Conditions: Hepatitis C Virus Infection
Keywords: HCV genotype 1 or 4 (GT-1 or GT-4) Direct Acting Antiviral Combination Therapy Hepatitis C, Chronic Liver Diseases Virus Diseases
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
The primary objectives of this study are to evaluate the efficacy, safety, and tolerability of ledipasvir/sofosbuvir (LDV/SOF) in treating hepatitis C virus (HCV) infection in pediatric participants who are undergoing cancer chemotherapy.

Detailed description:

Arms:
arm 1: Participants will receive LDV/SOF 90/400 mg fixed dose combination (FDC) (1x 90/400 mg tablet or 4 x 22.5/100 mg tablets based on swallowability assessment during screening) for 12 weeks.

Interventions: intervention 1: LDV/SOF
Intervention descriptions: intervention 1: Tablet(s) administered orally once daily

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2, Open-label Study to Investigate the Efficacy and Safety of 
Ledipasvir/Sofosbuvir Fixed Dose Combination in the Treatment of 
Hepatitis C Virus (HCV) Infection in Pediatric Subjects Undergoing 
Cancer Chemotherapy
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA USA
Indication:
Hepatitis C virus infection
Protocol ID:
GS-US-337-1904
Gilead Study 
Director/Medical 
Monitor:
Name:
Telephone:
Fax:
Protocol Version/Date:
Original:
06 October 2015
Amendment 1:
16 June 2017
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS......................................................................9
1.
INTRODUCTION ..............................................................................................................................................12
1.1.
Background ............................................................................................................................................12
1.2.
Ledipasvir/Sofosbuvir Fixed-dose combination (LDV/SOF FDC)........................................................13
1.2.1.
Additional Clinical Trial of LDV/SOF in Pediatric Patients with Chronic 
HCV Infection......................................................................................................................13
1.3.
Rationale for Study GS-US-337-1904 ...................................................................................................14
1.4.
Risk/Benefit Assessment for the Study GS-US-337-1904.....................................................................15
1.5.
Compliance ............................................................................................................................................15
2.
OBJECTIVES.....................................................................................................................................................16
3.
STUDY DESIGN................................................................................................................................................17
3.1.
Endpoints ...............................................................................................................................................17
3.2.
Study Design..........................................................................................................................................17
3.3.
Study Treatments ...................................................................................................................................17
3.4.
Duration of Treatment............................................................................................................................17
3.5.
HCV Virologic Response-Based Treatment Stopping Criteria..............................................................17
3.6.
Discontinuation Criteria.........................................................................................................................18
3.7.
Reconsent...............................................................................................................................................18
4.
SUBJECT POPULATION..................................................................................................................................19
4.1.
Number of Subjects and Subject Selection ............................................................................................19
4.2.
Inclusion Criteria....................................................................................................................................19
4.3.
Exclusion Criteria...................................................................................................................................20
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................21
5.1.
Description and Handling of LDV/SOF FDC........................................................................................21
5.1.1.
Formulation..........................................................................................................................21
5.1.2.
Packaging and Labeling .......................................................................................................21
5.1.3.
Storage and Handling...........................................................................................................22
5.2.
Dosage and Administration of LDV/SOF FDC .....................................................................................23
5.3.
Prior and Concomitant Medications.......................................................................................................23
5.3.1.
Allowed Maintenance Chemotherapy Medications..............................................................24
5.4.
Accountability for LDV/SOF FDC ........................................................................................................25
5.4.1.
Investigational Medicinal Product Return or Disposal.........................................................25
6.
STUDY PROCEDURES ....................................................................................................................................26
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................26
6.1.1.
Screening Visit .....................................................................................................................26
6.1.2.
Baseline Assessments...........................................................................................................27
6.2.
Treatment Assessments (± 3 days).........................................................................................................28
6.3.
Post-treatment Assessments (5 days)..................................................................................................29
6.4.
Unscheduled Visit ..................................................................................................................................29
6.5.
Assessments for Premature Discontinuation from Treatment and From the Study................................30
6.6.
End of Study...........................................................................................................................................30


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6.7.
Procedures and Specifications................................................................................................................30
6.7.1.
Clinical Laboratory Analytes ...............................................................................................30
6.7.2.
Medical History....................................................................................................................31
6.7.3.
Physical Examination...........................................................................................................31
6.7.4.
Vital Signs............................................................................................................................31
6.7.5.
Creatinine Clearance ............................................................................................................31
32
.32
6.7.8.
Pregnancy Testing................................................................................................................32
6.7.9.
Swallowability Assessment..................................................................................................32
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................33
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................33
7.1.1.
Adverse Events.....................................................................................................................33
7.1.2.
Serious Adverse Events........................................................................................................33
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................34
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................34
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................34
7.2.2.
Assessment of Severity ........................................................................................................35
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................35
7.3.1.
Requirements for collection prior to study drug initiation ...................................................35
7.3.2.
Adverse Events.....................................................................................................................35
7.3.3.
Serious Adverse Events........................................................................................................35
7.3.4.
Electronic Serious Adverse Event (eSAE) Reporting Process .............................................36
7.4.
Gilead Reporting Requirements.............................................................................................................37
7.5.
Toxicity Management ............................................................................................................................37
7.5.1.
Subject Stopping Rules ........................................................................................................37
7.6.
Special Situations Reports......................................................................................................................38
7.6.1.
Definitions of Special Situations..........................................................................................38
7.6.2.
Instructions for Reporting Special Situations.......................................................................38
8.
STATISTICAL CONSIDERATIONS................................................................................................................40
8.1.
Analysis Objectives and Endpoints........................................................................................................40
8.1.1.
Analysis Objectives..............................................................................................................40
8.1.2.
Primary Endpoint .................................................................................................................40
8.1.3.
Secondary Endpoint .............................................................................................................41
8.1.4.
Safety Endpoints ..................................................................................................................41
8.1.5.
Other Endpoints of Interest ..................................................................................................41
8.2.
Analysis Conventions.............................................................................................................................41
8.2.1.
Analysis Sets ........................................................................................................................41
8.3.
Data Handling Conventions ...................................................................................................................42
8.4.
Demographic Data and Baseline Characteristics ...................................................................................43
8.5.
Efficacy Analysis ...................................................................................................................................43
8.5.1.
Primary Analysis..................................................................................................................43
8.5.2.
Secondary Analyses .............................................................................................................43
8.6.
Safety Analysis.......................................................................................................................................44
8.6.1.
Extent of Exposure...............................................................................................................44
8.6.2.
Adverse Events.....................................................................................................................44
8.6.3.
Laboratory Evaluations ........................................................................................................45
8.6.4.
Other Safety Evaluations......................................................................................................45
8.7.
Sample Size............................................................................................................................................45
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9.
RESPONSIBILITIES..........................................................................................................................................46
9.1.
Investigator Responsibilities ..................................................................................................................46
9.1.1.
Good Clinical Practice..........................................................................................................46
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................46
9.1.3.
Informed Consent.................................................................................................................46
9.1.4.
Confidentiality......................................................................................................................47
9.1.5.
Study Files and Retention of Records ..................................................................................47
9.1.6.
Case Report Forms...............................................................................................................48
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................49
9.1.8.
Inspections............................................................................................................................49
9.1.9.
Protocol Compliance............................................................................................................49
9.2.
Sponsor Responsibilities ........................................................................................................................50
9.2.1.
Protocol Modifications.........................................................................................................50
9.2.2.
Study Report and Publications .............................................................................................50
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................50
9.3.1.
Payment Reporting...............................................................................................................50
9.3.2.
Access to Information for Monitoring..................................................................................51
9.3.3.
Access to Information for Auditing or Inspections ..............................................................51
9.3.4.
Study Discontinuation..........................................................................................................51
10.
REFERENCES ...................................................................................................................................................52
11.
APPENDICES ....................................................................................................................................................54
Appendix 1.
Investigator Signature Page....................................................................................................55
Appendix 2.
Study Procedures....................................................................................................................56
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............59
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................83
LIST OF IN-TEXT TABLES
Table 1-1.
Steady-state PK and Statistical Comparisons of LDV, SOF and GS-331007 PK in 
Adolescent Subjects (GS-US-337-1116; PK Lead-in) and Adult Subjects (Phase 2/3 
Population PK Analysis) ........................................................................................................14
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................24


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title: 
A Phase 2, Open-label Study to Investigate the Efficacy and Safety of 
Ledipasvir/Sofosbuvir Fixed Dose Combination in the Treatment of 
Hepatitis C Virus (HCV) Infection in Pediatric Subjects Undergoing 
Cancer Chemotherapy
Study Centers 
Planned:
Single center in Egypt
Objectives:
The primary objectives of this study are as follows:

To evaluate the efficacy of ledipasvir/sofosbuvir (LDV/SOF) in 
treating HCV infection in pediatric subjects who are undergoing 
cancer chemotherapy, as measured by the proportion who achieve 
a sustained virologic response 12 weeks after the end of HCV 
treatment (SVR12)

To evaluate the safety and tolerability of treatment with 
LDV/SOF for 12 weeks
The secondary objectives of this study are as follows: 

To determine the proportion of subjects who attain SVR at 4 and 
24 weeks after cessation of HCV treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during 
treatment and after cessation of HCV treatment
The exploratory objectives of this study are:
 
 
 
 
 
 
 
 
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Study Design:
Single-center, open-label study. Approximately 40 treatment naïve or 
experienced pediatric subjects with chronic HCV who are receiving a 
maintenance cancer chemotherapy regimen will be enrolled. 
All subjects will receive LDV/SOF FDC once daily for 12 weeks.
Number of Subjects 
Planned:
Approximately 40 pediatric subjects
Duration of 
Treatment:
LDV/SOF FDC daily for 12 weeks
Diagnosis and Main 
Eligibility Criteria:
Male and female treatment naïve or experienced children aged 12 to 
<18 years, with genotype 1 or 4 HCV infection, and are on a 
maintenance cancer chemotherapy regimen
Refer to Section 4.2 and 4.3 for detailed Inclusion and Exclusion 
Criteria
Study Procedures/
Frequency:
Screening assessments will be completed within 28 days of the 
Baseline/Day 1 visit. 
All subjects will complete the following study visits: Screening, 
Baseline/Day 1, on-treatment visits at the end of Weeks 1, 4, 8, and 
12. All subjects will complete the post treatment Weeks 4, 12 and 24
visits. 
Screening assessments will include physical examination, medical 
history, body height and weight, vital signs, adverse events related to 
screening procedures, concomitant medications, safety laboratory 
tests (including hematology, chemistry, and coagulation), HCV RNA, 
HCV genotype, serology (HIV antibody, HAV antibody, HCV 
antibody, hepatitis B surface antigen [HBsAg], hepatitis B surface 
antibody [HBsAb], hepatitis B core antibody [HBcAb]), assessment 
of the presence or absence of cirrhosis and fibrosis stage, serum β-
hCG (females of child bearing potential only), urinalysis, and 
LDV/SOF swallowability assessment (may be done up until Day 1).
Fibrosis will be assessed via Fibrotest,® APRI, and Fibroscan; liver 
biopsy may be performed if necessary.
Baseline/Day 1 assessments include medical history and host IL28B 
genotyping.  Additional Baseline/Day 1 and on-treatment assessments 
include adverse events (AEs), concomitant medications, study 
medication pill count, physical examination, height, weight, vital 
signs, laboratory tests for safety and fibrosis assessments (by 
Fibrotest at Day 1, Week 12, and ESDD as applicable and APRI at 
Week 12 and ESDD as applicable), HCV RNA, HBV DNA for 
subjects HBcAb positive at Screening, 
 pregnancy 
prevention counseling, and urine pregnancy tests (females of child 
bearing potential only). 
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Post-treatment assessments include AEs, concomitant medications, 
vital signs and physical examination (at 4 weeks post treatment),
safety laboratory tests, HCV RNA, HBV DNA for subjects HBcAb 
positive at Screening, fibrosis assessments (by Fibrotest and 
Fibroscan at 12 and 24 weeks post treatment, by APRI at Post 
Treatment Week 4),
 
 pregnancy prevention counseling (if applicable), and urine 
pregnancy tests (females of child bearing potential only).
 
