A Phase 2b, Open-Label Study of 200 mg or 400 mg Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and Ledipasvir/Sofosbuvir (LDV/SOF) Fixed Dose Combination (FDC) Tablet for 12 Weeks in Genotype 1 or 4 HCV Infected Subjects With Renal Insufficiency
Phase: PHASE2
Conditions: HCV Infection
Sponsor: Gilead Sciences

Study Title: 
Sponsor: 
IND No.: 
EudraCT No: 
Indication: 
Protocol ID: 
Gilead Sciences 
Study Director 
Gilead Sciences 
Medical Monitor 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2b, Open-Label Study of200 mg or 400 mg 
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and 
Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination 
(FDC) Tablet for 12 weeks in Genotype 1 or 4 HCV-Infected 
Subjects with Renal Insufficiency 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106739 
2013-002897-30 
Hepatitis C Vims Infection 
GS-US-3 34-0154 
Name: 
Telephone: 
Fax: 
E-mail: 
Name: 
Telephone: 
Fax: 
E-mail: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
PPD 
t-'t-'U 
PPD 
PPD 
Theo Sarif, MD 
PPD 
PPD 
t-'t-'U 
11 July 2013 
05 September 2013 
20 Febmmy 2014 
23 Febmmy 2015 
CONFIDENTIALITY STATEMENT 
I 
I 
The inf01mation contained in this document, pmiiculm·ly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 

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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................11
1.
INTRODUCTION ..............................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.2.
Sofosbuvir (formerly GS-7977) .............................................................................................................14
1.3.
Ribavirin (RBV).....................................................................................................................................14
1.4.
Ledipasvir/Sofosbuvir Fixed-Dose Combination...................................................................................15
1.5.
Preliminary Results of Study GS-US-334-0154, Cohort 1.....................................................................15
1.5.1.
Pharmacokinetics .................................................................................................................15
1.5.2.
Safety....................................................................................................................................16
1.5.3.
Efficacy ................................................................................................................................16
1.6.
Rationale for the Current Study .............................................................................................................16
1.6.1.
Cohorts 1 and 2 ....................................................................................................................17
1.6.2.
Cohort 3................................................................................................................................17
1.7.
Rationale for SOF Dose Selection .........................................................................................................19
1.8.
Rationale for RBV Dose Selection.........................................................................................................19
1.9.
Rationale for Ledipasvir/Sofosbuvir Fixed Dose Combination (FDC) Dose Selection.........................20
2.
OBJECTIVES.....................................................................................................................................................22
3.
STUDY DESIGN................................................................................................................................................23
3.1.
Treatment Plan and Regimen .................................................................................................................23
3.2.
Visit Schedule ........................................................................................................................................23
3.3.
Virologic Response-Based Stopping Criteria.........................................................................................24
3.4.
Treatment Discontinuation Criteria........................................................................................................24
4.
SUBJECT POPULATION..................................................................................................................................25
4.1.
Number of Subjects and Subject Selection ............................................................................................25
4.2.
Inclusion Criteria....................................................................................................................................25
4.3.
Exclusion Criteria...................................................................................................................................27
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................29
5.1.
Sofosbuvir (SOF) ...................................................................................................................................29
5.1.1.
Formulation..........................................................................................................................29
5.1.2.
Packaging and Labeling .......................................................................................................29
5.1.3.
Storage and Handling...........................................................................................................29
5.1.4.
Sofosbuvir (SOF) Dosage and Administration.....................................................................30
5.2.
Ribavirin (RBV).....................................................................................................................................30
5.2.1.
Formulation..........................................................................................................................30
5.2.2.
Packaging and Labeling .......................................................................................................30
5.2.3.
Storage and Handling...........................................................................................................30
5.2.4.
RBV Dosage and Administration.........................................................................................30
5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV) ..............................................................31
5.4.
Ledipasvir/ Sofosbuvir (LDV/SOF).......................................................................................................31
5.4.1.
Formulation..........................................................................................................................31
5.4.2.
Packaging and Labeling .......................................................................................................31
5.4.3.
Storage and Handling...........................................................................................................31
5.4.4.
LDV/SOF Dosage and Administration ................................................................................32

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5.5.
Study Drug Compliance.........................................................................................................................32
5.6.
Dispensing and Accountability of Study Drugs .....................................................................................32
5.7.
Study Drug Return or Disposal ..............................................................................................................32
5.8.
Concomitant Medications ......................................................................................................................33
5.8.1.
Cohorts 1 and 2 ....................................................................................................................33
5.8.2.
Cohort 3................................................................................................................................33
5.8.3.
All Cohorts...........................................................................................................................34
6.
STUDY PROCEDURES ....................................................................................................................................38
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................38
6.2.
Pretreatment Assessments......................................................................................................................44
6.2.1.
Screening Visit .....................................................................................................................44
6.2.2.
Medical History....................................................................................................................44
6.3.
Day 1 Assessments.................................................................................................................................45
6.3.1.
Dosing Diary ........................................................................................................................45
6.4.
Treatment Assessments..........................................................................................................................45
6.4.1.
Cohorts 1 and 2 ....................................................................................................................45
6.4.2.
Cohort 3................................................................................................................................45
6.5.
Safety Assessments ................................................................................................................................45
6.5.1.
Safety ECGs.........................................................................................................................45
6.5.2.
Safety Echocardiograms.......................................................................................................46
6.5.3.
Physical Examination...........................................................................................................46
6.5.4.
Vital Signs............................................................................................................................46
6.5.5.
BMI ......................................................................................................................................47
6.5.6.
Creatinine Clearance ............................................................................................................47
6.5.7.
Clinical Laboratory Tests/Assessments................................................................................47
6.5.8.
Adverse Events/Concomitant Medications/Protocol Restrictions........................................48
6.6.
Pharmacokinetic (PK) Assessments.......................................................................................................48
6.7.
Early Termination (ET)/Unscheduled Visit ...........................................................................................49
6.8.
Post-Treatment Assessments..................................................................................................................50
6.9.
Optional Samples for Pharmacogenetic Testing ....................................................................................50
6.10.
Archived Plasma Sample .......................................................................................................................51
6.11.
Blood Storage.........................................................................................................................................51
7.
ADVERSE EVENTS MANAGEMENT ............................................................................................................52
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................52
7.1.1.
Adverse Events.....................................................................................................................52
7.1.2.
Serious Adverse Events........................................................................................................52
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................53
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................53
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................53
7.2.2.
Assessment of Severity ........................................................................................................54
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................54
7.4.
Gilead Reporting Requirements.............................................................................................................56
7.5.
Toxicity Management ............................................................................................................................56
7.5.1.
Stopping Rules for Toxicity .................................................................................................56
7.5.2.
Sofosbuvir (SOF) or LDV/SOF............................................................................................56
7.5.3.
Ribavirin (RBV)...................................................................................................................57
7.6.
Special Situations Reports......................................................................................................................57
7.6.1.
Definitions of Special Situations..........................................................................................57
7.6.2.
Instructions for Reporting Special Situations.......................................................................57

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8.
STATISTICAL CONSIDERATIONS................................................................................................................59
8.1.
Analysis Objectives and Endpoints........................................................................................................59
8.1.1.
Analysis Objectives..............................................................................................................59
8.1.2.
Primary Endpoint .................................................................................................................59
8.1.3.
Secondary Endpoint .............................................................................................................60
8.1.4.
Other Endpoints of Interest ..................................................................................................60
8.2.
Analysis Conventions.............................................................................................................................60
8.2.1.
Analysis Sets ........................................................................................................................60
8.2.2.
Data Handling Conventions .................................................................................................61
8.2.3.
Interim Analysis ...................................................................................................................62
8.3.
Demographic Data and Baseline Characteristics ...................................................................................62
8.4.
Efficacy Analysis ...................................................................................................................................62
8.4.1.
Primary Analysis..................................................................................................................62
8.4.2.
Secondary Analysis..............................................................................................................62
8.5.
Safety Analysis.......................................................................................................................................63
8.5.1.
Extent of Exposure...............................................................................................................63
8.5.2.
Adverse Events.....................................................................................................................63
8.5.3.
Laboratory Evaluations ........................................................................................................64
8.6.
Pharmacokinetic Analysis......................................................................................................................64
8.7.
Stopping Rules for Individual Groups....................................................................................................64
8.8.
Sample Size............................................................................................................................................65
8.9.
Data Monitoring Committee ..................................................................................................................65
9.
RESPONSIBILITIES..........................................................................................................................................66
9.1.
Investigator Responsibilities ..................................................................................................................66
9.1.1.
Good Clinical Practice..........................................................................................................66
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval...............................................................................................................................66
9.1.3.
Informed Consent.................................................................................................................66
9.1.4.
Confidentiality......................................................................................................................67
9.1.5.
Study Files and Retention of Records ..................................................................................67
9.1.6.
Case Report Forms...............................................................................................................68
9.1.7.
Drug Accountability.............................................................................................................69
9.1.8.
Inspections............................................................................................................................69
9.1.9.
Protocol Compliance............................................................................................................69
9.2.
Sponsor Responsibilities ........................................................................................................................70
9.2.1.
Protocol Modifications.........................................................................................................70
9.2.2.
Study Report and Publications .............................................................................................70
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................70
9.3.1.
Access to Information for Monitoring..................................................................................70
9.3.2.
Access to Information for Auditing or Inspections ..............................................................71
9.3.3.
Study Discontinuation..........................................................................................................71
10.
REFERENCES ...................................................................................................................................................72
11.
APPENDICES ....................................................................................................................................................74
VERSION: 18 JUNE 2012..........................................................................................................................................79
Appendix 1.
Investigator Signature Page....................................................................................................75
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................76
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............79

