Clinical trial NCT03022981
Conditions: Hepatitis C Virus Infection
Sponsor: Gilead Sciences
Start date: 2017-01-26; Completion date: 2020-02-26
Enrollment: 216 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will have 2 parts: Pharmacokinetics (PK) Lead-in Phase and the Treatment Phase.

The primary objective of the PK Lead-in Phase is to evaluate the steady state PK and confirm the dose of sofosbuvir/velpatasvir (SOF/VEL) fixed-dose combination (FDC) in pediatric participants with chronic hepatitis C virus (HCV) infection.

The primary objective of the Treatment Phase is to evaluate the safety and tolerability of SOF/VEL for 12 weeks in pediatric participants with chronic HCV.

Detailed description:

Arms: arm 1: PK Lead-in Phase: Sofosbuvir/Velpatasvir (SOF/VEL) 400/100 mg once daily for 7 days. Participants who complete the PK lead-in phase, continue into the treatment phase with no interruption of study drug administration and additional participants will be enrolled into the treatment phase once the appropriateness of the dose is confirmed by PK results from the PK lead-in phase.

Treatment Phase: SOF/VEL 400/100 mg once daily for 12 weeks. arm 2: PK Lead-in Phase: SOF/VEL 200/50 mg once daily for 7 days. Participants who complete the PK lead-in phase, continue into the treatment phase with no interruption of study drug administration and additional participants will be enrolled into the treatment phase once the appropriateness of the dose is confirmed by PK results from the PK lead-in phase.

Treatment Phase: SOF/VEL 200/50 mg once daily for 12 weeks. arm 3: PK Lead-in Phase: SOF/VEL 200/50 mg once daily for 7 days for participants who weigh ≥ 17 kg. SOF/VEL 150/37.5 mg once daily for 7 days for participants who weigh \< 17 kg. Participants who complete the PK lead-in phase, continue into the treatment phase with no interruption of study drug administration and additional participants will be enrolled into the treatment phase once the appropriateness of the dose is confirmed by PK results from the PK lead-in phase.

Treatment Phase: SOF/VEL 200/50 mg once daily for 12 weeks for participants who weigh ≥ 17 kg. SOF/VEL 150/37.5 mg once daily for 12 weeks for participants who weigh \< 17 kg.
Interventions: intervention 1: SOF/VEL intervention 2: SOF/VEL
Intervention descriptions: intervention 1: SOF/VEL fixed-dose combination (FDC) 400/100 mg tablets or SOF/VEL FDC 200/50 mg tablets (based on swallowability assessment) intervention 2: SOF/VEL FDC 200/50 mg oral granules

Protocol documents:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Medical Monitor 
and Study Director: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, Multi-coho1i Study to 
Investigate the Safety and Efficacy of SofosbuvirN elpatasvir in 
Adolescents and Children with Chronic HCV Infection 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
118605 
2016-002446-23 
NCT03022981 
Hepatitis C Vims Infection 
GS-US-342-1143 
Name: 
Telephone: 
Fax: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
IPIPD 
IPIPD 
IPIPD 
20 June 2016 
20 September 2016 
01 December 2016 
31 August 2017 
15 June 2018 
CONFIDENTIALITY STATEMENT 
The info1mation contained in this document, paiiicularly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaiy to obtain infonned 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....................................................................14
1.
INTRODUCTION ..............................................................................................................................................18
1.1.
Background ............................................................................................................................................18
1.2.
Sofosbuvir/Velpatasvir Fixed-Dose Combination .................................................................................19
1.2.1.
General Information .............................................................................................................20
1.2.2.
Additional Clinical Trials of SOF/VEL FDC.......................................................................20
1.2.3.
Rationale for This Study.......................................................................................................24
1.3.
Rationale for Dose Selection of SOF/VEL FDC....................................................................................24
1.4.
Risk/Benefit Assessment for the Study..................................................................................................27
1.5.
Compliance ............................................................................................................................................28
2.
OBJECTIVES.....................................................................................................................................................29
3.
STUDY DESIGN................................................................................................................................................30
3.1.
Endpoints ...............................................................................................................................................30
3.2.
Study Design..........................................................................................................................................31
3.3.
Study Treatments ...................................................................................................................................31
3.3.1.
PK Lead-in Phase.................................................................................................................31
3.3.2.
Treatment Phase ...................................................................................................................32
3.4.
Duration of Treatment............................................................................................................................33
3.4.1.
PK Lead-in Phase.................................................................................................................33
3.4.2.
Treatment Phase ...................................................................................................................33
3.5.
Virologic Response-Based Stopping Criteria.........................................................................................33
3.6.
Discontinuation Criteria.........................................................................................................................33
3.7.
End of Study...........................................................................................................................................34
3.8.
Reconsent...............................................................................................................................................34
3.9.
.....................................................................................34
3.10.
Pediatric Registry Study.........................................................................................................................35
3.11.
Biomarker Testing..................................................................................................................................35
3.11.1.
............................................35
3.11.2.
Samples for Optional Future Research.................................................................................35
4.
SUBJECT POPULATION..................................................................................................................................36
4.1.
Number of Subjects and Subject Selection ............................................................................................36
4.2.
Inclusion Criteria....................................................................................................................................36
4.3.
Exclusion Criteria...................................................................................................................................37
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................39
5.1.
Description and Handling of SOF/VEL FDC ........................................................................................39
5.1.1.
Formulation..........................................................................................................................39
5.1.2.
Packaging and Labeling .......................................................................................................39
5.1.3.
Storage and Handling...........................................................................................................40
5.2.
Dosage and Administration of SOF/VEL FDC......................................................................................41
5.2.1.
SOF/VEL FDC Oral Granules Subject Dosing Instructions ................................................41
5.3.
Prior and Concomitant Medications.......................................................................................................43
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5.4. 
Accountability for SOFNEL FDC ......................................................................................................... 44 
5.4.1. 
Investigational Medicinal Product Retum or Disposal.. ....................................................... 44 
6. 
STUDY PROCEDURES .................................................................................................................................... 45 
6.1. 
Subject Enrollment and Treatment Assignment ..................................................................................... 45 
6.2. 
Preti·eatinent Assessments ...................................................................................................................... 45 
6.2.1. 
Screening Visit ..................................................................................................................... 45 
6.2.2. 
Day 1 Assessment.s ............................................................................................................... 47 
6.3. 
PK Lead-in Phase: Treatment Assessments ........................................................................................... 49 
6.3.1. 
Day 3 (Telephone Call) ........................................................................................................ 49 
6.3.2. 
Day 7 - Intensive PK (+3 days) ........................................................................................... 49 
6.4. 
Treatinent Phase: Treatment Assessments ............................................................................................. 51 
6.4.1. 
Weeks 1 (± 3 days) ............................................................................................................... 51 
6.4.2. 
Weeks 4 and 8 (± 3 days) ..................................................................................................... 51 
6.4.3. 
Week 12 (± 3 days) or Early Tennination ............................................................................ 52 
6.5. 
Post.treatment Assess1nents .................................................................................................................... 53 
6.5.1. 
4-Week Post.treatment Visit (± 5 days) ................................................................................. 53 
6.5.2. 
12-Week Postt1·eatment Visit (± 5 days) ............................................................................... 54 
6.5.3. 
24-Week Postt1·eatmentVisit +5 da s ............................................................................... 55 
6.6. 
55 
6.7. 
Unsc e u e Visit .................................................................................................................................. 57 
6.8. 
Assessments for Premature Discontinuation from Study ....................................................................... 57 
6.9. 
Breakthrough Futility Assess1nent ......................................................................................................... 57 
6.10. 
Procedures and Specifications ................................................................................................................ 58 
6.10.1. 
Clinical Laborato1y Analytes ............................................................................................... 58 
6.10.2. 
Medical Histo1y .................................................................................................................... 58 
6.10.3. 
Physical Examination ........................................................................................................... 59 
6.10.4. 
Tanner Pubertal Stage Assessment ....................................................................................... 59 
6.10.5. 
Height & WeightMeasw·ement.. .......................................................................................... 59 
6.10.6. 
Bone Age Assessment .......................................................................................................... 59 
6.10.7. 
Acceptability Assessment.. ................................................................................................... 59 
6.10.8. 
Vital Signs ............................................................................................................................ 60 
6.10.9. 
Body Mass Index (BMI) ....................................................................................................... 60 
6.10.10. 
Estimated Glomemlar Filtration Rate (GFR) ....................................................................... 61 
6.10.11. 
Viral Sequencing (Archive) .................................................................................................. 61 
6.10.12. 
HBV DNA ............................................................................................................................ 61 
6.10.13. 
Pregnancy Testing ................................................................................................................ 61 
6.10.14. 
Quality of Life Swv ey (PedsQL™) ..................................................................................... 61 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 62 
7.1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 62 
7 .1.1. 
Adverse Events ..................................................................................................................... 62 
7.1.2. 
Serious Adverse Events ........................................................................................................ 62 
7.1.3. 
Clinical Laborat01y Abnonnalities and Other Abno1mal Assessments as 
Adverse Events or Serious Adverse Events ......................................................................... 63 
7 .2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 63 
7.2.1. 
Assessment of Causality for Study Drngs and Procedw-es ................................................... 63 
7.2.2. 
Assess1nent ofSeverity ........................................................................................................ 64 
7.3. 
Investigator Requirements and Instrnct.ions for Reporting Adverse Events and Serious 
Adverse Events to Gilead ....................................................................................................................... 64 
Requirements for collect.ion prior to study diug initiation ..................................................................... 64 
7 .4. 
Gilead Repo1t ing Requirements ............................................................................................................. 66 
7.5. 
Toxicity Management ............................................................................................................................ 66 
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7.6.
Special Situations Reports......................................................................................................................66
7.6.1.
Definitions of Special Situations..........................................................................................66
7.6.2.
Instructions for Reporting Special Situations.......................................................................67
8.
STATISTICAL CONSIDERATIONS................................................................................................................69
8.1.
Analysis Objectives and Endpoints........................................................................................................69
8.1.1.
Analysis Objectives..............................................................................................................69
8.1.2.
Primary Endpoint .................................................................................................................70
8.1.3.
Secondary Endpoint .............................................................................................................70
8.1.4.
Other Endpoints of Interest ..................................................................................................71
8.2.
Analysis Conventions.............................................................................................................................71
8.2.1.
Analysis Sets ........................................................................................................................71
8.2.2.
Data Handling Conventions .................................................................................................72
8.3.
Demographic Data and Baseline Characteristics ...................................................................................73
8.4.
Efficacy Analysis ...................................................................................................................................73
8.4.1.
Analysis of the Key Efficacy Endpoint................................................................................73
8.4.2.
Secondary Analyses .............................................................................................................73
8.5.
Safety Analysis.......................................................................................................................................74
8.5.1.
Extent of Exposure...............................................................................................................74
8.5.2.
Adverse Events.....................................................................................................................74
8.5.3.
Laboratory Evaluations ........................................................................................................75
8.5.4.
Other Safety Evaluations......................................................................................................75
8.5.5.
Acceptability ........................................................................................................................76
8.6.
Pharmacokinetic Analysis......................................................................................................................76
8.7.
Data Monitoring Committee ..................................................................................................................77
8.8.
Sample Size............................................................................................................................................77
9.
RESPONSIBILITIES..........................................................................................................................................78
9.1.
Investigator Responsibilities ..................................................................................................................78
9.1.1.
Good Clinical Practice..........................................................................................................78
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................78
9.1.3.
Informed Consent.................................................................................................................79
9.1.4.
Confidentiality......................................................................................................................79
9.1.5.
Study Files and Retention of Records ..................................................................................79
9.1.6.
Case Report Forms...............................................................................................................81
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................81
9.1.8.
Inspections............................................................................................................................81
9.1.9.
Protocol Compliance............................................................................................................82
9.2.
Sponsor Responsibilities ........................................................................................................................82
9.2.1.
Protocol Modifications.........................................................................................................82
9.2.2.
Study Report and Publications .............................................................................................82
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................82
9.3.1.
Payment Reporting...............................................................................................................82
9.3.2.
Access to Information for Monitoring..................................................................................83
9.3.3.
Access to Information for Auditing or Inspections ..............................................................83
9.3.4.
Study Discontinuation..........................................................................................................83
10.
REFERENCES ...................................................................................................................................................84
11.
APPENDICES ....................................................................................................................................................86
Appendix 1.
Investigator Signature Page....................................................................................................87
Appendix 2.
Study Procedures Table..........................................................................................................88


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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............93
Appendix 4.
Tanner Stages* .....................................................................................................................115
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................116
LIST OF IN-TEXT TABLES
Table 1-1.
Steady-state PK and Statistical Comparisons of SOF, GS-331007 and VEL PK in 
Adolescent Subjects (12 to < 18 years old; PK Lead-in) and Adult Subjects 
(Phase 2/3 Population PK Analysis).......................................................................................22
Table 1-2.
Steady-state PK and Statistical Comparisons of SOF, GS-331007 and VEL PK in 
Pediatric Subjects (6 to <12 years old; PK Lead-in) and Adult Subjects (Phase 2/3 
Population PK Analysis) ........................................................................................................23
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................43
LIST OF IN-TEXT FIGURES
Figure 1-1.
Predicted SOF, GS-331007 and VEL AUCtau following administration of SOF/VEL 
FDC 200/50 mg or 150/37.5 mg to Children 3 to <6 years of age who are ≥17 kg 
or < 17 kg, respectively ..........................................................................................................26
Figure 3-1.
PK Lead-in Phase Study Schema ...........................................................................................32


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir in 
Adolescents and Children with Chronic HCV Infection
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
118605
2016-002446-23
NCT03022981
Study Centers Planned:
Approximately 30 centers in United States and Europe
Objectives:
The primary objective of the PK Lead-in Phase is:

To evaluate the steady state pharmacokinetics (PK) and confirm 
the dose of sofosbuvir/velpatasvir fixed dose combination 
(SOF/VEL FDC) in pediatric subjects with chronic hepatitis C 
virus (HCV) infection
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of SOF/VEL FDC for 
12 weeks in pediatric subjects with chronic HCV
The secondary objective of the PK Lead-in Phase is:

To evaluate the safety, tolerability, and antiviral activity of 
7 days of dosing of SOF/VEL FDC in pediatric subjects with 
chronic HCV
The secondary objectives of the Treatment Phase of this study are:

To determine the efficacy of SOF/VEL FDC for 12 weeks in 
pediatric subjects with chronic HCV infection, as assessed by the 
proportion of subjects with sustained virological response (SVR) 
12 weeks after cessation of treatment (SVR12)

To determine the proportion of subjects with SVR 4 and 
24 weeks after cessation of treatment (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure, 
including breakthrough/nonresponse and relapse


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
To evaluate the kinetics of circulating HCV RNA during 
treatment and after cessation of treatment

To evaluate the emergence of viral resistance to SOF and VEL 
during treatment and after cessation of treatment

To evaluate the effect of treatment with SOF/VEL FDC on 
quality of life as measured by PedsQL™ Pediatric Quality of 
Life survey

To evaluate the effect of SOF/VEL FDC on growth and 
development of pediatric subjects during and after treatment

To evaluate the acceptability, including palatability, of 
formulations used in the study
The exploratory objective of this study is:
Study Design:
Open-label, multi-cohort, two-part study evaluating the PK, safety, 
and antiviral activity of SOF/VEL FDC in pediatric subjects with 
chronic HCV infection.
Pediatric subjects with chronic HCV infection of any HCV 
genotype, including indeterminate or mixed genotypes, will be 
enrolled. Both treatment-naive and treatment-experienced subjects 
will be eligible, with at least 20 and up to 40 subjects overall 
allowed to be treatment-experienced.
PK Lead-in Phase: The PK Lead-in Phase will evaluate and/or 
confirm age appropriate SOF/VEL FDC doses by analyzing PK, 
safety, and antiviral activity of SOF/VEL FDC through 7 days of 
dosing with intensive PK sample collection at steady state on Day 7. 
Three sequential age-based cohorts of at least 17 subjects each will 
be enrolled:

Cohort 1: 12 to < 18 years old

Cohort 2: 6 to < 12 years old

Cohort 3: 3 to < 6 years old
At least 6 subjects weighing ≥ 17 kg
At least 6 subjects weighing < 17 kg
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PK Lead-in subjects in each cohort will immediately roll over into
the Treatment Phase as they complete Day 7 of the PK Lead-in 
Phase. They will continue dosing with the same dose of SOF/VEL
FDC with no interruption of study drug administration and will 
follow the Treatment Phase visit schedule for all subsequent visits.
The PK and safety data through Day 7 of each cohort will be 
reviewed to confirm the appropriateness of the SOF/VEL FDC dose 
for the Treatment Phase in that age group as well as to determine the 
dose to be evaluated in the PK Lead-in Phase of the next age cohort.
Treatment Phase: The Treatment Phase will be initiated 
sequentially by age group after confirmation of the age-appropriate 
SOF/VEL FDC dose as follows (including subjects that participated 
within the PK Lead-in Phase):

Group 1: Approximately 100 subjects aged 12 to < 18 years
Includes subjects enrolled in Cohort 1

Group 2: Approximately 100 subjects aged 3 to < 12 years
Includes subjects enrolled in Cohorts 2 and 3
Number of Subjects 
Planned:
200
Target Population:
Adolescent and pediatric subjects
Duration of 
Treatment:
12 weeks
Diagnosis and Main 
Eligibility Criteria:
Chronic HCV-infected, treatment-naïve and treatment-experienced
(at least 20 and up to 40 subjects), male and female subjects aged 
3 to < 18 as determined at Day 1.
See the Sections 4.2 and 4.3 for full eligibility criteria.
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the 
Day 1 visit. The screening window can be extended to 42 days for 
subjects in extenuating circumstances with Sponsor approval.
Screening assessments will include: informed consent, determine 
eligibility, medical history, biological parental height (unless 
unknown eg, subject adopted, biological parent(s) deceased, may be 
performed at screening up to Day 1). Complete physical examination, 
vital signs, height and weight, adverse events (AEs), concomitant 
medications, transient elastography test (if available, may be 
performed at Screening up to Day 1), SOF/VEL FDC swallowability 
assessment (may be performed at screening up to Day 1), safety 
laboratory tests (including hematology, chemistry, and coagulation), 


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hemoglobin Ale (HbAlc), thyroid stimulating ho1mone [TSH], 
alpha-I anti-trypsin (AAT), serology (hepatitis A vims [HA V], HCV, 
and hepatitis B vims [HBV]), serology and/or antigen testing for 
HIV, HBV DNA for HBcAb positive subjects, HCV RNA, HCV 
genotyping, semm ~-human chorionic gonadotropin (~-hCG -
females of childbearing potential only), urinalysis, urine dmg screen, 
Fibrotest®, and AST to Platelet Ratio Index (APRI). 
On-Treatment assessments will include: complete or 
symptom-directed physical examination (as applicable), vital signs, 
body height and weight, AEs and serious adverse events (SAEs ), 
concomitant medications, pregnancy prevention counseling 
(all subjects~ 12 years of age and subjects < 12 years of age at the 
discretion of the investigator based on subject's pube1ial status), 
medication compliance, subject dosing dia1y , safety laborat01y tests 
(including hematology, chemistiy , and coagulation), TSH 
(at Screening, Week 12 and Early Te1mination), HCV RNA, HBV 
DNA for HBcAb positive subjects at Screening, HCV viral 
sequencing sampling, urine pregnancy testing (females of 
childbearing potential only), urinalysis, IL28B (at Day 1 only), 
a quality of life survey (at Day 1, Week 12 and Early Te1mination), 
Tanner Pube1ial Stage assessment (at Day 1, Week 12 and Early 
Te1mination), and radiographic bone age assessment (at Day 1 and 
Early Te1mination). Acceptability will be completed by the subject 
(including palatability assessment) and parent/legal guardian 
(at Day 1, Week 12 and Early Te1mination). 
On-ti·eatment PK assessments include the following: 
• 
For subjects emolled in the PK Lead-in Phase (Coho1is 1, 2 
and 3) 
-
Completion of a Subject Dosing Diaiy from Day 1 through 7 
-
Intensive PK sampling on Day 7 
Coho1is 1 and 2: 
For Coho1is 1 and 2, plasma samples will be collected for PK 
analyses following dosing of study dmg on Day 7 at the following 
time points: 0 (predose), 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose 
(with predose also serving as t=24). 
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For Coho1i 3, plasma samples for PK analyses will be collected 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 all Coho1is, following completion of the Day 7 visit, subjects 
will then return for scheduled study visits outlined in the Treatment 
Phase and will continue dosing with SOFNEL FDC with no 
intenuption of study drng administration. 
• 
For all emolled subjects: 
-
Single sparse PK sample collected anytime at Week 1 and 
Week 12 
-
Twos arse PK sam les collected at Week 4 and Week 8 
Predose 
Posttreatment assessments will include: vital signs, body weight 
and height, symptom-directed physical examination, AEs 
( only SAEs will be captured at posttreatment Week 12 and 
posttreatment Week 24), conc01nitant medications, pregnancy 
prevention counseling for subjects of child bearing potential 
( only posttreatment Week 4), safety laboratory tests (including 
hematology and cheinistiy tests), (only posttreatinent Week 4), HBV 
DNA for HBcAb positive subjects, HCV RNA, HCV viral 
sequencing, and urine pregnancy test for females of child bearing 
potential (only postti·eatment Week 4), a quality of life survey 
(postti·eatinent Weeks 12 and 24), Tanner Pube1ial Stage Assessment 
(postti·eatinent Weeks 12 and 24), and radiographic bone age 
assessment (postti·eatment Week 24). 
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Test Product, Dose, and 
Mode of 
Administration:
Test product:
SOF/VEL FDC products for oral administration are available as:

400 mg SOF and 100 mg VEL tablet (adult strength tablet)

200 mg SOF and 50 mg VEL tablet (lower strength tablet)

50 mg SOF and 12.5 mg VEL oral granules in a packet 
(non-tablet product)
Dosages and formulations by age group:

12 to < 18 years of age:
SOF/VEL FDC 400/100 mg tablet; administered once daily
Subjects unable to swallow the SOF/VEL FDC 400/100 mg 
tablet formulation as determined by the Swallowability 
Assessment at Screening will be re-assigned to 
(2 x 200/50 mg tablets). If subjects are unable to swallow the 
reduced strength SOF/VEL FDC 200/50 mg tablet 
formulation they will be re-assigned to SOF/VEL FDC oral 
granule formulation (8 x 50/12.5 mg packets).
Subjects unable to swallow the reduced strength SOF/VEL 
FDC 200/50 mg tablet formulation as determined by the 
Swallowability Assessment at Screening will be re-assigned 
to SOF/VEL FDC oral granule formulation (4 x 50/12.5 mg 
packets).

6 to < 12 years of age:
SOF/VEL FDC 200/50 mg tablet; administered once daily
Subjects unable to swallow the reduced strength SOF/VEL 
FDC 200/50 mg tablet formulation as determined by the 
Swallowability Assessment at Screening will be re-assigned 
to SOF/VEL FDC oral granule formulation (4 x 50/12.5 mg 
packets).

3 to < 6 years of age:
SOF/VEL FDC 200/50 mg oral granules (4 x 50/12.5 mg 
packets) administered once daily, for subjects who weigh
≥17 kg.
SOF/VEL FDC 150/37.5 mg oral granules (3 x 50/12.5 mg 
packets) administered once daily, for subjects who weigh
< 17 kg.