Test Product, Dose, 
and Mode of 
Administration:
LDV/SOF is manufactured as a FDC tablet, consisting of 90 mg 
LDV and 400 mg SOF, for oral administration. Subjects will take 
1 tablet daily with or without food.
Subjects unable to swallow the LDV/SOF FDC 90 mg/400 mg tablets
and who are able to swallow LDV/SOF 22.5 mg/ 100 mg tablets (as 
determined by LDV/SOF FDC Swallowability Assessment at 
Screening or at any time up until Day 1) will be assigned to 4
LDV/SOF FDC 22.5 mg/ 100 mg tablets once daily with or without 
food.
Placebo tablets to match LDV/SOF FDC 90 mg/400 mg tablets and 
placebo tablets to match LDV/SOF 22.5 mg/ 100 mg tablets will be 
used for swallowability assessment.
Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for 
Evaluation:
Safety:
AEs and laboratory tests will be collected throughout the study.
Efficacy:
Efficacy will be evaluated using scheduled assessments of HCV 
RNA.
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Statistical Methods:
The primary efficacy endpoint for the study is SVR12 in all enrolled 
and treated subjects. A point estimate with a 2-sided 95% exact 
confidence interval using the binomial distribution (Clopper-Pearson 
method) will be constructed for the SVR12 rate. No hypothesis 
testing will be performed.
Secondary efficacy endpoints include:

SVR4 and SVR24

HCV viral kinetics
Exploratory endpoints include:
 
 
 
 
All continuous endpoints will be summarized using an 8-number
summary (n, mean, standard deviation [SD], median, 1st quartile [Q1], 
3rd quartile [Q3], minimum, maximum). All categorical endpoints 
will be summarized by the number and percentage of subjects who 
meet the endpoint definition.
Safety endpoints will be analyzed by the number and percent of 
subjects with events or abnormalities for categorical values or 
8-number summary (n, mean, SD, median, Q1, Q3, minimum, 
maximum) for continuous data.
With a sample size of 40 subjects, a 2-sided 95% exact confidence 
interval will extend at most 26.6% in length.
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
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APRI
AST platelet ratio index
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval 
(tau)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
CI
Observed drug concentration at the end of the dosing interval (tau)
confidence interval
CLcr
creatinine clearance
COPD
chronic obstructive pulmonary disease
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CSR
clinical study report
DAA
direct acting antiviral
dL
Deciliter
DNA
deoxyribonucleic acid
DMC
data monitoring committee
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
electronic case report form(s)
EDC
electronic data capture
ESA
erythropoiesis stimulating agent
Emax
maximal effect
EOT
End of Treatment
ESDD
Early Study Drug Discontinuation
EU
European Union
FAS
full analysis set


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FDA
(United States) Food and Drug Administration
FDC
Fixed-dose combination
GCP
Good Clinical Practice (Guidelines)
GCSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
HAV
genotype (viral)
Hepatitis A Virus
Hb
Hemoglobin
HBsAb
hepatitis B surface antibody
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
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
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IFN
interferon 
IL28B
IL28B gene
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
INR
International Normalized Ratio of prothrombin time
IRB
Institutional Review Board
IUD
intrauterine device
IV
Intravenous
IWRS
interactive web response system
Kg
Kilogram
kPa
Kilopascal
L
Liter
LDH
lactate dehydrogenase
LDL
low density lipoprotein
LDV
Ledipasvir
LLN
lower limit of the normal range
LOD
lower limit of detection
LLOQ
lower limit of quantification


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LLT
lower-level term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NIAID
National Institute of Allergy and Infectious Disease
NS (3/4A/5A/5B)
[HCV] non-structural protein
PCR
polymerase chain reaction
PEG
pegylated interferon
PHAC
Public Health Agency of Canada
PI
protease inhibitor
PK
Pharmacokinetic
PTT
Partial thromboplastin time
QD
once daily 
QTcF
QT interval corrected using Fridericia’ formula
RBC
red blood cell count 
RBV
Ribavirin
RDRP
RNA-dependent RNA polymerase
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
serious adverse drug reaction
SAE
serious adverse event
SD
standard deviation
SOC
standard of care
SOF
sofosbuvir (GS-7977; formerly PSI-7977)
SOP
standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
sustained virologic response
TND
target not detected
TPO
Thrombopoietin
ULN
upper limit of the normal range
US
United States
vRVR
very rapid virologic response 
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}. In Egypt, it is 
estimated that approximately 15% of the population has been infected with chronic hepatitis C, 
with genotype 4 accounting for approximately 90% of the infections and genotype 1 for the 
remainder {Nakano 2012}, {Ray 2000}. The proportion of children in Egypt with HCV 
antibodies was found to be 4% in those aged 15 to 19 years in a 2008 national population survey 
{El-Zanaty 2009} while earlier studies found 3% and 9% of screened subjects who were 19 
years of age or younger had HCV antibodies {El-Raziky 2007}. Reports from other countries
indicate the natural history of chronic HCV in children is relatively benign, but approximately 
4% to 6% 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}.
Chronic hepatitis C is highly prevalent in Egyptian children receiving cancer chemotherapy or 
following allogeneic bone-marrow transplantation. {El-Sayed 2011}, {El-Sayed 2004} In 1 
study, 33 of 100 children with cancer at 2 centers in Egypt were HCV RNA positive. {Sharaf-
Eldeen 2007} The progression of HCV-related liver disease in this population may be rapid and 
may be the main cause of death in Egyptian patients with allogeneic bone marrow transplantation 
{El-Sayed 2004}. Patients also may experience a flare in their HCV while receiving 
immunosuppressive chemotherapy; HCV flare, or “reactivation”, has been defined as an 
increase of ALT to >3x baseline level and/or increase of HCV RNA by 1 log10 IU/mL) {Mahale 
2012}. HCV flares were found to have resulted in interruptions of cancer chemotherapy in 
approximately half of HCV-infected adult patients in a retrospective study by Mahale et al {Hu 
1996}.
Although HCV flares may occur in patients with any tumor type, they are more common in those 
with hematological malignancies {Mahale 2012}; leukemias and lymphomas are among the most 
common childhood cancers {Ibrahim 2014}. The treatment of some of these such as acute 
lymphoblastic leukemia (ALL) and some types of non-Hodgkins lymphoma (NHL) include 
induction, consolidation, and maintenance phases of chemotherapy. The maintenance phase is
less intensive and may continue for 2 – 3 years.
Pediatric treatment of HCV is controversial primarily because the current treatment option 
(pegylated interferon [Peg-IFN] plus ribavirin [RBV]) has relatively low and variable rates of 
success {Wirth 2012}, (SVR24 36-53% with genotype GT1and 55% in GT4 and > 80% in GT2 
or GT3) and is limited by tolerability and severe side effects, including a potential effect on 
growth and development. HCV treatment is further complicated in patients receiving cancer 
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Successful treatment of HCV infection would greatly impact liver disease outcomes and rates of 
liver decompensation and hepatocellular carcinoma in these pediatric patients and may facilitate 
treatment of their cancer.
1.2.
Ledipasvir/Sofosbuvir Fixed-dose combination (LDV/SOF FDC)
Ledipasvir/sofosbuvir fixed-dose combination (LDV/SOF FDC; Harvoni®) combines two HCV 
specific DAA agents into a single tablet for the treatment of chronic HCV infection. Sofosbuvir 
is a nucleotide analog that is a potent and selective inhibitor of NS5B-directed HCV replication, 
irrespective of HCV genotype. Ledipasvir is a novel HCV NS5A inhibitor. LDV/SOF FDC has 
been approved in US, Europe, Japan, and other countries. It is also being evaluated in a study in 
Egypt in adult patients with chronic genotype 4 HCV infection (GS-US-337-1643).
Please refer to the latest version of the Investigator’s Brochure (IB) for additional information on 
the LDV/SOF FDC, and the individual components, including:

In Vitro Anti-Hepatitis C Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.2.1.
Additional Clinical Trial of LDV/SOF in Pediatric Patients with Chronic 
HCV Infection
Study GS-US-337-1116 is an ongoing Phase 2 study being conducted in multiple countries to 
assess the pharmacokinetics, safety and efficacy of LDV/SOF in pediatric subjects with chronic 
HCV infection.  Three cohorts of up to 10 subjects each will be sequentially enrolled in a 
stepwise manner, following review of safety and PK data in the preceding cohort:

Cohort 1: 12 to < 18 years old weighing ≥ 45kg

Cohort 2: 6 to < 12 years old weighing ≥ 17 kg and < 45 kg

Cohort 3: 3 to < 6 years old 
Steady state pharmacokinetics following 7 days of dosing will be assessed in a lead-in group in 
each cohort prior to enrolling subjects in the treatment phase.
Preliminary safety and PK data are available from adolescent subjects (N=10) who enrolled in 
the PK lead-in phase of Cohort 1 and received adult clinical doses of LDV/SOF 90 mg/400 mg. 
Mean exposures of LDV, SOF and GS-331007 in these subjects were comparable to observed 
exposures in the adult subjects in the Phase 2/3 LDV/SOF clinical program; thereby confirming 
the appropriateness of adult dose in the adolescent population (12 to < 18 years of age). Review 


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of safety data supported expansion of enrolment into the treatment phase of Cohort 1 and 
initiation of enrollment in to the PK lead-in group of Cohort 2.
No serious adverse events or treatment discontinuations due to adverse events have been 
reported in the study as of 25 September 2015. 
Table 1-1.
Steady-state PK and Statistical Comparisons of LDV, SOF and 
GS-331007 PK in Adolescent Subjects (GS-US-337-1116; PK Lead-in) 
and Adult Subjects (Phase 2/3 Population PK Analysis)
Mean (%CV)
Adolescents (N=10)
Phase 2/3 (N=2113)
GMR% (90% CI)
LDV
AUCtau (ng*hr/ml)
10200 (50.9)
8530 (60.8)
127 (94.9, 170)
Cmax (ng/ml)
564 (41.2)
364 (51.4)
162 (125, 209)
Ctau (ng/ml)
319 (71.5)
247 (59.2)
128 (95.2, 172)
SOF*
AUCtau (ng*hr/ml)
2180 (26.6)
1380 (34.0)
160 (138, 185)
Cmax (ng/ml)
1140 (57.2)
659 (34.0)
156 (127, 190)
GS-331007
AUCtau (ng*hr/ml)
12700 (13.7)
12500 (29.2)
105 (90.6, 122)
Cmax (ng/ml)
1010 (21.5)
736 (28.2)
139 (120, 161)
Data reported to 3 significant figures; *N=1542
1.3.
Rationale for Study GS-US-337-1904
LDV/SOF FDC is approved for use in HCV-infected adults in Europe, North America and other 
countries and is currently in clinical development for the treatment of chronic HCV infection in 
pediatric patients. The current standard of care for the treatment of children infected with HCV is 
Peg-IFN and RBV and these regimens are long in duration, relatively toxic, not well tolerated, 
and may be contraindicated in patients receiving chemotherapy.  Consequently, there is a need 
for new treatments for HCV that combine potent and sustained efficacy with improved 
tolerability and safety.


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1.4.
Risk/Benefit Assessment for the Study GS-US-337-1904
GS-US-337-1904 is being conducted in Egypt where the prevalence of HCV infection in 
pediatric patients receiving chemotherapy is high. This study will enroll subjects who are 12 to 
<18 years old, a group that is already being studied in another clinical trial and for whom
pharmacokinetic data support use of the planned doses of LDV and SOF (GS-US-337-1116). 
Eligible patients will also be limited to those with hematological malignancies who are receiving 
maintenance chemotherapy, in order to the mitigate side effects associated with more intensive 
chemotherapy regimens used in induction and consolidation phases. 
The combination of LDV plus SOF is anticipated to offer greater antiviral efficacy and avoid the 
adverse events associated with Peg-IFN+RBV. The improved tolerability may also result in 
fewer interruptions to cancer chemotherapy and may impact fibrosis progression in these 
patients. 
If high rates of SVR can be obtained with a short, well-tolerated regimen of LDV/SOF, 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.