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LIST OF IN-TEXT TABLES
Table 1-1.
Preliminary Comparison of the Effect of Severe Renal Impairment on GS-331007 
and SOF Exposure in HCV-infected and Non-HCV-Infected Subjects .................................16
Table 1-2.
SVR4 Rates in Genotype 4 Subjects from Study GS-US-337-1119 ......................................18
Table 1-3.
Observed and Predicted GS-331007 and SOF Exposure in Subjects with Renal 
Impairment .............................................................................................................................21
Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution .....................................34
Table 6-1.
Schedule of Assessments for Cohorts 1 and 2........................................................................39
Table 6-2.
Schedule of Assessments for Cohort 3 ...................................................................................42

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404, USA
Study Title:
A Phase 2b, Open-Label Study of 200 mg or 400 mg
Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and 
Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination (FDC) 
Tablet for 12 weeks in Genotype 1 or 4 HCV-Infected Subjects with 
Renal Insufficiency
IND Number:
Eudra CT Number:
106739
2013-002897-30
Study Centers Planned:
Multiple sites in New Zealand, Europe, North America and 
South America
Number of Subjects 
Planned:
Approximately 30 subjects
Target Population:
Adults with chronic renal insufficiency and HCV infection
Treatment Duration:
12 weeks or 24 weeks
Objectives:
The primary objectives of this study are:

To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg
+ ribavirin (RBV) for 24 weeks and LDV/SOF for 12 weeks as 
assessed by review of the accumulated safety data in each 
treatment arm

To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg
+ ribavirin (RBV) for 24 weeks and LDV/SOF for 12 weeks
measured by the proportion of subjects with renal insufficiency 
who have achieved a sustained viral response 12 weeks after 
treatment discontinuation (SVR12) in each treatment arm

To evaluate the steady state pharmacokinetics of SOF and its 
metabolites and LDV upon dosing SOF 200 mg or 400 mg or
LDV/SOF in subjects with renal insufficiency 

Sovaldi® (Sofosbuvir) 
Protocol GS-US-334-0154 
Gilead Sciences, Inc. 
Study Design: 
Diagnosis and Main 
Eligibility Criteria: 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
The secondruy objectives of this study ru·e: 
Final 
Amendment3 
• 
To evaluate the prop01tion of subjects with renal insufficiency 
who attain SVR at 4 and 24 weeks after discontinuation of 
u·eatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after 
u·eatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV 
during and after u·eahnent discontinuation 
The explorat01y objective of this study is: 
This study will emoll approximately 30 subjects with severe renal 
insufficiency. 
• 
Cohort 1: 10 subjects will receive SOF 200 mg QD + 
RBV 200 mg QD for 24 weeks. 
• 
Cohort 2: Following review of safety, efficacy and PK data 
through post-u·eatment Week 4 ofCoh01t 1, 
10 additional subjects will receive SOF 400 mg QD + 
RBV 200 mg QD for 24 weeks. 
• 
Cohort 3: Following review of safety and available PK data 
through Week 12 of Coh01t 2, 10 additional subjects will receive 
LDV/SOF QD for 12 weeks. 
Adults (~ 18 years) with chronic genotype 1 or genotype 3 
(for Coh01ts 1 and 2) or genotype 1 or 4 (for Coh01t 3) HCV 
infection. Reference Sections 4.2 and 4.3 for detailed Inclusion and 
Exclusion criteria. 
Screening assessments will be completed within 42 days of the 
Day 1 visit. 
Study visits will occur at Screening, Day 1, and at the end of 
Weeks 1, 2, 4, 6, 8, 10, 12 (all cohorts), and Weeks 16, 20 and 24 
(Cohorts 1 and 2 only) and at Post-Treatment Weeks 4, 12, and 24 
(all coh01ts). Screening assessments will include physical 
examination, height, weight, vital signs, 12-lead ECG, 
echocru·diogram, concomitant medications, safety laborat01y tests, 
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HCV RNA, serology (HIV, HCV, HBV), hemoglobin A1c (HbA1c), 
serum β-hCG (females of child bearing potential only), IL28B 
genotyping.
On-treatment assessments will include adverse events (AEs), 
concomitant medications, study medication pill count, physical 
examination, vital signs, 12-lead ECGs, echocardiogram, safety 
laboratory tests, HCV RNA, pharmacokinetic samples, and serum 
pregnancy tests (females of child bearing potential only). 
Post-treatment assessments will include AEs, concomitant 
medications, vital signs, safety laboratory tests, HCV RNA, and 
serum pregnancy tests (females of child bearing potential only).
Samples for viral RNA sequencing will be collected at Day 1 and 
every visit thereafter. Samples will be collected during treatment 
visits for PK analysis of study drug(s).
PK assessments
Intensive PK Assessments
Cohorts 1 and 2:
Serial blood samples will be collected on week 2 and 12 at the 
following timepoints:

0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours 
post-dose.
Cohort 3:
Serial blood samples will be collected once either on week 2 or 4 
(per investigator discretion) at the following timepoints:

0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours 
post-dose.
Plasma concentrations of SOF and its metabolites and LDV will be 
determined and PK parameters will be estimated as appropriate. 
Plasma concentrations of RBV may be determined, if necessary.
Trough PK Assessments:
Trough PK plasma samples for analyses of SOF, its metabolites,
RBV (as applicable) and LDV concentrations will be collected at all 
other on treatment visits beginning at the Week 1 visit.
PK Parameters for SOF, its metabolites, LDV and RBV will be 
estimated as appropriate. 

Sovaldi® (Sofosbuvir) 
Protocol GS-US-334-0154 
Gilead Sciences, Inc. 
Test Product, Dose, and 
Mode of Administration: 
Reference Therapy: 
Criteria for Evaluation: 
Safety: 
Efficacy: 
CONFIDENTIAL 
Optional Genetic Sample Collection 
PPD 
Archived Plasma Sample 
Final 
Amendment3 
Archive plasma samples are being collected for possible additional 
analyses, including but not limited to, study dmg or metabolite 
measmements, viral load, safety/efficacy assessments, HCV gene 
sequencing, HCV resistance testing and other possible predictors of 
response as detennined by Gilead. 
Sofosbuvir is manufactmed as 100 mg and 400 mg tablets for oral 
adminisu·ation. Subjects emolled to take the 200 mg dose will take 
2 x 100 mg tablets for a total dose of 200 mg orally QD in the 
moming with RBV and with food. Subjects emolled to take the 
400 mg dose will take 1 x 400 mg tablet for a total dose of 400 mg 
orally QD in the moming with RBV and with food. 
RBV will be supplied as a 200 mg tablet for oral adminisu·ation by 
Gilead Sciences. Subjects will take 1 x 200 mg tablet in the moming 
with SOF and with food. 
LDV/SOF is manufactmed as a fixed-dose combination tablet, 
consisting of90 mg LDV and 400 mg SOF, for oral adminisu·ation. 
All subjects will take 1 tablet daily with or without food. 
None 
AEs, SAEs, and safety labs will be collected throughout the study. 
Safety will be evaluated by assessment of clinicallaborat01y tests, 
ECG, echocardiogram, periodic physical examinations including 
vital signs at various time points dming the study, and by the 
documentation of adverse events. 
Efficacy will be evaluated usini scheduled assessments of HCV 
RNA perf01m ed using COBAS AmpliPrep/COBAS® TaqMan® 
HCV Test. 
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PK:
Plasma PK parameters will be calculated for sofosbuvir and its 
metabolites GS-566500 and GS-331007, LDV and RBV, as 
applicable. Examples are AUClast, AUCtau, Cmax, Clast, Ctau, and t1/2.
Statistical Methods:
Safety data will be listed by subject and summarized by treatment 
cohort using frequency of event/abnormality or descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean, % coefficient 
of variation [CV], standard deviation [SD], minimum, Q1, median, 
Q3, and maximum).
The steady state PK plasma concentrations and parameters will be 
listed by subject and summarized by treatment cohort using 
descriptive statistics for each analyte (SOF, GS-566500, GS-331007, 
RBV and LDV, as appropriate). 
In the efficacy analysis, no statistical hypothesis testing will be 
performed and no formal inferences will be made on the primary 
efficacy endpoint SVR12. A point-estimate with two-sided 95% 
exact confidence interval (CI) using the binomial distribution 
(Clopper-Pearson method) will be constructed for the SVR12 rate by 
treatment cohort. Similar analysis will be also performed for 
secondary endpoints SVR4 and SVR24.
To evaluate the kinetics of circulating HCV RNA during and after 
treatment discontinuation, viral load data will be listed by subject 
and summarized by treatment cohort and visit using descriptive 
statistics.
Due to the exploratory nature of this study, no formal power or 
sample size calculations were performed to determine treatment 
group size. The total sample size of 30 is largely based on 
feasibility.
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs) including archiving of essential documents.