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Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for Evaluation:
Safety:
AEs, laboratory tests, physical examinations, and vital sign 
measurements will be collected throughout the study.
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV 
RNA performed using COBAS® AmpliPrep/COBAS® TaqMan®
HCV test.
Pharmacokinetics:
For subjects in the PK Lead-in, the steady-state PK of VEL, SOF,
and its major metabolite (GS-331007) will be assessed at Day 7. 
Plasma PK parameters such as Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, 
CL/F, Vz/F and t1/2 will be estimated, as appropriate.
Intensive PK and safety results from the PK Lead-in Phase of each 
cohort will be reviewed to confirm the appropriateness of the 
evaluated SOF/VEL FDC dose for the Treatment Phase in that age 
group.
For all subjects in the Treatment Phase, sparse PK blood samples
will be collected at all visits while on treatment. The PK of SOF, its 
primary metabolite GS-331007, and VEL will be assessed.
Statistical Methods:
For the PK Lead-in, the primary plasma PK parameters are AUCtau, 
for SOF, GS-331007, and VEL. All PK parameters will be 
summarized by cohort. The effect of age and SOF/VEL FDC dose 
on PK will be explored.
For the Treatment Phase, the primary safety endpoint is review of 
any AEs with a focus on AEs that lead to discontinuation of study 
drug. The key efficacy endpoint is SVR12 in all enrolled and treated 
subjects. The point estimate of the SVR12 rate and the 2-sided
95% exact confidence interval based on the Clopper-Pearson method
will be provided. The secondary efficacy endpoints include SVR4 
and SVR24.
Clinically relevant subgroup analyses on SVR12 may be conducted 
as appropriate (ie, assuming that adequate numbers of patients in 
these subsets are available for analysis).


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All continuous endpoints will be summarized using an 8-number 
summary (n, mean, standard deviation, median, Q1, Q3, minimum, 
and maximum). All categorical endpoints will be summarized by 
number and percentage of subjects who meet the endpoint definition.
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnormalities for categorical values or by the 
8-number summary (n, mean, standard deviation, median, Q1, Q3, 
minimum, maximum) for continuous data.
With approximately 100 subjects enrolled into 12 to < 18 years of 
age group and approximately 100 subjects enrolled into 3 to 
< 12 years of age group, a 2-sided 95% exact confidence interval of 
the SVR12 rate in each age group will extend at most 20%
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
-hCG
beta-human chorionic gonadotropin
AAT
alpha-1 anti-trypsin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
ANOVA
analysis of variance
APRI
AST to platelet ratio index
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase (also SGOT)
AUCtau
area under the plasma concentration versus time curve over the dosing interval (tau)
BCRP
breast cancer resistance protein
BLQ
below the lower limit of quantification
BMI
body mass index
CatA
cathepsin A
CES1
carboxylesterase
CHF
congestive heart failure
CK
creatine kinase
Clast
last observed quantifiable drug concentration
CL/F
apparent oral clearance after administration of the drug
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CSR
clinical study report
CVA
cerebral vascular accident
DAA
direct acting antiviral
dL
deciliter
DNA
deoxyribonucleic acid
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form(s)
eSAE
electronic Serious Adverse Event
ESPGHAN
European Society for Paediatric Gastroenterology
EU
European Union
FAS
full analysis set


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FDA
(United States) Food and Drug Administration
FDC
Fixed-Dose Combination
FEV1
forced expiratory volume in one second
FSH
follicle stimulating hormone
GCP
Good Clinical Practice (Guidelines)
GCSF
granulocyte colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GLSM
geometric least-squares mean
GMR
geometric mean ratio
GSI
Gilead Sciences, Inc.
GT
genotype (viral)
HAV
hepatitis A Virus
Hb
hemoglobin
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HBsAb
hepatitis B surface antibody
HBcAb
hepatitis B core antibody
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
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
IFN
interferon
IL28B
IL28B gene
IMB
intermenstrual Bleeding
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IU/mL
international Units Per Milliliter
IUS
intrauterine hormone-releasing system
IWRS
interactive web response system
kg
kilogram
L
liter


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LAM
lactational amenorrhea method
LLN
lower limit of the normal range
LLOQ
lower limit of quantification
LLT
lower-Level Term 
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
Mg
milligram
MH
Mantel-Haenszel
mL
milliliter
Min
minute
mmHg
millimeters mercury
NASPGHAN
North American Society for Paediatric Gastroenterology, Hepatology, and Nutrition
NI
nucleotide Inhibitor
NS5A
nonstructural protein 5A
NS5B
nonstructural protein 5B
PBMC
peripheral blood mononuclear cell(s)
PEG
peginterferon alfa-2a
PG
pharmacogenomic
P-gp
P-glycoprotein
PI
protease inhibitor
PK
pharmacokinetic
PT
prothrombin time
PT
referred Term
PVE
Pharmacovigilance and Epidemiology
RAV
resistance-associated variants
RBC
ped blood cell count
RBV
ribavirin
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SAE
serious adverse event
SD
standard deviation
SNP
single nucleotide polymorphism
SOC
standard-of-care
SOC
system organ class
SOF
sofosbuvir
SOP
standard operating procedure
SUSAR
suspected Unexpected Serious Adverse Reaction
SVR
sustained Virologic Response
TEN
toxic epidermal necrolysis
Tlast
the time (observed time point) of Clast


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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
VEL
velpatasvir
VOX
voxilaprevir
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% {Esteban 2008}. The estimated 
prevalence of HCV infection in children is up to 0.4% in Europe and the United States (US) and 
up to 6% in resource-limited countries {El-Shabrawi 2013, Khaderi 2014}. In addition, in an 
internal analysis using administrative claims data and data from an epidemiology database, 
Gilead Sciences, Inc. (Gilead) estimated that there are approximately 7000 cases of HCV 
infection in the US among those 16 years of age or younger. Globally, there are estimated to be 
6.6 million viremic infections in those 15 years of age or younger {El-Sayed 2015}.
The natural history of chronic HCV-infection in children differs from that in adults since 
HCV-infection in children is relatively benign. Most children chronically infected with HCV are 
asymptomatic or have mild nonspecific symptoms. Clinical symptoms are present in 
approximately 20% of children in the first 4 years of life, with hepatomegaly being the most 
frequent sign (10%). Many, but not all, perinatally infected children will have intermittently or 
persistently abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
levels, particularly in the first 2 years of life. In children with vertical HCV-infection who have 
undergone liver biopsy, the histological spectrum is usually mild, although severe liver disease is 
encountered {Mohan 2010}. Despite the overall more favorable prognosis compared to adults, 
approximately 4% to 6% of children with chronic HCV-infection have evidence of advanced 
fibrosis or cirrhosis and some children eventually require liver transplantation for end-stage liver 
disease as a consequence of HCV-infection {Hu 2010}.
The goal of HCV treatment in both pediatric and adult populations is eradication of the virus, 
thereby preventing hepatic inflammation, hepatic fibrosis, cirrhosis, and liver failure resulting in 
either death or need for liver transplantation. This goal, however, is limited by the nature of the 
disease and the fact that not all patients are suitable candidates for currently approved treatments. 
In addition, pediatric treatment is controversial as the current treatment options are limited and 
severe side effects and tolerability can significantly limit or preclude their use. Despite 
well-established guidelines for the treatment of HCV in adults, there is no universal consensus 
on when or if to treat chronic HCV-infection in children. In 2010, the European Society for 
Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) issued guidance for clinical 
trial development for chronic HCV-infection in children and in 2012, the North American 
Society for Paediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) issued a 
practice guideline {Mack 2012, Wirth 2010}. In the guideline, the ESPGHAN and NASPGHAN 
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.


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Pegylated-interferon (Peg-IFN) and weight-based ribavirin (RBV) is 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-IFN+RBV for 24 weeks and those with 
GT-1 or GT-4 should receive 48 weeks of therapy. Successful treatment of GT-1, however, has 
proved very difficult to achieve in spite of additional therapy or increased duration of treatment. 
A number of pediatric studies have reported that despite 48 weeks of treatment, sustained 
virologic response (SVR24) was observed in only 36% to 53% of subjects with GT-1, while 
response rates were > 80% in subjects with GT-2 or GT-3 {Wirth 2012}. Safety and efficacy 
data in pediatric patients with GT-5 or GT-6 are limited.
Most children treated with Peg-IFN+RBV experience at least 1 adverse event due to treatment
{Wirth 2012}. Although most of these events are mild to moderate in severity, many of them 
result in dose reductions of 1 or both of the drugs. The most common adverse events have 
consisted of influenza-like illness (91%), headache (62%), and injection site reactions (45%), 
often leading to poor compliance and/or discontinuation from treatment.
Additionally, the concern for growth and development in this age group and the role that both 
Peg-IFN and RBV potentially play in reducing growth rates has initiated significant debate 
among pediatric hepatologists as to whether these treatments should even be considered in the 
pediatric population {Serranti 2011}. Many pediatricians currently advocate delay of treatment 
past adolescence or even into adulthood when options with DAAs are possible {Serranti 2011}. 
Unfortunately, in the 25% of pediatric patients who do meet the criteria for treatment (elevated 
transaminases and viral loads), the option of Peg-IFN+RBV therapy remains inadequate in 
regard to both efficacy and safety due to the many risks associated with this treatment.
Recently, the first direct-acting antivirals have been approved for treatment of HCV in children. 
Sofosbuvir and ledipasvir/sofosbuvir are indicated for use in adolescents {Harvoni 2017, 
HARVONI® 2017, SOVALDI® 2017} and were highly effective and well-tolerated regimens in 
clinical trials {Balistreri 2017, Wirth 2017}.
1.2.
Sofosbuvir/Velpatasvir Fixed-Dose Combination
Sofosbuvir/velpatasvir FDC is a coformulation of SOF 400 mg and VEL 100 mg into a 
single tablet for the treatment of chronic HCV infection. This fixed-dose combination combines 
two unique mechanisms of action into a single tablet:

Sofosbuvir, a nucleotide analog HCV NS5B polymerase inhibitor.

Velpatasvir, an HCV NS5A inhibitor that has potent in vitro anti-HCV activity across all 
genotypes.
Sofosbuvir/velpatasvir FDC is currently approved in the US, EU and other regions for the 
treatment of HCV.


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1.2.1.
General Information
Please refer to the SOF/VEL FDC IB for additional information on SOF/VEL FDC. Information 
in the IB includes:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology
1.2.2.
Additional Clinical Trials of SOF/VEL FDC
In addition to studies detailed in the IB, information from the following clinical studies with 
SOF/VEL FDC is provided: Study GS-US-342-1553, GS-US-342-1446, and preliminary 
Cohort 1 and 2 PK Lead-in Phase results from current study GS-US-342-1143.
1.2.2.1.
Study GS-US-342-1553
This open-label, multicenter study assessed the antiviral efficacy, safety, and tolerability of 
SOF/VEL FDC + RBV for 24 weeks in subjects with chronic HCV infection who have 
participated in prior Gilead sponsored HCV treatment studies. This study was conducted in the 
US, New Zealand, and Australia.
Study Design and Subject Population
A total of 69 subjects were enrolled and treated. The majority of subjects were male (76.8%), 
26.1% had cirrhosis and most subjects (78.3%) had baseline HCV RNA ≥800,000 IU/mL. Of 
the 69 subjects who received SOF/VEL FDC+RBV, a total of 32 subjects (46.4%) had HCV 
genotype 1a, 5 subjects (7.2%) had HCV genotype 1b, 14 subjects (20.3%) had HCV genotype 2, 
and 18 subjects (26.1%) had HCV genotype 3.
All of the subjects had been treated with a DAA regimen in a Gilead-sponsored study: 40.6% 
(28 subjects) had been treated with SOF/VEL FDC+VOX, 39.1% (28 subjects) had been treated 
with SOF/VEL FDC, and 20.3% (14 subjects) had been treated with SOF/VEL FDC+RBV.
Overall, 66 subjects (95.7%) completed study treatment. Three subjects prematurely 
discontinued study treatment: 1 subject due to an AE of irritability, 1 subject due to lack of 
efficacy, and 1 subject due to a protocol violation.
Conclusions
The conclusions from this study were as follows:

Treatment with SOF/VEL FDC+RBV for 24 weeks in subjects who had failed prior 
treatment with SOF+VEL ± VOX ± RBV resulted in a high SVR12 rate (91.3%)
Among subjects with genotype 1 HCV infection, the SVR rate was 97.3%
Among subjects with genotype 2 HCV infection, the SVR rate was 92.9%
Among subjects with genotype 3 HCV infection, the SVR12 rate was 77.8%


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
The presence of baseline resistance-associated variants (RAVs) had an impact on the SVR12 
rate in subjects with genotype 3 HCV infection, with an SVR12 rate of 76.9% for subjects 
with RAVs compared with an SVR12 rate of 100.0% for subjects without RAVs. Virologic 
relapse in subjects with genotype 3 was associated with enrichment or emergence of NS5A 
RAVs.

Treatment with SOF/VEL FDC+RBV for 24 weeks was safe and well tolerated. There was a 
low incidence of Grade 3 or 4 AEs, SAEs, and discontinuations due to AEs. Most 
Grade 3 and 4 laboratory abnormalities were consistent with the known effects of RBV.
1.2.2.2.
Study GS-US-342-1446
This open-label, multicenter study assessed the antiviral efficacy, safety, and tolerability of 
SOF/VEL for 12 weeks in subjects who received placebo in study GS-US-342-1138 
(ASTRAL1). This study was conducted in the US, Canada, Europe, and Asia.
Study Design and Population
A total of 111 subjects were enrolled and treated. The majority of subjects were male (58.6%), 
17.1% had cirrhosis and most subjects (73.0%) had baseline HCV RNA ≥800,000 IU/mL. Of 
the 111 subjects who received SOF/VEL FDC, a total of 63 subjects (56.8%) had HCV genotype 
1; 20 subjects (18.0%) had HCV genotype 2; 19 subjects (17.1%) had HCV genotype 4; 
9 subjects (8.1%) had HCV genotype 6. The majority of subjects (99.1%) completed study 
treatment; 1 subject (0.9%) prematurely discontinued study treatment due to an AE.
Conclusions
The conclusions from this study were as follows:

Treatment with SOF/VEL FDC for 12 weeks in treatment-naive and treatment-experienced 
subjects resulted in a high SVR12 rate (97.3%). High SVR12 rates were achieved across all 
HCV genotypes and subgroups, and the overall SVR12 rate was similar to that observed in 
subjects who received SOF/VEL FDC for 12 weeks in the parent study 
(Study GS-US-342-1138 [99.0%; 618 of 624 subjects]).

All subjects with pretreatment NS5A or NS5B NI RAVs achieved SVR12. Virologic relapse 
in a single subject with genotype 1a infection was associated with emergence of the NS5A 
RAV Y93H. No NS5B NI RAVs emerged at relapse.

SOF/VEL FDC was generally well tolerated with low rates of Grade 3 and 4 AEs, SAEs, 
discontinuations due to AEs and Grade 3 and 4 laboratory abnormalities.


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1.2.2.3.
Study GS-US-342-1143
Preliminary pharmacokinetic and safety data from the ongoing GS-US-342-1143 study are 
available for 74 adolescent subjects (N=17 from PK Lead-in Cohort 1 and N=57 from the 
Treatment Phase), and for 20 subjects 6 to < 12 years of age (N=20 from PK Lead-in Cohort 2).
Adolescent subjects 12 to < 18 years of age:
Preliminary pharmacokinetic data are available for 16 of the seventeen adolescent subjects 12 to 
<18 years of age enrolled in the intensive PK Lead-in Cohort 1 (Table 1-1). Mean exposures 
(AUCtau) of VEL and GS-331007 were comparable to observed exposures in the adult subjects in 
the Phase 2/3 SOF/VEL clinical program. Mean SOF exposures were higher in adolescents as 
compared with adults; however, the SOF exposures in adolescents were within the range of SOF 
exposures shown to be safe in the adult Phase 2/3 SOF/VEL clinical program (Table 1-1).
Based on preliminary safety data in 74 adolescent subjects, treatment with SOF/VEL FDC
400/100 mg for 12 weeks was generally safe and well tolerated. Fifty one subjects (69%) had an 
AE, and most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. One subject, with a 
medical history of depression, anxiety and post-traumatic stress disorder, had a Grade 3 SAE of 
exacerbated post-traumatic stress disorder, a Grade 3 SAE of suicidal ideation, and a Grade 4 
SAE of suicidal attempt; all SAEs were assessed as not related to study drug by the investigator. 
No subject discontinued study drug because of an AE. The most common AEs (≥10%) were 
headache (18, 24%), nausea (13, 18%) and fatigue (9, 12%). Most of the lab abnormalities were 
Grade 1 or Grade 2. Six subjects had Grade 3 lab abnormalities (hemoglobin [1 subject], 
hyperglycemia [1 subject], low neutrophils levels [2 subjects], and urinalysis positive for red 
blood cells [2 subjects, both females of child bearing potential with menses at the time of 
urinalysis]), and no subject had Grade 4 laboratory abnormalities.
Table 1-1.
Steady-state PK and Statistical Comparisons of SOF, GS-331007 and 
VEL PK in Adolescent Subjects (12 to < 18 years old; PK Lead-in) 
and Adult Subjects (Phase 2/3 Population PK Analysis)
PK Parameter
Mean (%CV)
%GLSM Ratio
(90% CI) 
Adolescents
N=16*
Adult Phase 2/3
N=1428**
SOF
AUCtau (ng•h/mL)
3070 (40.1)
1260 (37.2)
237 (205, 275)
Cmax (ng/mL)
1600 (48.2)
566 (31.4)
266 (232, 303)
GS-331007
AUCtau (ng•h/mL)
13900 (25.8)
14000 (28.0)
100 (89.5, 112)
Cmax (ng/mL)
1180 (37.1)
868 (27.6)
133 (119, 150)
VEL
AUCtau (ng•h/mL)
4480 (47.0)
2970 (50.2)
150 (122, 184)
Cmax (ng/mL)
630 (48.3)
259 (53.9)
245 (195, 307)
Note: preliminary data presented to 3 significant figures.
*
N=17 enrolled; N=16 evaluable for PK analysis due to 1 subject vomiting within ~ 3 hours of dosing
**
N= 982 (SOF) or 1425 (VEL) from Ph 2/3
I 


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Subjects 6 to < 12 years of age:
Preliminary pharmacokinetic data are available for 20 subjects 6 to <12 years of age, who 
enrolled in the intensive PK Lead-in Cohort 2 (Table 1-2). Seventeen subjects received 
SOF/VEL 200/50 mg, while 3 subjects erroneously received an adult dose of 400/100 mg
(one subject from Day 1 through Day 14 and two subjects from Day 1 through day 8) followed 
by the correct dose 200/50 mg for the remainder of the study. Mean exposures (AUCtau) of VEL 
and SOF were comparable to observed exposures in the adult subjects in the Phase 2/3 SOF/VEL 
clinical program. Mean GS-331007 exposures were lower as compared with adults; however, 
GS-331007 exposures in 6 to <12 year olds were within the range of GS-331007 exposures 
associated with efficacy in the adult Phase 2/3 SOF/VEL clinical program (Table 1-2).
Based on preliminary safety data available in 20 subjects enrolled in Cohort 2, treatment with 
SOF/VEL FDC for 12 weeks was generally safe and well tolerated. Twelve subjects (60%) had 
an AE, and most AEs were Grade 1 (mild) or Grade 2 (moderate) in severity. One subject, a 
6 year old female, had a Grade 3 SAE of auditory hallucinations from Day 37 to Day 49. The 
event was considered by the investigator as drug related and resulted in premature study drug 
discontinuation. The most common AEs (≥ 2 subjects) were abdominal pain (5, 25%), cough 
(3, 15%), vomiting (2, 10%), nasopharingitis (2, 10%), and pruritus (2, 10%). All lab 
abnormalities were Grade 1.
Table 1-2.
Steady-state PK and Statistical Comparisons of SOF, GS-331007 and 
VEL PK in Pediatric Subjects (6 to <12 years old; PK Lead-in) and 
Adult Subjects (Phase 2/3 Population PK Analysis)
PK Parameter
Mean (%CV)
%GLSM Ratio 
(90% CI) 
Pediatrics
N=17*
Adult Phase 2/3
N=1428**
SOF
AUCtau (ng•h/mL)
1760 (39.1)
1260 (37.2)
137 (119, 158)
Cmax (ng/mL)
1330 (52.1)
566 (31.4)
219 (192, 249)
GS-331007
AUCtau (ng•h/mL)
9910 (31.0)
14000 (28.0)
71.0 (63.7, 79.1)
Cmax (ng/mL)
992 (28.0)
868 (27.6)
115 (103, 128)
VEL
AUCtau (ng•h/mL)
3700 (44.7)
2970 (50.2)
121 (99.4, 148)
Cmax (ng/mL)
560 (48.5)
259 (53.9)
215 (172, 268)
Note: preliminary data presented to 3 significant figures.
*
N=20 enrolled; N=17 evaluable for PK analysis as 3 subjects received SOF/VEL FDC 400/100 mg during the PK Lead-in
**
N= 982 (SOF) or 1425 (VEL) from Ph 2/3


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In summary, based on preliminary data available, SOF/VEL FDC 400/100 mg administered to 
adolescents, and SOF/VEL FDC 200/50 mg administered to subjects 6 to <12 years of age, was 
safe and well tolerated, and resulted in SOF, GS-331007, and VEL exposures within the range of 
exposures associated with safety and efficacy in the adult Phase 2/3 SOF/VEL program. As such, 
the adult dose of SOF/VEL FDC 400/100 mg is considered appropriate for use in the adolescent 
population (12 to <18 years of age), and the reduced dose of SOF/VEL FDC 200/50 mg is 
considered appropriate for children 6 to <12 years of age.
1.2.3.
Rationale for This Study
This clinical study is designed to evaluate the efficacy and safety of treatment with SOF/VEL
FDC for adolescents and children with chronic HCV infection. The population of the study will 
be subjects with chronic HCV infection, with 20 to 40 having failed prior treatment.
Currently Peg-IFN and weight-based RBV is considered the SOC for the treatment of 
HCV-infection in children. Therefore, there is a need for new treatments for HCV in the 
pediatric population that combine potent and sustained efficacy with improved tolerability and 
safety. The primary aim for new treatments of pediatric patients with HCV is to eliminate the 
need to use Peg-IFN and RBV. In this way, pediatric patients would be able to avoid the 
necessity of weekly injections, which can be traumatic and burdensome, and significantly reduce 
the serious adverse events seen with Peg-IFN administration and the adverse events seen with its 
administration within HCV infected subjects.
A single regimen of SOF/VEL FDC for 12 weeks resulted in SVR rates >95% in subjects with 
all HCV genotypes and was well tolerated in the phase 3 clinical program. The availability of a 
single, pangenotypic regimen is anticipated to be especially beneficial in areas where genotype 
diversity is high and genotyping may not be readily available or routinely done. Access to 
treatment for patients with HCV infection would be expanded as a result.
1.3.
Rationale for Dose Selection of SOF/VEL FDC
Sofosbuvir is an approved pan-genotypic nucleotide analog HCV NS5B polymerase inhibitor, 
which, when combined with VEL, a second generation NS5A inhibitor, in a fixed-dose 
combination was well-tolerated and resulted in high SVR rates in a broad range of HCV 
genotypes after 12 weeks of treatment in Phase 3 studies.
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without Peg-IFN 
has demonstrated broad genotypic efficacy and favorable safety profile in over 
1700 HCV-infected subjects across multiple patient populations in Phase 2 and 3 trials. This 
dose is the approved marketed dose of sofosbuvir for the treatment of HCV-infection and, as 
such, was selected for co-formulation with VEL into a fixed-dose combination tablet.
Velpatasvir 100 mg was administered in combination with SOF 400 mg for 12 weeks to 
237 HCV-infected subjects in Phase 2 studies. VEL 100 mg was selected for co-formulation with 
SOF based on the Phase 2 safety, PK and antiviral activity (studies GS-US-342-0102, 
GS-US-342-0109, and GS-US-337-0122 [Cohort 4]).