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2.
OBJECTIVES
The primary objective of this study is:

To evaluate the efficacy of ledipasvir/sofosbuvir (LDV/SOF) in treating HCV infection in
pediatric subjects who are undergoing cancer chemotherapy, as measured by the proportion 
who achieve a sustained virologic response 12 weeks after the end of HCV treatment 
(SVR12)

To evaluate the safety and tolerability of treatment with LDV/SOF for 12 weeks
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
HCV treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
HCV treatment
The exploratory objectives of this study are:
 
 
 
 
 
 
PPD


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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint of this study is:

SVR12 in all enrolled and treated subjects. No hypothesis testing will be performed.
The secondary endpoints of this study are:

SVR4 and SVR24

HCV viral kinetics
Exploratory endpoints include:
 
3.2.
Study Design
This is a phase 2 single-center open-label study investigating the efficacy and safety of 
LDV/SOF FDC in treating pediatric subjects with chronic HCV who are receiving maintenance 
cancer chemotherapy. 
3.3.
Study Treatments
All subjects will receive LDV/SOF FDC once daily with or without food.  Subjects will peform a 
swallowability assessment (Sections 6.1.1 and 6.7.9) and will be assigned to receive 1 LDV/SOF 
FDC 90 mg/ 400 mg tablet daily or 4 LDV/SOF FDC 22.5 mg/ 100 mg tablets once daily or will 
be excluded from the study based on which tablet size they are able to swallow.
3.4.
Duration of Treatment
Subjects will be treated for a total of 12 weeks.
3.5.
HCV Virologic Response-Based Treatment Stopping Criteria
The following on-treatment HCV virologic response-based treatment stopping criteria will be 
utilized:

Confirmed HCV RNA ≥ LLOQ after 2 consecutive HCV RNA < LLOQ
PPD


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
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. All subjects who terminate treatment early will 
complete an Early Study Drug Discontinuation (ESDD) Visit, and should complete Post-
Treatment Weeks 4, 12, and 24 Visits.  
3.6.
Discontinuation Criteria
When medically feasible, the Medical Monitor must be consulted prior to subject 
discontinuation. 
Study drug must be discontinued in the following instances:

Unacceptable toxicity, as defined in Section 7.5 of the protocol, or toxicity that, in the 
judgment of the investigator, compromises the ability to continue study-specific procedures 
or is considered to not be in the subject’s best interest

Pregnancy of female subject

Efficacy failure as defined in Section 3.5

Significant protocol violation

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason

Discontinuation of the study at the request of Gilead, regulatory agency, or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)
If a subject meets discontinuation criteria during treatment, an ESDD visit will be required 
(Section 6.5). All subjects should complete a 4-week, 12-week, and 24-week Post Treatment 
visit regardless of the treatment duration.
3.7.
Reconsent
When a subject reaches the age of consent in their country/region, they will be invited to consent 
as adults to allow them to continue participating in the clinical trial.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 40 treatment naïve or experienced pediatric subjects will be enrolled in this 
study.  Male and female children 12 to < 18 years of age, with genotype 1 or 4 HCV infection, 
and who are receiving a maintenance cancer chemotherapy regimen will be enrolled. 
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 must be able to provide written informed consent prior to any 
screening evaluations and willing to comply with study requirements. A subject will provide 
assent if possible; written assent will be provided if the subject has the ability to read and 
write, as determined by the Ethics Committee and the Investigator’s assessment. 
2) Male or female, 12 to <18 years of age (consent of parent or legal guardian required)
3) Weight ≥35 kg
4) Chronic HCV infection (≥ 6 months) documented by medical history or, if available, liver 
biopsy
5) HCV genotype 1 or 4 at screening
6) Receiving a protocol-approved maintenance chemotherapy regimen for a hematological 
malignancy (see Section 5.3.1)
7) HCV RNA ≥ 1000 IU/mL at screening
8) Adequate hematologic function (absolute neutrophil count 500/mm3, hemoglobin 
10 g/dL)
9) Treatment naïve or experienced, where treatment-experienced is defined as prior treatment 
failure or intolerance to a regimen including interferon with or without ribavirin that was 
completed at least 8 weeks prior to Baseline/Day 1
10) Females of childbearing potential (as defined in Appendix 4) must have a negative pregnancy 
test at Screening and Baseline/Day 1.
11) Subject able to provide written assent, if they have the ability to read and write, as 
determined by IRB/IEC/local requirements and Investigator’s discretion


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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) Co-infection with HIV, acute hepatitis A virus (HAV) infection or chronic HBV coinfection 
(HBsAg positive [HBsAg+] at screening)
2) Decompensated liver disease defined as INR > 1.2 x ULN, platelets < 50,000/mm3, serum 
albumin < 3.0 g/dL, or prior history of clinical hepatic decompensation (eg, ascites, jaundice, 
encephalopathy, variceal hemorrhage)
3) Evidence of a gastrointestinal malabsorption syndrome that may interfere with absorption of 
orally administered medications
4) Chronic liver disease of non-HCV etiology (eg, hemochromatosis, Wilson’s disease, alpha-1 
antitrypsin deficiency)
5) Evidence of hepatocellular carcinoma (HCC) or other non-hematologic malignancy (with the 
exception of certain resolved skin cancers)
Note: liver imaging within 6 months of baseline/Day 1 is required in patients with cirrhosis 
to exclude HCC
6) History of solid organ or bone marrow transplantation
7) Active or recent history (≤ 1 year) of alcohol or drug abuse
8) Serum creatinine > 1.5 mg/dL
9) Estimated glomerular filtration rate < 90 mL/min/1.73m2, as calculated by the Schwartz
formula
10) Investigational agents taken within the past 28 days (except with the prior written approval of 
the Sponsor)
11) Use of any prohibited concomitant medications as described in Section 5.3
12) Pregnant or lactating subjects
13) Sexually-active males or females of childbearing potential who are not willing to use an 
effective method of contraception during the study (see Appendix 4 for further details)
14) Unable to swallow the LDV/SOF FDC  90mg/400mg  and the LDV/SOF FDC 
22.5mg/100mg placebo tablets
15) Known hypersensitivity to LDV, SOF, metabolites, or formulation excipients 
16) Subject unable to comply with the dosing instructions for study drug administration and/or
unable to complete the study schedule of assessments


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Description and Handling of LDV/SOF FDC
5.1.1.
Formulation
LDV/SOF FDC tablets are orange, diamond-shaped, film-coated tablets containing 90 mg of 
LDV and 400 mg of SOF. The tablets are debossed with “GSI” on one side and “7985” on the 
other side. The SOF/LDV FDC tablets contain the following inactive ingredients: lactose 
monohydrate, copovidone, microcrystalline cellulose, croscarmellose sodium, colloidal silicon 
dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, 
FD&C yellow # 6 /sunset yellow FCF Aluminium Lake.
Placebo to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment are 
orange, diamond-shaped, film-coated tablets debossed with “GSI” on one side and “7985” on the 
other side. The tablets contain lactose monohydrate, copovidone, microcrystalline cellulose, 
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, 
polyethylene glycol, FD&C yellow # 6 /sunset yellow FCF aluminum lake.
Age-appropriate formulations of LDV/SOF FDC have been developed for subjects who are 
unable to swallow the LDV/SOF FDC 90 mg/ 400 mg tablets which include a lower dose 
strength tablet (LDV/SOF FDC 22.5 mg/ 100 mg) formulation. LDV/ SOF FDC lower dose 
strength tablets are round, plain-faced, white film-coated tablets containing 22.5 mg of LDV and 
100 mg of SOF. The LDV/SOF FDC lower dose strength tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc 
and polyethylene glycol.
Placebos to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment are 
round, plain-faced, white film-coated tablets. The placebo tablets contain the following inactive 
ingredients: lactose monohydrate, copovidone, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc and polyethylene glycol.
5.1.2.
Packaging and Labeling
LDV/SOF FDC tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 or 30 tablets, silica gel desiccant and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant screw cap with an induction-sealed, 
aluminum-faced liner.
Placebo tablets to match LDV/SOF FDC 90 mg/ 400 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 28 or
30 tablets, a silica gel desiccant and polyester packing material. Each bottle is enclosed with a 
white, continuous thread, child resistant screw cap with an induction-sealed, aluminum faced 
liner.


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LDV/SOF FDC 22.5 mg/ 100 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 28 or 30 tablets, a silica gel desiccant, and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child resistant screw 
cap with an induction-sealed, aluminum faced liner.
Placebo tablets to match LDV/SOF FDC 22.5 mg/ 100 mg tablets for Swallowability Assessment 
are packaged in white, high density polyethylene (HDPE) bottles. Each bottle contains 28 or
30 tablets, a silica gel desiccant and polyester packing material. Each bottle is enclosed with a 
white, continuous thread, child resistant screw cap with an induction-sealed, aluminum faced 
liner.
All LDV/SOF FDC and placebo to match LDV/SOF FDC bottles to be distributed to centers 
shall be labeled to meet all applicable requirements of the US Food and Drug Administration 
(FDA), Annex 13 of Good Manufacturing Practices: Manufacture of investigational medicinal 
products (Feb 2010) and/or other local regulations as applicable.
5.1.3.
Storage and Handling
LDV/SOF FDC tablets (both 90 mg/400 mg and 22.5 mg/100 mg strength) and placebo to match 
LDV/SOF FDC tablets (for both both 90 mg/400 mg and 22.5 mg/100 mg strengths), for 
Swallowability Assessment should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25 C (77 F); excursions are 
permitted between 15 C and 30 C (59 F to 86 F).
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 LDV/SOF FDC.
Sufficient quantities of LDV/SOF FDC tabletsand placebo tablets will be shipped to the 
investigator or qualified designee from Gilead Sciences (or its designee).


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5.2.
Dosage and Administration of LDV/SOF FDC
LDV/SOF FDC 90 mg/ 400 mg tablet is to be administered once daily with or without food. 
Subjects determined unable to swallow the placebo to match the 90 mg/400 mg LDV/SOF FDC 
tablet (by LDV/SOF FDC Placebo Swallowability Assessment at Screening up to Day 1) will be 
re-assigned to 4 x 22.5 mg/ 100 mg tablets daily.  Each subject must be given instructions to 
maintain approximately the same daily dosing interval between study drug doses. In order to
maintain compliance with the treatment regimen, LDV/SOF FDC should be administered at 
approximately the same time each day.
For a missed dose of LDV/SOF FDC tablet, subjects should be instructed to take the missed dose
of study drug as soon as possible during the same day.  Subjects should be cautioned never to 
double the next dose with a missed dose of study drug under any circumstances.
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 electronic case 
report form(s) (eCRFs).
Investigational agents or devices for any indication are prohibited during the screening period 
and for a minimum of 28 days prior to the Baseline/Day 1 visit through the end of treatment.
Concomitant use of certain medications or herbal/natural supplements (inhibitors or inducers of 
drug transporters ie, P-gp) with study drug(s) may result in PK interactions resulting in increases 
or decreases in exposure of study drug(s).  Examples of representative medications which are 
prohibited from 21 days prior to Baseline/Day 1 through the end of treatment are listed below. 
The use of amiodarone is prohibited from 60 days prior to Baseline/Day 1 through the end of 
treatment:


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Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton- Pump Inhibitors, H2-Receptor 
Antagonists, Antacids
Anticonvulsantsb
Phenobarbital, Phenytoin, Carbamazepine, 
Oxcarbazepine
Antimycobacterialsb
Rifabutin, Rifapentine, Rifampin
Cardiac Medications
Amiodaronec
Digoxind
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 
Inhibitorse
Rosuvastatin
a
It is recommended to separate antacid and LDV/SOF administration by 4 hours. H2-receptor antagonists may be 
administered simultaneously with or staggered from LDV/SOF at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily.  Proton-pump inhibitor doses comparable to omeprazole 20 mg can be administered 
simultaneously with LDV/SOF. Proton-pump inhibitors should not be taken before LDV/SOF. 
b
May result in a decrease in the concentrations of study drug.
c
May result in symptomatic bradycardia. Mechanism is not currently known.  The use of amiodarone is prohibited from 
60 days prior to Baseline/Day 1 through the end of treatment. 
d
May result in an increase in the concentration of study drug and/or concomitant medications. Co-administration of 
LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration 
monitoring of digoxin is recommended when co-administered with LDV/SOF. 
e
Use with study drug may result in an increase in the concentration of rosuvastatin. Monitor for signs and symptoms of 
muscle weakness or myopathy, including rhabdomyolysis.
Medications for disease conditions excluded from the protocol (e.g., active cancer [other than 
hematological malignancy], transplantation) are not listed under this Concomitant Medication 
section and are disallowed in the study.
5.3.1.
Allowed Maintenance Chemotherapy Medications 
Acceptable maintenance chemotherapy medications allowed in this study include the following:

Vincristine

Methotrexate

6-mercaptopurine (6-MP)
L-aspariginase and aracytine and/or short courses of steroids such as prednisone may also be 
used.
Administration of these medications should be staggered relative to dosing of LDV/SOF to 
minimize any potential for drug-drug interactions. For example, if subjects receive their 
maintenance chemotherapy in the morning, LDV/SOF should be taken in the evening.