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase (also SGPT)
ANC
absolute neutrophil count
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase  (also SGOT)
AUC
area under the curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval 
(tau)
BID
twice a day 
BLQ
below the lower limit of quantification
BMI
body mass index
BW
body weight
CLcr
Creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Ctau
observed drug concentration at the end of the dosing interval (tau)
CRF
case report form(s)
CRO
Contract (or clinical) research organization 
DAA
direct-acting antiviral
dL
Deciliter
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
ESAs
Erythropoiesis stimulating agents
ESRD
End Stage Renal Disease
EU
European Union
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GT
Genotype (viral)
Hb
Hemoglobin
HbA1c
Hemoglobin A1c

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDPE
high-density polyethylene
HIV
Human Immunodeficiency Virus
HLGT
High-Level Group Term
HLT
High-Level Term
IBW
Ideal Body Weight
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL28B
IL28B gene
IND
Investigational New Drug (Application)
IRB
institutional review board
IUD
intrauterine device
IV
Intravenous
kg
Kilogram
L
Liter
LDH
Lactase dehydrogenase
LDV
Ledipasvir
LLN
lower limit of the normal range
LLOD
Lower limit of detection
LLOQ
Lower limit of quantification
LLT
Lower-Level Term 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MH
Mantel-Haenszel
mL
Milliliter
Min
Minute
mmHg
millimeters mercury
NS (3/4A/5A/5B)
Non-structural Protein
PBMC
peripheral blood mononuclear cell(s)
PEG
Pegylated interferon
P-gp
P-glycoprotein
PI
Protease inhibitor
PK
Pharmacokinetic
po
Per os (by mouth)
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’s formula
RBC
Red blood cell count 

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
RBV
Ribavirin
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
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
TSH
Thyroid stimulating hormone
t½
An estimate of the terinal elimination half-life of the drug in 
serum/plasma/PBMC, calculated by dividing the natural log of 2 by the terminal 
elimination rate contstant (λz)
ULN
upper limit of the normal range
US
United States
WBC
white blood cell count

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1.
INTRODUCTION
1.1.
Background
Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease worldwide 
and accounts for 70% of cases of chronic hepatitis in industrialized countries. The global 
prevalence of chronic hepatitis C is estimated to average 3% {19705}. The most common 
genotype worldwide is genotype 1 followed by genotypes 2 and 3 {19705}. Although there is 
evidence that the incidence of viral infection may be decreasing, the prevalence of liver disease 
caused by HCV is on the rise, primarily due to the lag between the onset of infection and the 
clinical manifestation of liver disease {19705}. The prevalence of chronic HCV is significantly 
higher among patients with chronic renal failure, and HCV itself is associated with impaired 
renal function. Treatment of these individuals is therefore recommended but is often complicated 
by the substantial increase in hematologic toxicities associated with the use of ribavirin in the 
setting of low creatinine clearance {23275}.
1.2.
Sofosbuvir (formerly GS-7977)
Sovaldi® (sofosbuvir) is a potent nucleotide analogue that inhibits HCV RNA replication in vitro 
and has demonstrated high rates of sustained viral response (SVR) when administered with RBV, 
with or without pegylated interferon, to subjects with chronic genotype 1-6 HCV infection 
{32081}, {23275}, {24713}, {24715}, {27832}. Sovaldi® has been approved in the United States 
(GT1-4) and in the European Union (GT1-6) for the treatment of chronic HCV infection 
including treatment naïve and experienced patients and HIV/HCV co-infected patients.
For further information on the clinical pharmacology, virology, safety and efficacy of sofosbuvir 
(SOF), please refer to the current version of the Investigator’s Brochure and US and EU 
prescribing information.
1.3.
Ribavirin (RBV)
Ribavirin is a guanosine analogue that inhibits the in vitro replication of a wide range of RNA 
and DNA viruses {15572}, {15668}. Ribavirin monotherapy has little or no effect on the 
replication of HCV but can result in short term normalization of serum ALT activity. When 
combined with interferon or PEG therapy, RBV decreases substantially the relapse rate seen after 
cessation of interferon therapy {12557}, {12558}.
Ribavirin is a known teratogen (FDA category X). Furthermore, RBV is known to accumulate 
intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, extreme care 
must be taken to avoid pregnancy during RBV therapy and for up to 6 months following 
completion of treatment. A comprehensive review of RBV is contained in the package 
insert/SmPC.

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1.4.
Ledipasvir/Sofosbuvir Fixed-Dose Combination
Harvoni® (ledipasvir/sofosbuvir fixed-dose combination (LDV/SOF) combines 
two HCV specific-direct acting antivirus (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 that has demonstrated potent anti-HCV activity against genotypes 1 and 4 HCV 
infection. Harvoni® has been approved in the United States and Europe for the treatment of 
chronic HCV infection including treatment naïve and experienced patients with genotype 1. 
For further information on the clinical pharmacology, virology, safety and efficacy of LDV/SOF, 
please refer to the current version of the Investigator’s Brochure and US prescribing information.
1.5.
Preliminary Results of Study GS-US-334-0154, Cohort 1
Preliminary results are available and presented below for Cohort 1: 10 subjects with estimated 
glomerular filtration rate (eGFR by Cockcroft-Gault) less than 30 mL/min within six months of 
screening, not on dialysis, treated with SOF 200 mg + RBV 200 mg daily for 24 Weeks. A 
review of the integrated safety, PK and efficacy from this first cohort demonstrate that 
SOF 200 mg + RBV 200 mg daily for 24 weeks is safe and relatively well tolerated.
1.5.1.
Pharmacokinetics
Preliminary pharmacokinetic data are available for subjects in Cohort 1 who received 
200 mg SOF + 200 mg RBV for 24 weeks. Exposure (from intensive PK sampling) of SOF and 
its predominant circulating renally eliminated metabolite (GS-331007) were similar at 
Week 2 and Week 12; as such further PK analyses are conducted with the Week 12 data 
(Table 1-1). 
As expected, in the Cohort 1 HCV-infected subjects, severe renal impairment increases 
GS-331007 and SOF exposures. In general, when normalized to subjects with normal renal 
function, the results are comparable to that observed in the non HCV-infected renal impairment 
study (P7977-0915, %GMR in Table 1-1). The only exception was the increase in GS-331007 
Cmax seen in severe renal impaired HCV-infected subjects as opposed to the non-infected subjects 
(%GMR HCV-infected vs. non-infected: 589% vs. 134%). This difference in GS-331007 Cmax is 
likely a result of expected accumulation of GS-331007 upon steady state dosing in the 
Study GS-US-334-0154 as compared to single dose administration in the P7977-0915 study.

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Table 1-1.
Preliminary Comparison of the Effect of Severe Renal Impairment 
on GS-331007 and SOF Exposure in HCV-infected and 
Non-HCV-Infected Subjects
Mean (%CV) PK Parameter
GS-331007
SOF
AUCinf or tau 
(ng•hr/ml)
Cmax
(ng/ml)
AUCinf or tau 
(ng•hr/ml)
Cmax
(ng/ml)
HCV-Infected Subjects
GS-US-334-0154 SOF 200 mg cohort
Week 12 (n = 10)
31,100 (53.9)
1730 (44.9)
1280 (50.3)a
904 (66.2)
Phase 2/3 Population Dose normalized to SOF 200 mg
(SOF n = 838, GS-331007 n = 1695)
3561 (30.7)
291 (36.3)
513 (36.5)
256 (32.5)
%GMR (90% CI)
817
(694, 963)
589
(481, 721)
233
(193, 282)
321
(261, 395)
Non HCV-Infected Subjects (P7977-0915)
%GMR (90% CI)
(Severe Impairment/Normal Function)
551
(313, 968)
134
(98.6, 183)
271
(183, 402)
177
(96.6, 324)
Note: PK parameters are presented as mean (%CV) to three significant digits.
a
n = 9
Source: Ad Hoc Table 6822.2, P7977-0915 Table 11.13
1.5.2.
Safety
Sofosbuvir was generally well-tolerated and safe when administered with RBV in Cohort 1. 
Most adverse events (AEs) were mild to moderate in severity. There were two serious AEs 
(SAEs) of unstable angina and hyperglycaemic hyperosmolar nonketotic syndrome which were 
assessed by the investigators as not related to the study drugs. Neither event led to change in 
study drug administration. The most frequently reported AEs were anemia, headache, pruritus, 
and rash. Renal function and cardiac function were stable during treatment as assessed by eGFR,
safety ECG and echocardiograms, respectively.
1.5.3.
Efficacy
All subjects experienced rapid on-treatment virologic decline similar to those with normal renal 
function and full-dose SOF+RBV. There were no subjects with virologic breakthrough. 
One subject withdrew consent and stopped treatment at Week 12; he did not return for 
post-treatment visits. One subject prematurely discontinued treatment at Week 21. Overall, 
4 of the 10 (40%) subjects achieved SVR4.
1.6.
Rationale for the Current Study
This study will evaluate the safety, efficacy and pharmacokinetics of treatment with SOF+RBV 
for 24 weeks (for genotype 1 or 3) and of treatment with LDV/SOF for 12 weeks (for genotype 1 
or 4) in subjects with chronic HCV infection and severe renal impairment.

