 4 x 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 SOF 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 SOF Oral Granulates is currently under 
development. The dose for this formulation will be dependent on the PK results obtained 
from cohorts 1 and/or 2 of this study. The strength, composition, and dosing administration 
will be available and reflected in a protocol amendment which will be submitted for approval
prior to dosing subjects who are unable to swallow tablets.
5.3.
Ribavirin 
5.3.1.
Description and Handling of RBV
5.3.1.1.
Formulation
REBETOL capsules consist of a white powder in a white, opaque, gelatin capsule. Each 
capsule contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose, 
lactose monohydrate (40 mg), croscarmellose sodium, and magnesium stearate. The capsule 
shell contains gelatin, titanium dioxide. The capsule shell imprint contains shellac, propylene 
glycol, ammonium hydroxide, coloring agent (E 132).The hard capsule is imprinted with 
blue ink.

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REBETOL RBV Oral Solution 40 mg per mL is a clear, colorless to pale or light yellow 
bubble gum-flavored liquid. In addition to the active ingredient, RBV oral solution contains
the following inactive ingredients: sucrose, glycerin, sorbitol, propylene glycol, sodium 
citrate, citric acid, sodium benzoate, natural and artificial flavor for bubble gum #15864, and 
water.
5.3.1.2.
Packaging and Labeling
The RBV capsules are packaged in blisters. Each blister card contains 20 capsules and seven 
cards (140 capsules) per carton.
The RBV oral solution is packaged in 4-oz amber glass bottles (100 mL/bottle) with 
child-resistant closures.
RBV capsules and oral solution to be distributed to centers in the US, EU and the rest of the 
countries shall be labeled to meet all applicable requirements of the US Food and Drug 
Administration (FDA) and Annex 13 of Good Manufacturing Practices: Manufacture of 
investigational medicinal products (February 2010) and/or other local regulations as 
applicable.
5.3.1.3.
Storage and Handling
RBV capsules should not be stored above 30 C (86 F).
RBV oral solution should not be stored above 30°C (86°F).
5.3.2.
Dosage and Administration of RBV
RBV dose will be administered by weight as follows:
Body Weight kg
(lbs)
RBV Daily Dose
RBV Number of Capsules
<47 (<103)
15 mg/kg/day
Use Oral Solution
47-49 (103-108)
600 mg/day
1 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
50-65 (110 –
143)
800 mg/day
2 x 200-mg capsules A.M.
2 x 200-mg capsules P.M.
65-80 (143 – 176)
1000 mg/day
2 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
81-105 (178-231)
1200 mg/day
3 x 200-mg capsules A.M.
3 x 200-mg capsules P.M.
>105 (>231)
1400 mg/day
3 x 200-mg capsules A.M.
4 x 200-mg capsules P.M.

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The morning dose of RBV will be taken with food and SOF. The evening dose of RBV will 
be taken with food.
RBV will be supplied by Gilead Sciences for all subjects.
5.4.
Co-administration of SOF and RBV
In the Treatment Phase of the study, each subject will be given instructions to maintain 
approximately the same daily dosing interval between study drug doses.
For morning doses, subjects will be instructed to take study drugs as follows:

SOF

Weight-based RBV (as per Section 5.3.2).
For evening doses, subjects will be instructed to take study drug as follows:

Weight-based RBV (as per Section 5.3.2).
If a subject forgets to take the medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF should be taken on any calendar day.  The 
subject should resume the standing dosing schedule on the next day.  Study medications 
should not be cut or split.  
5.5.
Study Drug Compliance
Subjects will be instructed to return any unused SOF and RBV in the original container on 
Day 7 (PK Lead-in) and/or at study treatment visits every 4 weeks (Treatment Phase).  
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.6.
Prior and Concomitant Medications
Concomitant medications taken within 30 days of Screening, up to and including the date of 
the visit four weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs. All concomitant medications should be recorded in the source 
documents.
The following medications are prohibited from 28 days prior to the Day 1 visit through the 
end of treatment:

Erythropoiesis-stimulating agents (ESAs); including but not limited to Procrit®, Aranesp®
and Epogen®

Granulocyte colony stimulating factor (GCSF)

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
Chronic systemic immunosuppressants including corticosteroids (prednisone equivalent 
of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab)

Investigational agents or devices for any indication

Drugs disallowed per prescribing information of REBETOL®

Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions 
resulting in decreases in exposure of study drug(s). Representative medications which are 
excluded from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutine, rifapentine
Decrease in concentration of study drug
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb sho-saiko-
to (or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, 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 (i.e., height and weight of parents, if known)
— Liver biopsy results (if available)

Complete physical examination 

Vital signs (temperature, blood pressure, pulse, respiratory rate), body weight and height

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
Obtain blood samples for tests as listed in Section 6.6.1:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Determination of HCV viral GT and subtype
— HCV antibody, HIV 1/2 antibody, and HBs antigen, HAV antibody
— HbA1c
— TSH
— IL28B
— Serum -hCG pregnancy test for females of childbearing potential only
— Alpha fetoprotein (AFP)
— Alpha-1 anti-trypsin (ATT)

Obtain urine sample for:
— Urinalysis
— Urine Drug Screen

Review of concomitant medications

Ask subject and/or parent/legal guardian if the subject is able to swallow and tolerate 
taking pills.