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Additional chemotherapy medications may be used after review and agreement by Gilead.
5.4.
Accountability for LDV/SOF FDC
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgement of receipt of each shipment of IMP (quantity and 
condition). All used and unused study drug dispensed to subjects must be returned to the site.
LDV/SOF FDC accountability records will be provided to each study site to:

Record the date received and quantity of study drug kits

Record the date, subject number, subject initials, the study drug kit number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.
Subjects must be instructed to bring back all study drug in the original container at 
every post-Day 1 study visit through the end of treatment.
5.4.1.
Investigational Medicinal Product Return or Disposal
Please refer to Section 9.1.7 for Investigational Medicinal Product Accountability and Return.


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6.
STUDY PROCEDURES
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
6.1.1.
Screening Visit
Subjects will be screened within 28 days of Day 1 to determine eligibility for participation in the 
study. The screening window can be extended to 42 days prior to Day 1 in extenuating 
circumstances with sponsor approval.
The following assessments will be done at screening:

Obtain parent or guardian consent and assent from the child; written assent should be 
provided if applicable

Collect medical history, demographics, and concomitant medications

Ask subject and/or parent/legal guardian if the subject is able to swallow and tolerate taking 
pills.

Perform LDV/SOF FDC swallowability assessment

Perform physical exam (PE) including vital signs (VS), body weight, and height

Collect blood samples for
HCV antibody, HAV antibody, HIV antibody, HBsAg, HBsAb, HBcAb
HCV RNA
HCV genotype
Clinical chemistry (including Fibrotest), hematology (including APRI calculation) , and 
coagulation
Pregnancy test (females of childbearing potential only)

Fibrosis assessment with Fibroscan; liver biopsy may be done if required


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For patients with cirrhosis, diagnostic imaging (CT or ultrasound) if results not available 
from imaging done within 6 months of Day 1 that excludes the presence of hepatocellular 
carcinoma (HCC) 

Collect urine sample for urinalysis

Review of all inclusion and exclusion criteria
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 (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 eCRF.  See 
Section 7 Adverse Events and Toxicity Management for additional details.
6.1.2.
Baseline Assessments
Day 1 tests and procedures must be completed prior to enrollment and dosing/dispensing of 
study drug.
At the Day 1 visit, complete the following:

Confirm subject eligibility

Review medical history since screening visit including adverse events and concomitant 
medications

Perform symptom-directed PE including VS, body weight, and height

Collect blood samples for clinical chemistry including Fibrotest, hematology, coagulation , 
HCV RNA, HBV DNA for subjects HBcAb positive at Screening, IL28B genotyping,
 

Collect urine sample for pregnancy testing for females of childbearing potential 

Pregnancy prevention counseling, if applicable

Perform LDV/SOF FDC swallowability (only if not previously completed at screening).  
Observe the subject taking the first dose of study drug (with or without food) and record the 
time of first dose

Dispense study drug(s) as directed by IWRS
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
Instruct the subject on the packaging, storage and administration of study drug

Subjects will be administered a dosing diary with instructions.
6.2.
Treatment Assessments (± 3 days)
Treatment procedures/assessments are to be completed at the end of Weeks 1, 4, 8, and 12, and
ESDD as applicable, for all subjects as outlined in Appendix 2.
At all visits:

Perform symptom-directed PE and VS measurement

Assess adverse events and concomitant medications since previous visit

Collect blood samples for HCV RNA measurement 

Assess study drug accountability 
Dispense study medication at Weeks 4 and 8

Review subject dosing diary
At Weeks 4, 8, and 12, and ESDD if applicable:

Obtain height and body weight

Collect blood samples for clinical chemistry and hematology

Collect blood samples for HBV DNA only in subjects HBcAb positive at Screening

Collect urine sample for pregnancy testing (females of childbearing potential)
At Weeks 4 and 12, and ESDD if applicable:
At Week 12 or ESDD:

Pregnancy prevention counseling, if applicable

Collect blood samples for Fibrotest and coagulation

APRI  Calculation
PPD
PPD


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6.3.
Post-treatment Assessments (5 days)
All subjects will complete the Post-Treatment Week 4, 12 and 24 visits, regardless of treatment 
duration. 
Assessments at the Post-Treatment Week 4 visit include:

Obtain height and body weight

Symptom directed PE and VS

Adverse events and concomitant medications

Blood samples for clinical chemistry and hematology including APRI calculation, HCV 
RNA, HBV DNA only in subjects HBVAb positive at Screening, 

Urine sample for pregnancy testing (females of childbearing potential)

Pregnancy prevention counseling, if applicable
Assessments at the Post-Treatment Week 12 and 24 visit include:

Collect any serious adverse events 

Obtain height and body weight

For those who achieved SVR at the preceding visit (ie, achieved SVR4 or SVR12): Collect 
blood samples for HCV RNA 

Collect blood samples for Fibrotest

Perform Fibroscan
6.4.
Unscheduled Visit 
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 information. 
If a subject has a chemotherapy interruption due to elevated ALT, a blood sample for HCV RNA 
measurement should be collected as soon as possible.   
 
The Sponsor (e.g. Medical Monitor and Clinical Program Manager)/CRO must be informed, as 
soon as possible, when a subject discontinues treatment.
PPD
PPD
PPD
PPD


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6.5.
Assessments for Premature Discontinuation from Treatment and From the 
Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to perform the ESDD assessments (Section 6.2 and Appendix 2) and continue the 
subject in the study to complete the Weeks 4, 12, and 24 Post-Treatment Visits (Section 6.3 and
Appendix 2). If this is not possible or acceptable to the subject or investigator, the subject may 
be prematurely discontinued (ie, withdrawn) from the study.
Discontinuation from study drug dosing and discontinuation from the overall study including 
follow-up will be collected as two separate events.  
The sponsor (eg, Medical Monitor and Clinical Program Manager)/CRO must be informed as 
soon as possible when a subject discontinues from the study.
6.6.
End of Study
Subjects are considered to have completed the study after the Post-Treatment Week 24 follow-up 
visit, regardless of treatment duration and early study drug discontinuation. 
6.7.
Procedures and Specifications
6.7.1.
Clinical Laboratory Analytes

Hematology: Hematocrit, hemoglobin (Hb), platelet count, red blood cell count (RBC), white 
blood cell count (WBC) with differential (absolute and percentage) including lymphocytes, 
monocytes, neutrophils, eosinophils, basophils, reticulocyte count and MCV.

Coagulation: INR, prothrombin time (PT), activated partial thromboplastin time (APTT).

Chemistry: Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase 
(AST/SGOT), albumin, alkaline phosphatase, creatinine, total bilirubin (reflex to direct
bilirubin), glucose (non-fasting), potassium, sodium; gamma-glutamyl transferase (GGT)

Fibrotest

APRI

Virological Tests: Serologies for HCV, HBV (HBsAg, HBsAb, HBcAb), HAV, and HIV. 
HCV RNA will be measured using the COBAS® AmpliPrep/COBAS® TaqMan® HCV 
Quantitative Test, version 2.0. HCV genotype and subtype will be determined using the 
Siemens VERSANT® HCV Genotype INNO-LiPA 2.0 Assay. HBV DNA testing will be 
performed only in subjects HBcAb positive at Screening. Alternate assays may be used if the 
above assays are not available or are not definitive.  


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
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the
SNP, rs12979860. Alternate assays may be used if this assay is not available.

Pregnancy Tests: Serum -hCG or urine -hCG (if positive, requires immediate confirmation 
with serum -hCG).
6.7.2.
Medical History
Medical history including details regarding illnesses and allergies, date(s) of onset, and whether 
condition(s) is currently ongoing, and medication history will be collected on all subjects during 
screening.
6.7.3.
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; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological.
6.7.4.
Vital Signs
Vital sign collection 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 mm Hg mark on the manometer or to 
the nearest whole number on an automatic device.
6.7.5.
Creatinine Clearance
Creatinine clearance is calculated by the Schwartz formula using actual height in cm (Ht).
CRCL (mL/min/1.73m2) = k * height (cm) / serum creatinine (mg/dL)
where k, proportionality constant, is:
0.70: for adolescent males ≥ 12 years old
0.55: for adolescent females ≥ 12 years old
0.55: for children (>=2 and <12 years old)


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6.7.8.
Pregnancy Testing
All females of childbearing potential will have urine pregnancy testing every month during the 
dosing period and for a minimum of 30 days following last dose of study drug. In the event of a 
positive urine pregnancy result, subjects will be instructed to stop study drug immediately (if 
applicable) and return to the clinic as soon as possible for a serum pregnancy test.
6.7.9.
Swallowability Assessment
A LDV/SOF FDC swallowability assessment will be performed at screening up to Day 1. 
Subjects who have indicated that they can take pills will be observed taking a placebo to match 
the 90 mg/ 400 mg LDV/SOF FDC tablet. This will confirm the swallowability of the 
90 mg/ 400 mg tablet size. If a subject is unable to swallow the 90 mg/ 400 mg LDV/SOF FDC 
tablet size, he/she will repeat the assessment with a placebo for the 22.5 mg/ 100 mg 
LDV/SOF FDC tablet. If unable to swallow the 22.5 mg/ 100 mg LDV/SOF FDC tablet, the 
subject will be screen failed and excluded from the study.
PPD
PPD


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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 post-treatment 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 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is 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 subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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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
Severity should be recorded and graded according to the Gilead Sciences, Inc. (GSI) Grading 
Scale for Severity of AEs and Laboratory Abnormalities (see 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 
7.3.1.
Requirements for collection prior to study drug initiation
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
7.3.2.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of study drug must be reported to the CRF/eCRF database 
as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow-up 
period.
7.3.3.
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 post treatment follow-up period, must be reported to the 
eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study drug, regardless of causality, should also be reported. 
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 participation has 
concluded and the event is deemed relevant to the use of study drug, he/she should promptly 
document and report the event to Gilead DSPH.
7.3.4.
Electronic Serious Adverse Event (eSAE) Reporting Process 

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:.
Gilead DSPH: 
Fax:  
E-mail

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
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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 drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Toxicity Management 
7.5.1.
Subject Stopping Rules
The Gilead Medical Monitor must be consulted prior to dose discontinuation of LDV/SOF FDC 
unless the investigator believes that immediate action is warranted to ensure the continued safety 
of the subject.
Due to a clinical or laboratory event, administration of study drug may be discontinued. If 
LDV/SOF FDC is stopped due to toxicity, it must not be restarted, and the subject must complete 
an ESDD visit. If possible, all subjects who terminate treatment early will complete the Early 
Study Drug Discontinuation (ESDD) Visit, and Post-Treatment Weeks 4, 12, and 24 Visits.
Subjects who meet any of the following laboratory criteria must stop study drug:

Elevation of ALT and/or AST > 5x Day 1 or nadir, confirmed by immediate repeat testing

Abnormal elevation of ALT > 3 x Day 1 and direct bilirubin > 2 x baseline, confirmed by 
immediate repeat testing.

Elevation of ALT > 15 x ULN, confirmed by immediate repeat testing

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 adverse event or laboratory abnormality assessed as related to LDV/SOF FDC


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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, and pregnancy reports regardless of an 
associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
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 DSPH by transmitting electronically and also by sending paper pregnancy
report form within 24 hours of becoming aware of the pregnancy.
Refer to Section 7.3 and the 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.


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A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead DSPH..
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: Email: 
 and Fax: 
 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy 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 DSPH, fax number 
 or email 
 
Refer to Appendix 4 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 electronic special situations report 
form and transmitted to Gilead DSPH within 24 hours of the investigator becoming aware of the 
situation. If for any reason it is not possible to record the special situation report (SSR)
information electronically, ie, the eCRF database is not functioning, record the SSR on the paper 
special situation reporting form and submit within 24 hours to:
Gilead DSPH: Fax: 
Email: 
As soon as it is possible to do so, any SSR reported via paper must be transcribed into the eCRF
Database according to instructions in the eCRF completion guidelines.
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do 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
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PPD
PPD
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are:

To evaluate the efficacy of ledipasvir/sofosbuvir (LDV/SOF) in treating HCV infection in
pediatric subjects who are undergoing cancer chemotherapy, as measured by the proportion
of subjects who achieve a sustained virologic response 12 weeks after the end of HCV 
treatment (SVR12)

To evaluate the safety and tolerability of treatment with LDV/SOF for 12 weeks
The secondary objectives of this study are:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
HCV treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
HCV treatment
The exploratory objectives of this study are:
 
 
 
 
 
8.1.2.
Primary Endpoint
The primary efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after discontinuation of
therapy) in the Full Analysis Set (FAS) population.
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8.1.3.
Secondary Endpoint
Secondary efficacy endpoints include the following:

The proportion of subjects with HCV RNA < LLOQ at 4 and 24 weeks after discontinuation 
of therapy (SVR4 and SVR24)

The proportion of subjects with HCV RNA < LLOQ while on treatment

HCV RNA change from Baseline/Day 1

The proportion of subjects with virologic failure
8.1.4.
Safety Endpoints
The primary safety endpoint is any AE leading to permanent discontinuation of the study drug.
8.1.5.
Other Endpoints of Interest
 
 
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 LDV/SOF. Last dose of study drug will be used in the definition 
of treatment emergent AEs and laboratory abnormalities as well as the efficacy endpoints of 
SVR at various post-treatment time points.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The analysis set for efficacy analyses will be the FAS which includes all enrolled subjects who 
took at least 1 dose of the study drug. 
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8.2.1.2.
Safety
The analysis set for safety analyses will include all subjects who took at least 1 dose of the study 
drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of 
study drug through the last dose date of the study drug plus 30 days.
8.3.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. Other than the 
endpoints discussed below, values for missing data will not be imputed. 
For the analyses of categorical HCV RNA data, missing post-treatment 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 (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 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 who did not complete the study will be included in 
summary statistics. For example,

If a subject took at least 1 dose of study drug, the subject will be included in a summary of 
AEs 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 the summary statistics for that time point. If the 
subject is missing a predose value, then the subject will be excluded from the calculation of
the 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 
Baseline/Day 1 result will be replaced with a screening result, if available. If no pretreatment 
laboratory value is available, the Baseline/Day 1 value will be assumed to be normal (i.e., no 
grade [Grade 0]) for the summary of graded laboratory abnormalities.