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Interferon monotherapy, however, is associated with poor tolerability, a 48 week treatment 
duration, and efficacy of approximately 40%. Furthermore, once patients have failed this course 
of treatment, they have no further treatment options and are at risk for progression of liver 
disease, cirrhosis, and hepatocellular carcinoma.
1.6.1.
Cohorts 1 and 2
To date, SOF+RBV has demonstrated safety and efficacy in a broad range of subjects with 
chronic HCV infection in Phase 2 and Phase 3 clinical trials. However, subjects with 
Cr clearance <60 mL/min have been excluded from these studies due to the recommendation 
that RBV not be administered to patients with Cr clearance <50 mL/min. In addition,
study P7977-0915 has shown the major circulating metabolite of SOF, GS-331007, is renally 
cleared and a single dose study conducted in subjects with severe renal impairment or end-stage 
renal disease on hemodialysis demonstrated exposures approximately 1.6-fold and 14 to 22-fold 
higher, respectively, than those observed in matched controls with normal renal function. Whilst 
dose reduction of SOF would reduce these exposures, viral efficacy is dependent on SOF 
exposures such that lower SOF doses or intermittent administration could be associated with 
reduced efficacy. Thus, this exploratory study of safety and efficacy of standard (400 mg) and 
reduced (200 mg) doses of SOF in combination with low-dose RBV in a small number of 
subjects will provide important data regarding dosing recommendations for use of SOF in this 
patient population with a high unmet medical need.
Phase 3 studies of SOF+RBV for 12 or 16 weeks in treatment-naïve and treatment-experienced 
genotype 3 HCV-infected subjects demonstrated SVR12 rates of 56% and 62%, respectively. 
Increasing treatment duration to 24 weeks may further improve response rates. In Phase 2 studies 
of SOF+RBV for 12 or 24 weeks in treatment-naïve genotype 1 HCV-infected subjects, SVR 
rates have varied from 47% to 84% depending on the study and patient population. In both 
genotypes 1 and 3, lower doses of RBV have been associated with reduced efficacy of the 
regimen. Given the safety need for a reduced RBV dose in the current study (Section 1.8), 
treatment with SOF+RBV will be administered for 24 weeks to maximize efficacy. Subjects with 
genotypes 1 or 3 HCV infection have been selected for this study since they represent the largest 
group of HCV-infected individuals in the regions where this study will be conducted and because 
the 24 week treatment regimen is appropriate. In contrast, genotype 2 HCV-infected subjects 
have been shown to have high response rates following 12 weeks of SOF+RBV therapy. If 
SOF+RBV is well tolerated for 24 weeks in patients with severe renal insufficiency, safety for 
12 weeks in this smaller HCV population may be inferred.
1.6.2.
Cohort 3
To date in subjects with a CrCl > 60 mL/min, LDV/SOF without RBV has an excellent safety 
profile, with efficacy > 93% in all patient populations {31179}. Cohort 3, in which LDV/SOF for 
12 weeks will be the treatment regimen, will generate clinical data in a patient population with a 
regimen which is the Standard of Care (SOC) for genotype 1. 

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Phase 3 trials with LDV/SOF demonstrated the addition of RBV to LDV/SOF for the treatment 
of HCV in genotype 1 subjects did not increase efficacy. As such, Cohort 3 will not include RBV 
which is of particular benefit for this patient population in which chronic anemia is common; the 
preliminary data from Cohort 1 with SOF 200mg + RBV indicate that anemia was the most 
frequent AE and led to increased epoetin use.
In Cohort 3, the safety, efficacy and pharmacokinetics of LDV/SOF 90/400 mg will be evaluated 
in subjects with severe renal impairment. Data from GS-US-344-0108 demonstrated that severe 
renal impairment had no effect on LDV exposure. As described above for Cohorts 1 and 2, 
impaired renal function significantly increases GS-331007 exposure. As such, progression of 
GS-331007 exposure across cohorts was a major consideration in determining the appropriate 
design for this study (see Section 1.9). 
Because over 70% of HCV-infected individuals in the US and Europe have genotype 1, they 
represent the greatest unmet medical need, and therefore will be the priority for generating data 
in renal impairment across cohorts of this study. For Cohort 3, both preclinical and clinical data 
support the inclusion of genotype 4 HCV-infected subjects. Activity of LDV was evaluated in a 
subgenomic genotype 4d HCV replicon. In the replicon system, the EC50 value of LDV against 
genotype 4d HCV was 0.60 nM and 0.39 nM for genotype 4a HCV (compared with EC50 values 
of LDV against genotype 1a and genotype 1b of 0.031 nM and 0.004 nM, respectively).
In the Phase 3 Study GS-US-337-0102 (ION-1), 2 subjects with genotype 4d HCV infection 
were inadvertently randomized in violation of the protocol inclusion/exclusion criteria. Both 
subjects achieved SVR12. Subject 
 was treated for 12 weeks with LDV/SOF and 
Subject
 was treated for 24 weeks with LDV/SOF+RBV.
In Study GS-US-337-1119, a European study investigating the efficacy and safety of LDV/SOF 
in treatment-naive and treatment-experienced subjects with chronic genotype 4 or genotype 
5 HCV infection, a total of 44 subjects with genotype 4 HCV infection, of whom 10 (23%) have 
cirrhosis and 22 (50%) are treatment experienced, have been enrolled to receive LDV/SOF for 
12 weeks. SVR4 data are available from Study GS-US-337-1119 in 25 subjects with genotype 4 
and18 subjects with genotype 5 HCV infection. 
Table 1-2.
SVR4 Rates in Genotype 4 Subjects from Study GS-US-337-1119
Genotype 4
Overall
96% (24/25)
Treatment Naive
100% (12/12)
Treatment Experienced
92% (12/13)
Cirrhosis
100% (7/7)
No Cirrhosis
94% (17/18)
PPD
PPD

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In addition, preliminary data are available from Group E of the NIAID/NIH collaborative 
Study CO-US-337-0117. In this group, 21 subjects with genotype 4 HCV infection, of whom 
13 are treatment naive and 8 are treatment experienced, are receiving 12 weeks of LDV/SOF 
treatment. In total, 6 subjects have cirrhosis. Post-treatment week 12 data is available for 
20 subjects, 19 of 20 subjects have achieved SVR12.
Study GS-US-337-0115 (ION-4) is investigating the efficacy and safety of LDV/SOF in 
genotype 1 and genotype 4 HCV-infected subjects coinfected with HIV. A total of 8 subjects 
with genotype 4 HCV infection have been enrolled. All 8 subjects have achieved SVR4. 
1.7.
Rationale for SOF Dose Selection
Sofosbuvir 400 mg, once daily, when dosed in combination with RBV with or without PEG has 
demonstrated broad genotypic efficacy and a favorable safety profile in over 3300 HCV-infected 
subjects across multiple patient populations in Phase 2 and 3 trials. This dose (400 mg) is the 
proposed to be marketed dose of sofosbuvir for the treatment of HCV-infection.
In study P7977-0915, a single dose PK study in subjects with varying degrees of renal 
impairment, exposure (AUCinf) of sofosbuvir and the renally eliminated metabolite, GS-331007, 
were 2.7- and 5.5-fold higher respectively in subjects with severe renal impairment compared to 
matched controls with normal renal function.  A significant dose reduction (eg, 2- to 4-fold) of 
sofosbuvir would be necessary to provide comparable GS-331007 exposures in subjects with 
severe renal impairment and those with normal renal function. Data from dose-finding and 
Phase 2 studies demonstrated that sofosbuvir, dosed once daily, was necessary to provide the 
active anabolite at the site of action (circulating GS-331007 cannot be phosphorylated to the 
active anabolite); therefore, dose interval modifications may not be appropriate. The efficacy of a 
substantially reduced dose of sofosbuvir in subjects with severe renal impairment has not been 
established.  
Cohorts 1 and 2 of this study will evaluate the safety, efficacy and pharmacokinetics of 2 doses 
of sofosbuvir (200 and 400 mg) in subjects with severe renal impairment. The reduced dose of 
200 mg sofosbuvir provided comparable systemic exposures of sofosbuvir, and approximately 
4-fold higher GS-331007 exposure compared to HCV-infected in subjects with normal renal 
function at the 400 mg dose. As such, GS-331007 and SOF exposures in Cohort 2 (400 mg SOF) 
are expected to increase 2-fold over that observed in Cohort 1. Review of safety, efficacy and 
pharmacokinetic data from Cohort 2 through 12 weeks of treatment will inform the initiation of 
Cohort 3 (90/400 mg LDV/SOF in subjects with severe renal impairment).
1.8.
Rationale for RBV Dose Selection
Ribavirin increases treatment response rates when administered with interferon or PEG. In 
addition, reducing the RBV dose from 1000-1200 mg/day to 600 or 800 mg/day when given in 
combination with SOF reduced SVR rates, as did SOF monotherapy. It is therefore desirable to 
keep RBV as part of the SOF treatment regimen. Since RBV is cleared renally and its main 
toxicity is hemolytic anemia which is poorly tolerated in patients with advanced renal 
insufficiency who are usually anemic at baseline and have little bone marrow reserve, the 