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 25
15 June 2018
Sofosbuvir 400 mg and VEL 100 mg are the doses evaluated in the Phase 3 ASTRAL program 
and in the commercially available FDC tablet.
Sofosbuvir is a substrate for efflux drug transporters P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP). SOF is extensively metabolized to the pharmacologically active 
nucleoside analog phosphate. The activation pathway involves hydrolysis by intestinal and 
hepatically expressed carboxylesterase (CES1) and Cathepsin A (CatA) enzymes {Yang 2009, 
Zhu 2009}. SOF is also converted to GS-331007, an inactive circulating metabolite, which is 
eliminated renally by active tubular secretion and glomerular filtration.
Velpatasvir is also a substrate for P-gp and BCRP. VEL has low systemic clearance in 
nonclinical species and low metabolic turnover by CYP2B6, CYP2C8 and CYP3A4. It is 
eliminated through biliary excretion as unchanged parent drug and metabolites (76.6% of the 
administered dose is recovered as VEL in feces).
Selection of doses of SOF/VEL FDC for adolescents and younger age groups will target 
systemic exposures similar to those observed in adults at the proposed marketed dose, and will 
take into account body weight/body surface area, the potential ontogenic changes in transporters 
and metabolic enzymes that govern the disposition of SOF and VEL, and the results obtained in 
older age groups. Available data suggest comparable hepatic expression of CYP2B6 and CES1 
in adolescents and adults with modestly decreased expression in children, and comparable levels 
of CYP2C8 and CYP3A4 to adults from a young age (~3-6 years of age) {Johnson 2006};
however, little is known about the developmental regulation of Pgp, CES, and CatA.
In this current study, the adult clinical dose of SOF/VEL FDC 400/100 mg is being evaluated in 
adolescents (12 to <18 years old), while a lower dose SOF/VEL FDC 200/50 mg is being 
evaluated in children (6 to <12 years old). As described in Section 1.2.2.3, the appropriateness of 
these doses is supported by data from the Cohort 1 and Cohort 2 PK Lead-in subjects, 
respectively, which demonstrated SOF, GS-331007 and VEL exposure to be within the range of 
adult exposures associated with safety and efficacy in the Phase 2/3 SOF/VEL adult population
(Table 1-1 and Table 1-2).
In Cohort 3 (3 to <6 years old), a dose of SOF/VEL FDC 200/50 mg is proposed for evaluation 
in children weighing ≥17 kg, whereas a dose of SOF/VEL FDC 150/37.5 mg is proposed for 
evaluation in children weighing < 17 kg. These proposed doses are supported by scaling of adult 
exposures based on correlations between body weight and clearance capacity (liver volume/size 
for VEL and SOF, and renal capacity for GS-331007) for the expected body weight range in 
children (3 to < 6 years of age) as demonstrated in Figure 1-1. Based on this scaling approach, 
these doses of SOF/VEL FDC are expected to achieve mean systemic exposures of SOF, 
GS-331007, and VEL within the range of those observed in the Phase 2/3 adult population. 
Safety and PK data in children who enroll in the PK Lead-in Cohort 3 will be evaluated to 
confirm the appropriateness of the dose for this age group.


SOFNELFDC 
Protocol GS-US-342-1143 
Final 
Gilead Sciences, Inc. 
Amendment 4 
Figure 1-1. 
Predicted SOF, GS-331007 and VEL AUC tau following administration 
of SOFNEL FDC 200/50 mg or 150/37.5 mg to Children 3 to <6 years 
of age who are :::, 17 kg or < 17 kg, respectively 
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(2:1 ?kg) 
•····················•······················································································max 
100+------...___, _____________________ 
....,......., 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 40 
42 44 
Body Weight (Kg) 
-o- 5th %tile 
-a- Q1 
-o- median 
-o- 03 
-.. 95th %tile 
100000 
150mg SOF 
(<17kg) 
Predicted GS-331007 exposure 
200mg SOF 
(2:17kg) 
min 
····················· 
....................................................................................... max 
10000 
····················· 
················································································· 
· ·· min 
1000+------r-''----r---------------------r--1 
10 12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
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CONFIDENTIAL 
Page 26 
15 June 2018 


SOFNELFDC 
Protocol GS-US-342-1143 
Gilead Sciences, Inc. 
37.5mg VEL 
(<17kg) 
Predicted VEL exposure 
50mg VEL 
(217kg) 
Final 
Amendment4 
10000 ········ 
............. ······ ................................................................................. max 
• .............................................. 95th 
i 
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·····················l······················································································· 
min 
10 12 14 16 18 20 
22 
24 
26 
28 
30 
32 
34 
36 
38 40 42 44 
Body Weight (Kg) 
-o- 5th %tile 
-o- 0 1 
--¢- median 
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Risk/Benefit Assessment for the Study 
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Although the majority of pediati·ic patients infected with HCV exhibit minimal hepatic sequelae 
despite active viral replication and inflammation, a subset of children and adolescents will 
require ti·eatment. Studies suggest that 3 major categories of disease can occur within 10 years 
after putative HCV exposure: (1) undetectable viremia and nonnal ALT, (2) persistent yet 
uncomplicated mild liver disease, and (3) progression to end-stage liver disease {Bortolotti 
2008}. It is the last two groups of children in whom therapy may be indicated to prevent 
end-stage disease, either during childhood/adolescence or in early adulthood. 
Given that the cmTent SOC for the ti·eatment of children infected with HCV is Peg-IFN and RBV 
and the regimens are long in duration, relatively toxic, and not well tolerated, there continues to 
be a need for new ti·eatments for HCV that combine potent and sustained efficacy with improved 
tolerability and safety. 
The combination of SOF plus VEL is anticipated to offer greater antiviral efficacy which could 
result in a shorter ti·eatment duration and/or lead to a regimen without RBV or interferon. These 
in tum could result in reduction in adverse events. SOFNEL FDC could also potentially be of 
benefit in patients who have failed prior ti·eatment with SOF+/-RBV+/- Peg-IFN. 
CONFIDENTIAL 
Page 27 
15 June 2018 


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 28
15 June 2018
If high rates of SVR can be obtained with short, well-tolerated regimens, the anticipated 
improvements in safety and tolerability would offer a favorable risk-benefit determination for 
individuals with chronic HCV-infection.
1.5.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 29
15 June 2018
2.
OBJECTIVES
The primary objective of the PK Lead-in phase is:

To evaluate the steady state pharmacokinetics (PK) and confirm the dose of 
sofosbuvir/velpatasvir (SOF/VEL FDC) in pediatric subjects with chronic hepatitis C virus 
(HCV) infection
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of SOF/VEL FDC for 12 weeks in pediatric subjects
with chronic HCV
The secondary objective of the PK Lead-in Phase is:

To evaluate the safety, tolerability, and antiviral activity of 7 days of dosing of SOF/VEL
FDC in pediatric subjects with chronic HCV
The secondary objectives of the Treatment Phase of this study are:

To determine the efficacy of SOF/VEL FDC for 12 weeks in pediatric subjects with chronic 
HCV infection, as assessed by the proportion of subjects with sustained virological response 
(SVR) 12 weeks after cessation of treatment (SVR12)

To determine the proportion of subjects with SVR 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure, including 
breakthrough/nonresponse and relapse

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment

To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment

To evaluate the effect of treatment with SOF/VEL FDC on quality of life as measured by
PedsQL™ Pediatric Quality of Life survey 

To evaluate the effect of SOF/VEL FDC on growth and development of pediatric subjects 
during and after treatment

To evaluate the acceptability, including palatability, of formulations used in the study
The exploratory objective of this study is:
CCI


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 30
15 June 2018
3.
STUDY DESIGN
3.1.
Endpoints
The appropriateness of the SOF/VEL FDC dose will be assessed by evaluating the steady-state 
PK of the VEL, SOF, and GS-331007 at Day 7 (Cmax, Tmax, Clast, Tlast, Ctau, AUCtau and t1/2). The 
primary endpoint of the PK Lead-in Phase is to determine steady-state PK, is AUCtau of VEL, 
SOF, and its major metabolite (GS-331007).
The primary endpoint of the Treatment Phase is assessment of any AEs with a focus on AEs that 
lead to discontinuation of study drug.
The secondary endpoints of the PK Lead-in Phase are:

Antiviral activity measurements, including assessment of HCV RNA from baseline through 
Day 7.

Any AE leading to permanent discontinuation of study drug.
The secondary endpoints of the Treatment Phase are:

The proportion of subjects with sustained virological response (SVR) 12 weeks after 
cessation of treatment (SVR12). SVR12 is the key efficacy endpoint.

The proportion of subjects with HCV RNA < LLOQ at 4 or 24 weeks after cessation of 
treatment (SVR4 and SVR24).

The proportion of subjects with virologic failure, including breakthrough/nonresponse and 
relapse

The proportion of subjects with HCV RNA < LLOQ on treatment

Emergence of viral resistance to SOF and /or VEL during treatment and treatment is 
discontinued

HCV RNA change from Day 1

Quality of life endpoints and neuropsychiatric assessments as measured by PedsQL™ 
Pediatric Quality of Life survey

Growth and development measurements including height and weight percentiles, Tanner 
Stage, parental height, and bone age

Acceptability assessed by swallowability and palatability


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
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15 June 2018
3.2.
Study Design
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and antiviral 
activity of SOF/VEL FDC in chronic HCV-infected pediatric subjects.
3.3.
Study Treatments
3.3.1.
PK Lead-in Phase
The PK Lead-in Phase will evaluate and/or confirm the age appropriate SOF/VEL FDC dose by 
analyzing PK, safety, and antiviral activity of SOF/VEL FDC through 7 days of dosing for each 
cohort. Three cohorts of at least 17 subjects each will be sequentially enrolled:

Cohort 1: 12 to < 18 years old

Cohort 2: 6 to < 12 years old

Cohort 3: 3 to < 6 years old
At least 6 subjects weighing ≥ 17 kg
At least 6 subjects weighing < 17 kg
The study will start with Cohort 1. Subjects will receive a SOF/VEL FDC 400/100 mg
adult tablet or 2 x 200/50 mg tablets (if determined necessary based on SOF/VEL swallowability 
assessment) once a day for 7 days with intensive PK conducted on Day 7. If unable to swallow 
the tablet formulations, the subjects will receive SOF/VEL FDC 400/100 mg oral granules
(8 x 50/12.5 mg packets).
Cohort 2: Subjects will receive SOF/VEL FDC 200/50 mg tablets once daily. If unable to 
swallow the tablet formulations, the subjects will receive SOF/VEL FDC 200/50 mg oral 
granules (4 x 50/12.5 mg packets).
Cohort 3: Subjects will receive SOF/VEL FDC 200/50 mg oral granules (4 × 50/12.5 mg
packets) once daily for subjects weighing ≥17 kg. SOF/VEL FDC 150/37.5 mg oral granules 
(3 × 50/12.5 mg packets) will be administered once daily for subjects weighing <17 kg.


SOFNELFDC 
Protocol GS-US-342-1143 
Final 
Gilead Sciences, Inc. 
Amendment 4 
Figure 3-1. 
PK Lead-in Phase Study Schema 
PK Lead-in 
Cohort 1: 
12 to< 18 years 
N=17 subjects 
Cohort 2: 
6 to < 12 years 
N=17 subjects 
Cohort 3: 
3 to < 6 years 
N=17 subjects 
3.3.2. 
Baseline 
Day 7 
(Day 1) 
Intensive PK 
Scre~nlng 
I 
I 
SOFNEL 
,-. -----+; Treatment 
:',28 days pnorto 
PK and safety 
Phase• 
6aselme 
lalysis 
(400/100 mg) 
Baseline 
Day 7 
• Subjects who participated in the PK 
Lead in will immediately roll into the 
treatment phase following the PK 
(Day 7) assessments 
(Day 1) 
Intensive PK 
Treatment Phase 
Scn:::~nir19 
~
----+ Treatment 
528day prior to 
PK and safety 
Phase• 
Basewie 
enatysis 
(200/50 mg) 
Baseline 
Day 7 
(Day 1) 
Intens ive PK 
Scre~ning 
I 
I 
t----"-1 
SOFNEL 
. 
::=:: 28 day prior to 
PK and safely 
Baseline 
analys.is 
(200/50 mg ;?:17 kg or 
150/37.5 mg < 17 kg) 
• Treatment 
Phase· 
The Treatment Phase will be initiated sequentially by age group (12 to < 18), (6 to <12) and (3 to 
<6) as defined in Coho1is 1, 2, and 3 of the PK Lead-in Phase. Subjects who participated in the 
PK Lead-in will immediately rollover into the Treatment Phase with no inte1n1ption of study 
diug adininistration until the appropriateness of the dose has been confmned by PK and safety 
results from the PK Lead-in. The first visit in the Treatment Phase for the subjects who 
paiiicipated within the PK Lead-in Phase will be the Week 4 visit. Additional subjects will be 
emolled in the Treatment Phase of each age group upon confnm ation of the appropriateness of 
the dose from the PK Lead-in Phase. If a subject is unable to swallow the tablet fonnulations, 
they will be assigned to SOFNEL FDC oral granules fo1mulation. 
The study will emoll both treatment nai've and treatment experienced pediatric subjects with at 
least 20 and up to 40 subjects allowed to be treatment experienced. Approximately 200 total 
subjects, including subjects from the PK Lead-in Phase, will be emolled in the Treatment Phase 
as follows: 
• 
Group 1: Approximately 100 adolescent subjects (12 to < 18 years of age) 
• 
Group 2: Approximately 100 pediatric subjects (3 to < 12 yeai·s of age) 
All subjects who do not attain SVR or have viral relapse will be encomaged to discuss treatment 
with SOC therapy with their healthcai·e provider. 
CONFIDENTIAL 
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15 June 2018 


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 33
15 June 2018
3.4.
Duration of Treatment
3.4.1.
PK Lead-in Phase
Subjects (at least 17 subjects per cohort) enrolled in the PK Lead-in Phase will receive treatment 
for 7 days and then participate in an intensive PK evaluation on Day 7.
Following completion of the Day 7 intensive PK visit, subjects will continue dosing with 
SOF/VEL FDC with no interruption of study drug administration and will continue in the 
Treatment Phase of the study to receive 12 weeks of treatment.
3.4.2.
Treatment Phase
Subjects enrolled in the Treatment Phase will receive treatment for 12 weeks and will then return 
for follow-up visits at 4, 12, and 24 weeks after discontinuation of therapy.
The total time to complete all study visits is approximately 40 weeks including:

28 day (4 week) screening period

12 week treatment period

24 week posttreatment period
3.5.
Virologic Response-Based Stopping Criteria
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 and must occur no later than 2 weeks after
an initial observation indicating virologic failure during the on-treatment phase.
3.6.
Discontinuation Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of
clinical status to a significant degree. Following resolution of intercurrent illness, the subject
may resume study dosing at the discretion of the investigator

Unacceptable toxicity (as defined in Section 7 of the protocol) or toxicity that, in the 
judgment of the investigator, compromises the ability to continue study-specific procedures 
or is considered to not be in the subject’s best interest.

Subject noncompliance


SOFNELFDC 
Protocol GS-US-342-1143 
Gilead Sciences, Inc. 
• 
Pregnancy of female subject or female partner of male subject. 
• 
Efficacy failure as defined in Section 3.5. 
• 
Significant protocol violation that impacts subject safety 
Final 
Amendment4 
• 
Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason. 
• 
Discontinuation of the study at the request of Gilead, regulato1y agency, or an Institutional 
Review Board (IRB)/lndependent Ethics Committee (IEC). 
Subjects who meet any of the following criteria must stop treatment with SOFNEL FDC: 
• 
Elevation of ALT and/or AST above the upper limit of nonnal and > 5x Day 1 or nadir, 
confnmed by immediate repeat testing 
• 
Elevation of ALT > 15x ULN, confnmed by immediate repeat testing 
• 
Elevation of ALT >3x Day 1 and total bilimbin >2x ULN, confinned by immediate repeat 
testing 
• 
Any Grade 3 or greater rash associated with constitutional symptoms 
• 
Any Grade 4 adverse event assessed as related to administration of SOFNEL FDC 
3.7. 
End of Study 
The end of study is defined as when the last subject has completed their final visit in the study. 
Discontinuation from study diug dosing and discontinuation from the overall study, including the 
Posttreatment period, will be collected as two separate events. 
The end of study will occur at the posttreatment Week 24 visit. 
3.8. 
Reconsent 
When a subject reaches the age of consent in their countiy/region, they will be invited to consent 
as an adult to allow them to continue paii icipating in the clinical ti·ial. 
CONFIDENTIAL 
Page 34 
15 June 2018 


SOFNELFDC 
Protocol GS-US-342-1143 
Gilead Sciences, Inc. 
3.10. 
Pediatric Registry Study 
Final 
Amendment4 
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 eligible to paiiicipate in the Pediatric 
Registry Study. The objectives of the registry study ai·e to evaluate growth, quality of life, and 
long-te1m viral suppression (if applicable). The pediatric registry study is described in a sepai·ate 
protocol (GS-US-334-1113). This follow-up study will continue for 5 yeai·s. 
3.11. 
Biomarker Testing 
3.11.1. 
3.11.2. 
Samples for Optional Future Research 
CONFIDENTIAL 
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15 June 2018 


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 36
15 June 2018
4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 200 subjects will be enrolled in this study.
In order to manage the total study enrollment, Gilead Sciences, Inc. at its sole discretion, may 
suspend screening and/or discontinue the enrollment at any site at any time (upon written notice 
to the site). Discontinuation of the enrollment phase may result in the immediate ineligibility of 
all subjects screened but not yet enrolled, regardless of the progress or outcome of the screening 
assessments performed.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Parent or legal guardian able to provide written informed consent prior to any screening 
evaluations and willing to comply with study requirements. Subjects will provide assent if 
possible, in accordance with IRB/IEC/local requirements and the investigator’s discretion.
2) 3 years to < 18 years of age as determined at Day 1
3) Chronic HCV-infection (≥ 6 months) as documented by prior medical history or liver biopsy
4) HCV RNA ≥ 1000 IU/mL at Screening
5) Subjects must have a determination of prior treatment status:
a) Treatment-naïve is defined as having never been exposed to an approved or experimental 
HCV-specific direct acting antiviral agents or prior treatment of HCV with interferon or 
ribavirin.
b) Treatment-experienced is defined as prior treatment failure or intolerance to a regimen 
containing interferon with or without RBV and with or without a protease inhibitor that 
was completed at least 8 weeks prior to Day 1.
c) Interferon intolerant: Subject who discontinued therapy (≤ 12 weeks total) due to 
≥1 adverse event
6) A negative serum pregnancy test is required at screening and a negative urine test is required 
at Day 1 for female subjects of child bearing potential.
7) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 5.
8) Lactating females must agree to discontinue nursing before the IMP is administered.
9) Subject must be able to comply with the dosing instructions for study drug administration 
and be able to complete the study schedule of assessments.


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Prior use of an HCV NS5A inhibitor
2) Current or prior history of clinical hepatic decompensation (eg, ascites, jaundice, 
encephalopathy, variceal hemorrhage)
3) Any of the following laboratory parameters at screening:
a) INR 1.2 ULN
b) Platelets 50,000/mm3
c) albumin 3.5 g/dL
d) ALT > 10 x the upper limit of normal (ULN)
e) AST > 10 x ULN
f)
Direct bilirubin > 1.5 x ULN
g) Estimated glomerular filtration rate 90 mL/min/1.73m2, as calculated by the 
Schwartz Formula
4) Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency)
5) Evidence of hepatocellular carcinoma (HCC) or other malignancy (with the exception of 
certain resolved skin cancers)
6) Co-infection with HIV, acute HAV, or HBV (Hepatitis B Surface Ag positive at screening)
7) Current or prior history of any of the following:
a) Significant cardiovascular, pulmonary, or neurological disease
b) Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption 
of orally administered medications
c) History of solid organ or bone marrow transplantation
d) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of 
their psychiatric illness within the last 5 years. Subjects with psychiatric illness 
(without the prior mentioned conditions) that is well-controlled on a stable treatment 
regimen for at least 6 months prior to enrollment or has not required medication in the 
last 12 months may be included.


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 38
15 June 2018
8) 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
9) Sexually-active males or females of childbearing potential who are not willing to use an 
effective method of contraception during the study
10) Use of any prohibited concomitant medications as described in Section 5.3.
11) Investigational agents taken within the past 28 days (except with the express approval of the 
Sponsor)
12) Known hypersensitivity to the study drug, the metabolites, or formulation excipients


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 39
15 June 2018
5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Description and Handling of SOF/VEL FDC
5.1.1.
Formulation
The SOF/VEL FDC 400/100 mg tablets are pink, diamond-shaped, film-coated tablets, debossed 
with “GSI” on one side and “7916” on the other side. In addition to the active ingredients, the 
SOF/VEL FDC tablets contain copovidone, microcrystalline cellulose, croscarmellose sodium, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and 
iron oxide red.
Placebo tablets to assess swallowability of SOF/VEL FDC 400/100 mg tablet are of similar size 
and shape. The placebo tablets are pink, diamond-shaped, film-coated tablets debossed with 
“GSI” on one side and “7916” on the other side. The tablets contain lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, 
titanium dioxide, talc, polyethylene glycol, and iron oxide red.
The SOF/VEL FDC 200/50 mg tablets are pink, oval-shaped, film-coated tablets, debossed with 
“GSI” on one side and “S/V” on the other side. In addition to the active ingredients, the 
SOF/VEL FDC tablets contain copovidone, microcrystalline cellulose, croscarmellose sodium, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and 
iron oxide red.
Placebo tablets to assess swallowability of SOF/VEL FDC 200/50 mg tablet are of similar size 
and shape. The placebo tablets are capsule-shaped, plain-faced, film-coated orange tablets and 
contain lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium 
stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, 
iron oxide red, and ferrosoferric oxide.
The SOF/VEL FDC 50/12.5 mg oral granules are white, round, and film-coated. In addition to 
the active ingredients, the SOF/VEL FDC oral granules contain the following inactive 
ingredients: copovidone, lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, colloidal silicon dioxide, magnesium stearate, hypromellose, titanium dioxide, 
polyethylene glycol, amino methacrylate copolymer, talc, stearic acid, and L-tartaric acid.
5.1.2.
Packaging and Labeling
SOF/VEL FDC 400/100 mg tablets are packaged in white, high density polyethylene (HDPE) 
bottles. Each bottle contains 28 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.


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Placebo tablets to assess swallowability of SOF/VEL FDC 400/100 mg tablet are packaged in 
white, high density polyethylene (HDPE) bottles. Each bottle contains 28 tablets and polyester 
packaging material. Each bottle is enclosed with a white, continuous thread, child resistant screw 
cap with an induction-sealed, aluminum faced liner.
SOF/VEL FDC 200/50 mg tablets are packaged in white, high density polyethylene (HDPE) 
bottles, with or without polyester packing material. Each bottle contains 28 tablets and is 
enclosed with a white, continuous thread, child-resistant screw cap with an induction-sealed, 
aluminum-faced liner.
Placebo tablets to assess swallowability of SOF/VEL FDC 200/50 mg tablet are packaged in 
white, high density polyethylene (HDPE) bottles. Each bottle contains 30 tablets and polyester 
packing material, and desiccant. Each bottle is enclosed with a white, continuous thread, child 
resistant screw cap with an induction-sealed, aluminum faced liner.
SOF/VEL FDC oral granules are packaged in aluminum foil packets. Each packet contains
twenty five (25) oral granules, which is equivalent to 50 mg of SOF and 12.5 mg of VEL.
Twenty eight (28) packets are packed in a carton.
All SOF/VEL FDC tablet and placebo tablet bottles as well as oral granule packets to be 
distributed to centers in participating countries shall be labeled to meet all applicable 
requirements of the United States Food and Drug Administration (FDA), EU Guideline to Good 
Manufacturing Practice - Annex 13 (Investigational Medicinal Products), and/or other local 
regulations.
5.1.3.
Storage and Handling
SOF/VEL FDC 400/100 mg and 200/50 mg tablets as well as oral granules packets 50/12.5 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).
All placebo tablets to assess swallowability of SOF/VEL FDC tablets should be stored at 
controlled room temperature until required for administration. Controlled room temperature is 
defined as 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C (59 °F to 86 °F).
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF/VEL FDC tablets.
Sufficient quantities of SOF/VEL FDC to complete the entire study will be shipped to the 
investigator or qualified designee from the Gilead Supply Management Team (or its designee).