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Values for missing vital signs data will not be imputed; however, a missing Baseline/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 the 
calculation of summary statistics for the actual HCV RNA values and the change from baseline
values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to 
the logarithmic (base 10) scale (log10 IU/mL).
8.4.
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, presence or absence of cirrhosis, HCV 
RNA level (log10 IU/mL), HCV genotype, IL28B genotype, prior HCV treatment experience, 
and additional endpoints as necessary.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of 
therapy) in the FAS population. The primary analysis will be performed after all subjects have 
been followed through 12 weeks post-treatment or discontinued from study.
A point estimate with a 2-sided 95% exact confidence interval using the binomial distribution 
(Clopper-Pearson method) {Clopper 1934} will be constructed for the SVR12 rate. No statistical 
hypothesis testing will be performed.
8.5.2.
Secondary Analyses
The proportion of subjects with HCV RNA below the LLOQ over time (including SVR 
endpoints) will be presented in tabular and graphical form.
Descriptive summaries and listings will be provided for additional efficacy evaluations of HCV 
RNA actual values, and change from baseline. 
 
Details on efficacy analyses will be described in the statistical analysis plan.
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8.6.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests, physical examinations, 
vital signs measurements at various time points during the study, and by the documentation of 
AEs.
All safety data collected on or after the first dose of study drug administration up to 30 days after 
the last dose of study drug will be summarized according to the study drug received. 
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug
administration page of the eCRF. Exposure data will be summarized according to the study drug 
received.
8.6.2.
Adverse Events
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Term (HLGT), 
High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be attached to 
the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
AE will be defined as any AE 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 AE leading to premature 
discontinuation of the study drug.
Summaries (number and percentage of subjects) of treatment-emergent AEs (by SOC and PT) 
will be provided for:

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 

All AEs leading to premature discontinuation of the study drug

Deaths


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All AEs collected during the course of the study will be presented in data listings.
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, median, Q1, Q3, minimum, and 
maximum) by study visit along with corresponding change from baseline/day 1.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading defined in 
Appendix 3 of this protocol. The incidence of treatment-emergent laboratory abnormalities, 
defined as values that increase by at least one toxicity grade from baseline/day 1 at any time 
post-baseline up to 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 baseline/day 1 
result will be replaced with a screening result, if available. If no pre-treatment laboratory value is 
available, the baseline/day 1 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.
8.6.4.
Other Safety Evaluations
Individual data for vital signs measurements will be listed by subject and summarized by 
incidence of events/abnormalities or descriptive statistical summaries (n, mean, SD, median, Q1, 
Q3, minimum, and maximum), as appropriate. 
8.7.
Sample Size
With approximately 40 subjects enrolled into the study, a 2-sided 95% confidence interval of the 
SVR12 rate will extend at most 26.6% in length, assuming the expected SVR12 rate is 80%.


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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.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from a parent or legal 
guardian and assent 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 


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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 local requirements.
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 or IEC or laboratory. Laboratory 
specimens must be labeled in such as way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. 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, CRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data 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);


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
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.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  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 


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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 study drug disposal 
procedures and provide appropriate instruction for destruction of unused study drug 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 study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the study drug. 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 or IEC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB or IEC
in accordance with local requirements and receive documented IRB or IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. 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 
eCRF.
The monitor is responsible for routine review of the 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 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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10.
REFERENCES
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Dec. Biometrika 1934;26 (4):pp. 404-13.
El-Raziky MS, El-Hawary M, Esmat G, Abouzied AM, El-Koofy N, Mohsen N, et al. 
Prevalence and risk factors of asymptomatic hepatitis C virus infection in 
Egyptian children. World J Gastroenterol 2007;13 (12):1828-32.
El-Sayed MH, El-Haddad A, Fahmy OA, Salama, II, Mahmoud HK. Liver disease is a major 
cause of mortality following allogeneic bone-marrow transplantation. Eur J 
Gastroenterol Hepatol 2004;16 (12):1347-54.
El-Sayed MH, Nasr E, Zekri A, El-Beblawy N, Aziz AOA, Zalata KR, et al. Factors Associated 
with Fibrosis Among HCV Infected Children and Adolescents Receiving Cancer 
Chemotherapy [Abstract 715]. American Association for the Study of Liver 
Diseases; 2011 06-09 November; San Francisco, CA. p. 704A.
El-Zanaty F, Way A. Egypt Demographic and Health Survey 2008. Published: March 2009.
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus infection in 
Europe. J Hepatol 2008;48 (1):148-62.
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.
Hu J, Seeger C. Hsp90 is required for the activity of a hepatitis B virus reverse transcriptase. 
Proc Natl Acad Sci USA 1996;93 (3):1060-4.
Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in egypt: results of 
the national population-based cancer registry program. Journal of cancer 
epidemiology 2014;2014:437971.
Mahale P, Kontoyiannis DP, Chemaly RF, Jiang Y, Hwang JP, Davila M, et al. Acute 
exacerbation and reactivation of chronic hepatitis C virus infection in cancer 
patients. J Hepatol 2012;57 (6):1177-85.
Nakano T, Lau GM, Sugiyama M, Mizokami M. An updated analysis of hepatitis C virus 
genotypes and subtypes based on the complete coding region. Liver Int 2012;32 
(2):339-45.
Ray SC, Arthur RR, Carella A, Bukh J, Thomas DL. Genetic epidemiology of hepatitis C virus 
throughout egypt. J Infect Dis 2000;182 (3):698-707.
Sharaf-Eldeen S, Salama K, Eldemerdash, Hassan HMS, Semesem M. Hepatitis B and C Viruses 
in Egyptian Children with Malignancy. J. Med. Sci 2007;7 (6):1003-8.


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Wirth S. Current treatment options and response rates in children with chronic hepatitis C. World 
J Gastroenterol 2012;18 (2):99-104.


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


PPD
PPD
PPD
IDV/SOFFDC 
Protocol GS-US-337-1904 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDYACKNOWLEDGE~NT 
Amendment I 
A Phase 2, Open-label Study to Investigate the Efficacy and Safety ofLedipasvir/Sofosbuvir 
Fixed Dose Combination in the Treatment of Hepatitis C Virus (HCV) infection in Pediatrics 
Undergoing Cancer Chemotherapy 
GS-US-337-1904, Amendment 1, 16 June 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Study Director/Medical Monitor 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully infonned about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 55 
16 June 2017 


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Appendix 2.
Study Procedures
Appendix Table 1.
Screening, On-Treatment Visits
Screening
Treatment
ESDD
Day -28
to Day -1
Baseline/
Day 1a
Week 1
(3 days)
Week 4
(3 days)
Week 8
(3 days)
Week 12
(3 days)
Consent /Assent
X
Demographics
X
Medical History
X
X
Physical exam (PE)
X
Symptom directed PE
X
X
X
X
X
X
Height and weight
X
X
X
X
X
X
Vital signsb
X
X
X
X
X
X
X
Swallowability Assessment
X
AEs and Con-Meds
X
X
X
X
X
X
X
HBsAg, HBsAb, HBcAb, HIV antibody, HAV 
antibody, HCV antibody
X
HCV RNA
X
X
X
X
X
X
X
HCV genotype
X
HBV DNA c
X
X
X
X
X
IL28B genotype
X
Urinalysis
X
Hematology and Blood Chemistry (including 
ALT)
X d
X
X
X
X
X


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Screening
Treatment
ESDD
Day -28
to Day -1
Baseline/
Day 1a
Week 1
(3 days)
Week 4
(3 days)
Week 8
(3 days)
Week 12
(3 days)
Fibrotest
X
X
X
X
FibroScan
X
APRI Calculation
X
X
X
Coagulation
X
X
X
X
Pregnancy test e
X
X
X
X
X
X
Pregnancy prevention counselingf
X
X
X
Dispense drug 
X
X
X
Review subject dosing diary 
X
X
X
X
X
Review of Study Drug Adherence and Drug 
Accountability
X
X
X
X
X
a
Baseline/Day 1 assessments must be performed prior to dosing.
b
Vital signs include resting blood pressure, pulse, respiratory rate, and temperature. SAE and study procedure related AEs are to be collected form informed consent. Other 
AEs are to be collected from Baseline/Day1.
c
HBV DNA testing done only when subjects are HBcAb positive at Screening
e
For females of childbearing potential only: serum β-hCG at Screening, urine test thereafter. If urine is positive, confirm immediately with serum β-hCG
f
If applicable
PPD
PPD


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Appendix Table 2.
Post-Treatment Study Visits
4 Weeks Post-Treatment
(5 days)
12 Weeks Post-Treatmenta
(5 days)
24 Weeks Post-Treatment
(5 days)
Clinical Assessments
Symptom-directed PE
X
Height and Weight
X
X
X
Vital Signs
X
AEs
X
Xa
Xa
Concomitant Medications
X
Fibrosis assessmentb
X
X
Pregnancy prevention counselingc
X
Laboratory Assessments
Hematology and Blood Chemistry
X
X
APRI Calculation
X
HCV RNA
X
X
X
HBV DNAd
X
X
X
Urine Pregnancy Testf
X
a
All SAEs, including deaths, regardless of cause or relationship, must be reported after patient signs the informed consent through the end of the study
b
Fibroscan and Fibrotest
c
If applicable
d
HBV DNA testing done only when subjects are HBcAb positive at Screening
 
f
Females of childbearing potential
PPD
PPD


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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 25 August 2015 modified for Pediatric Studies
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


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
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


LDV/SOF FDC
Protocol GS-US-337-1904
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 61
16 June 2017
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%
# An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


LDV/SOF FDC
Protocol GS-US-337-1904
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 62
16 June 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L


LDV/SOF FDC
Protocol GS-US-337-1904
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 63
16 June 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                          
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL                      
1.51 to < 1.74 mmolL
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L


LDV/SOF FDC
Protocol GS-US-337-1904
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 64
16 June 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L


LDV/SOF FDC
Protocol GS-US-337-1904
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 65
16 June 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
Adult 
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
Pediatric < 18 Years
1.1 – 1.3 x ULN†
>1.3 – 1.8 x ULN†
>1.8 – 3.4 x ULN†
>3.4 x ULN
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L


LDV/SOF FDC
Protocol GS-US-337-1904
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 66
16 June 2017
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
** An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


LDV/SOF FDC
Protocol GS-US-337-1904
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 67
16 June 2017
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT) 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase 
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase 
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


LDV/SOF FDC
Protocol GS-US-337-1904
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 68
16 June 2017
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


LDV/SOF FDC
Protocol GS-US-337-1904
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 69
16 June 2017
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


LDV/SOF FDC
Protocol GS-US-337-1904
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 70
16 June 2017
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV 
block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


LDV/SOF FDC
Protocol GS-US-337-1904
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 71
16 June 2017
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak flow 
25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in affected 
eye(s) 
Visual Changes (from 
baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in affected 
eye(s)


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


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


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


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


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


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


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


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


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


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


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Protocol GS-US-337-1904
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Amendment 1
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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated
Urinary Tract 
obstruction (eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (eg, septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


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Amendment 1
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Appendix 4.
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 are considered to be in a postmenopausal state when they are ≥54 years of age with 
cessation of previously occurring menses for ≥12 months without an alternative cause.  
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) Contraception Requirements for Female Subjects
a. 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 LDV have demonstrated that there is 
no reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies of 
LDV have demonstrated no adverse effect on fertility or embryo-fetal development.
However, the risks of treatment with LDV/SOF during pregnancy in human have not been 
evaluated. Please refer to the latest version of the IB for additional information.
b. Contraceptive 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 Baseline/Day 1 visit prior to randomization. A pregnancy 
test will be performed at the Post Treatment Week 4 visit. They must also agree to one of the 
following from Screening until 30 days of the last dose of LDV/SOF.