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starting dose of RBV must be substantially lower than 1000-1200 mg/day. For this study, a dose 
of 200 mg/day has been selected based on investigator input in light of the high frequency of 
hemotoxicity of RBV and the general desire to optimize the efficacy of the treatment regimen
{24149}.
To date there has been no safety signal identified that is attributable to SOF when administered 
as part of a combination regimen. Furthermore, SOF does not exacerbate the toxicities associated 
with RBV, most notably hemolytic anemia. Clinical data with SOF in severe renal insufficiency 
and in subjects requiring hemodialysis is limited to a single dose study in non-HCV infected 
subjects. No specific safety signals were identified. The current study is designed to assess the 
safety and efficacy of therapeutic treatment with SOF+RBV in a small number of subjects with 
severe renal insufficiency. 
The potential benefit of successful treatment of HCV in these subjects is substantial. Few 
patients with severe renal insufficiency can tolerate combination therapy with PEG+RBV due to 
profound anemia. SVR rates to interferon monotherapy administered for 48 weeks are less than 
50%. Interferon-free treatment for 24 weeks could provide substantial improvements in safety, 
tolerability and efficacy for individuals with chronic HCV infection.
1.9.
Rationale for Ledipasvir/Sofosbuvir Fixed Dose Combination (FDC) Dose 
Selection
A fixed-dose combination tablet (FDC) of ledipasvir/sofosbuvir 90/400 mg with or without RBV 
has demonstrated favorable safety and efficacy profiles in over 3000 HCV-infected subjects 
across different patient populations in Phase 2 and 3 trials. This FDC represent the marketed 
doses of ledipasvir and sofosbuvir (Harvoni®, LDV/SOF) approved in the US and Europe for the
treatment of chronic HCV infection including treatment naïve and experienced patients with 
GT1.
In support of dosing LDV/SOF to HCV-infected subjects with severe renal impairment, available 
pharmacokinetic data has been evaluated to project mean exposures of GS-331007 and SOF that 
may be achieved in these subjects (Table 1-3). Overall, increased GS-331007 exposures are 
expected in the context of LDV/SOF as compared to SOF administered as single agent 
(SOF USPI and LDV/SOF NDA, Module 2.7.2). Minimal safety data is available at these high 
exposures, irrespective of SOF being administered with LDV or as a single agent. The study 
design allows for consistent progression (~2-3 fold increase) of GS-331007 exposure across 
cohorts enabling assessment of exposure vs. safety relationships while potentially providing 
greater efficacy with the two-drug combination. 

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Table 1-3.
Observed and Predicted GS-331007 and SOF Exposure in Subjects 
with Renal Impairment
Mean (%CV, if applicable)
PK Parameter
GS-331007
SOF
AUCtau 
(ng•hr/ml)
Cmax 
(ng/ml)
AUCtau 
(ng•hr/ml)
Cmax
(ng/ml)
Observed Data
GS-US-334-0154 Cohort 1 SOF 200 mg
Week 12 (n = 10)
31,100
(53.9)
1730
(44.9)
1280
(50.3)
904
(66.2)
Predicted Data
Cohort 3:
LDV/SOF 90/400 mg in Severe RIa
111,000
4400
3430
2330
Pharmacokinetic parameters are shown to 3 significant digits
a
Predicted as the LDV/SOF Phase 2/3 population multiplied times the ratio of predicted SOF 400 mg in severe RI to 
SOF Phase 2/3 population.

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2. 
OBJECTIVES 
The prima1y objectives of this study are: 
Final 
Amendment3 
• 
To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks as assessed by review of the accumulated safety data 
in each treatment rum 
• 
To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks measured by the prop01iion of subjects with renal 
insufficiency who have achieved a sustained viral response 12 weeks after treatment 
discontinuation (SVR12) in each treatment ann 
• 
To evaluate the steady state phrum acokinetics ofSOF and its metabolites and LDV upon 
dosing SOF 200 mg or 400 mg or LDV/SOF in subjects with renal insufficiency 
The secondruy objectives of this study ru·e: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR at 
4 and 24 weeks after discontinuation of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV during and after treatment 
discontinuation 
The explorat01y objective of this study is: 
PPO 
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3.
STUDY DESIGN
This is a multicenter, open label study that will evaluate the safety, tolerability and antiviral 
efficacy of SOF with RBV or LDV/ SOF in chronic renal insufficiency and HCV infection
subjects with genotype 1, 3 or genotype 4 HCV infection, including those with compensated 
cirrhosis.
This study will have 3 cohorts.
Approximately 30 subjects with severe renal insufficiency will be enrolled. 

Cohort 1: 10 subjects will receive SOF 200 mg QD + RBV 200 mg QD for 24 weeks.

Cohort 2: Following review of safety, efficacy and PK data through post-treatment Week 4 
of Cohort 1, 10 additional subjects will receive SOF 400 mg QD + RBV 200 mg QD for 
24 weeks.

Cohort 3: Following review of safety and available PK data through Week 12 of Cohort 2, 
10 additional subjects will receive LDV/SOF QD for 12 weeks.
3.1.
Treatment Plan and Regimen
Following screening procedures and Day 1 assessments, eligible subjects will receive 
one of the following treatments:
Cohort 1: SOF 200 mg QD + RBV 200 mg QD for 24 weeks
Cohort 2: SOF 400 mg QD + RBV 200 mg QD for 24 weeks
Cohort 3: LDV/SOF QD for 12 weeks
Additional information about study drug administration can be found in Section 5.
3.2.
Visit Schedule
All subjects will complete screening, on-treatment and post-treatment assessments. Screening 
assessments will be completed within 42 days of the Day 1 visit. All subjects will complete the 
Week 4 Post-Treatment visit. Weeks 12 and 24 Post-Treatment visits will be dependent on 
subject viral load.
The assessments performed at each visit are described in Section 6.

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3.3.
Virologic Response-Based Stopping Criteria
The following stopping criteria will be used for subjects on treatment:

Confirmed HCV RNA ≥LLOQ after 2 consecutive HCV RNA <LLOQ

Confirmed >1 log10 increase from nadir 

Confirmed HCV RNA ≥LLOQ after 8 weeks of treatment
Confirmation should be performed as soon as possible but within 2 weeks after determination of 
initial observation.
Cardiac Function-Based Stopping Criterion
The following stopping criterion will be used for subjects on treatment:

Left ventricular ejection fraction ≤40%
3.4.
Treatment Discontinuation Criteria
The Medical Monitor should be consulted prior to subject discontinuation when medically 
feasible. Study medication must be discontinued in the following instances:

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest.

Pregnancy of female subject, or female partner of male subject.

Efficacy failure as defined in Section 3.3.

Declining cardiac function, defined as left ventricular ejection fraction ≤40%.

Significant protocol violation including non-compliance with study assessments. 

Subject request to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy or other reason.

Discontinuation of the study at the request of Gilead, regulatory agency or an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
Subjects who discontinue treatment earlier than the assigned 12 or 24-week treatment duration 
will complete an Early Termination Visit (Section 6.7).

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 30 subjects will be treated in this study.
In order to manage the total study enrollment, Gilead Sciences, Inc., at its sole discretion, may 
suspend screening and/or enrollment at any site or study-wide at any time.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Willing and able to provide written informed consent
2) Male or female, age ≥18 years
3) Chronic HCV infection documented by either:
a) a positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping test 
at least 6 months prior to the Day 1 visit, or
b) a liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV infection
4) Infection with HCV GT 1, 3 or 4 as determined at Screening, as applicable to cohort
5) Subjects must have the following laboratory parameters at Screening: 
a) HCV RNA ≥104 IU/mL
b) ALT ≤10 the upper limit of normal (ULN)
c) AST ≤10 ULN
d) Hemoglobin ≥9 g/dL 
e) Albumin ≥3.0 g/dL
f)
Direct bilirubin ≤1.5 ULN
g) HbA1c ≤10%

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h) Creatinine clearance (CLcr) 30 mL/min, as calculated by the Cockcroft-Gault equation 
{2202} using ideal body weight (IBW).
Male:
CLcr (mL/min) = [140 −age (years)] IBW (kg)
72 Scr
Female:
CLcr (mL/min) = [140 −age (years)] IBW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
Ideal body weight (IBW) is estimated by the following equations: 
Males:
IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
Females:
IBW (kg) = 45.5 kg + 2.3 kg for each inch over 5 feet
a.
Subjects with CLcr 30-40 mL/min are eligible if they have a prior CLcr ≤30 mL/min
within 6 months of Screening
6) INR ≤1.5 ULN unless subject has known hemophilia or is stable on an anticoagulant 
regimen affecting INR.
7) A negative serum pregnancy test for female subjects of childbearing potential 
(see Appendix 2 for definition). 
8) Male subjects and female subjects of childbearing potential (see Appendix 2 for definition) 
must agree to use protocol specified method(s) of contraception as described in Appendix 2.
9) Lactating females must agree to discontinue nursing before administration of study drug.
10) Subject must be of generally good health as determined by the Investigator. 
11) Subject must be able to comply with the dosing instructions for study drug administration 
and able to complete the study schedule of assessments.
12) Cirrhosis Determination (For all cohorts)

Cirrhosis is defined as any one of the following:
Liver biopsy showing cirrhosis
Fibroscan (in countries where locally approved) showing cirrhosis or results 
> 12.5 kPa
FibroTest® score of > 0.75 AND an AST: platelet (APRI) ratio of > 2 during 
Screening

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
Absence of cirrhosis is defined as any one of the following:
Liver biopsy within 2 years of Screening showing absence of cirrhosis
Fibroscan (in countries where locally approved) with a result of ≤12.5 kPa within 
≤6 months of Day 1
FibroTest® score of ≤ 0.48 AND APRI of ≤1 during Screening
In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, 
a liver biopsy is required.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) BMI < 18
2) Prior exposure to an direct-acting antiviral targeting HCV NS5B (all cohorts) or HCV NS5A 
(Cohort 3 only)
3) Prior null response to PEG+RBV therapy (Cohorts 1 and 2) or for patients with cirrhosis, 
prior treatment failure with IFN-based therapy not resulting from treatment intolerance
(Cohort 3)
4) Male with pregnant female partner (Cohorts 1 and 2 only)
5) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency, cholangitis)
6) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
7) Unstable psychiatric condition 
8) Significant cardiac disease including or resulting in:
a) Cardiomyopathy
b) Left ventricular ejection fraction ≤50%
c) Hospital admission for myocardial infarction, heart failure within 1 year of Screening 
d) Pulmonary hypertension within 1 year of Screening
9) Clinically significant abnormality on ECG at Screening, including a QTcF > 500 msec, or 
> 450 msec in patients who concomitantly use methadone.