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5.2.
Dosage and Administration of SOF/VEL FDC
Subjects 12 to < 18 years old enrolled in the PK Lead-in Cohort 1 or in the Treatment 
Phase
SOF/VEL FDC 400/100 mg tablets will be administered once daily with or without food.
Subjects determined unable to swallow the placebo to match the 400/100 mg SOF/VEL FDC 
tablet will be re-assigned to 2 x 200/50 mg SOF/VEL FDC tablets daily. Subjects unable to 
swallow the reduced strength SOF/VEL FDC 200/50 mg tablets will be reassigned to SOF/VEL 
FDC oral granule formulation (8 x 50/12.5 mg packets).
Subjects 6 to < 12 years old enrolled in the PK Lead-in Cohort 2 or in the Treatment Phase
SOF/VEL FDC 200/50 mg tablets will be administered once daily with or without food. Subjects 
determined unable to swallow the placebo tablet 200/50 mg SOF/VEL FDC will be reassigned to 
SOF/VEL FDC oral granule formulation (4 x 50/12.5 mg packets).
Subjects 3 to < 6 years old enrolled in the PK Lead-in Cohort 3 or in the Treatment Phase
SOF/VEL FDC 50/12.5 mg oral granules in a packet will be administered once daily with or 
without food. Subjects who weigh ≥17kgs will be assigned to 200/50 mg SOF/VEL FDC oral 
granules (4 x 50/12.5 mg packets) and subjects who weigh < 17 kgs will be assigned to 
150/37.5 mg SOF/VEL FDC oral granules (3 x 50/12.5 mg packets). The instructions dosing of 
oral granules are defined in Section 5.2.1.
Subjects should be instructed that if vomiting occurs within 3 hours of dosing an additional tablet 
or granules packets should be taken according to the dosing instructions above. If vomiting 
occurs more than 3 hours after dosing, no replacement dose is required that day.
If a dose is missed and it is within 18 hours of the normal regular scheduled time, subjects should 
be instructed to take the tablet or granules as soon as possible and then follow with the next dose 
at the usual scheduled time.
If it is after 18 hours then it is considered a missed dose. Subjects should be instructed to take the 
next dose at the usual next scheduled time. Subjects should be instructed not to take a double dose.
5.2.1.
SOF/VEL FDC Oral Granules Subject Dosing Instructions
The SOF/VEL 50/12.5 mg oral granules are packaged in aluminum foil packets for oral 
administration. The administration of the full dose from all of the packets must be completed
within 30 minutes. After each dose, ensure the packets are empty and the subject should be 
instructed that all empty packets should to be returned at the next study visit.
Due to the bitter taste of the active ingredient(s), the oral granules have been taste-masked. Oral 
granules may be taken directly by mouth and swallowed or mixed into food as directed below.


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If oral granules are swallowed without food:
1) Carefully cut with scissors or tear open 1 packet. Avoid crushing or spilling the contents. If 
any granules are crushed, do not administer and open new packet.
2) Parent/legal guardian should be instructed to empty the content of packet into the child’s 
mouth and chase with water or milk. The oral granules should not be chewed. The oral 
granules should not be poured directly into a liquid as they may sink and stick to the bottom 
of the container.
3) Repeat these steps immediately for any additional packets assigned.
4) If the child cannot take the whole packet at one time the granules may be divided into two or 
three portions until each packet is completely empty.
5) The full dose should be administered within 30 minutes.
If oral granules are administered with food:
The granules should not be chewed and the selected food should be a soft, non-acidic food that is 
at or below room temperature. Examples of foods that can be used include: pudding
(except fruit-flavored varieties), chocolate syrup, whipped cream, and ice cream
(except fruit-flavored varieties). Foods to avoid include: yogurt and fruit-based foods such as 
applesauce, thick/sticky foods such as peanut butter and foods that have chunks that require 
chewing.
Once a food is selected, administer the granules as follows:
1) Carefully cut with scissors or tear open 1 packet. Avoid crushing or spilling the contents. 
If any granules are crushed, do not administer and open new packet.
2) Carefully sprinkle the packet contents onto a spoon and take care to avoid spilling the 
granules. Without spilling the granules, carefully add the selected food to the spoon and 
mix/cover the granules as needed. If necessary, the granules from the packet may be divided 
into two or three portions and administered to the child.
3) Parent/legal guardian should be instructed to immediately have the child swallow the 
granules and food without chewing. If not immediately, the granules need to be swallowed 
within 15 minutes after placing on the food. If the granules have not been taken within 
15 minutes after placing on the food, discard and prepare a new dose.
4) After dosing, ensure that no oral granules remain on the spoon or in the child’s mouth.
5) Repeat these steps immediately for any additional packets assigned.
6) The full dose should be administered within 30 minutes.


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5.3.
Prior and Concomitant Medications
Concomitant medications taken within 30 days prior to screening, up to and including 30 days 
after the last dose of study drug need to be recorded in the source documents and eCRFs 
(including all blood products).
Investigational agents or devices for any indication are prohibited from 28 days prior to the 
Day 1 visit through the end of treatment.
Concomitant use of certain medications or herbal/natural supplements (such moderate to potent 
inducers of drug transporters or metabolizing enzymes, eg, P-gp, CYP2B6, CYP2C8, or CYP3A) 
with the study drug may result in pharmacokinetic interactions resulting in increases or decreases 
in exposure of the study drug or these medications.
The use of amiodarone is prohibited from 60 days prior to Day 1 through the end of treatment. 
Additionally, investigators should refer to the product/package inserts of other medications for 
age-related recommendations or contraindications related to their use.
Table 5-1 below contains examples of medications that are prohibited from 21 days prior to 
Day 1 through the end of treatment and those medications which may be used with caution. 
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton-Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsb
Phenytoin, Carbamazepine, Phenobarbital, 
Antimycobacterialsb
Rifampicin, Rifabutin, Rifapentine
Cardiac Medications
Amiodaroned
Digoxine, vitamin K antagonistsf
Herbal/Natural Supplementsb
St. John’s Wort, Echinacea, Milk thistle (i.e., 
silymarin), Chinese herb sho-saiko-to (or Xiao-
Shai-Hu-Tang)
HMG-CoA Reductase Inhibitorsf
Rosuvastating , Atorvastatin
Other
Bosentanb, Modafinilb, Sulfasalazinec, 
Methotrexatec
a
Co-administration of omeprazole or other proton pump inhibitors is not recommended. If it is considered medically 
necessary to co-administer, SOF/VEL FDC should be administered with food and taken 4 hours before omeprazole 20 mg. 
Use with other proton pump inhibitors has not been studied. H2-receptor antagonists must not exceed a dose of 40 mg 
famotidine or equivalent and can be taken simultaneously with SOF/VEL FDC and/or staggered by 12 hours. Antacids that 
directly neutralize stomach acid (ie Tums, Maalox) may not be taken within 4 hours (before or after) of SOF/VEL FDC
administration.
b
May result in a decrease in the concentration of study drugs.
c
May result in an increase in the concentration of study drugs and/or concomitant medications
d
May result in symptomatic bradycardia. Mechanism is not currently known. The use of amiodarone is prohibited from
60 days prior to Day 1 through the end of treatment.
e
Monitor for signs and symptoms of digoxin toxicity.
f
If vitamin K antagonists are used, close monitoring of International Normalized Ratio (INR) is recommended as liver 
function may improve during treatment with study drug.
g
Use with SOF/VEL FDC may result in an increase in the concentration of HMG-CoA Reductase Inhibitors, rosuvastatin and 
atorvastatin. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. 
Use atorvastatin with caution and at the lowest necessary dose. Monitor for signs and symptoms of muscle weakness or 
myopathy, including rhabdomyolysis.


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Medications for disease conditions excluded from the protocol (eg, HIV infection) are not listed
under this Concomitant Medication section and are disallowed in the study. Should subjects have 
a need to initiate treatment with any excluded concomitant medication, the Medical Monitor 
must be consulted prior to initiation of the new medication. In instances where an excluded 
medication is initiated prior to discussion with the Sponsor, the investigator must notify Gilead 
as soon as he/she is aware of the use of the excluded medication.
Subjects may not take any approved HCV medications during their participation in the study 
period.
5.4.
Accountability for SOF/VEL FDC
The investigator is responsible for ensuring adequate accountability of all used and unused IMP 
bottles. This includes acknowledgement of receipt of each shipment of IMP (quantity and 
condition). All used and unused IMP bottles dispensed to subjects must be returned to the site.
SOF/VEL FDC accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits

Record the date, subject number, subject initials, the IMP kit number dispensed

Record the date, quantity of used and unused IMP kits returned, along with the initials of the 
person recording the information.
5.4.1.
Investigational Medicinal Product Return or Disposal
Refer to Section 9.1.7 for information on return and disposal of study drugs.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
An IWRS will be employed to manage subject enrollment and treatment assignment. The study
will not be randomized; subjects will be enrolled in the appropriate age-based group.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 28 days prior to enrollment to determine eligibility for 
participation in the study. The screening window can be extended to 42 days with Sponsor
approval for subjects with extenuating circumstances. The following procedures/assessments are 
to be performed and documented at screening:

Obtain written informed consent

Obtain medical history, including:
Hepatitis C treatment history:
■
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)

Complete physical examination

Vital signs

Body weight and height


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
Biological parental height, unless unknown (eg, subject adopted, biological parent (s) 
deceased), will be collected at screening up to Day 1 visit.

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form.

Review of concomitant medications

Ask subject and/or parent/legal guardian if the subject is able to swallow and tolerate taking 
pills. Perform SOF/VEL FDC swallowability assessment.

Perform transient elastrography (if available); may be done at any time during Screening up 
to and including on Day 1

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
HCV Genotyping
Serum -hCG pregnancy test for females of childbearing potential only
HIV testing, HCV antibody, HBV surface antigen (HBsAg), HBV surface antibody 
(HBsAb), HBV core antibody (HBcAb), HAV antibody
HBV DNA testing for subjects HBcAb positive at Screening
HbA1c
Fibrotest®
APRI
TSH
Alpha-1 anti-trypsin (AAT)

Obtain urine sample for:
Urinalysis
Urine Drug Screen


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Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 28 days after screening for enrollment into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (CRF/eCRF). 
All other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history CRF/eCRF. 
See Section 7 Adverse Events and Toxicity Management for additional details.
6.2.2.
Day 1 Assessments
After confirmation of eligibility has been evaluated, the following tests and procedures must be 
completed prior to enrollment and dosing/dispensing on Day 1:

Reconfirm eligibility

Perform complete physical examination

Tanner Pubertal Stage Assessment

Vital signs

Body weight and height

Biological parental height, unless unknown (eg, subject adopted, biological parent (s) 
deceased), will be collected at screening up to Day 1 visit.

A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment

Assessment of AEs and concomitant medications

Perform transient elastrography (if available); if not performed at screening

Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the investigator based on subject’s pubertal status)

Ask subject and/or parent/legal guardian if the subject is able to swallow and tolerate taking 
pills. Perform SOF/VEL FDC swallowability assessment if not performed at screening.

SOF/VEL Acceptability Questionnaires

Quality of life survey: Subject is to review questionnaire and write/mark answers directly 
onto the questionnaire. Parent/legal guardian completes the parent/guardian questionnaire.


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• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-HCVRNA 
-
IL28B Genotype 
-
Viral sequencing (archive) 
• 
Obtain urine samples for the following procedures: 
-
Urinalysis 
-
Urine pregnancy test for females of childbearing potential only 
6.2.2.1. 
Dmg Administi·ation 
The following procedures/assessments are to be completed at this visit: 
Final 
Amendment4 
• 
Perfo1m SOF NEL FDC swallowability assessment (if not previously completed at 
screening). 
• 
Dispense study dmg(s) as directed by the IWRS 
• 
Instiuct the subject on the packaging, storage, administi·ation of study diug, and provide 
dosing diary and insti11ctions. 
• 
Observe the subject taking the first dose of study dmg (with or without food) and record the 
time of first dose. 
• 
Subject or parent/legal guardian (as applicable) will complete the relevant acceptability 
questionnaires . 
• 
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6.3.
PK Lead-in Phase: Treatment Assessments
6.3.1.
Day 3 (Telephone Call)
The site staff will perform the following assessments over the telephone with the subject and/or 
subject’s parent/legal guardian on Day 3:

Assessment of AEs and concomitant medications

Review Subject Dosing Diary with subject and/or subject’s parent/legal guardian
6.3.2.
Day 7 – Intensive PK (+3 days)
The Day 7 intensive PK visit should occur on the protocol-specified visit date based on the 
baseline 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).
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). Subject and/or parent/legal 
guardians should be instructed that the Day 7 dose of SOF/VEL FDC must not be taken prior to 
the visit and 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 parent/legal 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 per Subject Dosing Diary or study drug count on or prior 
to the Day 7 visit, the Day 7 intensive PK assessments must not be completed. The subject 
and/or parent/legal 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 should be reminded or the parent/legal guardian 
should be reminded that the subject should not to take the SOF/VEL FDC 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

Body weight and height


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
Assessment of AEs and concomitant medications

Perform study drug accountability

Review Subject Dosing Diary

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)

Obtain urine samples for the following procedures:
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.
Urinalysis

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/VEL FDC per dosing requirements.
Postdose blood samples will be collected as follows:
■
For Cohorts 1 and 2: 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose (with predose also 
serving as t= 24).
■
For Cohort 3 only: 0.5, 1, 2, 3, 4, 8, and 12 hours postdose (with predose also serving 
as t = 24).
Subjects will be restricted from food intake until after collection of the 4-hour postdose 
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 4 visit in 
Treatment Phase (described in Section 6.5.2) with no interruption in dosing.


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6.4.
Treatment Phase: Treatment Assessments
6.4.1.
Weeks 1 (± 3 days)
Subjects who participated in the PK Lead-in will start study visits in the Treatment Phase at 
Week 4.
The following procedures/assessments are to be completed at this visit:

Perform symptom-directed physical examination

Vital signs

Body weight and height

Assessment of AEs and concomitant medications

Review Subject Dosing Diary

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
Single sparse PK sample collected anytime
6.4.2.
Weeks 4 and 8 (± 3 days)
The following procedures/assessments are to be completed at this visit:

Perform symptom-directed physical examination

Vital signs

Body weight and height

Assessment of AEs and concomitant medications
CCI


SOFNELFDC 
Protocol GS-US-342-1143 
Gilead Sciences, Inc. 
• 
Obtain blood samples for: 
-
Hematology 
-
Chemistiy 
-
Coagulation tests 
-HCVRNA 
-
Viral sequencing (archive) 
-
Two sparse PK samples collected at Week 4 and Week 8 
15 minutes and 4 hours ostdose 
-
HBV DNA testing for subjects HBcAb positive at Screening 
• 
Obtain urine sample for: 
-
Urine pregnancy test for females of childbearing potential only 
Final 
Amendment4 
• 
Review medication compliance with subject and/or parent/legal guardian (subject should 
return all study drug at these visits) 
• 
Review Subject Dosing Diaiy 
• 
Dispense study chug as directed by the IWRS 
6.4.3. 
Week 12 (::1: 3 days) or Early Termination 
The following procedures/assessments are to be completed at this visit: 
• 
Perfo1m complete physical examination 
• 
Tanner Pubertal Staging Assessment 
• 
Vital signs 
• 
Body weight and height 
• 
Assessment of AEs and concomitant medications 
• 
Pregnancy prevention counseling including partner pregnancy prevention for male 
paiiicipants (all subjects ~ 12 yeai·s of age and subjects < 12 yeai·s of age at the discretion of 
the investigator based on subject's pube1ial status) 
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
Subjects and parent/legal guardian will complete the relevant acceptability questionnaires.

Quality of life survey: Subject is to review questionnaire and write/mark answers directly 
onto the questionnaire. Parent/legal guardian completes the parent/guardian questionnaire.

Obtain blood samples for:
Hematology
Chemistry
Coagulation tests
HCV RNA
Viral sequencing (archive)
TSH
Single sparse PK sample collected anytime
HBV DNA testing for subjects HBcAb positive at Screening

Obtain urine sample for:
Urine pregnancy test for females of childbearing potential only

Review medication compliance with subject and/or parent/legal guardian.

Review Subject Dosing Diary

Subjects should return all bottles/packets of study drug at the Week 12 Visit
6.5.
Posttreatment Assessments
6.5.1.
4-Week Posttreatment Visit (± 5 days)
The following procedures/assessments are to be completed at this site visit:

Perform symptom-directed physical examination

Vital signs

Body weight and height

Assessment of AEs and concomitant medications


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
Pregnancy prevention counseling including partner pregnancy prevention for male 
participants (all subjects ≥ 12 years of age and subjects < 12 years of age at the discretion of 
the investigator based on subject’s pubertal status)

Obtain blood samples for:
Hematology
Chemistry
HCV RNA
Viral sequencing (archive)
HBV DNA testing for subjects HBcAb positive at Screening

Obtain urine sample for:
Urine pregnancy test for females of childbearing potential only
6.5.2.
12-Week Posttreatment Visit (± 5 days)
The following procedures/assessments are to be completed at this visit:

Perform symptom-directed physical examination

Tanner Pubertal Stage assessment

Vital signs

Body weight and height

Assessment of SAEs

Quality of life survey: Subject is to review questionnaire and write/mark answers directly 
onto the questionnaire. Parent/legal guardian completes the parent/guardian questionnaire.

Obtain blood samples for:
HCV RNA
Viral sequencing (archive)
HBV DNA testing for subjects HBcAb positive at Screening


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24-Week Posttreatment Visit (+5 days) 
The following procedures/assessments are to be completed at this visit: 
• 
Perfo1m symptom-directed physical examination 
• 
Tanner Pubertal Stage Assessment 
• 
Vital signs 
• 
Body weight and height measurements 
• 
Assessment of SAEs 
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• 
Quality of life survey: Subject is to review questionnaire and write/mark answers directly 
onto the questionnaire. Parent/legal guardian completes the parent/guardian questionnaire. 
• 
A single X-ray of the left wrist, hand, and fingers for Bone Age Assessment 
• 
Obtain blood samples for: 
-HCVRNA 
-
Viral sequencing (archive) 
-
HBV DNA testing for subjects HBcAb positive at Screening 
6.6. 
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Unscheduled Visit 
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A subject should attend an unscheduled visit if requested by the Sponsor or the investigator. The 
assessments are at the investigator's discretion as clinically indicated, but the investigator should 
at a minimum collect AE and concomitant medication infonnation. At all unscheduled visits 
initiated for the purpose of confinning virologic failure, a sample for a viral RNA 
sequencing/phenotyping must be collected. Unscheduled visits can be initiated to collect the 
sparse PK sample if not collected during the ti·eatment visits. 
6.8. 
Assessments for Premature Discontinuation from Study 
If a subject discontinues study dosing ( eg, as a result of an AE), eve1y attempt should be made to 
keep the subject in the study and continue to perf01m the required study-related follow-up and 
procedures (see Section 3.6, Criteria for Discontinuation of Study Treatinent). If this is not 
possible or acceptable to the subject or investigator, the subject may be withdrawn from the study. 
6.9. 
Breakthrough Futility Assessment 
A futility assessment will be perfo1med after the first 10 subjects complete Week 8 on study or 
have viral breakthrough at or prior to Week 8. If 3 or more of the first 10 subjects enrolled have 
viral breakthrough at or prior to Week 8 or are non-responders (HCV RNA 2:, LLOQ through 
8 weeks of ti·eatment), then fuii her enrollment of subjects will be suspended. Virologic 
breakthrough is defined as confnmed HCV RNA 2:, LLOQ while on treatinent after 
two consecutive visits with HCV RNA < LLOQ. 
If a holding rnle has been met and following an internal safety review, it is deemed appropriate 
to restaii enrollment, a request to restaii enrollment with pe1iinent data will be submitted to the 
appropriate regulato1y agencies. Enrollment will only resume after review by the appropriate 
regulato1y agencies. Any subject on u-eatment when a holding rnle has been met will be allowed 
to continue to ti·eatinent. 
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Subjects with known or suspected study drug non-adherence will not be considered to meet the 
definition of virologic breakthrough, relapse, or non-responder for the purpose of this futility 
assessment.
6.10.
Procedures and Specifications
6.10.1.
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 mean corpuscular volume 
(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) and creatine kinase (CK).
Urinalysis: Appearance, blood, color, glucose, leukocyte esterase, pH, protein, urobilinogen. 
Reflex to microscopic urinalysis if dipstick result is abnormal.
Virological Tests: Serologies for HCV, HBV (HBsAg, HBsAb, HBcAb) and HAV. HBV DNA 
testing will be performed in subjects HBcAb positive at Screening. Serology and/or antigen 
testing for HIV (including reflex testing as necessary). HCV RNA will be measured using the 
COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System. 
HCV GT and subtype will be determined using the Siemens VERSANT® HCV Genotype 
INNO-LiPA 2.0 Assay. Gilead reserves the right to use alternate assays for HCV RNA and HCV 
GT should the above assays become unavailable.
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the 
SNP, rs12979860, with sequence specific forward and reverse primers and allele specific 
fluorescently labeled TaqMan® MGB probes. Gilead reserves the rights to use alternate assays 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: Serum -hCG, Urine -hCG (if positive, requires immediate confirmation with 
Serum -hCG)
Additional Tests: Urine drug screen (for amphetamines, cocaine, methadone, opiates), 
hemoglobin A1c (HbA1c), TSH (reflex Free T4), alpha-1 anti-trypsin (AAT), Fibrotest, and 
APRI.
6.10.2.
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 for all subjects during 
screening.


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6.10.3.
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 (including ECG, as applicable); lymph
nodes, abdomen; skin, hair, nails; musculoskeletal; neurological.
The focus of a symptom-directed physical examination will be determined by the investigator 
based on subject complaint. For example, if a subject complains of a cough, a lung exam should 
be performed. If consistent with pneumonia (rales/crackles on exam) then an AE would be 
documented.
6.10.4.
Tanner Pubertal Stage Assessment
The Tanner Stage scale is available in Appendix 4. All subjects will receive a baseline Tanner 
Pubertal Stage Assessment. If the assessment determines that the subject is at a Tanner 5 at 
Day 1, no further Tanner Pubertal Stage Assessments are to be completed.
6.10.5.
Height & Weight Measurement
Height and weight measurement will be collected at each study visit. The difference in body 
weight and height measurements between Day 1 and End of Treatment, posttreatment Week 12, 
and posttreatment Week 24 will be calculated. Parental heights will be recorded at Screening or 
Day 1, unless unknown (eg, subject adopted, biological parent(s) deceased, etc).
6.10.6.
Bone Age Assessment
A single X-ray of the left wrist, hand, and fingers will be performed at Day 1 Visit and 
posttreatment Week 24. Local radiologist will determine bone age from x-ray.
6.10.7.
Acceptability Assessment

Swallowability:
A SOF/VEL FDC swallowability assessment for the tablet formulation will be performed at 
screening up to Day 1.
12 to < 18 years of age:
Subjects who have indicated that they can take pills will be observed taking a placebo to match
the 400/100 mg SOF/VEL FDC tablet. This will confirm the swallowability of the 400/100mg 
tablet formulation size.

If a subject is unable to swallow the 400/100 mg SOF/VEL FDC placebo tablet, the subject 
will repeat the assessment with a placebo to assess swallowability of the 200/50 mg 
SOF/VEL FDC tablet.

If unable to swallow the 200/50 mg low dose SOF/VEL FDC tablet, the subject will be 
assigned to SOF/VEL FDC oral granules formulation.


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6 to < 12 years of age:
Subjects who have indicated that they can take pills will be observed taking a placebo to match 
the 200/50 mg low dose SOF/VEL tablet. This will confirm the swallowability of the 200/50 mg 
tablet size.