Complete abstinence from intercourse of reproductive potential. Abstinence is acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.
Or 


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Amendment 1
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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
bilateral tubal occlusion
Vasectomy in 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
■
Implants of levonorgestrel
■
Injectable progesterone
■
Oral contraceptives (either combined or progesterone only)
■
Contraceptive vaginal ring
■
Transdermal contraceptive patch
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 LDV/SOF.
3) Contraceptive Requirements for Males Subjects 
During the study, male subjects with female partners of childbearing potential should use 
condoms until 30 days after the last dose of LDV/SOF 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 study drug. 
Male subjects must agree to refrain from sperm donation for at least 30 days after the last dose of 
study drug.


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Amendment 1
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4) Procedures to be Followed in the Event of Pregnancy
Subjects should be instructed to notify the investigator if they (or their partner) become pregnant 
at any time during the study, or if they become pregnant within 30 days of last study drug dose.
Subjects who become pregnant or who suspect that they are pregnant during the study 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: 
SOF/LDV Fixed-Dose Combination
GS-US-337-1904 Statistical Analysis Plan                                                                                       Final 1.0
CONFIDENTIAL
Page 1
01March2019
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Open-label Study to Investigate the Efficacy and 
Safety of Ledipasvir/Sofosbuvir Fixed Dose Combination in 
the Treatment of Hepatitis C Virus (HCV) Infection in 
Pediatric Subjects Undergoing Cancer Chemotherapy
Name of Test Drug:
Ledipasvir/Sofosbuvir Fixed-Dose Combination 
(LDV/SOF FDC)
Study Number:
GS-US-337-1904
Protocol Version (Date):
Original:              06 Oct 2015
Amendment 1.0: 16 June 2017
Analysis Type:
Final Analyses
Analysis Plan Version:
1.0
Analysis Plan Date:
01 Mar 2019
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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GS-US-337-1904 Statistical Analysis Plan                                                                                       Final 1.0
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF ABBREVIATIONS .......................................................................................................................................4
1.
INTRODUCTION ................................................................................................................................................6
1.1.
Study Objectives ......................................................................................................................................6
1.2.
Study Design............................................................................................................................................7
1.3.
Sample Size and Power............................................................................................................................7
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................8
2.1.
Data Monitoring Committee ....................................................................................................................8
2.2.
Interim Analysis.......................................................................................................................................8
2.3.
Final Analysis ..........................................................................................................................................8
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES..............................................................................9
3.1.
Analysis Sets............................................................................................................................................9
3.1.1.
All Enrolled Analysis Set.......................................................................................................9
3.1.2.
Full Analysis Set ....................................................................................................................9
3.1.3.
Safety Analysis Set ................................................................................................................9
3.2.
Subject Grouping .....................................................................................................................................9
3.3.
Strata and Covariates ...............................................................................................................................9
3.4.
Examination of Subject Subsets...............................................................................................................9
3.5.
Missing Data and Outliers......................................................................................................................10
3.5.1.
Missing Data ........................................................................................................................10
3.5.2.
Outliers.................................................................................................................................11
3.6.
Data Handling Conventions and Transformations .................................................................................11
3.7.
Visit Windows .......................................................................................................................................12
3.7.1.
Definition of Study Day.......................................................................................................12
3.7.2.
Analysis Windows ...............................................................................................................13
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis 
Window................................................................................................................................14
4.
SUBJECT DISPOSITION..................................................................................................................................15
4.1.
Subject Enrollment and Disposition.......................................................................................................15
4.2.
Extent of Exposure.................................................................................................................................16
4.2.1.
Duration of Exposure to Study Drug....................................................................................16
4.2.2.
Adherence to Study Drug.....................................................................................................16
4.3.
Protocol Deviations................................................................................................................................17
5.
BASELINE CHARACTERISTICS....................................................................................................................18
5.1.
Demographics ........................................................................................................................................18
5.2.
Other Baseline Characteristics ...............................................................................................................18
5.3.
Swallowability Assessment for LDV/SOF Tablets................................................................................19
5.4.
Medical History .....................................................................................................................................19
6.
EFFICACY ANALYSES ...................................................................................................................................20
6.1.
Primary Efficacy Endpoint.....................................................................................................................20
6.1.1.
Definition of the Primary Efficacy Endpoint .......................................................................20
6.1.2.
Primary Analysis of the Primary Efficacy Endpoint............................................................20
6.1.3.
Subgroup Analysis of the Primary Efficacy Endpoint .........................................................20
6.2.
Secondary Efficacy Endpoints ...............................................................................................................20
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................20
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................21
6.3.
Exploratory Endpoints of Interest ..........................................................................................................22


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6.3.1.
Definition of Exploratory Endpoints....................................................................................22
6.3.2.
Analysis Methods for Other Endpoints of Interest...............................................................22
6.4.
Changes From Protocol-Specified Efficacy Analyses ...........................................................................23
7.
SAFETY ANALYSES........................................................................................................................................24
7.1.
Adverse Events and Deaths....................................................................................................................24
7.1.1.
Adverse Event Dictionary....................................................................................................24
7.1.2.
Adverse Event Severity........................................................................................................24
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................24
7.1.4.
Serious Adverse Events........................................................................................................24
7.1.5.
Treatment-Emergent Adverse Events ..................................................................................24
7.1.5.1.
Definition of Treatment Emergent..................................................................24
7.1.5.2.
Incomplete Dates ............................................................................................24
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................25
7.2.
Laboratory Evaluations..........................................................................................................................26
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................27
7.2.2.
APRI Calculation .................................................................................................................27
7.2.3.
Graded Laboratory Values ...................................................................................................27
7.2.3.1.
Treatment-Emergent Laboratory Abnormalities.............................................28
7.2.3.2.
Summaries of Laboratory Abnormalities .......................................................28
7.3.
Body Weight, Height, and Vital Signs...................................................................................................28
7.4.
Prior and Concomitant Medications.......................................................................................................29
7.4.1.
Prior Medications.................................................................................................................29
7.4.2.
Concomitant Medications ....................................................................................................29
7.5.
Other Safety Measures...........................................................................................................................29
7.6.
Changes From Protocol-Specified Safety Analyses...............................................................................30
8.
PHARMACOKINETIC ANALYSES ................................................................................................................31
9.
REFERENCES ...................................................................................................................................................32
10.
SOFTWARE.......................................................................................................................................................33
11.
SAP REVISION .................................................................................................................................................34
12.
APPENDICES ....................................................................................................................................................35
Appendix 1.
Schedule of Assessments ......................................................................................................36
LIST OF IN-TEXT-TABLES
Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs, Height and 
Weight, Fibrotest a, and Safety Laboratory Data....................................................................13
Table 3-2.
Analysis Windows for Posttreatment HCV RNA, Vital Sign, Height and 
Weight, FibroScan, Fibrotest, and Safety Laboratory Data....................................................13


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GS-US-337-1904 Statistical Analysis Plan                                                                                       Final 1.0
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LIST OF ABBREVIATIONS
. 
AE
adverse event
ALT
alanine aminotransferase
APRI
AST to Platelet Ratio Index
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CFR
Code of Federal Regulations
CI
confidence interval
CrCL
Creatinine clearance
CRF
case report form
CSR
clinical study report
dL
deciliter
DMC
data monitoring committee
EC
Ethnic Committee
ECG
electrocardiogram
eCRF
electronic case report form(s)
EOT
End of Treatment
ESDD
Early Study Drug Discontinuation
FAS
full analysis set
FDC
fixed-dose combination
FU
follow-up
Gilead
Gilead Sciences, Inc.
HCV
hepatitis C virus
HLGT
high-level group term
HLT
high level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
ID
identification
INR
International Normalized Ratio of prothrombin time
LDV
ledipasvir
LDV/SOF
ledipasvir/sofosbuvir
LLT
lower level term
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute, Egypt
PK
pharmacokinetics
PT
preferred term
Q1
first quartile


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Q3
third quartile
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SAS
statistical analysis software
SD
standard deviation
SE
standard error
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
TEAEs
Treatment-emergent adverse events
TFLs
tables, figures, and listings
TND
target not detected
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report 
(CSR) for Study GS-US-337-1904. This SAP is based on the protocol amendment 1.0 
16 June 2017. Related documents are the original study protocol and electronic case report 
form (eCRF). The SAP will be finalized before database finalization. Any changes made 
after the finalization of the SAP will be documented in the CSR.
An interim analysis for safety was performed after a total of 11 subjects had completed Week 
12 assessment or prematurely discontinued from the study before proceeding to recruitment 
of remaining subjects. The purpose of this interim analysis was to respond to EC committee 
request of safety concern on pediatric population.
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate the efficacy of ledipasvir/sofosbuvir (LDV/SOF) in treating HCV 
infection in pediatric subjects who are undergoing cancer chemotherapy, as measured 
by the proportion who achieve a sustained virologic response 12 weeks after the end 
of HCV treatment (SVR12)

To evaluate the safety and tolerability of treatment with LDV/SOF for 12 weeks
The secondary objectives of this study are as follows:

To determine the proportion of subjects who attain SVR at 4 and 24 weeks after 
cessation of HCV treatment (SVR4 and SVR24)

To evaluate the kinetics of circulating HCV RNA during treatment and after cessation 
of HCV treatment
The exploratory objectives of this study are:
 
 
 
 
 
PPD


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1.2.
Study Design
This is a phase 2 single-center open-label study investigating the efficacy and safety of 
LDV/SOF FDC in pediatric subjects with chronic HCV who are receiving maintenance 
cancer chemotherapy. 
Approximately 40 treatment naïve or experienced pediatric subjects will be enrolled in this 
study.  Male and female children 12 to < 18 years of age, with genotype 1 or 4 HCV 
infection, and who are receiving a maintenance cancer chemotherapy regimen will be 
enrolled.
All subjects will receive LDV/SOF FDC once daily with or without food for 12 weeks.  
Subjects will be assigned to receive 1 LDV/SOF FDC 90 mg/ 400 mg tablet daily or 4 
LDV/SOF FDC 22.5 mg/100 mg tablets once daily based on a swallowability assessment 
performed at screening up to Day 1.
Subjects who have indicated that they can take pills will be observed taking a placebo to 
match the 90 mg/ 400 mg LDV/SOF FDC tablet. If a subject is unable to swallow the 90 mg/ 
400 mg LDV/SOF FDC tablet size, he/she will repeat the assessment with a placebo to match 
the 22.5 mg/ 100 mg LDV/SOF FDC tablet. If unable to swallow the 22.5 mg/ 100 mg 
LDV/SOF FDC tablet, the subject will be screen failed and excluded from the study.
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

Up to 24-week posttreatment period
The schedule of assessments is provided as an appendix to the SAP (Appendix 1Error! 
Reference source not found.).
1.3.
Sample Size and Power
With approximately 40 subjects enrolled into the study, a 2-sided 95% confidence interval of 
the SVR12 rate will extend at most 26.6% in length, assuming the expected SVR12 rate is 
80%.
The study was terminated after 19 subjects were enrolled due to extremely slow enrollment 
rate.
PPD


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee
This study does not have a data monitoring committee (DMC).
2.2.
Interim Analysis
There was 1 planned interim safety analysis after 11 subjects had completed Week
12 assessment or prematurely discontinued from the study before proceeding to recruitment
of remaining subjects. Decision to continue recruitment of remaining subjects was contingent 
on review of safety data (adverse events and laboratory abnormalities) from the first 11
subjects who completed the treatment period.
No formal interim efficacy analysis with the possibility of early termination for efficacy or 
futility is planned.
2.3.
Final Analysis
The final analysis will be conducted when all subjects have completed the 24 week post 
treatment visit or prematurely discontinued from the study. The data will be finalized after all 
data queries are resolved for study visits through completion of the 24-week posttreatment 
visit. At the conclusion of data finalization, the study statistician and statistical programmers 
will run the final version TFLs.