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10) History of clinically significant hemoglobinopathy (Cohorts 1 and 2 only)
11) History of porphyria (Cohorts 1 and 2 only)
12) Malignancy within the 5 years prior to screening, with the exception of specific cancers that 
are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for 
possible malignancy are not eligible.
13) Chronic use of systemically administered immunosuppressive agents 
(e.g., prednisone equivalent > 10 mg/day)
14) Clinically-relevant drug or alcohol abuse within 12 months of Screening
15) Current or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, 
encephalopathy or variceal hemorrhage)
16) History of clinically-significant illness or any other major medical disorder that may interfere 
with subject treatment, assessment or compliance with the protocol
17) History of a primary gastrointestinal disorder (or post operative condition) that could 
interfere with the absorption of the study drug 
18) Excessive alcohol ingestion, defined as > 3 glasses/day (1 glass is equivalent to: 
beer [284 mL], wine [125 mL], or distilled spirits [25 mL]) for females and > 4 glasses/day 
for males)
19) Inability to collect blood for safety, PK, and efficacy throughout the study
20) Donation or loss of more than 400 mL blood within 2 months prior to Day 1 
21) Use of any prohibited concomitant medications as described in Section 5.8 within 21 days of 
the Day 1 visit
22) Known hypersensitivity to RBV (Cohorts 1 and 2 only), the study investigational medicinal 
product, the metabolites, or formulation excipients
23) Receipt of any investigational product within a time period equal to 10 half-lives of the 
product, if known, or a minimum of 4 weeks prior to study drug administration
24) Subjects with hepatocellular carcinoma (HCC) are excluded from the study. In cirrhotic 
patients, liver imaging (e.g., ultrasound) within 6 months of Day 1 is required to exclude 
hepatocellular carcinoma (HCC)

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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Sofosbuvir (SOF)
5.1.1.
Formulation
SOF tablets, 100 mg, are yellow, round, film-coated, plain-faced tablets. 
SOF tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets debossed with “GSI” on 
one side and “7977” on the other side. 
In addition to the active ingredient, SOF tablets contain the following inactive ingredients: 
mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc, and yellow iron oxide.
5.1.2.
Packaging and Labeling
SOF tablets, 100 mg, are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 28 tablets and polyester packing material. Each bottle is enclosed with a white, 
continuous thread, child-resistant screw cap with an induction-sealed, aluminum-faced liner.
SOF tablets, 400 mg, are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains either 28 or 30 tablets and a silica gel desiccant canister or sachet and polyester 
packing material. Each bottle is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner.
SOF bottles to be distributed to centers in the US and other countries shall be labeled to meet all 
applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of 
Good Manufacturing Practices: Manufacture of investigational medicinal products 
(February 2010) and/or other local regulations as applicable.
5.1.3.
Storage and Handling
SOF bottles should be stored at a controlled room temperature until required for administration. 
Controlled room temperature is defined as 25 C (77 F); excursions are permitted between 
15 C and 30 C (59 F to 86 F).
All drug products should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of the study drug and to ensure proper product identification, 
the drug product should not be stored in a container other than the container in which they are 
supplied. Consideration should be given to handling, preparation, and disposal through measures 
that minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling SOF.
Sufficient quantities of SOF tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Clinical Supply Management
(or its designee).

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5.1.4.
Sofosbuvir (SOF) Dosage and Administration
SOF will be administered as 200 mg or 400 mg po daily. SOF (100 mg or 400 mg) tablets will be 
supplied by Gilead Sciences for all subjects.
5.2.
Ribavirin (RBV)
5.2.1.
Formulation
RBV tablets, 200 mg, are blue, capsule-shaped, film-coated tablets debossed with “3RP” on one 
side and “200” on the other side. In addition to the active ingredient, RBV tablets contain the 
following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose 
sodium, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol, talc,
FD&C blue #2.
5.2.2.
Packaging and Labeling
The RBV tablets are packaged in white, HDPE bottles. Each bottle contains 168 tablets and 
rayon coil packing material and is enclosed with a white, continuous thread, child-resistant screw 
cap with an induction-sealed, aluminum-faced liner.
RBV bottles to be distributed to centers in the US and other countries shall be labeled to meet all 
applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 of Good 
Manufacturing Practices: Manufacture of investigational medicinal products (February 2013) 
and/or other local regulations as applicable.
5.2.3.
Storage and Handling
RBV tablets should be stored at 25 C (77 F); excursions are permitted between 15 and 30 C 
(59 and 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 RBV.
5.2.4.
RBV Dosage and Administration
RBV will be administered as 200 mg po daily. RBV should be dosed with food and with SOF to 
maximize adherence. RBV dose may be managed at the discretion of the Investigator in 
communication with the Medical Monitor.
RBV tablets (200 mg) will be supplied by Gilead Sciences for all subjects.

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5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV)
Each subject will be given instructions to maintain approximately the same daily dosing interval 
between study drug doses.  
If a subject forgets to take the medication at the correct time, it may be taken later in the day; 
however, no more than 400 mg dose of SOF should be taken on any calendar day. The subject 
should resume the standing dosing schedule on the next day.  Study medications should not be 
cut or split. No food restrictions apply to SOF; however, SOF should be taken with RBV and 
with food for optimal adherence.
On the day of clinic visits, subjects will be instructed to take their study medication on the day 
prior to clinic visits, 20-28 hours before the administration of the study medication at the clinic.
Subjects should bring their medication with them to the clinic and take their study medication
after all pre-dose assessments are completed. 
5.4.
Ledipasvir/ Sofosbuvir (LDV/SOF)
5.4.1.
Formulation
Ledipasvir 90mg/ sofosbuvir 400mg fixed dose combination (FDC) tablets are orange, 
diamond-shaped, film-coated tablets containing 400 mg of SOF and 90 mg of LDV. The tablets 
are debossed with “GSI” on one side and “7985” on the other side. The LDV/SOF
(90mg/400mg) 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.
5.4.2.
Packaging and Labeling
Ledipasvir 90 mg/ sofosbuvir 400 mg tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle will contain 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. 
LDV/SOF bottles to be distributed to centers in the US and other countries shall be labeled to 
meet all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 
of Good Manufacturing Practices: Manufacture of investigational medicinal products 
(February 2010) and/or other local regulations as applicable.
5.4.3.
Storage and Handling
LDV/SOF bottles should be stored at controlled room temperature until required for 
administration. Controlled room temperature is defined as 25 C (77 F); excursions are 
permitted between 15 C and 30 C (59 F to 86 F).

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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 tablets.
Sufficient quantities of LDV/SOF tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Clinical Supply Management
(or its designee).
5.4.4.
LDV/SOF Dosage and Administration
LDV/SOF will be administered as one 90 mg/400 mg tablet po daily with or without food for 
12 weeks. LDV/SOF tablets will be supplied by Gilead Sciences for all subjects.
5.5.
Study Drug Compliance
On Day 1, subjects will be administered study drugs and the assigned bottles will be dispensed to 
them along with a dosing diary to be used to document at home dosing. Subjects will be 
instructed to return dosing diaries and any unused study drug in the original container at each 
visit following Day 1 for study drug compliance assessment.
Returned medication will be reconciled by the investigator in order to monitor the subject’s 
compliance with the medication regimen.
5.6.
Dispensing and Accountability of Study Drugs
The Investigator (or designee, e.g., study center pharmacist) will acknowledge receipt of the 
study drugs (after reviewing the shipment’s content and condition) from Gilead Sciences 
(or designee). The Investigator will maintain an accurate inventory of all study drugs. Each dose 
of the study drug(s) administered at the study center will be administered by qualified study 
center personnel. All doses of study drug(s) administered to subjects in the clinic under the 
supervision of staff will be accurately recorded on the Investigational Product Inventory Logs 
provided by Gilead Sciences (or on equivalent documentation maintained by the study center), 
which indicates the date and quantity of all doses of study drug(s) dispensed to individual 
subjects. The requirements of all applicable Federal and State drug dispensing laws will apply to 
all doses of study drugs dispensed by the Investigator (or designee). At the end of the study, all 
unused study drugs (both bulk and individual subject returns) will be returned to a location 
designated by Gilead Sciences.
5.7.
Study Drug Return or Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, 