Review of all inclusion and exclusion criteria

Perform SOF swallowability assessment (for subjects administered SOF in tablet form 
only)
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 
Final 
Amendment2 
After confnmation of eligibility has been evaluated, the following tests and procedmes must 
be completed prior to enrollment and dosing/dispensing on Day 1: 
• 
Perf01m complete physical examination 
• 
Tanner Pubertal Stage Assessment 
• 
Vital signs, including body weight and height measmements 
• 
A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pruiicipants (Subjects 12 to < 18 yeru·s of age only) 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (ru·chive) 
PD 
• 
Obtain mine samples for the following procedmes: 
-
Urinalysis 
-
~ -hCG pregnancy test for females of childberu·ing potential only 
• 
Subject completes quality of life smvey: Subject is to review questionnaire with a 
parent/guardian and write/mru·k answers directly onto the questionnaire. 
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6.3.1.1.
Drug Administration

Dispense study drugs as directed by the IWRS

Instruct the subject on the appropriate RBV dose after weight-based dosage is calculated 
using Day 1 weight

Instruct the subject on the packaging, storage and administration of all study drugs

Perform SOF swallowability assessment (for subjects administered SOF in tablet form 
only if not previously completed at screening).  Observe the subject taking the first dose 
of study drugs (with 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 parent/guardian

Obtain blood samples for:
— Hematology
— Chemistry
— HCV RNA
— Viral sequencing (archive)

Review subject dosing diary
6.3.3.
Day 7 – Intensive PK 
The Day 7 Intensive PK visit should occur on the protocol-specified visit date based on the 
Day 1 visit. For the purposes of scheduling, the Day 7 Intensive PK visit may 
be performed within +3 days of the protocol-specified visit date (subjects will continue daily 
dosing through the Intensive PK Visit).

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Subjects should come in a fasted state for the Day 7 Intensive PK visit (i.e., no food or drink 
except water at least 8 hours prior to the Day 7 Intensive PK visit). Subjects and/or 
parents/guardians should be instructed that the Day 7 dose of SOF+RBV must not be taken 
until the evaluations listed below are completed. 
If the subject has already dosed prior to the Day 7 clinic visit or is not in a fasted state, the 
Day 7 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 8, 9, or 10) 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 7 visit, the Day 7 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 7 intensive PK visit no sooner than 3 days following compliant dosing and 
no later than Day 11 (i.e., return on Day 10 or Day 11).  If dosing non-compliance is due to 
an AE, consultation with the Gilead Medical Monitor is required regarding the potential of
rescheduling the Day 7 intensive PK visit.
In both scenarios described above, the subject and/or parents/guardians should be reminded 
not to take the SOF + RBV prior to arriving at the clinic on the day of the re-scheduled 
intensive PK visit. All Day 7 intensive PK assessments listed below should be completed 
when the subject returns.
The following evaluations are to be completed at the Day 7 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 medication compliance with subject and/or parent/guardian.

Obtain urine samples for the following procedures:
— Urinalysis
— Urine pregnancy test (females of childbearing potential only). If the urine pregnancy 
test is positive, the Intensive PK sampling will not be completed. The positive result 
will be confirmed with a serum pregnancy test. 

Obtain blood samples for the following laboratory analyses:
— Hematology 
— Chemistry 

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— Coagulation tests
— HCV RNA
— Viral sequencing (archive)

Perform intensive PK sampling: 
— Blood samples will be collected at 0 (predose, ≤30 minutes prior to dosing). After 
collection of the predose sample, subjects will be provided a standardized meal. 
Within 5 minutes after consuming the standardized meal, subjects will be dosed with 
SOF + RBV per dosing requirements.
— Post-dose blood samples will be collected as follows: 

For Cohorts 1 and 2:  0.5, 1, 2, 3, 4, 8, and 12 hours post-dose (with predose also 
serving as t= 24).