If a subject is unable to swallow the 200/50 mg SOF/VEL low dose placebo tablet, the 
subject will be assigned to SOF/VEL FDC oral granules formulation.
3 to < 6 years of age:
Subjects will be administered SOF/VEL oral granules. There will not be any placebo provided to 
assess swallowability for this formulation.
Acceptability and palatability:
For all age groups, a questionnaire will be administered to subjects to assess acceptability and 
palatability of the formulation they received on Day 1, Week 12 and Early Termination 
(as applicable). If the subject is unable to complete the questionnaires, the parent/legal guardian 
will assist to complete the questionnaire on their behalf. The subject’s parent/legal guardian will 
also complete a questionnaire on Week 12 or Early Termination (as applicable) for their 
assessment of acceptability of the formulation the subject received.
6.10.8.
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.
6.10.9.
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


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6.10.10.
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)]
6.10.11.
Viral Sequencing (Archive)
Plasma samples will be collected at Day 1 and each subsequent visit for viral sequence analysis. 
Unused samples may be archived.
6.10.12.
HBV DNA
HBV DNA will only be tested in subjects who test positive for the hepatitis B core antibody 
(HBcAb) test at Screening. HBV DNA testing will occur at Screening, Weeks 4, 8, and 12 or 
early termination and all posttreatment visits.
6.10.13.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every 4 weeks during the 
dosing period and for a minimum of 30 days following the last dose of SOF/VEL. If required by 
local regulations, additional pregnancy tests beyond 30 days may be added. In the event of a 
positive urine pregnancy result, subjects will be instructed to stop study drugs immediately 
(if applicable) and return to the clinic as soon as possible for a serum pregnancy test.
6.10.14.
Quality of Life Survey (PedsQL™)
The PedsQL™Pediatric Quality of Life Inventory V4.0 Short Form (SF15) will be completed by 
the subject and the parent/legal guardian at Day 1, End of Treatment, Early Termination
(if applicable), 12-Week Posttreatment, and 24-Week Posttreatment 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.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal 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 posttreatment complications that occur as a 
result of protocol specified 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 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
eCRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

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
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 a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
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 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified sub-investigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting.
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
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.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation
After obtaining informed consent, but prior to initiation of study medication, the following types 
of events should be reported on the case report form (CRF/eCRF): all SAEs and adverse events 
related to protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of study IMP and report to the CRF/eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol-defined follow-up 
period.
Serious Adverse Events
All SAEs, regardless of cause or 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 posttreatment follow-up period, must be reported to the 
eCRF database and Gilead Pharmacovigilance and Epidemiology (PVE) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
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Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after study pa1ticipation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and repo1t 
the event to Gilead PVE. 
• 
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
Electronic Serious Adverse Event ( eSAE) Repo1ting Process 
• 
Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
infonnation to Gilead PVE within 24 hours of the investigator's knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infonnation electr·onically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
fo1m and submit within 24 hours to: 
Gilead Sciences, 
Phaimacovigilance and Epidemiology: 
Fax: 
E-mail: 
PD 
PD 
• 
As soon as it is possible to do so, any SAE reported via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repo1ted via a paper fonn because the eCRF database has been locked, no 
futther action is necessaiy. 
• 
For fatal or life-threatening events, copies of hospital case repo1ts, autopsy repo1ts, and other 
documents ai·e also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
repo1ts. 
• 
Any medications necessaiy for tr·eatinent 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 
fo1m. 
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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable.
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
To minimize the possibility of exposing study subjects to unusual risk, the safety information 
from this study will also be reviewed periodically by an independent DMC. The DMC will have 
access to unblinded data and will make recommendations regarding the study according to the 
DMC charter.
7.5.
Toxicity Management
See Section 3.6 for Subject Stopping Rules.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, occupational exposure with an AE, 
pregnancy reports regardless of an associated AE and AE in an infant following exposure from 
breastfeeding.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.


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An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
Occupational exposure with an AE is defined as exposure to a medicinal product as a result of 
one’s professional or non-professional occupation
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead PVE using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post study
must be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE 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 PVE. Gilead PVE contact information is as follows:
Email:
 and Fax: 
PPD
PPD


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Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead PVE using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead PVE, fax number 
 or email 
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to or Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications.
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form.
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 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 CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
PPD
PPD


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of the PK Lead-in phase is:

To evaluate the steady state pharmacokinetics (PK) and confirm the dose of 
sofosbuvir/velpatasvir (SOF/VEL FDC) in pediatric subjects with chronic hepatitis C virus 
(HCV) infection
The primary objective of the Treatment Phase of this study is:

To evaluate the safety and tolerability of SOF/VEL FDC for 12 weeks in pediatric subjects
with chronic HCV
The secondary objective of the PK Lead-in Phase is:

To evaluate the safety, tolerability, and antiviral activity of 7 days of dosing of SOF/VEL
FDC in pediatric subjects with chronic HCV
The secondary objectives of the Treatment Phase of this study are:

To determine the efficacy of SOF/VEL FDC for 12 weeks in pediatric subjects with chronic 
HCV infection, as assessed by the proportion of subjects with sustained virological response 
(SVR) 12 weeks after cessation of treatment (SVR12)

To determine the proportion of subjects with SVR 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24)

To evaluate the proportion of subjects with virologic failure, including 
breakthrough/nonresponse and relapse

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment

To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment

To evaluate the effect of treatment with SOF/VEL FDC on quality of life as measured by
PedsQL™ Pediatric Quality of Life survey

To evaluate the effect of SOF/VEL on growth and development of pediatric subjects during 
and after treatment

To evaluate the acceptability, including palatability, of formulations used in the study


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The exploratory objective of this study is:
8.1.2.
Primary Endpoint
The appropriateness of the SOF/VEL FDC dose will be assessed by evaluating the steady-state 
PK of the VEL, SOF, and GS-331007 at Day 7. Estimated PK parameters will include Cmax, 
Tmax, Clast, Tlast, Ctau, AUCtau, CL/F, Vz/F and t1/2,as appropriate). The primary PK endpoint of 
the PK Lead-in Phase is AUCtau of VEL, SOF, and its major metabolite (GS-331007).
The primary endpoint of the Treatment Phase is assessment of any AEs with a focus on AEs that 
lead to discontinuation of study drug.
8.1.3.
Secondary Endpoint
The secondary endpoints of the PK Lead-in Phase are:

Antiviral activity measurements, including assessment of HCV RNA from baseline through 
Day 7.

Any AE leading to permanent discontinuation of study drug.
The secondary endpoints of the Treatment Phase are:

The proportion of subjects with sustained virological response (SVR) 12 weeks after 
cessation of treatment (SVR12). SVR12 is the key efficacy endpoint.

The proportion of subjects with HCV RNA < LLOQ at 4 or 24 weeks after cessation of 
treatment (SVR4 and SVR24).

The proportion of subjects with virologic failure, including breakthrough/nonresponse and 
relapse

The proportion of subjects with HCV RNA < LLOQ on treatment

Emergence of viral resistance to SOF and /or VEL during treatment and treatment is 
discontinued

HCV RNA change from Day 1

Quality of life endpoints and neuropsychiatric assessments as measured by PedsQL™ 
Pediatric Quality of Life survey

Growth and development measurements including height and weight percentiles, 
Tanner Stage, parental height, and bone age 

Acceptability assessed by swallowability and palatability
CCI


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8.1.4.
Other Endpoints of Interest
Other endpoint of interest may include ALT normalization.
8.2.
Analysis Conventions
All individual subject data will be listed as measured. All statistical summaries and analyses will 
be performed using SAS® software (SAS Institute, Cary, North Carolina, USA).
The study drug in this study is SOF/VEL FDC. Last dose of the study drug refers to the last dose 
of SOF/VEL FDC and will be used in the definition of treatment-emergent AEs and laboratory 
abnormalities as well as the efficacy endpoints of SVR at various posttreatment timepoints.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy Analysis Set
The analysis set for antiviral activity analyses is defined as the Full Analysis Set (FAS) which 
includes who were enrolled into the study and took at least one dose of the study drug.
8.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses will include subjects who took at least one dose of 
the study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of the 
study drug through the date of the last dose of the study drug plus 30 days.
8.2.1.3.
Pharmacokinetics Analysis Sets
Intensive PK Lead-in Analysis Set
The intensive PK analysis set will include all PK Lead-in subjects who took at least one dose of 
the study drug and for whom at least one non-missing PK concentration data, during the 
intensive sampling period was reported by PK lab. The PK analysis set will be used for detailed 
pharmacokinetic analysis of VEL, SOF, or its primary metabolite(s).
PK Analysis Set
The PK analysis set will include all enrolled subjects who took at least one dose of study drug 
and for whom at least one observed concentration data VEL, SOF, or its primary metabolite(s) 
are available. The PK analysis set will be used for analysis of general PK and single sample 
plasma concentrations and used for Population PK analysis.


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8.2.2.
Data Handling Conventions
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 analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have
the missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed
up to the time of the last dose.
If a data point is missing and is preceded and followed in time by values that are “< LLOQ target
not detected (TND),” then the missing data point will be set to “< LLOQ TND.” If a data point is
missing and preceded and followed by values that are “< LLOQ detected,” or preceded by
“< LLOQ detected” and followed by “< LLOQ TND,” or preceded by “< LLOQ TND” and
followed by “< LLOQ detected,” then the missing value will be set to “< LLOQ detected.” In
these situations the data point will be termed a bracketed success; otherwise, the data point will
be termed a bracketed failure (i.e., ≥ LLOQ detected). If a data point is missing and is not
bracketed, the missing data point will also be termed a failure (i.e., ≥ LLOQ detected) except for
SVR24, which will be imputed according to the SVR12 status. Success for SVR12 who have no
further HCV RNA measurements collected will be counted as a success for SVR24 due to the
high correlation between these 2 endpoints.
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example:

If a subject received at least 1 dose of study drug, 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 predose value, then the subject will be excluded from the calculation of summary 
statistics for the predose value and the change from predose values.
Values for missing safety laboratory data will not be imputed; however, a missing Day 1 result 
will be replaced with a screening result, if available. If no pretreatment laboratory value is 
available, the Day 1 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 Day 1 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.


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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).
For PK plasma concentrations and analysis of PK parameters natural logarithmic transformation 
will be used. Plasma concentration values that are below the lower limit of quantitation (BLQ) 
will be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated 
as 0 at predose time points, and one-half the value of the lower limit of quantitation (LLOQ) at 
post baseline time points, where LLOQ is corrected for the dilution factor (i.e., reported 
LLOQ/dilution factor) for determination of summary and order statistics.
For the presentation of summary and order statistics, if at least 1 subject has a concentration
value of BLQ for the time point, then the minimum value will be displayed as “BLQ.” If more
than 25% of the subjects have a concentration data value of BLQ for a given time point, then the
minimum and Q1 values will be displayed as “BLQ.” If more than 50% of the subjects have a
concentration data value of BLQ for a given time point, then the minimum, Q1, and median
values will be displayed as “BLQ.” If more than 75% of the subjects have a concentration data
value of BLQ for a given time point, then the minimum, Q1, median, and Q3 values will be
displayed as “BLQ.” If all subjects have concentration data values of BLQ for a given time point,
then all order statistics (minimum, Q1, median, Q3, and maximum) and summary statistics will
be displayed as “BLQ.”
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body mass index, HCV RNA level (log10 IU/mL), 
genotype of HCV infection, IL28B genotype, and additional endpoints as necessary.
8.4.
Efficacy Analysis
8.4.1.
Analysis of the Key Efficacy Endpoint
The key efficacy endpoint is SVR12 on the FAS. The analysis of SVR12 will be performed after 
all enrolled subjects have been followed through posttreatment Week 12 or discontinued from 
the study. The point estimate of the SVR12 rate and the 2-sided 95% exact CIs based on 
Clopper-Pearson method will be calculated.
8.4.2.
Secondary Analyses
The proportion of subjects with HCV RNA below the LLOQ over time (including SVR4 and 
SVR24) will be presented in tabular and graphical form. Descriptive summaries and listings will 
be provided for additional efficacy evaluations of the proportion of subjects who experience 
virologic failure, serum HCV RNA actual values and change from baseline, quality of life 
endpoints and other endpoint of interest may include ALT normalization.


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Exploratory analyses may be performed to assess the relationship between demographic, baseline
characteristics (including baseline viral load, genotype, age, sex, race, ethnicity, baseline ALT 
level), and antiviral activity (HCV RNA reduction, proportion of subjects with HCV 
RNA < LLOQ at various time points during and following discontinuation of active therapy).
Details on efficacy analyses will be described in the statistical analysis plan.
8.5.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, vital
signs measurements at various time points during the study, and by the documentation of AEs.
All safety data collected on or after the first dose of the study drug administration up to 30 days 
after the last dose of the study drug will be summarized.
8.5.1.
Extent of Exposure
A subject’s extent of exposure to the study drug will be generated from the study drug 
administration page of eCRF. Exposure data will be summarized.
8.5.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event with an onset date on or after the study drug 
start date and no later than 30 days after permanent discontinuation of the study drug or any 
adverse event leading to premature discontinuation of the study drug.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
and PT) will be provided:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above


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
All SAEs

All treatment-related SAEs

All AEs leading to premature discontinuation of the study drug
All AEs collected during the study will be presented in the data listings
8.5.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized (n, mean, SD, median, 
Q1, Q3, minimum, and maximum) by study visit along with the corresponding change from 
baseline.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
defined 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.
Values for missing safety laboratory data will not be imputed; however, a missing Day 1 result 
will be replaced with a screening result, if available. If no pretreatment 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.
All laboratory abnormalities will be included in the listings of laboratory data.
8.5.4.
Other Safety Evaluations
8.5.4.1.
Tanner Pubertal Stage Assessment
Tanner Stages (Appendix 4) will be summarized by baseline Tanner Stage using frequency and 
percentage by gender.
8.5.4.2.
Vital Signs (including Body Weight and Height)
Vital signs including body weight and height and change from baseline will be summarized at 
each visit.
8.5.4.3.
Bone Age Assessment
Bone age will be summarized.


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8.5.5.
Acceptability
Acceptability of the study treatments will be evaluated by assessing swallowability of the solid 
dosage tablet formulations (if subject is able to swallow the tablet), evaluation of palatability of 
all formulations, and a questionnaire administered to subjects and their parent/legal guardian on 
Day 1, Week 12, and Early Termination (as applicable).
8.6.
Pharmacokinetic Analysis
PK analysis will be performed for PK Lead-in using the intensive PK Lead-in analysis set. The 
concentration data of VEL, 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, Cmax, Tmax, Clast, Tlast, Ctau, and t½) will be listed and summarized by cohort using 
descriptive statistics (eg, sample size, arithmetic mean, geometric mean, % coefficient of 
variation, standard deviation, median, minimum, and maximum). Plasma concentrations of the 
analytes over time will be plotted in semi logarithmic and linear formats as mean ± standard 
deviation.
To evaluate if the exposures of SOF, GS-331007 and VEL achieved in pediatric subjects of this 
study are similar to the exposures observed in adult subjects, SOF, GS-331007 and VEL 
exposure data from this study will be compared to the integrated adult data. The primary 
endpoint of this analysis will be evaluated by carrying out an analysis of variance (ANOVA) for 
log-transformed SOF, GS-331007 and VEL AUCtau. The secondary endpoints of this analysis 
will be the Cmax of SOF, VEL and GS-331007 and Ctau of VEL. The 90% confidence intervals 
will be constructed for the ratio of geometric means of each PK parameters. The equivalence 
boundary is set as 70% to 200%.
Dose ranging studies for SOF established that a dose of 200 mg results in suboptimal exposure 
compared to the 400 mg dose, and no clinically significant exposure-safety relationships were 
observed across a broad range of GS-331007 exposure. The Phase 1 dose ranging study 
GS-US-281-0102 established the anti-HCV activity of VEL and the Emax models indicated that 
subjects will experience near maximal antiviral response (99.5% of Emax) at a VEL dose of 
100 mg. In the Phase 2/3 population treated with SOF/VEL FDC 400/100 mg, virologic response 
rates were high across all HCV genotypes and quartiles of exposure for VEL, SOF and 
GS-331007, including for subjects with cirrhosis, with no consistent trends in exposure-efficacy 
or exposure-safety relationships. Given the observed safety and efficacy profile and the lack of 
exposure-response across all quartiles of SOF/VEL exposure, the bounds of 70-200% support 
identification of a clinically relevant difference in SOF, GS-331007 or VEL exposure in the 
pediatric population.
In all pediatric age groups, the targeted exposures for SOF, GS-331007 and VEL are the adult 
equivalent for which safety and efficacy has been established. Assuming similar variability for 
SOF, GS-331007 or VEL AUCtau in the pediatric population compared to adults, the predicted 
90% CIs of the geometric mean ratio (GMR) will be contained within the bounds of 70% to 
200%.


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In the event more than one subject in each cohort exhibits VEL, SOF, or GS-331007 AUCtau
exposures less than the 2.5th percentile of adult values, a dose adjustment may be required for the 
cohort as appropriate.
8.7.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data at intervals of approximately every 6 months
from the first subject enrolled in order to protect subject welfare and preserve study integrity. 
The DMC is to provide recommendation to the sponsor whether the nature, frequency, and 
severity of adverse effects associated with study treatment warrant the early termination of the 
study in the best interests of the participants, whether the study should continue as planned, or 
the study should continue with modifications. The DMC may also provide recommendations as 
needed regarding study design, conduct, and the need for additional meetings or an alternative 
meeting schedule.
The DMC’s specific activities will be defined by a mutually agreed upon charter, which will 
define the DMC’s membership, conduct, and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
8.8.
Sample Size
With approximately 100 subjects enrolled into the 12 to < 18 years of age group and 
approximately 100 subjects enrolled into the 3 to < 12 years of age group, a 2-sided 95% exact 
confidence interval of the SVR12 rate in each age group will extend at most 20%.


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


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9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. 
The investigator must use the most current IRB or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or 
local requirements. The consent form will inform subjects about pharmacogenomic testing and
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
9.1.4.
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, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB/IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions or in accordance 
with local regulations. NOTE: The investigator must keep a screening log showing codes, names, 
and addresses for all subjects screened and for all subjects enrolled in the trial. Subject data will
be processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead 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. 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.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC, and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.


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


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


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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation.
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.


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9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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Amendment 4
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10.
REFERENCES
Balistreri WF, Murray KF, Rosenthal P, Bansal S, Lin CH, Kersey K, et al. The Safety and 
Effectiveness of Ledipasvir-Sofosbuvir in Aolescents 12-17 Years Old With 
Hepatitis C Virus Genotype 1 Infection. Hepatology 2017;66 (2):371-8.
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.
El-Sayed MH, Razavi H. Global Estimate of HCV Infection in the Pediatric and Adolescent 
Population [Abstract P1263]. European Association for the Study of the Liver 
(EASL); 2015 22-26 April; Vienna, Austria p. S831.
El-Shabrawi MH, Kamal NM. Burden of pediatric hepatitis C. World J Gastroenterol 2013;19 
(44):7880-8.
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus infection in 
Europe. J Hepatol 2008;48 (1):148-62.
Harvoni, Gilead Sciences Ltd. Harvoni 90 mg/400 mg film-coated tablets. Summary of Product 
Characteristics (SMPC). London, United Kingdom. Revised May.  2017:
HARVONI®, Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. 
US Prescribing Information. Foster City, CA. Revised: April.  2017:
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.
Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and 
associated variability in neonates, infants and children. Clin Pharmacokinet 
2006;45 (9):931-56.
Khaderi S, Shepherd R, Goss JA, Leung DH. Hepatitis C in the pediatric population: 
transmission, natural history, treatment and liver transplantation. World J 
Gastroenterol 2014;20 (32):11281-6.
Mack CL, Gonzalez-Peralta RP, Gupta N, Leung D, Narkewicz MR, Roberts EA, et al. 
NASPGHAN practice guidelines: Diagnosis and management of hepatitis C 
infection in infants, children, and adolescents. J Pediatr Gastroenterol Nutr 
2012;54 (6):838-55.
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of disease 
in childhood 1969;44 (235):291-303.


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Amendment 4
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Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of 
disease in childhood 1970;45 (239):13-23.
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.
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.
SOVALDI®, Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing 
Information. Foster City, CA. Revised April 2017:
Wirth S. Current treatment options and response rates in children with chronic hepatitis C. World 
J Gastroenterol 2012;18 (2):99-104.
Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti F, Zancan L, Jara P, et al. High sustained 
virologic response rates in children with chronic hepatitis C receiving 
peginterferon alfa-2b plus ribavirin. J Hepatol 2010;52 (4):501-7.
Wirth S, Rosenthal P, Gonzalez-Peralta RP, Jonas MM, Balistreri WF, Lin CH, et al. Sofosbuvir 
and Ribavirin in Adolescents 12-17 Years Old With Hepatitis C Virus Genotype 2 
or 3 Infection. Hepatology 2017;66 (4):1102-10.
Yang D, Pearce RE, Wang X, Gaedigk R, Wan YJ, Yan B. Human carboxylesterases HCE1 and 
HCE2: ontogenic expression, inter-individual variability and differential 
hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem 
Pharmacol 2009;77 (2):238-47.
Zhu HJ, Appel DI, Jiang Y, Markowitz JS. Age- and sex-related expression and activity of 
carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos 2009;37 
(9):1819-25.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Tanner Stages*
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


SOF/VELFDC 
Protocol GS-US-342-1143 
Final 
Gilead Sciences, Inc. 
Amendment 4 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety and Efficacy 
of SofosbuvirN elpatasvir in Adolescents and Children with Chronic HCV Infection 
GS-US-342-1143, Protocol Amendment 4, 15 June 2018 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
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 
CONFJDENTIAL 
Page 87 
15 June 2018 


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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 1i
Day 3
Telephone call
Day 7
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Parental Height
Xa
Xa
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
Tanner Pubertal Stage Assessmentb
X
Vital Signsc
X
X
X
Body Weight and Heightd
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Transient Elastography, if available 
Xe
Xe
Pregnancy Prevention Counselingf
X
SOF/VEL Swallowability Assessment
Xg
Xg
SOF/VEL Acceptability Questionnaires
X
Quality of Life Survey
Xh
Review of Study Medication Compliance
X
Study Drug Dispensingi
X
Subject Dosing Diaryj
X
X
X
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
HbA1c, Fibrotest®, APRI
X
TSH 
X
Alpha-1 anti-trypsin
X


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Screening
(-28 days)
On-treatment
Day 1i
Day 3
Telephone call
Day 7
(+ 3 days)
HIV testing, HCV antibody, HBsAg, HBsAb, 
HBcAb, and HAV antibody
X
HBV DNAk
X
HCV RNA
X
X
X
HCV Genotyping
X
Viral Sequencingl
X
X
Serum or Urine Pregnancy Testingm
X
X
X
IL28B Genotyping
X
Urinalysis
X
X
X
Urine Drug Screen
X
Intensive PK
Xo
a
Biological parental height, if not collected at Day 1.
b
If the assessment determines that the subject is at a Tanner 5 at Day 1, no further Tanner Pubertal Stage Assessments are to be completed.
c
Vital signs include blood pressure, pulse, respiratory rate and temperature.
d
Height should be without shoes and should be collected by the same personnel, if possible.
e
May be performed at Screening up to Day 1.
f
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years old and subjects < 12 years old at the discretion of the investigator based on subject’s 
pubertal status).
g
Swallowability can occur at Day 1 if not completed during screening.
h
Quality of life survey will be completed by all subjects and their parent/legal guardian. Subject and parent/legal guardian is to review questionnaire and write/mark answers 
directly onto the questionnaire.
i
Day 1 assessments must be performed prior to dosing. The IWRS system will provide direction on the specifics of each subject’s study drug dispensing.
j
.
k
HBV DNA testing done only when subjects are HBcAb positive at Screening.
l
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies.
m
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test.
n
For subjects who provide consent, a blood sample should be drawn at the Day 1 visit. If not obtained at this visit, the sample may be drawn at any time during the study.
o
Cohorts 1 and 2, plasma samples will be collected for PK analyses following dosing of study drug on Day 7 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 6, 8, and 
12 hours postdose. Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 8, and 12 hours postdose. Subjects 
should come in a fasted state for the Week 4 or Week 8 intensive PK visit (i.e., no food or drink except water at least 8 hours prior to the Week 4 or Week 8 intensive PK 
visit). Subjects and/or parents/legal guardians should also be instructed that the Week 4 or Week 8 dose of SOF/VEL FDC must not be taken prior to the visit and until the 
evaluations listed below are completed.
CCI
CCI