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the site may destroy used and unused study drug supplies performed in accordance with the 
site’s (hospital/pharmacy) SOP. If the site does not have acceptable procedures in place for 
drug destruction, arrangements will be made between the site and Gilead Sciences 
(or Gilead Sciences’ representative) for return of unused study drug supplies. Where possible, 
study drug will be destroyed at the site.  If drug is destroyed on site, the investigator must 
maintain accurate records for all study drug destroyed. All study drug records must be 
maintained at the site and copies must be submitted to Gilead Sciences at the end of the study.
5.8.
Concomitant Medications
Concomitant medications taken within 30 days of Screening, up to and including the date of the 
visit four weeks after discontinuation of study treatment, need to be recorded in the source 
documents and eCRFs.
5.8.1.
Cohorts 1 and 2
The following medications are prohibited from 21 days prior to the Day 1 visit through the end 
of treatment:

Drugs disallowed per prescribing information of RBV (COPEGUS®)

Concomitant use of certain medications or herbal/natural supplements (inducers of 
drug transporters i.e. P-gp) with study drug(s) may result in pharmacokinetic interactions 
resulting in decreases in exposure of study drug(s).  Representative medications which are 
excluded from 21 days prior to Day 1 through the end of treatment are listed below:
Drug
Agents Disallowed
Concomitant use with study drug may 
potentially result in changes of study 
drug concentration as listed below
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Decrease in concentration of study drug
Antimycobacterials
Rifampin, rifabutin, rifapentine
Decrease in concentration of study drug
Herbal/Natural Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
Decrease in concentration of study drug
Other
Modafinil
Decrease in concentration of study drug
5.8.2.
Cohort 3
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:

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Table 5-1.
Disallowed and Concomitant Medications to be Used with Caution
Drug Class
Agents Disallowed
Use with Caution
Acid Reducing Agentsa
Proton-Pump Inhibitors, 
H2-Receptor Antagonists, Antacids
Antiarrhythmics b
Quinidine
Anticonvulsantsc
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Antimycobacterialsc
Rifabutin, Rifapentine, Rifampin
Cardiac Medications b
Digoxin
Herbal/Natural Supplementsc
St. John’s Wort, Echinaccea, Milk 
thistle (i.e., silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
HMG-CoA Reductase Inhibitorsd
Rosuvastatin
Pravastatin, Pitavastatin
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 an increase in the concentration of study drugs and/or concomitant medications. Coadministration of 
LDV/SOF with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration 
monitoring of digoxin is recommended when coadministered with LDV/SOF. 
c
May result in a decrease in the concentrations of study drugs.
d
Use with study drugs may result in an increase in the concentration of the HMG-CoA Reductase Inhibitors. Monitor for 
signs and symptoms of muscle weakness or myopathy, including rhabdomyolysis.
5.8.3.
All Cohorts
Medications for disease conditions excluded from the protocol (e.g., HIV-1 infection, active 
cancer, transplantation are not listed under this Concomitant Medication section and are 
prohibited in the study.
Should it become medically necessary for patients to start treatment with any excluded 
concomitant medication, the sponsor must be consulted prior to initiation of the new medication 
and the subject’s continued participation must be discussed with the Gilead Medical Monitor.
5.8.3.1.
Medications Associated with QT Prolongation
Medications that are known to cause or are associated with QT prolongation and/or a risk of 
causing torsades de pointes should be avoided in patients with risk factors for developing long 
QT intervals or those receiving other QT-prolonging medications. These medications include, 
but may not be limited to those listed below (see table below) and must be approved by the 
Gilead Medical Monitor prior to study enrollment or coadministration during the study.

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Representative List of Medications Known or Associated with QT Prolongation
QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with QT Prolongation
Antibiotics/Anti-infectives:
Macrolide Antibiotics
azithromycin, clarithromycin, erythromycin, 
roxithromycin, telithromycin
Quinolone Antibiotics
gatifloxacin, gemifloxacin, levofloxacin, 
moxifloxacin, ofloxacin, sparfloxacin
ciprofloxacin
Certain antimalarials/pneumocystis prophylaxis; others
artenimool+piperaquine, bedaquiline, chloroquine, 
halofantrine, pentamidine
trimethoprim-sulfa, quinine sulfate
Antipsychotics:
Phenothyazine Antipsychotics
chlorpromazine, mesoridazine, thioridazine
Other Antipsychotics
clozapine, haloperidol, iloperidone, olanzepine, 
paliperidone, pimozide, quetiapine, risperidone, 
sertindole, ziprasidone
amisulpride,
Anit-mania Bipolar Disorders:
lithium
Anti-depressants:
Serotonin re-uptake inhibitors
citalopram, escitalopram, venlafaxine
fluoxetine, paroxetine, sertraline
Tricyclic anti-depressants
amitriptyline, clomipramine, desipramine, 
doxepin, imipramine, nortriptyline, 
protriptyline trimipramine,
Tetracyclic anti-depressants
mirtazepine
trazodone

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QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with QT Prolongation
Cardiology Medications:
Class I (Na+) and III (K+) anti-arrhythmics
amiodarone, disopyramide, dofetilide, 
dronedarone, flecainide, ibutilide, mexiletine, 
procainamide, quinidine
Class II (β blockers) and IV (Ca2+) anti-arrythmics
isradipine, sotalol (Class II/III)
Certain anti-anginals/ calcium blocker
bepridil, nicardipine, ranolazine
Anesthetics, Pain Medications and Additional 
Treatment:
levomethadyl, methadone
general anesthetics 
(e.g., enflurane, halothane, isoflurane, 
sevoflurane)
Anti-nausea:
domperidone, droperidol, dolasetron, granisetron, 
ondansentron, promethazine
Azole anti-fungals (systemic use only)
ketoconazole, voriconazole
fluconazole, itraconazole
Others:
alfuzosin, amantadine, astemizole, cisapride, 
famotidine, felbamate, fosphenytoin, galantamine, 
indapamide, moexipril/HCTZ, octreotide, 
oxytocin, pasireotide, perflutren lipid 
microspheres, probucol, sibutramine, terfenadine,   
tizanidine, tolterodine, vardenafil
chloral hydrate, diphenhydramine, 
solifenacin

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Should it become medically necessary for patients to start treatment with any excluded 
concomitant medication, the sponsor must be consulted prior to initiation of the new medication 
and the subject’s continued participation must be discussed with the Gilead Medical Monitor.
5.8.3.2.
Hematopoietic Growth Factors
Erythropoiesis stimulating agents (ESAs) should not be used during Screening solely to elevate 
hematology laboratory parameters to facilitate entry into the study.  Patients taking ESAs for 
anemia related to chronic kidney disease may enter the study. Granulocyte colony-stimulating 
agents and thrombopoietic growth factors should not be used while the subject is receiving study 
treatment.

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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in
Table 6-1 and Table 6-2 and described in the following text. 
Any deviation from protocol procedures should be noted in the subject’s clinical chart and 
appropriate eCRFs. In addition, the Sponsor should be promptly notified of any protocol 
deviations. 
The study center will not be released to initiate dosing until:

The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) reviewed and 
approved the study and the informed consent document;

All requested regulatory documents have been submitted to and approved by 
Gilead Sciences;

A Master Services Agreement and/or Study Agreement is executed;

The study initiation meeting has been conducted by the Gilead Sciences clinical monitor 
(or designee).
The initiation meeting will include a review of the protocol, the Investigator’s Brochure, and 
Investigator responsibilities.
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific informed consent form (ICF), is required before initiating the screening process. 
Generic screening consent forms should not be used in lieu of the study-specific ICF.
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study.
Once consent has been obtained, all screening tests and procedures have been assessed, and
study eligibility has been confirmed, subjects will be enrolled and assigned a unique subject 
identification number.
Subjects will receive the study treatment as described in Section 5.

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Table 6-1.
Schedule of Assessments for Cohorts 1 and 2
Study 
Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Written Informed 
Consent
X
Medical History 
X
HCV RNA 
Genotype
X
IL28B 
Genotyping
X
HbA1c
X
HCV, HBV, 
HIV Serology
X
TSH
X
Physical Exam, 
including 
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram 
X
X
X
Height
X
Weight
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Study 
Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Coagulation 
(PT, PTT, and 
INR)
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Viral 
Load
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA 
Sequencing 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
Teste
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine 
Clearance
X
Optional 
Pharmacogenetic 
Samplek
X
Intensive PK
Xf
Xf
Trough PK 
Sampleg
X
X
X
X
X
X
X
X
X
Archive Plasma 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Administration
X
Weeks 1-24

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Study 
Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
4
Week
12
Week
24
Review Dosing 
Diary/Perform 
Accountabilityh
X
X
X
X
X
X
X
X
X
X
AEs/
Concomitant 
Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Screening evaluations must be completed within 42 days prior to Day 1.
b
Day 1 tests and procedures must be completed prior to administration of the first dose of study drugs 
c
Within 72 hours of permanently discontinuing study drug.
d
Full PE at Day 1 and ET visits only; symptom-directed PE at all other timepoints. Vital signs include blood pressure, pulse, respiration rate, and temperature
e
Females of childbearing potential only. To confirm eligibility at Day 1, a urine pregnancy test may be collected for subjects able to pass urine. For subjects unable to pass 
urine, a serum pregnancy test at Day 1 must be performed at a local lab prior to dosing to confirm eligibility along with sample collected and send to central lab. During 
post-treatment of the study, serum or urine pregnancy testing will occur every month during non-clinic post treatment visits. The subject will be contacted by telephone to 
confirm that pregnancy testing has been performed post-treatment during non-clinic visits.
f
Intensive plasma PK evaluations will be assessed at the following timepoints: 0 (predose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose.
g
Trough plasma PK samples will be drawn prior to dosing. 
h
Dosing Diaries will be completed for all non-observed doses and will be reviewed at every visit. Unused study drug will be returned to perform study drug accountability in 
the original container at each visit following Day 1 for study drug compliance assessment.
i
A window of ± 2 days is allowed for the treatment visits on weeks 1, 2, and 12.  A window of ± 4 days is allowed for the treatment visits weeks, 4-10, and 16-24. Subjects 
who cannot complete their study visit per the visit schedule should ensure they do not run out of study drug prior to their next study visit.  Compliance is critical to ensure 
adequate drug exposure.
j
A window of ± 7 days is allowed for the post treatment visits.
k
The sample should be collected on Day 1 prior to dosing, but may be collected at any time during the study or at a separate post-study visit, if necessary.