For Cohort 3 only: 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 7 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 with percentiles 

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Review of AEs and concomitant medications

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• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
pmi icipants (Subjects 12 to < 18 years of age only). 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemis1:Iy 
-
Coagulation tests 
-
HCVRNA 
-
Viral sequencing (m·chive) 
PD 
• 
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 
pm·ent/gum·dian and write/mark answers directly onto the questionnaire. 
• 
Perf01m SOF swallowability assessment (for subjects administered SOF in tablet f01m 
only if not previously completed at screening). 
6.4.1.1. 
Dmg Adminisu·ation 
• 
Dispense study <hugs as directed by the IWRS 
• 
lns1:Iuct the subject on the appropriate RBV dose after weight-based dosage is calculated 
using Day 1 weight 
• 
lns1:Iuct the subject on the packaging, storage and adminisu·ation of all study <hugs 
• 
Observe the subject taking the first dose of study dm gs (with food) and record the time of 
first dose 
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6.4.2.
Weeks 1 and 2 (3 days)
Subjects who participated in the PK Lead-in will start study visits in Treatment Phase at 
Week 2.  The following procedures/assessments are to be completed at these visits:

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— Single PK 
6.4.3.
Weeks 4 and 8 (3 days)

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— Single PK 

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
Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should 
return all study drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.4.
Week 12 (3 days)

Perform complete physical examination

Tanner Pubertal Staging Assessment

Vital signs, including body weight and height measurements with percentiles 

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)

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. (GT-2 Subjects 
only)

Review medication compliance with subject and/or parent/guardian.

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
Dispense study drugs as directed by the IWRS (GT-3 Subjects Only)

GT-2 Subjects should return all bottles and kits at the Week 12 Visit
6.4.5.
Week 16 and 20 (3 days) – GT-3 Subjects only

Vital signs, including body weight and height measurements 

Perform symptom-directed physical examination

Assessment of AEs and concomitant medications

Obtain blood samples for
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— Single PK 

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/guardian (subject should 
return all study drugs at these visits)

Dispense study drugs as directed by the IWRS
6.4.6.
Week 24 (3 days) – GT-3 Subjects only

Perform complete physical examination

Tanner Staging Assessment

Vital signs, including body weight and height measurements with percentiles 

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)

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
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.

GT-3 Subjects should return all bottles and kits at the Week 24 Visit
6.4.7.
Unscheduled Visit/Early Termination Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. 
The assessments are at the investigator’s discretion.
The Sponsor/CRO should be informed when a subject comes off treatment due to an adverse 
event. If a subject discontinues treatment then the assessments outlined below should be 
performed.

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs, including body weight and height measurements with percentiles 

Assessment of AEs and concomitant medications

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)

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
Obtain blood samples for:
— Hematology
— Chemistry
— Coagulation tests
— HCV RNA
— Viral sequencing (archive)
— TSH
— Single PK 

Obtain urine sample for:
— -hCG pregnancy test for females of childbearing potential only

Subject completes quality of life survey: Subject is to review questionnaire with a
parent/guardian and write/mark answers directly onto the questionnaire.

Review medication compliance with subject and/or parent/guardian.

Subjects should return all bottles and kits 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.
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

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— 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 (Subjects 12 to < 18 years of age only) 
Female subjects of childbearing potential should be provided with Urine Pregnancy 
Test-Kits, instructed on their use and requested to continue to self-monitor for pregnancy for 
6-months after their last dose of RBV. If required by local regulations, additional pregnancy 
tests beyond 6 months may be added.  The subject should be contacted every 4 weeks and 
asked to report results of the urine pregnancy tests. If a positive urine pregnancy test is 
reported, the subject should return to the clinic for a serum pregnancy test.
6.5.2.
12-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements with percentiles 

Perform symptom-directed physical examination

Perform Tanner Pubertal Stage assessment

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 (Subjects 12 to < 18 years of age 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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6.5.3.
24-Week Post-Treatment Visit (5 days)

Vital signs, including body weight and height measurements with percentiles 

Perform symptom-directed physical examination

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)

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.

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (Subjects 12 to < 18 years of age only)
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) 
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.

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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: 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.
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.  Perform Tanner Pubertal Stage 
assessment for subjects until Tanner Stage 5 has been reached. Date of first menses will be 
documented.  
6.6.5.
Height & Weight Measurement with Percentiles
Height and weight measurement will be collected at Day 1, End of Treatment, post-treatment 
Week 12 and post-treatment Week 24.  Percentiles will be calculated using the WHO 
reference charts and tables by age and gender for height and weight.  
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.