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GS-US-337-1904 Statistical Analysis Plan                                                                                       Final 1.0
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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 each analysis set will be summarized or 
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 all enrolled subjects who took at least 1 dose of study 
drug. The study drug in this study is LDV/SOF 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. This is 
the primary analysis set for safety analyses.
3.2.
Subject Grouping
This is a single arm study. All subjects received LDV/SOF 90mg/400mg daily for 12 weeks 
(including 90/400mg tablet or 4 22.5/100mg tablets). 
3.3.
Strata and Covariates
This study does not use a stratified randomization schedule for enrolling subjects.
3.4.
Examination of Subject Subsets
The primary efficacy endpoint, SVR12, will be analyzed for the following subsets:

Age group (≥12- <=  15 years old, > 15 years old)


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
Sex (male, female)

baseline weight (<= median, > median)

IL28B (CC, non-CC; with non-CC further broken down to CT, TT)

cirrhosis (presence, absence, missing)

HCV genotype subtypes (4a, 4b, 4c or 4d, 4h etc.)

baseline HCV RNA (< 800,000, ≥800,000 IU/mL)

baseline alanine aminotransferase  (ALT) (≤1.5 × upper limit of normal (ULN), 
> 1.5 × ULN)

prior HCV treatment (treatment naive, treatment experienced ) 

most recent HCV treatment response (non-responder, relapse/breakthrough, Other)
for treatment-experienced subjects

study treatment status (completed study treatment, discontinued study treatment)

adherence to study regimen (<80%, ≥80%)
3.5.
Missing Data and Outliers
3.5.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
For missing last dose date of study drug, imputation rules are described in Section 3.7.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for
prior and concomitant medications in Section 7.4.
For analyses of categorical HCV RNA data, missing posttreatment HCV RNA data will have 
the missing data imputed. Missing on-treatment HCV RNA will have the missing data 
imputed up to the time of the last dose (for on-treatment displays). If the study day associated 
with the last dosing date is greater than or equal to the lower bound of a visit window, and 
the value at the visit is missing, the value will be imputed. If the study day associated with 
the last dosing date is less than the lower bound of a visit window then the on-treatment
value at that visit will remain missing. 
If a data point is missing and is preceded and followed in time by values that are “< LLOQ 
target not detected (TND)”, then the missing data point will be set to “< LLOQ TND”. If a 
data point is missing and preceded and followed by values that are “< LLOQ detected”, or 
proceeded 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 “< 


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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.
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.
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 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 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. 
Data that are continuous in nature but are less than the lower limit of quantitation or above 
the upper limit of quantitation will be imputed as follows:

A value that is one unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “x” (where x is considered 
the limit of quantitation). For example, if the values are reported as < 50 and < 5.0, values 
of 49 and 4.9, respectively, will be used for calculation of summary statistics.  An 
exception for this rule is any value reported < 1. For the values reported as < 1 or < 0.1, 
value of 0.9 or 0.09 will be used for calculation of summary statistics.

A value that is one unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “> x” (where x is considered 
the limit of quantitation). Values with decimal points will follow the same logic as above.

The limit of quantitation will be used for calculation of descriptive statistics if the datum
is reported in the form of “≤ x” or “≥ x” (where x is considered the limit of quantitation).
The artus® HCV RG RT-PCR Kit by QIAGEN March 2015 was used to determine HCV 
RNA results in this study. The lower limit of quantitation (LLOQ) of this assay is 50 IU/mL.


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When the calculated IU/mL 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 “HCV RNA not 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 “<50 
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, 49 HCV RNA IU/mL). HCV RNA values returned as “No HCV RNA detected” will also 
be set to 49 IU/mL.
For selected analyses, HCV RNA data (IU/mL) will be transformed to the logarithmic (base 
10) scale (log10 IU/mL).
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
The last dose date for an individual study drug will be the end date on study drug 
administration eCRF for the record where the “subject permanently discontinued” flag is 
‘Yes’. The last dose date will be defined as the maximum of the last dose dates of individual 
study drugs in a treatment group.
If there are subjects for whom the date of last study drug is unknown due to the reason that 
the subject was lost to follow-up and not able to be contacted, the date of last dose will be 
estimated using the maximum of nonmissing study drug start or stop dates, visit dates and 
laboratory collection dates (posttreatment visits and unscheduled visits are not included).


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GS-US-337-1904 Statistical Analysis Plan                                                                                       Final 1.0
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3.7.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of 
analysis, observations will be assigned to analysis windows. In general, the baseline value 
will be the last nonmissing value on or prior to the first dose date of study drug. 
Safety laboratory data, HCV RNA, vital signs, height and weight, FibroScan, and Fibrotest, 
collected up to the last dose date + 3 days are considered to be on-treatment data. The 
analysis windows for on-treatment HCV RNA, vital signs, height and weight, and safety 
laboratory data are provided in Table 3-1.
Table 3-1.
Analysis Windows for On-treatment HCV RNA, Vital Signs, 
Height and Weight, Fibrotest a, and Safety Laboratory Data
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 1
7
2
11
Week 4
28
12
42
Week 8
56
43
70
Week 12
84
71
≥85
a
Analysis windows for coagulation parameters and Fibrotest are only defined for Baseline and Week 12.
b
FibroScan is collected at screening, posttreatment week 12 and posttreatment week 24.
Safety laboratory data, HCV RNA, vital signs, height and weight, FibroScan, and Fibrotest, 
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.
Table 3-2.
Analysis Windows for Posttreatment HCV RNA, Vital Sign,
Height and Weight, FibroScan, Fibrotest, and Safety Laboratory 
Data
HCV RNA, Height and Weight, FibroScan 
and Fibrotest
Vital Signs and Safety Laboratory Data b
Nominal 
FU a Visit
Nominal FU 
Day
Lower 
Limit
Upper Limit
Nominal FU 
Day
Lower 
Limit
Upper Limit
FU-4c
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 and safety labs will only be summarized for the FU-4 visit (up to 30 days after last dose).
c
Doesn’t apply to FibroScan and Fibrotest.


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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.

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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GS-US-337-1904 Statistical Analysis Plan                                                                                       Final 1.0
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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject disposition will be provided. This summary will present the number of 
subjects screened, the number of subjects enrolled, and the number and percentage of 
subjects in each of the categories listed below. For the “Treated” category, the denominator 
for the percentage calculation will be the total number of subjects enrolled for each column. 
For all other categories, the denominator for the percentage calculation will be the total 
number of subjects in the Safety Analysis Set for each column.

Treated (Safety Analysis Set)

In FAS

Completed study treatment

Did not complete study treatment with reason for premature discontinuation of study 
treatment

Completed the study  (completed posttreatment  Week 24 visit)

Did not complete the study with reason for premature discontinuation of study
Among subjects who completed study treatment and who discontinued study treatment, the 
number and percentage of subjects will be summarized for:

Who had no HCV posttreatment Week 4 assessment and thereafter (No HCV FU-4 and 
thereafter)

Who had HCV posttreatment Week 4 assessment but no HCV posttreatment Week 12 
assessment and thereafter (With HCV FU-4 but No FU-12 and thereafter)
If a subject did not have any HCV RNA assessment ≥ 21 days after the last dose of any study 
drug (ie, lower bound of FU-4 visit for HCV RNA data), the subject is categorized as having 
“No HCV FU-4 and thereafter”. If a subject had the HCV FU-4 assessment but did not have 
any HCV RNA assessment ≥ 70 days after the last dose of any study drug (ie, lower bound of 
FU-12 visit for HCV RNA data), the subject is categorized as having “With HCV FU-4 but 
No FU-12 and thereafter”.
In addition, the total number of subjects who were enrolled in the study, and the number and 
percentage 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:


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
Disposition for subjects who complete study treatment and study

Disposition for 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
4.2.
Extent of Exposure 
Extent of exposure to study drug will be examined by assessing the total duration of study 
drug exposure and the level of adherence to the study drug regimen specified in the protocol. 
4.2.1.
Duration of Exposure to Study Drug
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). If subjects are continuing 
on study drug, use the last study drug end date, clinical visit date, or laboratory visit date,
whichever occurred last during the on-treatment period [or use the data cutoff date for 
analysis] to impute the last dose date for the calculation of the duration of study drug
exposure.
The total duration of exposure to study drug will be summarized using descriptive statistics 
(number of subjects [n], mean, standard deviation [SD], median, first quartile [Q1], third 
quartile [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), 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 total number of tablets administered will be summarized using descriptive statistics (n, 
mean, SD, median, Q1, Q3, minimum, and maximum). 
The presumed total number of tablets administered to a subject will be determined by the 
data collected on the drug accountability CRF using the following formula:







ed
administer
not 
Tablets
of
No.
Dispensed
Tablets
of
No.
ed
Administer
Doses
of
Number 
Total
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 at baseline. 
The level of adherence will be expressed in percentage using the following formula:


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100
  
baseline
at 
Prescribed
Drug
Study 
of
Amount 
Total
  
ed
Administer
Drug
Study 
of
Amount 
Total
(%)
Adherence
of
Level








Note: If calculated adherence is greater than 100%, the result will be set to 100%.
In this study, the total amount of LDV/SOF (90 mg/400 mg) prescribed for 12 weeks of 
treatment would require 84 tablets. For LDV/SOF (22.5 mg/ 100 mg), the total amount of 
tablets would be 336.
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 (eg, < 80%, ≥ 80 to < 90%, ≥ 90%) will be provided for the Safety Analysis Set.
No inferential statistics will be provided. 
A separate by-subject listing of study drug administration and drug accountability will be 
provided by subject ID number (in ascending order) and visit (in chronological order).
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. 


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics 
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for age, and 
using the numbers and percentages of subjects for age categories (<= 15 years old, > 15 years 
old), 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) as a continuous variable 

IL28B (CC, Non-CC (CT, TT)

HCV genotype and subtypes

cirrhosis (presence, absence, unknown)

baseline HCV RNA (log10 IU/mL) as a continuous variable and as categories < 800,000 
IU/mL, ≥ 800,000 IU/mL)

baseline ALT (U/L) as a continuous variable and as categories (≤1.5 x ULN, > 1.5 x 
ULN)

prior HCV treatment experience (treatment naïve or treatment experienced)

most recent HCV treatment response (Non-Responder, Relapse/Breakthrough, other 
including early treatment discontinuation, met a virologic stopping rule, or unknown) for 
treatment-experienced subjects

Creatinine clearance (CrCL) using the Schwartz formula as follows:
Creatinine clearance (mL/min/1.73m2) = k * height (cm) / serum creatinine (mg/dL) where k, 
proportionality constant, is:
                   0.70: for adolescent males ≥ 12 years old


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                   0.55: for adolescent females ≥ 12 years old
                   0.55: for children (>=2 and <12 years old)
These baseline characteristics will be summarized 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.
A separate by-subject data listing for prior HCV treatment and response will be provided for 
all subjects. The listing will display the prior HCV treatment experience for all subjects as 
well as the prior HCV regimen and treatment, the treatment duration, and the prior HCV 
treatment response for treatment experienced subjects.
5.3.
Swallowability Assessment for LDV/SOF Tablets
Swallowability Assessment (Able to swallow LDV/SOF FDC 90mg/400 mg or LDV/SOF 
FDC 22.5 mg/100 mg placebo tablet) will be summarized using the numbers and percentages 
of subjects in each swallowability category (ie, Able to Swallow, Unable to Swallow). 
A by-subject listing of Swallowability of LDV/SOF FDC tablets will be provided by subject 
ID number in ascending order.
5.4.
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.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint is SVR12 defined as HCV RNA < LLOQ (ie, < 50 IU/mL) 12 
weeks after discontinuation of all study drugs in the FAS. The artus® HCV RG RT-PCR Kit 
by QIAGEN March 2015 are used to measure HCV RNA.
6.1.2.
Primary Analysis of the Primary Efficacy Endpoint
The SVR12 rate in each of the HCV genotypes and overall will be calculated along with 2-
sided 95% exact CI based on Clopper-Pearson method {20839}. No statistical hypothesis 
testing will be performed.
6.1.3.
Subgroup Analysis of the Primary Efficacy Endpoint
Point estimates and 95% exact CIs of the SVR12 rates will be displayed for each subgroup 
outlined in Section 3.4.
A Forest plot will graphically present estimates and 95% CIs in SVR12 rates for each of the 
subgroups.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include the following:

The proportion of subjects with HCV RNA < LLOQ at 4 and 24 weeks after 
discontinuation of treatment (SVR4 and SVR24)