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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningj,k
(-28 days)
Day 1k
Week 1k
Week 4
Week 8
Week 12
Early Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Parental Height
Xa
Xa
Complete Physical Examination
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
Tanner Pubertal Stage Assessmentb
X
X
X
Vital Signsc
X
X
X
X
X
X
X
Body Weight and Heightd
X
X
X
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
Transient Elastography, (if available)
Xe
Xe
Pregnancy Prevention Counselingf
X
X
X
SOF/VEL Swallowability Assessment
Xg
Xg
SOF/VEL Acceptability Questionnaireh
X
X
X
Quality of Life Surveyi
X
X
X
Review of Study Medication Compliance
X
X
X
X
Study Drug Dispensingj
X
X
X
Subject Dosing Diaryl
X
X
X
X
X
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
X
X
X
X
HbA1c, Fibrotest®, APRI
X
TSH
X
X
X
Alpha-1 anti-trypsin
X
HIV testing, HCV Antibody, HBsAg, HBsAb, 
HBcAb, HAV Antibody
X
HBV DNAm
X
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
HCV Genotyping
X


SOFNELFDC 
Protocol GS-US-342-1143 
Gilead Sciences, Inc. 
· 1euec
0 
Serum or Urine Pregnancy Testing0 
a 
Biological parental height, if not collected at Day I. 
Screeningi,k 
(-28 days) 
X 
Day l k 
X 
Week4 
Week8 
Week12 
X 
X 
X 
b 
If the assessment detennines that the subject is at a Tanner 5 at Day I, no further Tanner Pubertal Stage Assessments are to be completed. 
c 
Vital signs include blood pressm·e, pulse, respiratory rate, and temperature. 
d 
Height should be without shoes and should be collected by the same personnel, if possible. 
e 
May be pe1fo1med at Screening up to Day I. 
Final 
Amendment4 
Early Termination 
X 
f 
Including partner pregnancy prevention for male pa,ticipants (all subjects~ 12 years old and subjects < 12 years old at the discretion of the investigator based on subject's 
pube,tal status). 
g 
Swallowability can occtu· at Day I if not completed dtu-ing screening. 
h 
A questionnaire will be administered to subjects to assess acceptability and palatability of the fonuulation they received on Day I, Week 12, and Early Tenuination 
(as applicable). If the subject is unable to complete the questionnaires, the parent/legal guardian will complete the questionnaire on their behalf. The subjects' parent/legal 
guardian will also complete a questionnaire on Week 12 or Early Tellll.lllation (as applicable) for their assessment of acceptability of the fo,mulation the subject received. 
Quality of life survey will be completed by all subjects and their parent/legal guardian. Subject and parent/legal guardian is to review questionnaire and \¥rite/mark answers 
directly onto the questionnaire. 
J 
Day I assessments must be pe,fonued prior to dosing. The IWRS system will provide direction on the specifics of each subject's study dmg dispensing. 
k 
Sub' ects rollin over from PK Lead-in will not be re uired tor eat scre.ening Da I or Week I visits in the Treatment Phase. 
1 
m 
n 
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies. 
o 
Females of childbea,-ing potential only. Senuu pregnancy test performed at screening and for confinuation of positive tu-ine pregnancy test. 
. 
. 
'. 
' 
' 
. . 
p 
q 
r 
CONFIDENTIAL 
Page 91 
15 June 2018 


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Amendment 4
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Appendix Table 3.
Treatment Phase: Posttreatment Visits Following Primary Study
4 Weeks Posttreatment
12 Weeks Posttreatment
24 Weeks Posttreatment
Clinical Assessments
Vital Signs
X
X
X
Body Weight and Heighta
X
X
X
Symptom-directed Physical Exam
X
X
X
AEs
X
Xb
Xb
Concomitant Medications
X
Quality of Life Surveyc
X
X
Tanner Pubertal Stage Assessmentd
X
X
Bone Age Assessment
X
Pregnancy Prevention Counselinge
X
Laboratory Assessments
Hematology, Chemistry
X
HCV RNA
X
X
X
Viral Sequencingf
X
X
X
Urine Pregnancy Testg
X
HBV DNAh
X
X
X
a
Height should be without shoes and should be collected by the same personnel, if possible.
b
At Posttreatment Week 12 and 24, only SAEs will be captured.
c
Quality of life survey will be completed by all subjects and their parent/legal guardian at 12-Week and 24-Week Posttreatment visits. Subject and parent/legal guardian is to 
review questionnaire and write/mark answers directly onto the questionnaire.
d
If the assessment determines that the subject is at a Tanner 5 at Day 1, no further Tanner Pubertal Stage Assessments are to be completed.
e
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years old and subjects < 12 years old at the discretion of the investigator based on subject’s 
pubertal status).
f
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies.
g
Females of childbearing potential only.
h
HBV DNA testing done only when subjects are HBcAb positive at screening.


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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 
≥ 7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL


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


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


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 96
15 June 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL
1.74 to <1.94 mmolL
6.1 to <7.0 mg/dL 
1.51 to < 1.74 mmolL
< 6.1 mg/dL
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88 mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10 mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23 mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38 mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to 1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 97
15 June 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63 to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia 
Adult and Pediatric
≥ 1 year
Infant < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 98
15 June 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/L to <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to 4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs. Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 99
15 June 2018
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years 
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 100
15 June 2018
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.


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 101
15 June 2018
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


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 102
15 June 2018
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


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 103
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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)


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 104
15 June 2018
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


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 105
15 June 2018
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 106
15 June 2018
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)


SOF/VEL FDC
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Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 107
15 June 2018
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (eg, 
agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others (eg, 
suicidal/homicidal ideation or 
attempt, acute psychosis) OR 
Causing inability to perform 
basic self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual
social & functional activities 
Disabling ataxia causing 
inability to perform basic self-
care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 108
15 June 2018
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or
other neurologic function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social &
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 109
15 June 2018
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase 
from Previous Level of 
Control to Any of These 
Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure 
Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 110
15 June 2018
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


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 111
15 June 2018
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]


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
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15 June 2018
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


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 113
15 June 2018
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


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 114
15 June 2018
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.


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 115
15 June 2018
Appendix 4.
Tanner Stages*
1. Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2. Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of testes and scrotum and increased darkening 
of scrotal skin (13.5-15)
Tanner V
Genitalia adult in size and shape
3. Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen 
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which continues to widen but remains in contour with 
surrounding breast 
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from the contour of the surrounding breast
Tanner V
breast reaches final adult size; areola returns to contour of the surrounding breast, with a projecting central papilla. 
*
Chart referenced from Marshall WA, Tanner JM, variations in the pattern of pubertal changes in boys and girls {Marshall 1969, Marshall 1970}


SOF/VEL FDC
Protocol GS-US-342-1143
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 116
15 June 2018
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following menarche until becoming post-menopausal, unless permanently sterile or with 
medically documented ovarian failure.
Women of any age with amenorrhea of > 12 months may be considered post-menopausal if their 
follicle stimulating hormone (FS) level is in the post-menopausal range and they are not using 
hormonal contraception or hormonal replacement therapy. Permanent sterilization includes 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of SOF have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies of SOF 
have demonstrated no adverse effect on fertility or embryo-fetal development
Data from clinical pharmacokinetic interaction studies of VEL have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies of 
GS-5816 have demonstrated no adverse effect on fertility or embryo-fetal development.
However, the risks of treatment with SOF/VEL FDC during pregnancy in humans have not been 
evaluated. Please refer to the latest version of the investigator’s brochure for additional 
information.
3) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable 
effective contraceptive measure. They must have a negative serum pregnancy test at Screening 
and a negative pregnancy test on the Day 1 visit prior to enrollment. A pregnancy test will be 
performed at the Posttreatment Week 4 visit. They must also agree to one of the following from 
Screening until 30 days of the last dose of SOF/VEL FDC.

Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or


SOF/VEL FDC
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Amendment 4
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
Consistent and correct use of 1 of the following methods of birth control listed below.
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
Tubal sterilization
Essure micro-insert system
Vasectomy in the male partner
Barrier methods (one female barrier and one male barrier must be used in combination)
■
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
■
Male barriers: Male condom (with or without spermicide)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel or etonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the last dose of SOF/VEL FDC.
4) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms until 30 days after the last dose of SOF/VEL FDC treatment when engaging in 
intercourse of reproductive potential. 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 30 days after the last dose of SOF/VEL FDC.
Male subjects must agree to refrain from sperm donation until 30 days after the last dose of 
SOF/VEL FDC.


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Amendment 4
CONFIDENTIAL
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5) Unacceptable Methods of Contraception
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal and post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM). Female condom and male condom 
should not be used together.
6) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of the last dose of SOF/VEL FDC. Subjects 
who become pregnant or who suspect that they are pregnant must report the information to the 
investigator and discontinue study drug immediately. Subjects whose partner has become 
pregnant or suspects she is pregnant must report the information to the investigator.
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.6.2.1.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Open-Label, Multicenter, Multi-cohort Study to 
Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir in 
Adolescents and Children with Chronic HCV Infection 
Name of Test Drug:
Sofosbuvir/Velpatasvir Fixed Dose Combination
Study Number:
GS-US-342-1143
Protocol Version (Date):
Original:
20 June 2016
Amendment 1: 20 September 2016
Amendment 2: 01 December 2016
Amendment 3: 31 August 2017
Amendment 4: 15 June 2018
Analysis Type:
Final Analysis
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
20 April 2020
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


Sofosbuvir/Velpatasvir
GS-US-342-1143
Statistical Analysis Plan - Final Analysis
Version 1.0
CONFIDENTIAL
Page 2
20 April 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
PHARMACOKINETIC ABBREVIATIONS AND DEFINITIONS ............................................................................6
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Design............................................................................................................................................8
1.2.1.
PK Lead-in Phase...................................................................................................................8
1.2.2.
Treatment Phase .....................................................................................................................9
1.2.3.
Study Duration .......................................................................................................................9
1.3.
Sample Size and Power..........................................................................................................................10
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................11
2.1.
DMC Analyses.......................................................................................................................................11
2.2.
Final Analysis ........................................................................................................................................11
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................12
3.1.
Analysis Sets..........................................................................................................................................12
3.1.1.
All Enrolled Analysis Set.....................................................................................................12
3.1.2.
Full Analysis Set ..................................................................................................................12
3.1.3.
Safety Analysis Set...............................................................................................................12
3.1.4.
Pharmacokinetic Analysis Set..............................................................................................12
3.2.
Subject Grouping ...................................................................................................................................13
3.3.
Strata and Covariates..............................................................................................................................13
3.4.
Examination of Subject Subsets.............................................................................................................13
3.5.
Missing Data and Outliers......................................................................................................................14
3.5.1.
Missing Data ........................................................................................................................14
3.5.2.
Outliers.................................................................................................................................15
3.6.
Data Handling Conventions and Transformations .................................................................................15
3.7.
Visit Windows........................................................................................................................................16
3.7.1.
Definition of Study Day .......................................................................................................16
3.7.2.
Analysis Windows................................................................................................................17
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis 
Window................................................................................................................................18
4.
SUBJECT DISPOSITION ..................................................................................................................................19
4.1.
Subject Enrollment and Disposition.......................................................................................................19
4.2.
Extent of Exposure.................................................................................................................................20
4.2.1.
Durations of Exposure to Study Regimen ............................................................................20
4.2.2.
Adherence to Study Drug.....................................................................................................20
4.3.
Protocol Deviations................................................................................................................................21
5.
BASELINE CHARACTERISTICS....................................................................................................................22
5.1.
Demographics ........................................................................................................................................22
5.2.
Other Baseline Characteristics ...............................................................................................................22
5.3.
Medical History......................................................................................................................................23
6.
EFFICACY ANALYSES ...................................................................................................................................24
6.1.
Key Efficacy Endpoint...........................................................................................................................24


Sofosbuvir/Velpatasvir
GS-US-342-1143
Statistical Analysis Plan - Final Analysis
Version 1.0
CONFIDENTIAL
Page 3
20 April 2020
6.1.1.
Definition of the Key Efficacy Endpoint..............................................................................24
6.1.2.
Analysis Methods for the Key Efficacy Endpoint................................................................24
6.1.3.
Subgroup Analysis of the Key Efficacy Endpoint................................................................24
6.2.
Secondary Efficacy Endpoints ...............................................................................................................24
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................24
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................25
6.3.
Exploratory Efficacy Endpoints.............................................................................................................27
6.3.1.
Definition of Exploratory Efficacy Endpoints......................................................................27
6.3.2.
Analysis Methods for Exploratory Efficacy Endpoints........................................................27
6.4.
Changes From Protocol-Specified Efficacy Analyses............................................................................27
7.
SAFETY ANALYSES........................................................................................................................................28
7.1.
Adverse Events and Deaths....................................................................................................................28
7.1.1.
Adverse Event Dictionary ....................................................................................................28
7.1.2.
Adverse Event Severity........................................................................................................28
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................28
7.1.4.
Serious Adverse Events........................................................................................................28
7.1.5.
Treatment-Emergent Adverse Events...................................................................................28
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................29
7.2.
Laboratory Evaluations ..........................................................................................................................30
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................31
7.2.2.
Graded Laboratory Values ...................................................................................................31
7.3.
Vital Signs..............................................................................................................................................33
7.4.
Body Weight, Height and BMI ..............................................................................................................33
7.5.
Mid-Parental Height Assessment...........................................................................................................34
7.6.
Bone Age Assessment............................................................................................................................34
7.7.
Tanner Pubertal Stage Assessment.........................................................................................................34
7.8.
Prior and Concomitant Medications.......................................................................................................34
7.9.
Swallowability Assessment for SOF/VEL FDC Placebo Tablets ..........................................................35
7.10.
Acceptability and Palatability of SOF/VEL FDC ..................................................................................35
7.11.
Other Safety Measures ...........................................................................................................................36
7.12.
Changes From Protocol-Specified Safety Analyses...............................................................................36
8.
PHARMACOKINETIC ANALYSES ................................................................................................................37
8.1.
PK Analysis in the PK Lead-in Phase (Intensive PK Analysis).............................................................37
8.2.
Population PK Analysis .........................................................................................................................37
9.
REFERENCES ...................................................................................................................................................38
10.
SOFTWARE.......................................................................................................................................................39
11.
SAP REVISION..................................................................................................................................................40
12.
APPENDICES ....................................................................................................................................................41
Appendix 1.
Study Procedures Table..........................................................................................................42
Appendix 2.
Tanner Stages* .......................................................................................................................47
Appendix 3.
PedsQL™ Score Calculation Algorithms...............................................................................48
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs and Safety Laboratory 
Data ........................................................................................................................................17
Table 3-2.
Analysis Windows for Posttreatment HCV RNA, Body Weight, Height, Vital Sign 
and Safety Laboratory Data....................................................................................................18


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CDC 
Centers for Disease Control
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatine kinase
CSR
clinical study report
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EOT
end of treatment
FAS
Full Analysis Set
FDC
Fixed Dose Combination
FU
follow-up
Gilead
Gilead Sciences, Inc.
GT
genotype
Hb
hemoglobin
HCV
hepatitis C virus
HLT
high level term
HLGT
high level group term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
ID
identification
IFN
interferon
LLT
lower level term
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
PedsQLTM
Pediatric Quality of Life Inventory™
PK
pharmacokinetics
PT
preferred term
Q1
first quartile
Q3
third quartile
RBV
ribavirin
RNA
ribonucleic acid


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SAE
serious adverse event
SAP
statistical analysis plan
SI (units)
International system of units
SOC
system organ class
SOF
sofosbuvir 
SVR
sustained virologic response
SVRx
sustained virologic response x weeks after stopping study drug
TEAE
treatment-emergent adverse events
TFLs
tables, figures, and listings
TND
target not detected
ULN
upper limit of normal
VEL
velpatasvir
VF
virologic failure
WBC
white blood cell
WHO
World Health Organization


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


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) for Study GS-US-342-1143. This 
SAP is based on study Protocol Amendment 4 dated 15 June 2018 and electronic case report 
form (eCRF). Any changes made after the finalization of the SAP will be documented in the 
clinical study report (CSR).
1.1.
Study Objectives
The primary objectives of this study are as follows:

The primary objective of the pharmacokinetics (PK) Lead-in Phase of this study is to
evaluate the steady state PK and confirm the dose of SOF/VEL FDC in pediatric subjects 
with chronic HCV infection. 

The primary objective of the Treatment Phase of this study is to evaluate the safety and 
tolerability of SOF/VEL FDC for 12 weeks in pediatric subjects with chronic HCV.
The secondary objectives of this study are as follows:

The secondary objective of the PK Lead-in Phase of this study is to evaluate the safety, 
tolerability, and antiviral activity of 7 days of dosing of SOF/VEL FDC in pediatric subjects 
with chronic HCV.

The secondary objectives of the Treatment Phase of this study are:
To determine the efficacy of SOF/VEL FDC for 12 weeks in pediatric subjects with 
chronic HCV infection, as assessed by the proportion of subjects with sustained 
virological response (SVR) 12 weeks after cessation of treatment (SVR12)
To determine the proportion of subjects with SVR 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24)
To evaluate the proportion of subjects with virologic failure, including 
breakthrough/nonresponse and relapse
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment
To evaluate the emergence of viral resistance to SOF and VEL during treatment and after 
cessation of treatment
To evaluate the effect of treatment with SOF/VEL FDC on quality of life as measured by
PedsQL™ Pediatric Quality of Life survey
To evaluate the effect of SOF/VEL FDC on growth and development of pediatric 
subjects during and after treatment
To evaluate the acceptability, including palatability, of formulations used in the study


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The exploratory objective of this study is as follows:
1.2.
Study Design
This is an open-label, multi-cohort, two-part study evaluating the PK, safety, and antiviral 
activity of SOF/VEL FDC in chronic HCV-infected pediatric subjects.
Overall, the study will enroll both treatment-naive and treatment experienced pediatric subjects 
with at least 20 and up to 40 treatment experienced subjects. Approximately 200 total subjects
will be enrolled as follows:

Approximately 100 adolescents aged 12 to < 18 years 

Approximately 100 children aged 3 to < 12 years
Subjects will be enrolled in a sequential fashion by 3 age groups: 12 to <18 years old, followed 
by 6 to <12 years old, and 3 to <6 years old.
Eligible subjects will receive SOF/VEL FDC once daily for 12 weeks.
The schedules of assessments for the study are provided as appendices to the SAP 
(see Study Procedures Table, Appendix 1). 
1.2.1.
PK Lead-in Phase
The PK Lead-in Phase will evaluate and/or confirm the age appropriate SOF/VEL FDC dose by 
analyzing PK, safety, and antiviral activity of SOF/VEL FDC through 7 days of dosing.
At least 17 subjects will be sequentially enrolled into each of the following 3 cohorts:

Cohort 1: 12 to < 18 years old

Cohort 2: 6 to < 12 years old

Cohort 3: 3 to < 6 years old
At least 6 subjects weighing ≥ 17 kg
At least 6 subjects weighing < 17 kg
CCI


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Intensive PK and safety results through Day 7 of each Cohort will be reviewed to confirm the 
appropriateness of the SOF/VEL FDC dose for that age group as well as to determine the 
age-appropriate dose to be evaluated in the PK Lead-in Phase of the next age Cohort.
Subjects enrolled in the PK Lead-in Phase will immediately enroll in the Treatment Phase as 
subjects complete Day 7 of PK Lead-in. Subjects will continue dosing with SOF/VEL FDC with 
no interruption of study drug administration until the appropriateness of the dose is confirmed by 
PK and safety data from the PK Lead-in Phase.
Cohort 1 subjects will receive a SOF/VEL FDC 400/100 mg adult tablet or 2 × 200/50 mg tablets
(if determined necessary based on SOF/VEL swallowability assessment) once a day for 7 days 
with intensive PK conducted on Day 7. 
Cohort 2 subjects will receive SOF/VEL FDC 200/50 mg tablets once daily. If unable to swallow 
the tablet formulations, the subjects will receive SOF/VEL FDC 200/50 mg oral granules 
(4 × 50/12.5 mg packets) for 7 days with intensive PK conducted on Day 7. 
Cohort 3 subjects weighing ≥17 kg will receive SOF/VEL FDC 200/50 mg oral granules 
(4 × 50/12.5 mg packets) for 7 days with intensive PK conducted on Day 7. Cohort 3 subjects 
weighing <17 kg will receive SOF/VEL FDC 150/37.5 mg oral granules (3 × 50/12.5 mg 
packets) for 7 days with intensive PK conducted on Day 7. 
1.2.2.
Treatment Phase
Additional HCV-infected children will be enrolled into the Treatment Phase upon confirmation 
of the appropriateness of the dose from the PK Lead-in Phase. The Treatment Phase will be
initiated sequentially by age group as defined in Cohorts 1, 2, and 3 of the PK Lead-in Phase. 
Subjects who participated in the PK Lead-in Phase will immediately roll over into the Treatment 
Phase with no interruption of study drug administration until the appropriateness of the dose has
been confirmed by PK and safety results from the PK Lead-in Phase. The first visit in the 
Treatment Phase for these subjects will be the Week 4 visit. 
After dose confirmation in the PK Lead-in Phase of each age group, the same dose will be used 
in subjects of the corresponding age group enrolled in the Treatment Phase.
1.2.3.
Study Duration
The total time to complete all study visits is up to approximately 40 weeks including the 
following periods:

28-day (4-week) screening period

12-week treatment period

24-week posttreatment period


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1.3.
Sample Size and Power
With approximately 100 subjects enrolled into the 12 to < 18 years of age group and 
approximately 100 subjects enrolled into the 3 to < 12 years of age group, a 2-sided 95% exact 
confidence interval of the SVR12 rate in each age group will extend at most 20%.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
DMC Analyses
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of 
the study and perform interim reviews of the safety data in order to protect subject welfare and 
preserve study integrity. To ensure the best interests of the participants, the DMC will 
recommend to the sponsor if the nature, frequency, and severity of adverse effects associated 
with the study treatment warrant the early termination of the study, the continuation of the study, 
or the continuation of the study with modifications.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
provided in a mutually agreed upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency.
2.2.
Final Analysis
After all subjects have completed through the post-treatment week 24 visit or have prematurely 
discontinued from the study, outstanding data queries have been resolved, and the database has 
been cleaned and finalized, the final analysis of the data will be performed.