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6.6.7.
Swallowability Assessment
A SOF 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 for the 400 mg SOF 
tablet. This will confirm the swallowability of the 400 mg tablet size. If, a subject is unable to 
swallow the 400 mg tablet size he/she will repeat the assessment with a placebo for the
100 mg SOF tablet.    If unable to take the 100 mg SOF 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.
Body Mass Index (BMI)
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.6.10.
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)]
6.6.11.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each visit for viral sequence analysis. Unused 
samples may be archived.
6.6.12.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every 4 weeks during 
the dosing period and for a minimum of 6 months following the last dose of RBV. If required 

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by local regulations, additional pregnancy tests beyond 6 months may be added. In the event 
of a positive urine pregnancy result, subjects will be instructed to stop study drugs 
immediately and return to the clinic as soon as possible for a serum pregnancy test.
Pregnancy test kits will be dispensed to female subjects of child bearing potential at the 
4-Week Post-Treatment visit. The subject will be contacted by telephone monthly to confirm 
that urine pregnancy testing has been performed post-treatment and to record the outcome. 
Alternatively, if required by local regulations or preferred by the investigator or subject, the 
subject may return to the clinic for urine pregnancy tests.
6.6.13.
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 (Week 12 for GT-2 
subjects, Week 24 for GT-3 subjects, or at 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.
Modification of Dose/Schedule Due to Toxicity
Dose reduction of RBV due to toxicity should be performed according to the product label. 
Information is provided in Table 7-1.
Table 7-1.
RBV Dose Reduction Guidelines
Laboratory Values
Reduce RBV Dose by 200 mg/day if:
Discontinue RBV if:
Hemoglobin in subjects with 
no cardiac disease
<10 g/dL
<8.5 g/dL
Hemoglobin in subjects with 
history of stable cardiac 
disease
2 g/dL decrease in hemoglobin during 
any 4 week period treatment
<12 g/dL despite 4 weeks at 
reduced dose
Dose reduction in pediatric patients is accomplished by modifying the recommended RBV 
dose from original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, 
then to 8 mg/kg/day, if needed.
7.2.
Subject Stopping Rules for SOF
The Gilead Medical Monitor should be consulted prior to dose discontinuation of SOF unless 
the investigator believes that immediate action is warranted to ensure the continued safety of 
the subject.
Administration of SOF may be discontinued due to a clinical or laboratory event. There is no 
option for SOF dose reduction. If SOF is stopped for toxicity, it should not be restarted, RBV 
should be stopped and the subject should complete an Early Termination Visit.
Subjects who meet any of the following laboratory criteria should stop treatment with SOF
and RBV:

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 

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event or lab abnormality assessed as related to treatment with SOF

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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 
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 from screening onwards.
All AEs, regardless of causal relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP must be reported to the CRF/eCRF database 
as instructed. 
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the post-treatment follow 
up period.
Investigators are not obligated to actively seek SAEs after the 24 week post-treatment 
follow-up period.  However, if the investigator learns of any SAEs that occur after this time 
and the event is deemed relevant to the use of IMP, he/she should promptly document and 
report the event directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com or Fax: +1 (650) 522-5477.  All AEs and SAEs will be
recorded in the CRF/eCRF database within the timelines outlined in the CRF/eCRF 
completion guideline.

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• 
All SAEs will be recorded on the serious adverse event repmi fmm and submitted by 
emailing or faxing the repmi fmm within 24 hours of the investigator's knowledge of the 
event to the attention of the designated CRO Phrumacovigilance Representative. 
Electronic Serious Adverse Event (eSAE) Repmiing Process 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines 
outlined in the CRF/eCRF completion guideline. 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
infmmation 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 infmmation electr·onically, ie, the 
eCRF database is not ftmctioning, record the SAE on the paper serious adverse event 
repmiing fmm and submit within 24 hours as described above. 
• 
As soon as it is possible to do so, any SAE repmied via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repmied via a paper fonn because the eCRF database has been 
locked, no fmiher action is necessruy. 
Conta.ct infonnation is as follows: 
Gilead Sciences, 
Dmg Safety and 
Public Health: 
PRA Intemational 
Phrumacovigilance 
Representative: 
Gilead Sciences, 
Medical Monitor: 
CONFIDENTIAL 
Fax: 
E-mail: 
Fax: 
E-mail: 
Nrune: 
Phone: 
Mobile: 
Fax: 
E-mail: 
+ 1 650 522-5477 
Safety _FC@gilead.com 
+1 888 772 6919 (NmihAmerica); 
+49 621 8782 181 (Rest of World) 
CHOSafety@praintl.com 
Luisa Stamm, MD, PhD 
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. 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.  Also includes reports of adverse reactions 
in infants following exposure from breastfeeding, and reports of adverse reactions associated 
with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure 
to the medicinal product. 
Medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by 
a subject.