The proportion of subjects with HCV RNA < LLOQ while on treatment by study visit

HCV RNA (log10 IU/mL) and change from baseline in HCV RNA (log10 IU/mL) 
through end of treatment (EOT)

The proportion of subjects with virologic failure as the following:
On-treatment virologic failure
o
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)


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o
> 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)
o
HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (ie, nonresponse)
Relapse
o
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

Characterization of HCV drug resistance substitutions at baseline, during, and after 
therapy with LDV/SOF
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
For analyses of HCV RNA < LLOQ by visit while on treatment and during the posttreatment
(SVR) follow-up period, subjects will be assigned a value at each visit based on the analysis 
visit windows specified in Section 3.7.2. Missing values will be imputed based on the 
categorical imputation rules described in Section 3.5.1. The 2-sided 95% exact confidence 
interval based on Clopper-Pearson method will be provided for the percentage of subjects 
with HCV RNA < LLOQ at each visit. The overall category for “HCV RNA < LLOQ” will 
be split into the following 2 subcategories: “< LLOQ TND” for subjects with target not 
detected and “< LLOQ detected” for subjects with < LLOQ detected in tabular displays. 
Graphs for the percentage of subjects with HCV RNA < LLOQ over time during treatment 
will be displayed.
Summary statistics will be presented for absolute values and change from baseline in HCV 
RNA (log10 IU/mL) by visit through EOT. Imputation rules described in Section 3.5.1 will be 
used to assign HCV RNA values for missing values at a visit that are bracketed by “< LLOQ 
TND” and/or “< LLOQ detected”. Otherwise, a missing = excluded analysis will be 
performed. Plots of the mean ± SD and median (Q1, Q3) of absolute values and changes 
from baseline in HCV RNA through EOT will be presented.
For the SVR12 endpoint analysis, a summary table of the number and percentage of subjects 
with SVR12, virologic failure (VF), and Other will be created. All subjects who achieve 
SVR12 will be categorized as SVR12. Virologic failure will be descriptively summarized as 
“on-treatment virologic failure” and relapse (which will be broken down by study drug 
completed yes/no). Subjects who do not achieve SVR12 and do not meet criteria for VF will 
be categorized as Other. The denominator for relapse will be the number of subjects who had 
HCV RNA < LLOQ on their last observed on-treatment HCV RNA measurement; otherwise, 
the denominator will be the number of subjects in the FAS. 
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 


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reasons for imputed) will be provided for each posttreatment follow-up visit. 95% 
Clopper-Pearson exact CIs may be presented for the overall proportion of subjects with HCV 
RNA < LLOQ.
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. 
Drug resistant substitutions will be analyzed as part of the Virology Study Report.
6.3.
Exploratory Endpoints of Interest
6.3.1.
Definition of Exploratory Endpoints
 
 
 
 
 
 
 
6.3.2.
Analysis Methods for Other Endpoints of Interest
 
 
 
 
PPD
PPD


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


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
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 Drug 
Safety and Public Health 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.
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 


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stop date is not prior to the first dose date of study drug. The event is considered treatment 
emergent if both of the following 2 criteria are met:

The AE onset and end dates are the same as or after the month and year (or year) of 
the first dose date of study drug

The AE onset date is the same as or before the month and year (or year) of the 30th 
day after the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a 
stop date later than the first dose date of study drug, will be considered to be treatment
emergent.
7.1.6.
Summaries of Adverse Events and Deaths
A brief high-level summary of TEAEs will be provided by 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 LDV/SOF (90mg/400mg) or LDV/SOF(22.5mg/100mg); 
any AE leading to interruption of  LDV/SOF (90mg/400mg) or LDV/SOF(22.5mg/100mg). 
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, 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 

All AEs leading to premature discontinuation of LDV/SOF 

Deaths


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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 of the pooled treatment groups within each SOC. In summaries by 
severity grade, the most severe grade will be used for those AEs that occurred more than 
once in an individual subject during the study. 
In addition to the above summary tables, TEAEs will be summarized by PT only, in order of 
descending incidence for:

AEs of Grade 3 or above

All treatment-related AEs

All SAEs

AEs leading to premature discontinuation of LDV/SOF 
In addition to the by-treatment summaries described above, data listings will be provided for 
the following:

All AEs (with a variable indicating whether the event is treatment emergent)

AEs of Grade 3 or above

SAEs

Deaths

AEs leading to premature discontinuation of LDV/SOF 
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 
30 days for subjects who have permanently discontinued study drug or all available data at 
the time of the database snapshot for subjects those who were ongoing at the time of an 
interim analysis. The analysis will be based on values reported in conventional units. When 
values are below the limit of quantitation, they will be listed as such, and the closest imputed 
value will be used for the purpose of calculating summary statistics. For example, if “< 0.2” 
was recorded, a value of 0.1 will be used for the purpose of calculating summary statistics; if 
“< 0.1” was recorded, a value of 0.09 will be used for the purpose of calculating summary 
statistics. Hemolyzed test results will not be included in the analysis, but they will be listed in 
by-subject laboratory listings.
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 


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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 for ALT, aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, 
hemoglobin, reticulocytes, white blood cell (WBC), neutrophils, lymphocytes, platelets, 
activated partial thromboplastin time (APTT), International Normalized Ratio of prothrombin 
time(INR), creatinine and CrCL (Schwartz formula) as follows:

Baseline values

Values at each postbaseline time visit

Change from baseline at each postbaseline visit
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 ALT, AST, total bilirubin, alkaline phosphatase, 
creatinine, hemoglobin, reticulocytes, WBC, neutrophils, lymphocytes, and platelets 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 3.8.3 (Selection of Data in the Event of Multiple Records in a Window). 
7.2.2.
APRI Calculation
AST to Platelet Ratio Index (APRI) is assessed at screening, week 12, Early Study Drug 
Discontinuation (ESDD) as applicable, and Post Treatment Week 4. APRI is derived by 
corresponding AST, platelet value with formula: [AST (U/L)/upper limit of normal (U/L)] × 
100/platelets (10^9/L). Local lab National Cancer Institute, Egypt (NCI) ULN of AST is 46 
U/L. Descriptive statistics and change from baseline will be provided. 
7.2.3.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will 
be used for assigning toxicity grades (0 to 4) to laboratory results for analysis. 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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7.2.3.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of 
last dose of study drug plus 30 days for subjects who permanently discontinued study drug,
or all available data in the database snapshot for subjects who were still on treatment at the 
time of an interim analysis. If the relevant baseline laboratory value is missing, then any 
abnormality of at least Grade 1 will be considered treatment emergent.
7.2.3.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline 
visit.
The following summaries (number and percentage of subjects) for treatment-emergent 
laboratory abnormalities will be provided by analyte and treatment group; subjects will be 
categorized according to the most severe postbaseline abnormality grade for a given analyte:

Graded laboratory abnormalities

Grade 3 or above laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects 
with nonmissing postbaseline values up to 30 days after last dose for the laboratory 
parameter of interest.
A by-subject listing of treatment-emergent Grade 3 or above laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all 
test results that were collected throughout the study for the analyte of interest, with all 
applicable severity grades or abnormal flags displayed.
7.3.
Body Weight, Height, and Vital Signs
Vital signs (systolic and diastolic blood pressure [mmHg], pulse [beats/min]) , body weight
(kg), height (cm), and BMI(kg/m2) at each visit, and change from baseline at each visit will 
be summarized for the Safety Analysis Set using descriptive statistics (n, mean, SD, median, 
Q1, Q3, minimum, and maximum). 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 [oC]) will be provided by 


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subject ID number and visit in chronological order. In the same manner, a by-subject listing 
of body weight, height, and BMI will be provided separately.
7.4.
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.
7.4.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first study 
drug.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. 
Use of concomitant medications will be summarized by preferred name using the number 
and percentage of subjects for each treatment group. A subject reporting the same medication 
more than once will be counted only once when calculating the number and percentage of 
subjects who received that medication. The summary will be ordered by generic name in 
descending overall frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
For the purposes of analysis, any medications with a start date prior to or on the first dosing 
date of study drug and continued to be taken after the first dosing date, or started after the 
first dosing date but prior to or on the last dosing date of study drug will be considered 
concomitant medications. Medications started and stopped on the same day as the first dosing 
date or the last dosing date of study drug will also be considered concomitant. Medications 
with a stop date prior to the date of first dosing date of study drug or a start date after the last 
dosing date of study drug will be excluded from the 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 date of first study drug administration will be 
excluded from the concomitant medication summary. If a partial start date is entered, 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 start and stop dates will be included in the 
concomitant medication summary, unless otherwise specified. Summaries will be based on 
the Safety Analysis Set. No formal statistical testing is planned.
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. Anatomical Therapeutic Chemical (ATC) drug class will not be listed.
7.5.
Other Safety Measures
A data listing for cirrhosis determination will be provided for all subjects at screening.


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A data listing will be provided for subjects who become pregnant during the study.
No additional safety measures are specified in the protocol.
7.6.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
No pharmacokinetics (PK) sample was collected. As such, no PK analysis is planned for this 
study.


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9.
REFERENCES
16978
Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical Data 
Analysis. Chapter 13 in Berry, D.A. (ed.).  Statistical Methodology in the 
Pharmaceutical Sciences. New York: Marcel Dekker, Inc., 1989:pp. 414-21. 
20503
Chan IS, Zhang Z. Test-based exact confidence intervals for the difference of 
two binomial proportions. Biometrics 1999;55 (4):1202-9.
20839
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated 
in the Case of the Binomial. Biometrika 1934 Dec; 26 (4):pp. 404-13.


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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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APPENDICES


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12.


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Appendix 1.
Schedule of Assessments
Appendix Table 1.
Screening, On-Treatment Visits
Screening
Treatment
ESDD
Day -28
to Day -1
Baseline/
Day 1a
Week 1
(3 days)
Week 4
(3 days)
Week 8
(3 days)
Week 12
(3 days)
Consent /Assent
X
Demographics
X
Medical History
X
X
Physical exam (PE)
X
Symptom directed PE
X
X
X
X
X
X
Height and weight
X
X
X
X
X
X
Vital signsb
X
X
X
X
X
X
X
Swallowability Assessment
X
AEs and Con-Meds
X
X
X
X
X
X
X
HBsAg, HBsAb, HBcAb, HIV antibody, HAV 
antibody, HCV antibody
X
HCV RNA
X
X
X
X
X
X
X
HCV genotype
X
HBV DNA c
X
X
X
X
X
IL28B genotype
X
Urinalysis
X
Hematology and Blood Chemistry (including 
ALT)
X d
X
X
X
X
X
PPD


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Screening
Treatment
ESDD
Day -28
to Day -1
Baseline/
Day 1a
Week 1
(3 days)
Week 4
(3 days)
Week 8
(3 days)
Week 12
(3 days)
Fibrotest
X
X
X
X
FibroScan
X
APRI Calculation
X
X
X
Coagulation
X
X
X
X
Pregnancy test e
X
X
X
X
X
X
Pregnancy prevention counselingf
X
X
X
Dispense drug 
X
X
X
Review subject dosing diary 
X
X
X
X
X
Review of Study Drug Adherence and Drug 
Accountability
X
X
X
X
X
a
Baseline/Day 1 assessments must be performed prior to dosing.
b
Vital signs include resting blood pressure, pulse, respiratory rate, and temperature. SAE and study procedure related AEs are to be collected form informed consent. Other 
AEs are to be collected from Baseline/Day1.
c
HBV DNA testing done only when subjects are HBcAb positive at Screening
 
e
For females of childbearing potential only: serum β-hCG at Screening, urine test thereafter. If urine is positive, confirm immediately with serum β-hCG
f
If applicable
PPD


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Appendix Table 2.
Post-Treatment Study Visits
4 Weeks Post-Treatment
(5 days)
12 Weeks Post-Treatmenta
(5 days)
24 Weeks Post-Treatment
(5 days)
Clinical Assessments
Symptom-directed PE
X
Height and Weight
X
X
X
Vital Signs
X
AEs
X
Xa
Xa
Concomitant Medications
X
Fibrosis assessmentb
X
X
Pregnancy prevention counselingc
X
Laboratory Assessments
Hematology and Blood Chemistry
X
X
APRI Calculation
X
HCV RNA
X
X
X
HBV DNAd
X
X
X
Urine Pregnancy Testf
X
a
All SAEs, including deaths, regardless of cause or relationship, must be reported after patient signs the informed consent through the end of the study
b
Fibroscan and Fibrotest
c
If applicable
d
HBV DNA testing done only when subjects are HBcAb positive at Screening
 
f
Females of childbearing potential
PPD
PPD