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


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Population PK Analysis Set
The Population PK Analysis Set includes all enrolled subjects who received at least one dose of 
study drug and for whom at least one non-missing PK concentration data value is available from 
all types of PK sampling. This is the primary analysis set for the Population PK modeling and 
PK exposure analyses.
The PK Analysis Set is equivalent to the Population PK Analysis Set.
3.2.
Subject Grouping
For analyses based on the All Enrolled Analysis Set or FAS, subjects will be grouped according 
to the treatment to which they were enrolled. For analyses based on the Safety Analysis Set, 
subjects will be grouped according to the actual treatment received. The actual treatment 
received is defined as the enrolled treatment except for subjects who received treatment that 
differs from the enrolled treatment for the entire treatment duration. In this case, the actual 
treatment received is defined as the treatment received for the entire treatment duration.
Generally speaking, the efficacy analyses will be performed on the FAS by age group and by 
HCV genotype (1 [further broken down to 1a and 1b], 2, 3, 4, 5, 6, or other, as appropriate), as 
determined by sequencing or, if sequencing is not available, by LIPA. The primary analysis will 
be performed on the FAS as described in Section 6.1.
For the safety analysis, because all subjects receive SOF/VEL FDC for 12 Weeks, subjects will 
be summarized by age group.
For selected analyses, for example, the summary of subject enrollment and disposition, the 
summary of demographics and baseline characteristics, the summary of responses to the 
acceptability and palatability questionnaire, and the analysis of Tanner pubertal stage assessment
data, please refer to the relevant sections for the detailed description of subject grouping.
3.3.
Strata and Covariates
This study does not use a stratified randomization schedule for enrolling subjects. No covariates 
will be included in efficacy and safety analyses.
3.4.
Examination of Subject Subsets
The efficacy endpoint SVR12 will be analyzed for the following subsets:

sex (male, female)

race (black, non-black)

ethnicity (Hispanic or Latino, non-Hispanic or Latino)

baseline weight (≤ median, > median)


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
IL28B (CC, non-CC [further broken down to CT, TT])

baseline HCV RNA (< 800,000 IU/mL, ≥ 800,000 IU/mL)

baseline alanine aminotransferase (ALT) (≤1.5 × ULN, > 1.5 × ULN)

prior HCV treatment experience (treatment naive, treatment experienced)

most recent response to prior HCV treatment (non-response, relapse/breakthrough, 
Unknown) for treatment experienced subjects

cirrhosis status (presence, absence, not determined)

study treatment status (completed study treatment, discontinued study treatment)

adherence to study drug (< 80%, ≥ 80%).
3.5.
Missing Data and Outliers
3.5.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
For missing last dosing date of study drug, imputation rules are described in Section 3.7.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in 
Section 7.1.5.2, and for prior and concomitant medications in Section 7.8.
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed up to 
the time of the last dose (for on-treatment displays). If the study day associated with the 
last dosing date is greater than or equal to the lower bound of a visit window, and the value at the 
visit is missing, the value will be imputed. If the study day associated with the last dosing date is 
less than the lower bound of a visit window then the on-treatment value at that visit will remain 
missing. 
If a data point is missing and is preceded and followed in time by values that are “< lower limit 
of quantitation (LLOQ) target not detected (TND)”, then the missing data point will be set to 
“< LLOQ TND”. If a data point is missing and preceded and followed by values that are 
“< LLOQ detected”, or preceded by “< LLOQ detected” and followed by “< LLOQ TND”, or 
preceded by “< LLOQ TND” and followed by “< LLOQ detected”, then the missing value will 
be set to “< LLOQ detected”. In these situations the data point will be termed a bracketed 
success; otherwise, the data point will be termed a bracketed failure (ie, ≥LLOQ detected). If a 
data point is missing and is not bracketed, the missing data point will also be termed a failure 
(ie, ≥LLOQ detected) except for SVR24, which will be imputed according to SVR12 status. 
Success for SVR12 who have no further HCV RNA measurements collected will be counted as a 
success for SVR24 due to the high correlation between these 2 endpoints.


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For the analyses of continuous HCV RNA efficacy data, when and only when a missing HCV 
RNA value is imputed as < LLOQ TND or < LLOQ detected according to the imputation rule 
described above, the corresponding continuous value will be imputed to LLOQ
1 IU/mL. No 
other imputation will be performed for continuous HCV RNA data.
In the analysis of the PedsQL™Pediatric Quality of Life Inventory V4.0 Short Form (SF15) 
questionnaire, missing data at on-treatment visits and posttreatment follow-up Week 12 (FU-12) 
visit will not be imputed. Last posttreatment observation carried forward will be used for 
imputation of missing data at posttreatment follow-up Week 24 visit.
3.5.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.6.
Data Handling Conventions and Transformations
By-subject listings will be presented for all subjects in the Safety Analysis Set and sorted by 
subject ID number, visit date, and time (if applicable) unless otherwise specified. Data collected 
on log forms, such as AEs, will be presented in chronological order within subject. 
Age (in years) on the date of the first dose of study drug and sex at birth will be used for analyses 
and presentation in listings.
If a subject was not dosed with study drug at all, then the date the informed consent was signed 
will be used instead of the first dose date of study drug. For some countries, only birth year is 
collected on the eCRF. In those cases, “01 July” will be used for the unknown birth day and 
month for the purpose of age calculation, unless age is captured on the eCRF. 
Non-PK data that are continuous in nature but are less than the LLOQ or above the upper LOQ
will be imputed as follows:

A value that is one unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “x” (where x is considered the 
limit of quantitation). For example, if the values are reported as < 50 and < 5.0, values of 
49 and 4.9, respectively, will be used for calculation of summary statistics. An exception for 
this rule is any value reported < 1. For the values reported as < 1 or < 0.1, value of 0.9 or 
0.09 will be used for calculation of summary statistics.

A value that is one unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “> x” (where x is considered the 
limit of quantitation). Values with decimal points will follow the same logic as above.

The limit of quantitation will be used for calculation of descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the limit of quantitation).
The COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 for use with the High Pure 
System was used to determine HCV RNA results in this study. The LLOQ of the assay is 
15 IU/mL.


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When the calculated HCV RNA value is within the linear range of the assay, then the result will 
be reported as the “<< numeric value>> IU/mL”. This result will be referred to in this document 
as the numeric result or as “≥ LLOQ detected” for categorical result.
When HCV RNA is not detected, the result is reported as “No HCV RNA detected” or “target 
not detected”. This result will be referred to in this document as “< LLOQ target not detected” or 
“< LLOQ TND”.
When the HCV RNA IU/mL is less than LLOQ of the assay, the result is reported as 
“< 15 IU/mL HCV RNA detected”. This result will be referred to in this document as “< LLOQ 
detected”.
The overall category of HCV RNA < LLOQ includes “< LLOQ TND” and “< LLOQ detected.”
For numerical HCV RNA data, values below LLOQ will be set to the LLOQ 1 IU/mL 
(ie, 14 HCV RNA IU/mL). HCV RNA values returned as “No HCV RNA detected” will also be 
set to 14 IU/mL.
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data (eg, log10 scale) or nonparametric analysis 
methods may be used, as appropriate.
Natural logarithm transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma concentration values that are below the lower limit of quantitation (BLQ) 
will be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated 
as 0 at predose time points, and one-half the value of the LLOQ at postdose time points for 
summary purposes.
For the presentation of summary and order statistics, if at least 1 subject has a concentration 
value of BLQ for the time point, then the minimum value will be displayed as “BLQ” If more 
than 25% of the subjects have a concentration data value of BLQ for a given time point, then the 
minimum and Q1 values will be displayed as “BLQ” If more than 50% of the subjects have a 
concentration data value of BLQ for a given time point, then the minimum, Q1, and median 
values will be displayed as “BLQ” If more than 75% of the subjects have a concentration data 
value of BLQ for a given time point, then the minimum, Q1, median, and Q3 values will be 
displayed as “BLQ” If all subjects have concentration data values of BLQ for a given time point, 
then all order statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ”.
3.7.
Visit Windows
3.7.1.
Definition of Study Day
Study day is the day relative to the date of the first dose of study drug. Study Day 1 will be 
defined as the day of first dose of study drug administration.
Study day will be calculated from the date of first dose of study drug administration and derived 
as follows:

For postdose study days: Assessment Date First Dose Date + 1

For days prior to the first dose: Assessment Date First Dose Date


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The last dose date for the study drug will be the end date on study drug administration eCRF for 
the record where the “subject permanently discontinued” flag is ‘Yes’.
If there are subjects for whom the date of last study drug is unknown due to the reason that the 
subject was lost to follow-up and not able to be contacted, the date of last dose will be estimated 
using the maximum of nonmissing study drug start or stop dates, visit dates and laboratory 
collection dates (posttreatment visits and unscheduled visits are not included).
3.7.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
The baseline value will be the last nonmissing value on or prior to the first dose date of study 
drug. 
HCV RNA, vital signs, and safety laboratory data collected up to the last dose date + 3 days are 
considered to be on-treatment data and HCV RNA, vital signs and safety laboratory data 
collected after the last dose date + 3 days are considered posttreatment data. The analysis 
windows for on-treatment HCV RNA, vital signs and safety laboratory data are provided in
Table 3-1.
Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs and 
Safety Laboratory Data
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 1
7
2
18
Week 4
28
19
42
Week 8
56
43
70
Week 12
84
71
≥85
Subjects who participated in PK Lead-in Phase will immediately roll over 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 4 
visit of the Treatment Phase. Week 1 records for these subjects will be chosen from Day 7 in the 
PK Lead-in Phase.
HCV RNA, vital sign, and safety laboratory data collected after the last dose date + 3 days will 
be assigned to the posttreatment follow-up (FU) visits. Visit windows will be calculated from the 
last dose date (ie, FU Day  collection date minus the last dose date) as shown in Table 3-2.


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Table 3-2.
Analysis Windows for Posttreatment HCV RNA, Body Weight, 
Height, Vital Sign and Safety Laboratory Data
Nominal 
FUa Visit
HCV RNA, Body weight and Height
Vital Signs and Safety Laboratory Datab
Nominal FU Day
Lower Limit
Upper Limit
Nominal FU Day
Lower Limit
Upper Limit
FU 4
28
21
69
28
4
30
FU 12
84
70
146
NA
NA
NA
FU 24
168
147
210
NA
NA
NA
a
FU x visit  posttreatment Week x follow up visit.
b
Vital signs (blood pressure, pulse, respiratory rate, and temperature) and safety labs will only be summarized for the FU 4
visit (up to 30 days after last dose).
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. 
If multiple valid nonmissing numeric observations exist in an analysis window, records will be 
chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, average (arithmetic mean) will be used for the baseline value. 

For postbaseline visits: 
The record closest to the nominal day for that visit will be selected except for HCV RNA 
posttreatment follow-up visits, for which the latest record in the analysis window will be 
selected. 
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.
If multiple valid nonmissing categorical observations exist in a window, records will be selected
as follows:

For baseline, the last available record on or prior to the date of the first dose of study drug
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, the value with the lowest severity will be selected (eg, normal will be selected over 
abnormal).

For postbaseline visits, follow the same rules described above for postbaseline numeric 
observations, except that if there are multiple records on the same day, the most conservative 
value will be selected (eg, abnormal will be selected over normal).


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by age group for each country, investigator 
within a country, and overall. The summary will present the number and percentage of subjects 
in the Safety Analysis Set. For each column, the denominator for the percentage calculation will 
be the total number of subjects analyzed for that column. 
A summary of subject disposition will be provided by HCV genotype (1 [further broken down to 
1a and 1b], 2, 3, 4, 5, 6, or other, as appropriate, and total) for each age group. This summary 
will present the number of subjects screened, enrolled, enrolled but never treated, and the 
number and percentage of subjects in each of the categories listed below. For the “Treated” 
category, the denominator for the percentage calculation will be the total number of subjects 
enrolled. For all other categories, the denominator for the percentage calculation will be the total 
number of subjects in the Safety Analysis Set. 

Treated (Safety Analysis Set) 

In FAS

In Lead-in Phase PK Analysis Set

In Population PK Analysis Set

Completed study treatment

Did not complete study treatment with reasons for premature discontinuation of study 
treatment

Completed the study

Did not complete the study with reason for premature discontinuation of study
Among subjects who completed the study treatment and who discontinued study treatment, the 
following number and percentage of subjects will be summarized:

Subjects who had no HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 
and thereafter)

Subjects who had HCV posttreatment Week 4 assessment but no HCV posttreatment 
Week 12 assessment and thereafter (With HCV FU-4 but no FU-12 and thereafter)
If a subject did not have any HCV RNA assessment ≥ 21 days after the last dose of any study 
drug (ie, lower bound of FU-4 visit for HCV RNA data), the subject is categorized as having 
“No HCV FU-4 and thereafter”. If a subject had the HCV FU-4 assessment but did not have any 
HCV RNA assessment ≥ 70 days after the last dose of any study drug (ie, lower bound of FU-12 
visit for HCV RNA data), the subject is categorized as having “With HCV FU-4 but No FU-12 
and thereafter”.


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In addition, the total number of subjects who were enrolled, and the number of subjects in each 
of the disposition categories listed above will be displayed in a flowchart.
The following by-subject listings will be provided by subject ID number in ascending order to 
support the above summary tables:

Disposition of subjects who complete study treatment and study

Disposition of subjects who did not complete study treatment and/or study with reasons for 
premature discontinuation of study drug and/or study

Lot number and kit ID (if applicable)
4.2.
Extent of Exposure
Extent of exposure to study drug will be examined by assessing the total durations of study drug 
exposure and the level of adherence to the study drug regimen specified in the protocol. 
4.2.1.
Durations of Exposure to Study Regimen 
Total duration of exposure to study drug will be defined as last dose date minus first dose date 
plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.5 weeks).
The total durations of exposure to study drug will be summarized for each age group using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) and using the 
number (ie, cumulative counts) and percentage of subjects exposed through the following time 
periods: Baseline (Day 1), Week 1 (Day 7), Week 4 (Day 28), Week 8 (Day 56), and Week 12 
(Day 84). A 3-day window is applied to the last planned on-treatment visit to match with the 
protocol-specified visit window. Summaries will be provided for the Safety Analysis Set. 
4.2.2.
Adherence to Study Drug
The level of adherence to the study drug regimen will be assessed based on the total amount of 
study drug administered relative to the total amount of study drug prescribed.
Given the fact that multiple formulations of the study drug have been used in this study, the 
adherence will be calculated based on the amount of SOF/VEL (mg) by the following formula:
100
  
baseline
at 
Prescribed
Drug
Study 
of
Amount 
Total
  
ed
Administer
Drug
Study 
of
Amount 
Total
(%)
Adherence
of
Level










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Where the presumed total amount of study drug (mg) administered to a subject will be 
determined by the data collected on the drug accountability eCRF using the following formula:





Returned
(mg)
Drug
Study 
  
of
Amount 
Total
Dispensed
(mg)
Drug
Study 
  
of
Amount 
Total
ed
Administer
(mg)
Drug
Study 
of
Amount 
Total
Note: If calculated adherence is greater than 100%, the result will be set to 100%.
The total amount of prescribed SOF/VEL (mg) for 12 weeks are as follows:
Age Group and Body Weight 
SOF/VEL Daily Dose
Total Amount of SOF/VEL
Prescribed for 12 Weeks
12 to <18 years any weight
500 mg/day
42000 mg
6 to <12 years any weight
250 mg/day
21000 mg
3 to <6 years weighing ≥17 kg
250 mg/day
21000 mg
3 to < 6 years weighing <17 kg
187.5 mg/day
15750 mg
Subjects who prematurely discontinue study drug for lack of efficacy (ie, virologic failure) will 
have the total amount of study drug prescribed calculated up to the first date when virologic 
failure criteria were met. For virologic failure confirmed by 2 consecutive measurements the date 
of the first measurement will be used. If there are study drug bottles dispensed on or after the 
subject first met virologic failure criteria, these bottles will not be included in the calculation of 
adherence. If a bottle is dispensed and the bottle is returned empty, then the number of tablets 
returned will be entered as zero. If a bottle is dispensed but not returned (missing), the number of 
tablets taken from that bottle will be counted as zero.
Descriptive statistics for the level of adherence (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) with the number and percentage of subjects belonging to adherence categories 
(e.g. < 80%, ≥ 80 to < 90%, ≥ 90%) will be provided by age group for the Safety Analysis Set. 
No inferential statistics will be provided for duration of exposure and adherence to study drug. 
A separate by-subject listing of study drug administration and drug accountability will be 
provided by subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations
A summary of important protocol deviations will be provided by the Clinical Operations group 
for subjects in the Safety Analysis Set.
Subjects who received study drug other than their enrolled treatment assignment will be listed 
with the start and stop dates that they received incorrect study treatment.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by HCV 
genotype (1 [further broken down to 1a and 1b], 2, 3, 4, 5, 6, or other, as appropriate, and total)
in each age group using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) for age, and using the numbers and percentages of subjects for sex, race, and 
ethnicity. Age is calculated in years at the date of initial study drug administration. If a subject 
did not receive study drug after enrollment, the subject’s age will be calculated from the date that 
the subject signed the informed consent form. The summary of demographic data will be 
provided for the Safety Analysis Set.
A by-subject demographic listing will be provided by subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include:

weight in kg

height in cm

body mass index (BMI; in kg/m2)

HCV genotype (1 [further broken down to 1a and 1b], 2, 3, 4, 5, 6, or other, as appropriate)

cirrhosis (presence, absence, not determined)

IL28B (CC, CT, TT) 

baseline HCV RNA (IU/mL) (< 800,000 IU/mL, ≥800,000 IU/mL)

baseline HCV RNA (log10 IU/mL) as a continuous variable and as categories 
(< 6 log10 IU/mL, ≥ 6 log10 IU/mL)

baseline ALT (U/L) as a continuous variable and as categories (≤1.5 × ULN, > 1.5 × ULN)

estimated glomerular filtration rate (eGFR) using Schwartz Formula (mL/min/1.73m2)

prior treatment experience (treatment naïve, treatment experienced)

most recent response to prior HCV treatment (non-response, relapse/breakthrough, unknown)
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
mode of HCV Infection

bone age in years

Tanner Stage 
Estimated glomerular filtration rate will be calculated using Schwartz Formula (mL/min/1.73m2) 
 k L/Scr [(k is a proportionality constant, for adolescent females ≥12 years old is 0.55; for 
adolescent males ≥ 12 years old is 0.70, and for children 3- <12 years old is 0.55); L is height in 
centimeters (cm); and Scr is serum creatinine (mg/dL)].
These baseline characteristics will be summarized by HCV genotype (1 [further broken down to 
1a and 1b], 2, 3, 4, 5, 6, or other, as appropriate, and total) in each age group using descriptive 
statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for continuous variables and 
using the numbers and percentages of subjects for categorical variables. The summary of 
baseline characteristics will be provided for the Safety Analysis Set.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
General medical history (ie, conditions not specific to the disease being studied) data will be 
collected at screening and listed only. General medical history data will not be coded. A 
by-subject listing of disease-specific medical history will be provided by subject ID number 
(in ascending order) and medical history of abnormalities (in chronological order).


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6.
EFFICACY ANALYSES
6.1.
Key Efficacy Endpoint
6.1.1.
Definition of the Key Efficacy Endpoint
The key efficacy endpoint is SVR12 defined as HCV RNA < LLOQ (ie, < 15 IU/mL) 12 weeks 
after discontinuation of the study drug in the FAS. The COBAS® AmpliPrep/COBAS® TaqMan®
HCV Test, v2.0 for use with the High Pure System will be used to measure HCV RNA.
6.1.2.
Analysis Methods for the Key Efficacy Endpoint
No inferential statistics will be provided for efficacy endpoints. No statistical comparison will be 
conducted.
The point estimates of SVR12 rate and 2-sided 95% exact CI based on Clopper-Pearson method 
{Clopper 1934} will be provided by age group for the FAS.
6.1.3.
Subgroup Analysis of the Key Efficacy Endpoint
The point estimates of SVR12 rate and 2-sided 95% exact CIs based on Clopper-Pearson method 
{Clopper 1934} will be provided for each age group by HCV genotype (1 [further broken down 
to 1a and 1b], 2, 3, 4, 5, 6, or other, as appropriate, and total) within each subgroup specified in 
Section 3.4
A Forest plot will graphically present estimates and 95% confidence intervals of SVR12 rates for 
each subgroup.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints of the PK Lead-in Phase include the following:

HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) to Day 7
Secondary efficacy endpoints of the Treatment Phase include the following:

The percentage of subjects who attain SVR at 4 and 24 weeks after stopping therapy, defined 
as HCV RNA < LLOQ (ie, < 15 IU/mL) 4 and 24 weeks after stopping treatment (SVR 4 and 
SVR 24)

The percentage of subjects with HCV RNA below LLOQ by study visit

HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) through end 
of treatment (EOT)


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
The percentage of subjects with virologic failure as the following:
On-treatment virologic failure
HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ, while on 
treatment, confirmed with 2 consecutive values (note, second confirmation value can be 
posttreatment), or last available on-treatment measurement with no subsequent follow-up
values (ie, breakthrough)
> 1 log10IU/mL increase in HCV RNA from nadir while on treatment, confirmed with 
2 consecutive values (note, second confirmation value can be posttreatment), or last 
available on-treatment measurement with no subsequent follow-up values (ie, rebound)
HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (ie, nonresponse)
Relapse 
HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA 
< LLOQ at end of treatment, confirmed with 2 consecutive values or last available 
posttreatment measurement

The proportion of subjects with ALT normalization (defined as ALT > ULN at baseline and 
ALT ≤ ULN at each visit), presented by study visit

Changes in subject and their parent/legal guardian reported outcomes including
neuropsychiatric assessments based on the Pediatric Quality of Life (PedsQL™ SF-15) 
Questionnaires

Characterization of HCV drug resistance substitutions at baseline, during, and after therapy 
with SOF/VEL
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
For analyses of HCV RNA < LLOQ by visit while on treatment and during the posttreatment 
(SVR) follow-up period, subjects will be assigned a value at each visit based on the analysis visit 
windows specified in Section 3.7.2. Missing values will be imputed based on the categorical 
imputation rules described in Section 3.5.1. The 2-sided 95% exact confidence interval based on 
Clopper-Pearson method will be provided by HCV genotype (1 [further broken down to 1a and 
1b], 2, 3, 4, 5, 6, or other, as appropriate, and total) for the percentage of subjects in each age 
group with HCV RNA < LLOQ at each visit. The overall category for “HCV RNA < LLOQ” 
will be split into the following 2 subcategories: “< LLOQ TND” for subjects with target not 
detected and “< LLOQ detected” for subjects with < LLOQ detected in tabular displays. 
Graphs for the percentage of subjects with HCV RNA < LLOQ over time during treatment will 
be displayed by HCV genotype (1 [further broken down to 1a and 1b], 2, 3, 4, 5, 6, or other, as 
appropriate, and total).