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Misuse is defined as any intentional and inappropriate use of a medicinal product that is not 
in accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal product given per administration or cumulatively which is above the maximum 
recommended dose as per protocol or in the product labelling (as it applies to the daily dose 
of the subject in question). In cases of a discrepancy in drug accountability, overdose will be 
established only when it is clear that the subject has taken the excess dose(s). Overdose 
cannot be established when the subject cannot account for the discrepancy except in cases in 
which the investigator has reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging or distribution of the medicinal product.  
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 the CRO Pharmacovigilance 
Representative using the pregnancy report form within 24 hours of becoming aware of the 
pregnancy.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate 
a pregnancy without medical reasons.
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 CRO Pharmacovigilance Representative using 
the pregnancy outcome report form. If the end of the pregnancy occurs after the study has 
been completed, the outcome should be reported directly to Gilead DSPH. Gilead DSPH 
contact information is as follows: Email: Safety_FC@gilead.com 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 the CRO 
Pharmacovigilance Representative 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 

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completed, the outcome should be reported directly to Gilead DSPH, fax number 
+1 (650) 522-5477 or email Safety_FC@gilead.com. 
Clinical staff should also report any pregnancies to the Ribavirin Pregnancy Registry at 
1-800-593-2214 (see also http://www.ribavirinpregnancyregistry.com).
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements.
8.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to the CRO Pharmacovigilance Representative within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study 
IMP, but do not apply to concomitant medications. Except for situations that result in AEs, 
special situations involving concomitant medications will not be reported. Any inappropriate 
use of contraindicated medications should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
Refer to Section 8.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or 
SAEs at the same time using the AE eCRF and/or the SAE report form. Details of the 
symptoms and signs, clinical management and outcome will be reported, when available.

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Objectives and Endpoints 
9.1.1. 
Analysis Objectives 
The prima1y objective ofPK Lead-in Phase of this study is: 
Final 
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• 
To evaluate the steady state phrumacokinetics (PK) and confnm the dose of SOF in 
HCV -infected pediatric subjects 
The secondruy objective ofPK Lead-in of this study is: 
• 
To evaluate the safety and tolerability of 7 days of dosing of SOF + RBV in 
HCV -infected pediatric subjects 
The primru·y objectives of Treatment Phase of this study are: 
• 
To evaluate the safety and tolerability of SOF + RBV for 12 or 24 weeks in 
HCV-infected pediatric subjects with GT-2 or GT-3, respectively 
The secondruy objectives of Treatment Phase of this study are: 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects sepru·ately, as assessed by the proportion of subjects with SVR 
12 weeks after completion oftreatment (SVR12) 
• 
To dete1mine the antiviral efficacy of SOF + RBV treatment in GT-2 and GT-3 
HCV-infected subjects sepru·ately, 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 SOF during treatment and after 
completion of treatment 
The explorat01y objective of this study is: 
• 
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9.1.2.
Primary Endpoints
For the PK Lead-in Phase, AUCtau of GS-331007 is considered as the primary PK parameter 
for determining the appropriate SOF dose.
For 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 include AUCtau, Cmax, AUClast, Tmax, 
Clast, Tlast, Ctau and t1/2for GS-331007 and SOF as appropriate. AEs leading to permanent 
discontinuation of study drug(s) will be evaluated as a secondary safety endpoint.
For 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 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 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. 

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Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of 
adverse events according to the treatment received; otherwise, if the subject is not dosed 
then they will be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the 
subject will be excluded from the calculation of summary statistics for that time point. If 
the subject is missing a pre-dose value, then the subject will be excluded from the 
calculation of summary statistics for the pre-dose value and the change from pre-dose 
values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline 
result will be replaced with a screening result, if available. If no pre-treatment laboratory 
value is available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) 
for the summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
calculation of summary statistics for the actual HCV RNA values and the change from 
baseline values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed 
to the logarithmic (base 10) scale (log10 IU/mL).
9.2.3.
Interim Analysis
No formal interim analyses are planned for this study.
9.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by age group and overall for PK Lead-in and 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.

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9.4.
Pharmacokinetic Analysis
PK analysis will be performed for PK Lead-in using the intensive PK analysis set. The 
concentration data of 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 SOF and metabolites (as applicable) using descriptive statistics (e.g., sample 
size, arithmetic mean, geometric mean and its 95% confidence interval, coefficient of 
variation %, standard deviation, median, Q1, Q3, minimum, and maximum) by cohort and 
overall. Plasma concentrations over time will be plotted in semilogarithmic and linear 
formats as mean ± standard deviation, and median (Q1, Q3).
To evaluate the exposures of GS-331007 achieved in pediatric subjects of this study are 
similar to the exposures observed in adult subjects, GS-331007 exposure data from this study 
will be compared to the integrated adult data by carrying out an analysis of variance 
(ANOVA) for log-transformed AUCtau of GS-331007 as the primary endpoint while Cmax of 
GS-331007 as secondary endpoints. 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%. Individual patient management will be performed by maintaining exposures 
comparable to adults.  AUCtau less than the 2.5th percentile of adult values may require dose 
adjustment as appropriate.
The effect of age and SOF dose on PK (SOF and GS-331007) will be assessed.
9.5.
Safety Analysis
Safety analysis will be performed for PK Lead-in and overall study Treatment 
Phaserespectively. 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.

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9.5.2.
Adverse Events
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Term (HLGT), 
High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A 
treatment-emergent adverse event will be defined as any new or worsening adverse event that 
begins on or after the date of first dose of study drug up to the date of last dose of study drug 
plus 30 days. 
Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC and preferred term) will be provided by cohort:

All AEs,

All study drug-related AEs,

Combined Grade 2, 3 and 4 AEs,

Combined Grade 3 and 4 AEs,

Combined Grade 2, 3 and 4 study drug-related AEs,

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 

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baseline data are missing, then any graded abn01mality (i.e., at least a Grade 1) will be 
considered treatment emergent. 
Alllaborat01y abn01malities will be included in the listings of laborat01y data. 
9.5.4. 
Other Safety Evaluations 
9.5.4.1. 
Tanner Pube1ial Stage Assessment 
Tanner Stages (Appendix 4) will be summarized by baseline Tanner Stage using frequency 
and percentage. Age of first menses will be summarized descriptively. 
9.6. 
Efficacy Analysis 
Efficacy will be evaluated using scheduled assessments of HCV RNA perf01med using 
COBAS® TaqMan® HCV Test, v2.0 for use with the High Pure System. 
Efficacy analysis will be perf01med by age group, by GT, by overall, and by age group and 
GT for Treatment Phase. 
All continuous endpoints will be summarized using an 8-number summruy (n, mean, 
standru·d deviation, median, Q1, Q3, minimum, maximum). All categorical endpoints will be 
smnmru·ized by number and percentage of subjects who meet the endpoint definition. 
9.6.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after completion of 
treatment) in the F AS population. Point estimate and its 95% confidence interval will be 
provided. 
9.6.2. 
Secondary Efficacy Analysis 
The prima1y efficacy endpoint of SVR12 will be compru·ed with historical SVR12 rate of 
80% from pegylated interferon + ribavirin for pediatric GT2 and 3 subjects {20280}, using 
two-sided exact one-sample binomial test at the 0.05 significance level. 
The proportion of subjects with HCV RNA below LLOQ over time (including SVR 
endpoints SVR4 and SVR24) will be presented in Treatment Phase in tabulru· and graphical 
f01m. 
Descriptive summru·ies and listings will be provided for additional efficacy evaluations 
including senun HCV RNA actual values and change from baseline, prop01iion of subjects 
with virologic failures, and other endpoints of interest including ALT n01malization. 
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9.6.3. 
Subgroup Analysis 
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Subgroup analysis on SVR12 will be perf01m ed by treatment experience (treatment-naive vs. 
experienced), 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). 
Details on efficacy analyses will be described in the statistical analysis plan. 
9.7. 
Quality of Life Analysis 
The data from PedsQL TM Pediau·ic Quality of Life survey will be summarized by visit and 
age group and overall. 
9.8. 
Data Monitoring Committee 
An extemal multidisciplinruy data monitoring committee (DMC) will review the progress of 
the study and perf01m 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 u·eahnent wan ant the early te1mination of the study in the best interests of the 
pruiicipants, whether the study should continue as planned, or the study should continue with 
modifications. 
The DMC's specific activities will be defmed by a mutually agreed chruier, which will defme 
the DMC's membership, conduct and meeting schedule. 
While the DMC will be asked to advise Gilead regru·ding future conduct of the study, 
including possible early study tennination, Gilead retains fmal decision-making authority on 
all aspects of the study. 
9.9. 
Sample Size 
With approximately 50 subjects enrolled into each age group of Treahnent Phase, a two-
sided 95.0% confidence inte1val of the SVR12 rate will extend at most 11.1% in both 
directions from the obse1ved SVR12 rate, assuming the expected SVR12 rate is 80%. In 
addition, a sample size of 100 subjects will provide over 80% power to detect a 11% 
improvement in SVR12 rate from 80% to 91% using two-sided one-sample binomial test at 
significance level of 0.05. 
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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of 
the “Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. For studies conducted under a United States IND, the 
investigator will ensure that the basic principles of “Good Clinical Practice,” as outlined in 
21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 
1998, and 21 CFR, part 56, 1998, are adhered to.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, 
is adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted 
in a marketing application or reclassification petition subject to this part that the applicant or 
FDA relies on to establish that the product is effective (including studies that show 
equivalence to an effective product) or that make a significant contribution to the 
demonstration of safety.” This requires that investigators and all subinvestigators must 
provide documentation of their financial interest or arrangements with Gilead Sciences, or 
proprietary interests in the drug being studied. This documentation must be provided before 
participation of the investigator and any subinvestigator. The investigator and subinvestigator 
agree to notify Gilead Sciences of any change to reportable interests during the study and for 
one year following completion of the study. Study completion is defined as the date that the 
last subject has completed the protocol defined activities.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 
1993, “Retention of Bioavailability and Bioequivalence Testing Samples.”
10.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent/assent) will be submitted by the investigator to an IRB (for studies 
conducted in the United States) or IEC (for studies conducted outside of the United States). 
Approval from the IRB or IEC must be obtained before starting the study and should be 
documented in a letter to the investigator specifying the protocol number, protocol version, 
protocol date, documents reviewed, and date on which the committee met and granted the 
approval.
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation.