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Summary statistics for each age group will be presented for absolute values and change from 
baseline in HCV RNA (log10 IU/mL) to Day 7 for PK Lead-in Phase and will be presented by 
HCV genotype (1 [further broken down to 1a and 1b], 2, 3, 4, 5, 6, or other, as appropriate, and 
total) by visit through EOT for Treatment Phase. Imputation rules described in Section 3.5.1 will 
be used to assign HCV RNA values for missing values at a visit that are bracketed by “< LLOQ 
TND” and/or “< LLOQ detected”. Otherwise, a missing  excluded analysis will be performed. 
Plots of the mean ± SD and median (Q1, Q3) of absolute values and changes from baseline in 
HCV RNA to Day 7 will be presented for PK Lead-in Phase. Plots of the mean ± SD and median 
(Q1, Q3) of absolute values and changes from baseline in HCV RNA through EOT will be 
presented by HCV genotype (1 [further broken down to 1a and 1b], 2, 3, 4, 5, 6, or other, as 
appropriate, and total) for Treatment Phase.
For the SVR12 endpoint analysis, a summary table of the number and percentage of subjects 
with SVR12, virologic failure (VF), and Other will be created for each age group by HCV 
genotype (1 [further broken down to 1a and 1b], 2, 3, 4, 5, 6, or other, as appropriate, and total). 
All subjects who achieve SVR12 will be categorized as SVR12. Virologic failure will be 
descriptively summarized as “on-treatment virologic failure” and relapse (which will be broken 
down by study drug completed yes/no). Subjects who do not achieve SVR12 and do not meet 
criteria for VF will be categorized as Other. The denominator for relapse will be the number of 
subjects who had HCV RNA < LLOQ on their last observed on-treatment HCV RNA 
measurement; otherwise, the denominator will be the number of subjects in the FAS. 
A concordance table between SVR12 and SVR24 will be provided. Subjects with both observed 
SVR12 and observed SVR24 data will be included for this analysis.
In addition, a summary table of the number and percentage of subjects with HCV RNA < LLOQ 
and ≥LLOQ at the posttreatment follow-up visit (observed and imputed, with reasons for 
imputed) will be provided by HCV genotype (1 [further broken down to 1a and 1b], 2, 3, 4, 5, 6, 
or other, as appropriate, and total) for each posttreatment follow-up visit. 95% Clopper-Pearson 
exact CIs will be presented for the overall proportion of subjects with HCV RNA < LLOQ.
Tables for ALT normalization by visit will use similar methodology to the analyses of HCV 
RNA < LLOQ, but will use a missing  excluded analysis. Only those subjects with ALT greater 
than the ULN range at baseline (defined as the last ALT value collected prior to first dose of 
study drug) will be included in the analysis of ALT normalization.
The Pediatric Quality of Life (PedsQL™ SF 15) Questionnaires will be completed by all subjects 
and their parent/legal guardian up to 24-Week Posttreatment visits. The transformed scale scores 
(0 to 100 scale) at baseline, EOT, or at Early Termination, if applicable, 12-Week Post-
Treatment, and 24-Week Post-Treatment visits and change from baseline, change from EOT to 
posttreatment will be presented for each of the 4 domains of the SF-15 (physical functioning, 
emotional functioning, social functioning, and school functioning), the psychosocial health 
summary (emotional, social, and school functioning domains), and the Total Score.
Neuropsychiatric assessment will be based on the psychosocial health summary and domains.
Scoring of the SF15 scales will be performed as described in Scaling and Scoring of the Pediatric 
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be used to explore changes in status from baseline to EOT, or at Early Tenn ination, if applicable, 
and from EOT to each of the posttreatment time points. Results (p values) will be presented but 
should be interpreted with caution as multiple endpoints are being tested, and the study has not 
been powered to test these endpoints. Plot of the mean ± SD of change from baseline in SF 15 
summary scores will be presented. 
Drug resistant substitutions will be analyzed as part of the Virology Study Report. 
6.3. 
Exploratory Efficacy Endpoints 
I 
6.4. 
Changes From Protocol-Specified Efficacy Analyses 
There are no changes from protocol-specified efficacy analyses. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA). System organ class (SOC), high-level group term (HLGT), 
high-level term (HLT), preferred term (PT), and lower-level term (LLT) will be provided in the 
AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria 
specified in the protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings and the most 
severe will be considered (for sorting purpose only) in data presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE eCRF to the 
question of “Related to Study Treatment”. Events for which the investigator did not record 
relationships to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing from that captured on the 
CRF.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE specified in the study protocol. Serious adverse events captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead Pharmacovigilance and 
Epidemiology Department before database finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment Emergent
Treatment-emergent adverse events (TEAEs) are defined as one or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.

Any AEs leading to premature discontinuation of study drug.


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


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Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and then by PT in order of descending
incidence overall within each SOC. In summaries by severity grade, the most severe grade will 
be used for those AEs that occurred more than once in an individual subject during the study. 
In addition to the above summary tables, TEAEs will be summarized by PT only, in order of 
descending incidence for:

AEs that occurred in at least 5% of subjects within any age group

AEs of Grade 3 or above

All treatment-related AEs

All SAEs

AEs leading to premature discontinuation of SOF/VEL

AEs leading to interruption of SOF/VEL
In addition to the summaries described above, data listings will be provided for the following:

All AEs (with a variable indicating whether the event is treatment emergent)

AEs of Grade 3 or above

SAEs

Deaths

AEs leading to premature discontinuation of SOF/VEL

AEs leading to interruption of SOF/VEL
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days
for subjects who have permanently discontinued study drug. The analysis will be based on values 
reported in conventional units. When values are below the limit of quantitation, they will be 
listed as such, and the closest imputed value will be used for the purpose of calculating summary 
statistics. For example, if “< 0.2” was recorded, a value of 0.1 will be used for the purpose of 
calculating summary statistics; if “< 0.1” was recorded, a value of 0.09 will be used for the 
purpose of calculating summary statistics.


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A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
flagged in the data listings, as appropriate.
No inferential statistics will be generated.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
by age group for ALT, aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, 
hemoglobin, reticulocytes, white blood cell (WBC), neutrophils, lymphocytes, platelets, and 
international normalized ratio (INR) as follows:

Baseline values

Values at each postbaseline analysis window

Change from baseline at each postbaseline analysis window
A baseline laboratory value will be defined as the final assessment performed on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
will be displayed to the reported number of digits; SD to the reported number of digits plus 1.
Median (Q1, Q3) of the observed values for these laboratory parameters will be plotted using a 
line plot by visit. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3 (Selection of Data in the Event of Multiple Records in a Window). 
The number of subjects with hemoglobin < 10 g/dL and < 8.5 g/dL at any postbaseline visits 
(up to 30 days after the last dose of any study drug) will be summarized.
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used for assigning toxicity grades to laboratory results for analysis as Grade 0, Grade 1, Grade 2, 
Grade 3, or Grade 4. Grade 0 includes all values that do not meet the criteria for an abnormality 
of at least Grade 1. Some laboratory tests have criteria for both increased and decreased levels; 
analyses for each direction (ie, increased, decreased) will be presented separately. 


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7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of 
last dose of study drug plus 30 days for subjects who permanently discontinued study drug. If the 
relevant baseline laboratory value is missing, then any abnormality of at least Grade 1 will be 
considered treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by analyte in each age group; subjects will be categorized 
according to the most severe postbaseline abnormality grade for a given analyte:

Graded laboratory abnormalities

Grade 3 or above laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dose for the laboratory parameter of 
interest.
A by-subject listing of treatment-emergent Grade 3 or above laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the analyte of interest, with all applicable 
severity grades or abnormal flags displayed.
For subjects with at least one event of treatment-emergent Grade 3 or above laboratory 
abnormality of creatine kinase (CK) or lipase, a listing of AEs will be provided.
7.2.2.3.
On-Treatment Liver-Related Laboratory Events
The following liver-related laboratory events will be summarized for each age group using data 
from all the on-treatment postbaseline visits (up to 3 days after the last dose of any study drug):

AST or ALT > 3 × ULN and total bilirubin > 2 × ULN

ALT > 5 × ULN

Total bilirubin > 2 × ULN


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


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7.5.
Mid-Parental Height Assessment
The calculation of mid-parental height has been a standard procedure for assessing individual 
child’s future adult height since it was first described by Tanner {Tanner 1970}. Mid-parental 
height will be calculated as the average of father's and mother's height. For boys, the 
sex-adjusted mid-parental height will be calculated by adding 2.5 inch or 6.5 cm from the mean 
of the parents' heights. For girls, will be calculated by subtracting 2.5 inch or 6.5 cm from the 
mean of the parents' heights. If any one of parents’ heights is missing, the calculation will be 
excluded.
A by-subject listing of parents’ heights and derived mid-parental height will be provided by 
subject ID number in ascending order.
7.6.
Bone Age Assessment
Bone age at baseline visit, FU-24 visit and change from baseline visit will be summarized for the 
Safety Analysis Set in each age group using descriptive statistics (n, mean, SD, median, Q1, Q3, 
minimum, and maximum). 
A by-subject listing of bone age will be provided by subject ID number in ascending order and 
visit in chronological order.
7.7.
Tanner Pubertal Stage Assessment
The Tanner stages will be used to evaluate the onset and progression of pubertal changes. 
Females will be rated for pubic hair growth and breast development, and males will be rated for 
pubic hair growth and genitalia development. If the subject is at a Tanner 5 at Day 1, no further 
Tanner Pubertal Stage Assessments are to be completed. The Tanner stages (Pubic Hair and 
Breasts for female; Pubic Hair and Genitalia for male) at EOT, FU-12 and FU-24 visit will be 
summarized by baseline Tanner stages using frequency count and percentage by sex for each age 
group.
Tanner stage results at baseline and during the study will be listed.
7.8.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version
of the World Health Organization (WHO) Drug dictionary. The medications will be categorized 
as prior or concomitant using the following definitions:

Prior medications: any medications taken and stopped prior to or on the date of first study 
drug administration

Concomitant medications: any medications taken after the date of first study drug 
administration and up to the last dosing date of study drug


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Concomitant medications will be summarized by preferred name using the number and 
percentage of subjects for the Safety Analysis Set in each age group. A subject reporting the 
same medication more than once will be counted only once when calculating the number and 
percentage of subjects who received that medication. The summary of concomitant medications 
will be ordered by preferred term in descending frequency. For drugs with the same frequency, 
sorting will be done alphabetically.
Summaries will be based on the Safety Analysis Set. No inferential statistics will be generated. 
For purposes of analysis, any medication with a stop date that is on or prior to the initial study 
drug dosing date or a start date that is after the last study drug dosing date will be excluded from 
a concomitant medication summary. If a partial stop date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) prior to the initial 
study drug dosing date will be excluded from the concomitant medication summary. If a partial 
start date is entered, then any medication with the month and year (if day is missing) or year 
(if day and month are missing) after the study drug stop date will be excluded from the 
concomitant medication summary. Medications with completely missing dates will be included 
in the concomitant medication summary.
A summary of prior medications will not be provided.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.9.
Swallowability Assessment for SOF/VEL FDC Placebo Tablets
For subjects in the 12 to <18 and 6 to <12 years of age groups, swallowability of SOF/VEL FDC 
placebo tablets will be summarized using the numbers and percentages of subjects in each 
swallowability category (ie, Able to Swallow, Unable to Swallow). 
A by-subject listing of Swallowability of SOF/VEL FDC placebo tablets will be provided by 
subject ID number in ascending order.
7.10.
Acceptability and Palatability of SOF/VEL FDC
A questionnaire will be administered to subjects to assess acceptability and palatability of the 
formulation they received on Day 1, Week 12 and Early Termination (as applicable). If the 
subject is unable to complete the questionnaires, the parent/legal guardian will assist to complete 
the questionnaire on their behalf. The subject’s parent/legal guardian will also complete a 
questionnaire on Week 12 or Early Termination (as applicable) for their assessment of 
acceptability of the formulation the subject received.


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Acceptability and palatability will be assessed by numeric response marked on line between 
numbers 0-100 (higher scores indicate better acceptability and/or palatability) in response to 
questions about how the study drug tasted, how easy it was to swallow the study drug, and, for 
those who received that tablet formulation, how they felt about the number of tablets they had to 
swallow.
Responses to the acceptability and palatability questionnaire by subjects and their parent/legal 
guardian at Day 1, Week 12 and Early Termination (as applicable) will be respectively 
summarized by formulation (ie, SOF/VEL FDC400/100 mg adult tablet, 200/50 mg low dose 
tablets and oral granules) and by dose (SOF/VEL 400/100 mg tablet, SOF/VEL 200/50 mg, 
SOF/VEL 150/37.5 mg) for each age group using the numbers and percentages of subjects in the 
following categories, as applicable:

Did not taste the study drug (for question regarding study drug taste only)

Score marked > 60 to 100

Score marked 40 to 60

Score marked 0 to < 40
A by-subject listing of acceptability and palatability of SOF/VEL FDC will be provided by 
subject ID number in ascending order.
7.11.
Other Safety Measures
Neuropsychiatric assessment will be based on the psychosocial health summary and domains of 
the PedsQL™ SF 15.
A data listing will be provided for subjects who become pregnant during the study.
7.12.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.
1l1111lu1.1l.,11 
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8.
PHARMACOKINETIC ANALYSES
8.1.
PK Analysis in the PK Lead-in Phase (Intensive PK Analysis)
Intensive PK Analysis will be performed using the Lead-in Phase PK Analysis Set.
Concentrations of SOF, GS-331007, GS-566500 and VEL from subjects in the PK lead-in Phase 
over sampling time will be listed and summarized for each age cohort using descriptive statistics 
(n, arithmetic mean, geometric mean and its 95% confidence interval, coefficient of variation 
[%CV], SD, median, Q1, Q3, minimum, and maximum) by nominal time. For Cohort 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, 6, 8, and 12 hours postdose. For Cohort 3, 
plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 
1, 2, 3, 4, 8, and 12 hours postdose. PK parameters from subjects in the PK lead-in Phase for 
each age cohort will be summarized (e.g; AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau, T1/2, 
volume of distribution and clearance [CL/F], as appropriate).
SOF, GS-331007 and VEL exposures (AUCtau, Cmax, and Ctau, if applicable) in each age cohort 
will be compared with SOF/VEL adult populations. The primary endpoint of this analysis will be 
evaluated by carrying out an analysis of variance (ANOVA) for log-transformed SOF, 
GS-331007 and VEL AUCtau. The secondary endpoints of this analysis will be the Cmax of SOF, 
VEL and GS-331007 and Ctau of VEL. The 90% confidence intervals will be constructed for the 
ratio of geometric means of each PK parameters.
8.2.
Population PK Analysis
Population PK modeling will be applied on the combined data from both PK samples collected 
in PK Lead-in Phase and PK samples collected in the Treatment Phase to characterize the PK of 
SOF, GS-331007 and VEL using mixed-effect modeling techniques. Estimated PK parameters 
using the population PK model will be presented in a separate Population PK report.


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


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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


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


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Appendix 1.
Study Procedures Table
Appendix Table 1.
PK Lead-in Phase: Screening and On-Treatment Study Visits
Screening
(-28 days)
On-treatment
Day 1i
Day 3
Telephone call
Day 7
(+ 3 days)
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Parental Height
Xa
Xa
Complete Physical Examination
X
X
Symptom-directed Physical Examination
X
Tanner Pubertal Stage Assessmentb
X
Vital Signsc
X
X
X
Body Weight and Heightd
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
Transient Elastography, if available 
Xe
Xe
Pregnancy Prevention Counselingf
X
SOF/VEL Swallowability Assessment
Xg
Xg
SOF/VEL Acceptability Questionnaires
X
Quality of Life Survey
Xh
Review of Study Medication Compliance
X
Study Drug Dispensingi
X
Subject Dosing Diaryj
X
X
X
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
HbA1c, Fibrotest®, APRI
X
TSH 
X
Alpha-1 anti-trypsin
X


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Screening
(-28 days)
On-treatment
Day 1i
Day 3
Telephone call
Day 7
(+ 3 days)
HIV testing, HCV antibody, HBsAg, 
HBsAb, HBcAb, and HAV antibody
X
HBV DNAk
X
HCV RNA
X
X
X
HCV Genotyping
X
Viral Sequencingl
X
X
Serum or Urine Pregnancy Testingm
X
X
X
IL28B Genotyping
X
Urinalysis
X
X
X
Urine Drug Screen
X
Intensive PK
Xo
a
Biological parental height, if not collected at Day 1.
b
If the assessment determines that the subject is at a Tanner 5 at Day 1, no further Tanner Pubertal Stage Assessments are to be completed.
c
Vital signs include blood pressure, pulse, respiratory rate and temperature.
d
Height should be without shoes and should be collected by the same personnel, if possible.
e
May be performed at Screening up to Day 1.
f
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years old and subjects < 12 years old at the discretion of the investigator based on subject’s 
pubertal status).
g
Swallowability can occur at Day 1 if not completed during screening.
h
Quality of life survey will be completed by all subjects and their parent/legal guardian. Subject and parent/legal guardian is to review questionnaire and write/mark answers 
directly onto the questionnaire.
i
Day 1 assessments must be performed prior to dosing. The IWRS system will provide direction on the specifics of each subject’s study drug dispensing.
j
.
k
HBV DNA testing done only when subjects are HBcAb positive at Screening.
l
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies.
m
Females of childbearing potential only. Serum pregnancy test performed at screening and for confirmation of positive urine pregnancy test.
n
For subjects who provide consent, a blood sample should be drawn at the Day 1 visit. If not obtained at this visit, the sample may be drawn at any time during the study.
o
Cohorts 1 and 2, plasma samples will be collected for PK analyses following dosing of study drug on Day 7 at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 6, 8, and 
12 hours postdose. Cohort 3, plasma samples for PK analyses will be collected at the following time points: 0 (predose), 0.5, 1, 2, 3, 4, 8, and 12 hours postdose. Subjects 
should come in a fasted state for the Week 4 or Week 8 intensive PK visit (i.e., no food or drink except water at least 8 hours prior to the Week 4 or Week 8 intensive PK 
visit). Subjects and/or parents/legal guardians should also be instructed that the Week 4 or Week 8 dose of SOF/VEL FDC must not be taken prior to the visit and until the 
evaluations listed below are completed.
CCI
CCI


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Appendix Table 2.
Treatment Phase: Screening and On-Treatment Study Visits
Screeningj,k
(-28 days)
Day 1k
Week 1k
Week 4
Week 8
Week 12
Early Termination
Clinical Assessments
Informed Consent / Assent
X
Determine Eligibility
X
X
Medical History
X
Parental Height
Xa
Xa
Complete Physical Examination
X
X
X
X
Symptom-Directed Physical Examination
X
X
X
Tanner Pubertal Stage Assessmentb
X
X
X
Vital Signsc
X
X
X
X
X
X
X
Body Weight and Heightd
X
X
X
X
X
X
X
Bone Age Assessment
X
AEs and Concomitant Medications
X
X
X
X
X
X
X
Transient Elastography, (if available)
Xe
Xe
Pregnancy Prevention Counselingf
X
X
X
SOF/VEL Swallowability Assessment 
Xg
Xg
SOF/VEL Acceptability Questionnaireh
X
X
X
Quality of Life Surveyi
X
X
X
Review of Study Medication Compliance
X
X
X
X
Study Drug Dispensingj
X
X
X
Subject Dosing Diaryl
X
X
X
X
X
Laboratory Assessments
Hematology, Chemistry, Coagulation
X
X
X
X
X
X
X
HbA1c, Fibrotest®, APRI
X
TSH
X
X
X
Alpha-1 anti-trypsin
X
HIV testing, HCV Antibody, HBsAg, HBsAb, 
HBcAb, HAV Antibody
X
HBV DNAm
X
X
X
X
X
HCV RNA
X
X
X
X
X
X
X
HCV Genotyping
X


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iral Seq encin 
Serum or Urine Pregnancy Testing
0 
a 
Biological parental height, if not collected at Day I. 
Screeningi,k 
-28 days 
X 
Day Jk 
Week Jk 
X 
Week 4 
Week8 
Week 12 
X 
X 
X 
b 
If the assessment detem1ines that the subject is at a Tanner 5 at Day I, no further Tanner Pubertal Stage Assessments are to be completed. 
c 
Vital signs include blood pressure, pulse, respiratory rate, and temperature. 
d 
Height should be without shoes and should be collected by the same personnel, if possible. 
e 
May be perfom1ed at Screening up to Day I. 
Version 1.0 
Early Termination 
X 
f 
Including partner pregnancy prevention for male participants (all subjects 2:: 12 years old and subjects < 12 years old at the discretion of the investigator based on subject's 
pubertal status). 
g 
Swallowability can occur at Day I if not completed during screening. 
h 
A questionnaire will be administered to subjects to assess acceptability and palatability of the fomrnlation they received on Day I, Week 12, and Early Tem1ination 
(as applicable). If the subject is unable to complete the questionnaires, the parent/legal guardian will complete the questionnaire on their behalf. The subjects' parent/legal 
guardian will also complete a questionnaire on Week 12 or Early Tem1ination (as applicable) for their assessment of acceptability of the fomrnlation the subject received. 
Quality of life survey will be completed by all subjects and their parent/legal guardian. Subject and parent/legal guardian is to review questionnaire and write/mark answers 
directly onto the questionnaire. 
j 
Day I assessments must be perfomied prior to dosing. The IWRS system will provide direction on the specifics of each subject's study dmg dispensing. 
k 
Sub·ects rolling over from PK Lead in will not be re uired to re eat screenin , Da I or Week I visits in the Treatment Phase. 
I 
m 
HBV DNA testmg done only when subjects are HBcAb pos111ve at Screenmg. 
n 
Plasma samples will be collected and stored for potential I-ICY sequencing and other virology studies. 
o 
Females of childbearing potential only. Semm pregnancy test perfomied at screening and for confim1ation of positive urine pregnancy test. 
p 
For sub·ects who rovide consent a blood sam le should be drawn at the Da I visit. If not obtained at this visit the sam le ma be drawn at an 
q 
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Appendix Table 3.
Treatment Phase: Post Treatment Visits Following Primary Study
4 Weeks Posttreatment
12 Weeks Posttreatment
24 Weeks Posttreatment
Clinical Assessments
Vital Signs
X
X
X
Body Weight and Heighta
X
X
X
Symptom-directed Physical Exam
X
X
X
AEs
X
Xb
Xb
Concomitant Medications
X
Quality of Life Surveyc
X
X
Tanner Pubertal Stage Assessmentd
X
X
Bone Age Assessment
X
Pregnancy Prevention Counselinge
X
Laboratory Assessments
Hematology, Chemistry
X
HCV RNA
X
X
X
Viral Sequencingf
X
X
X
Urine Pregnancy Testg
X
HBV DNAh
X
X
X
a
Height should be without shoes and should be collected by the same personnel, if possible.
b
At Posttreatment Week 12 and 24, only SAEs will be captured.
c
Quality of life survey will be completed by all subjects and their parent/legal guardian at 12 Week and 24 Week Posttreatment visits. Subject and parent/legal guardian is to 
review questionnaire and write/mark answers directly onto the questionnaire.
d
If the assessment determines that the subject is at a Tanner 5 at Day 1, no further Tanner Pubertal Stage Assessments are to be completed.
e
Including partner pregnancy prevention for male participants (all subjects ≥ 12 years old and subjects < 12 years old at the discretion of the investigator based on subject’s 
pubertal status).
f
Plasma samples will be collected and stored for potential HCV sequencing and other virology studies.
g
Females of childbearing potential only.
h
HBV DNA testing done only when subjects are HBcAb positive at screening.


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


Sofosbuvir/Velpatasvir
GS-US-342-1143
Statistical Analysis Plan - Final Analysis
Version 1.0
CONFIDENTIAL
Page 48
20 April 2020
Appendix 3.
PedsQL™Score Calculation Algorithms
The Parent Report for Toddlers (ages 2-4) and the Child & Parent Reports for Young 
Children (ages 5-7), Children (ages 8-12) and Teens (ages 13-18) of the PedsQL™ 4.0 SF15 
Generic Core Scales are composed of 15 items comprising 4 dimensions.
DESCRIPTION OF THE SF15 QUESTIONNAIRE:
Dimensions
Number of 
Items
Cluster of Items
Reversed Scoring
Direction of Dimensions
Physical Functioning
5
1-5
1-5
Higher scores indicate 
better HRQOL
Emotional Functioning
4
1-4
1-4
Social Functioning
3
1-3
1-3
School Functioning
3
1-3
1-3
SCORING OF DIMENSIONS:
Item Scaling
5-point Likert scale from 0 (Never) to 4 (Almost always)
3-point scales: 0 (Not at all), 2 (Sometimes) and 4 (A lot) for the Young Child 
self-report
Weighting of Items
No
Extension of the Scoring 
Scale
Scores are transformed on a scale from 0 to 100
Scoring Procedure
Step 1: Transform Score
Items are reversed scored and linearly transformed to a 0-100 scale as follows:
0=100, 1=75, 2=50, 3=25, 4=0.
Step 2: Calculate Scores
Score by Dimensions:

If more than 50% of the items in the scale are missing, the scale scores should 
not be computed,

Mean score = Sum of the items over the number of items answered.
Psychosocial Health Summary Score = Sum of the items over the number of items 
answered in the Emotional, Social, and School Functioning Scales.
Physical Health Summary Score = Physical Functioning Scale Score
Total Score: Sum of all the items over the number of items answered on all the 
Scales.
Interpretation and 
Analysis of Missing Data
If more than 50% of the items in the scale are missing, the Scale Scores should not 
be computed.


SAP GS-US-342-1143_Final_Analysis
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Kathryn Kersey
Clinical Research eSigned
23-Apr-2020
15:54:22
Lijie Zhong
Biostatistics eSigned
23-Apr-2020
16:37:19