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

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
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.
Biological samples at the conclusion of this study may be retained in storage by the Sponsor 
for a period up to 10 years for purposes of this study.

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10.1.6.
Case Report Forms
For each subject enrolled, a CRF (or eCRF) must be completed and signed by the principal 
investigator or 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
12557
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. 
Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks 
versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic 
infection with hepatitis C virus. International Hepatitis Interventional Therapy 
Group (IHIT). Lancet 1998;352 (9138):1426-32.
12558
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et 
al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for 
chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 
1998;339 (21):1485-92.
15572
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: January 2010.
15668
Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Roche Products Limited, Welwyn Garden City, United Kingdom. 
Revised: March 2010.
19705
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48 (1):148-62.
19799
Hu J, Doucette K, Hartling L, Tjosvold L, Robinson J. Treatment of hepatitis C in 
children: a systematic review. PLoS ONE 2010;5 (7):e11542.
19801
Mohan N, Gonzalez-Peralta RP, Fujisawa T, Chang MH, Heller S, Jara P, et al. 
Chronic hepatitis C virus infection in children. J Pediatr Gastroenterol Nutr 
2010;50 (2):123-31.
20273
Bortolotti F, Verucchi G, Camma C, Cabibbo G, Zancan L, Indolfi G, et al. Long-
term course of chronic hepatitis C in children: from viral clearance to end-stage 
liver disease. Gastroenterology 2008;134 (7):1900-7.
20280
Schwarz KB, Gonzalez-Peralta RP, Murray KF, Molleston JP, Haber BA, Jonas 
MM, et al. The combination of ribavirin and peginterferon is superior to 
peginterferon and placebo for children and adolescents with chronic hepatitis C. 
Gastroenterology 2011;140 (2):450-8 e1.
20282
Serranti D, Buonsenso D, Ceccarelli M, Gargiullo L, Ranno O, Valentini P. 
Pediatric hepatitis C infection: to treat or not to treat...what's the best for the child? 
European review for medical and pharmacological sciences 2011;15 (9):1057-67.
20285
Wirth S. Current treatment options and response rates in children with chronic 
hepatitis C. World J Gastroenterol 2012;18 (2):99-104.

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20286
Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti F, Zancan L, Jara P, et al. 
High sustained virologic response rates in children with chronic hepatitis C 
receiving peginterferon alfa-2b plus ribavirin. J Hepatol 2010;52 (4):501-7.
20288
Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and sex-related expression and 
activity of carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos 
2009;37 (9):1819-25.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without 
treatment options. N Engl J Med 2013;368 (20):1867-77.
24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 
2013;368 (20):1878-87.
27503
SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information. Gilead 
Sciences, Inc. Foster City, CA. December 2013.  

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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities
Appendix 4.
Tanner Stages
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements

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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Arm Study to Investigate the 
Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children with 
Genotype 2 or 3 Chronic HCV Infection 
GS-US-334-1112, Protocol Amendment 2, 14 March 2014 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PD 
tiTTVO 
Bittoo Kanwar, MD (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 81 
14 March 2014 

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Appendix 2.
Study Procedures Table
Appendix Table 1.
PK Lead-in: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 7
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
X
Tanner Pubertal Stage Assessment
X
Collect Height & Weight Measurement 
with Percentiles
X
Vital Signsa
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Pregnancy Prevention Counselingf
X
SOF Swallowability Assessment
X
Xh
Quality of Life Survey
Xi
Review of Study 
Medication Compliance
X
X
Study Drug Dispensingb
X

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Screening
(-28 days)
On-treatment
Day 1b
Day 3
Day 7
(+ 3 days)
Laboratory Assessments
Hematology, Chemistry
X
X
X
X
Coagulation Tests
X
X
X
HCV RNA
X
X
X
X
Viral Sequencing c
X
X
X
Serum or Urine Pregnancy Testinge
X
X
X
Urinalysis
X
X
X
Urine Drug Screen
X
Subject Dosing Diary
X
X
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
PPD

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c
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
d
For Cohorts 1 and 2, plasma samples will be collected for PK analyses following dosing of study drugs on Day 7 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 8, 
and 12 hours post-dose. For Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 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 (subjects 12 to < 18 years of age only).
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.
PPD

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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Complete Physical Examination
X
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
X
X
X
Tanner Pubertal Stage Assessment
X
X
X
X
Collect Height & Weight Measurement 
with Percentiles
X
X
X
X
Vital Signsa
X
X
X
X
X
X
X
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Prevention Counselingh
X
X
X
X
SOF Swallowability Assessment
X
Xj
Quality of Life Surveye
X
X
X
X
Review of Study 
Medication Compliance
X
X
X
X
X
X
X
Study Drug Dispensingb
X
X
X
Xi
X
X

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Screeningc
Day 1c
Visit identified by on-treatment study week
1c
2
4
8
12g
16g
20g
24g
Early 
Termination
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
X
X
X
X
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
X
X
X
X
Viral Sequencing d
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Testing
X
X
X
X
X
X
X
X
X
Single PK
X
X
X
X
X
X
X
X
X
Urinalysis, 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
X
Alpha fetoprotein, Alpha-1 anti-trypsin
X
a
Vital signs include blood pressure, pulse, respiratory rate and temperature, 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 (only GT-2 subjects), Week 24 (only GT-3 subjects) 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
GT-2 subjects will complete through the Week 12 visit; GT-3 subjects will complete through the Week 24 visit. 
h
Including partner pregnancy prevention for male participants (subjects 12 to < 18 years of age only).
i
Study Drug Dispensing at the Week 12 visit for GT-3 subjects only
j
Swallowability can occur at Day 1 if not completed during screening.
PPD
PPD

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Appendix Table 3.
Treatment Phase: Post Treatment Visits Following Primary Study
4 Weeks Post Treatment
12 Weeks Post Treatment
24 Weeks Post Treatment
Clinical Assessments
Vital Signs, Body weight and Height
X
X
X
Symptom-directed Physical Exam
X
X
X
AEs
X
Xd
Xd
Concomitant Medications
X
Quality of Life Survey a
X
X
Tanner Pubertal Stage Assessment 
X
X
Collect Height & Weight Measurement with Percentiles
X
X
Bone Age Assessment
X
Pregnancy Prevention Counseling e
X
X
X
Laboratory Assessments
Hematology, Chemistry
X
X
HCV RNA
X
X
X
Viral Sequencing b
X
X
X
Urine Pregnancy Testc
X
X
X
a
Quality of life survey will be completed by all subjects at 12-Week and 24-Week Post Treatment visits if a site is approved to use the survey.  Subject is to review 
questionnaire with a parent/guardian and write/mark answers directly onto the questionnaire.
b
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies
c
Female subjects of childbearing potential should be provided with Urine Pregnancy Test Kits, instructed on their use and requested to continue to self-monitor for pregnancy 
for 6 months after their last dose of RBV. If required by regulations, additional pregnancy tests beyond 6 months may be added. The subject should be contacted every 
4 weeks and asked to report results of the urine pregnancy tests. If a positive urine pregnancy test is reported, the subject should return to the clinic for a serum pregnancy test.

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d
At Post Treatment Week 12 and 24, only SAEs will be captured
e
Including partner pregnancy prevention for male participants (subjects 12 to < 18 years of age only).

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

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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L

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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0% 

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

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Amendment 2
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L

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Amendment 2
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.14 mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L

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Amendment 2
CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L
Bicarbonate
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL

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

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

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

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

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

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

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Final
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Amendment 2
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

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

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

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

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

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

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

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

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

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

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

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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Background
RBV is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Pregnancy must be excluded before the start 
of treatment with study drugs and prevented thereafter by reliable contraceptive methods. 
Pregnancy tests will be performed regularly throughout this study. Furthermore, RBV is 
known to accumulate intracellularly where it is cleared slowly, and is also excreted in semen. 
Therefore, extreme care must be taken to avoid pregnancy during RBV therapy and for up to 
6 months following completion of treatment (7 months for males). Please refer to the latest 
version of the product insert for additional information. 
Non-clinical toxicity studies of sofosbuvir demonstrated no adverse effect on fertility or 
embryo-fetal development. However, there are no clinical studies of sofosbuvir 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 6 months after last dose of RBV:

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 
6 months after the last dose of RBV:
— 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

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— implants of levonorgestrel
— injectable progesterone
— oral contraceptives (either combined or progesterone only)
— contraceptive vaginal ring 
— transdermal contraceptive patch
3. Contraceptive Requirements for Male Subjects (and their female partners)
All male study participants must agree to consistently and correctly use a condom from 
Baseline until 7 months after the last dose of RBV. If their female partner is of childbearing 
potential (as defined above), their female partner must use 1 of the methods of birth control 
listed above from the date of Screening until 7 months after last dose of RBV.
Male subjects must agree to refrain from sperm donation for at least 7 months after the last 
dose of RBV.
4. Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time 
during the study, or if they become pregnant within 6 months (7 months for partners of male 
subjects) of last RBV dose. 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.