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Table 6-2.
Schedule of Assessments for Cohort 3
Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
4
Week
12
Week
24
Written Informed Consent
X
Medical History 
X
HCV RNA Genotype
X
IL28B Genotyping
X
HbA1c
X
HCV, HBV, HIV Serology
X
TSH
X
Physical Exam, including 
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
Echocardiogram 
X
X
Height
X
Weight
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
(PT, PTT, and INR)
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Viral Load
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV RNA Sequencing 
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy Teste
X
X
X
X
X
X
X
X
X
Creatinine Clearance
X

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Study Procedure
Screena
Day 1b
Treatment Visitsi
Post-Treatment Visitsj
ETc
Week
1
Week
2
Week
4
Week
6
Week
8
Week
10
Week
12
Week
4
Week
12
Week
24
Optional Pharmacogenetic 
Samplek
X
Intensive PK
Xf
Xf
Trough PK Sampleg
X
X
X
X
X
X
Archive Plasma Sample
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Administration
X
Weeks 1-12
Review Dosing Diary/
Perform Accountabilityh
X
X
X
X
X
X
X
AEs/Concomitant Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Screening evaluations must be completed within 42 days prior to Day 1.
b
Day 1 tests and procedures must be completed prior to administration of the first dose of study drugs 
c
Within 72 hours of permanently discontinuing study drug.
d
Full PE at Day 1 and ET visits only; symptom-directed PE at all other timepoints. Vital signs include blood pressure, pulse, respiration rate, and temperature
e
Females of childbearing potential only. To confirm eligibility at Day 1, a urine pregnancy test may be collected for subjects able to pass urine. For subjects unable to pass 
urine, a serum pregnancy test at Day 1 must be performed at a local lab prior to dosing to confirm eligibility along with sample collected and send to central lab. During post-
treatment of the study, serum or urine pregnancy testing will occur every month during non-clinic post treatment visits. The subject will be contacted by telephone to confirm 
that pregnancy testing has been performed post-treatment during non-clinic visits.
f
Intensive plasma PK evaluations will be assessed at the following timepoints: 0 (predose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose once either on 
Week 2 OR 4, per investigator discretion.
g
Trough plasma PK samples will be drawn prior to dosing. 
h
Dosing Diaries will be completed for all non-observed doses and will be reviewed at every visit. Unused study drug will be returned to perform study drug accountability in 
the original container at each visit following Day 1 for study drug compliance assessment.
i
A window of ± 2 days is allowed for the treatment visits on weeks 1, 2, and 12.  A window of ± 4 days is allowed for the treatment visits weeks, and 4-10. Subjects who 
cannot complete their study visit per the visit schedule should ensure they do not run out of study drug prior to their next study visit.  Compliance is critical to ensure adequate 
drug exposure.
j
A window of ± 7 days is allowed for the post treatment visits. 
k
The sample should be collected on Day 1 prior to dosing, but may be collected at any time during the study or at a separate post-study visit, if necessary.

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6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Prospective subjects should be screened within 42 days prior to first dose on Day 1. If the subject 
does not begin the treatment phase within this 42-day window, all screening evaluation 
procedures must be repeated. No more than one repeat screen visit is allowed for each subject, 
unless prior written approval has been provided by the Sponsor.
Written informed consent must be obtained from each subject before initiation of any screening 
procedure. After a subject has provided informed consent, the investigator and other study 
personnel will determine if the subject is eligible for participation in the study. This assessment 
will include a review of the inclusion/exclusion criteria and completion of all screening 
procedures as outlined in Table 6-1 and Table 6-2.
Once eligibility is confirmed, the study site will complete an eligibility worksheet for each 
screened subject and submit for Sponsor review. The sponsor will assign a unique subject 
number for each eligible subject and provide the subject number information to the site prior to 
Day 1 visit. 
6.2.2.
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. Information related to HCV infection will be collected. In addition, a cirrhosis 
determination will be made as follows:
Cirrhosis determination

Cirrhosis is defined as any one of the following:
Liver biopsy showing cirrhosis
Fibroscan (in countries where locally approved) showing cirrhosis or results > 12.5 kPa
within 6 months of Day 1
FibroTest® score of > 0.75 AND an AST:platelet (APRI) ratio of > 2 during Screening

Absence of cirrhosis is defined as any one of the following:
Liver biopsy within 2 years of Screening showing absence of cirrhosis
Fibroscan (in countries where locally approved) with a result of ≤12.5 kPa 
within ≤6 months of Day 1
FibroTest® score of ≤ 0.48 AND APRI of ≤1 during Screening

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In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, 
a liver biopsy is required.
In addition, a determination of cardiac function will be made as follows:

Echocardiogram demonstrating left ventricular ejection fraction > 50% performed prior to 
Day 1 visit. Enrollment allowed based on local read of study if central read is not available.
6.3.
Day 1 Assessments
Subjects meeting all eligibility criteria following the screening evaluation will return to the study 
site within 42 days for Day 1 assessments as outlined in Table 6-1 and Table 6-2.
6.3.1.
Dosing Diary
Subjects will be provided with self-administration instructions and study drug diaries to record 
the exact date, time and number of tablets of study drug administration. The site staff will record 
the information from the study drug dosing diary into the eCRF. In the event that the dosing 
diary is not available, the site may obtain dosing information via subject interview and record 
this information in the source notes
6.4.
Treatment Assessments
6.4.1.
Cohorts 1 and 2
Study visits will occur at the end of Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24.
Study procedures and assessments are outlined in Table 6-1.
6.4.2.
Cohort 3
Study visits will occur at the end of Weeks 1, 2, 4, 6, 8, 10, and 12
Study procedures and assessments are outlined in Table 6-2.
6.5.
Safety Assessments
Safety will be evaluated throughout the study. Refer to Table 6-1 and Table 6-2 for a schedule of 
assessments.
6.5.1.
Safety ECGs
Subjects should rest quietly in the supine position for a minimum of 10 minutes prior to each 
scheduled ECG acquisition and should remain in that position until the recording is complete. 
There must be no environmental distractions (television, radio, conversation, etc.) while the 
subjects are resting prior to and during the recordings.

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ECGs will be recorded at a sampling frequency of 500+ Hz, at a speed of 25 mm/sec and at a 
standard duration of 10 seconds. All ECGs will be obtained using instruments that analyze data 
using the same algorithms and produce the same data for interpretation. When ECGs are 
performed on an ECG machine, site standard operating procedures (SOPs) will be used.
ECG measurements will be collected pre-dose at time-points as per Table 6-1 and Table 6-2.
The Investigator or other qualified individuals at the study center will review ECGs to assess for 
changes in ECG intervals and morphology as compared to pre-dose ECGs. Collection of 
additional ECGs for routine safety monitoring at additional time-points or days is at the 
discretion of the Investigator based on GCP.
6.5.2.
Safety Echocardiograms
Safety echocardiograms will be performed as outlined in Table 6-1 and Table 6-2. A window of 
± 10 days is allowed for the on-treatment visits. These safety echocardiograms will be performed
locally and sent to a central location for standardized reading.
6.5.3.
Physical Examination
Complete physical examinations or a symptom directed physical examination will be conducted 
pre-dose as outlined in Table 6-1 and Table 6-2. 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. 
6.5.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and temperature and will be conducted pre-dose as outlined in Table 6-1 and Table 6-2.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm supported 
so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to 
the nearest whole number on an automatic device.

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6.5.5.
BMI
Height and weight will be collected at the times shown in the schedule of assessments 
Table 6-1 and Table 6-2.
BMI is calculated by the following equation.
BMI =
weight (pounds) 703
(height in inches)2
or
weight in kilograms
(height in meters)2
6.5.6.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} using 
ideal body weight (IBW). 
Male:
CLcr (mL/min) = [140 −age (years)] IBW (kg)
72 Scr
Female:
CLcr (mL/min) = [140 −age (years)] IBW (kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
Ideal body weight (IBW) is estimated by the following equations: 
Males: 
IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet
Females: 
IBW (kg) = 45.5 kg + 2.3 kg for each inch over 5 feet
6.5.7.
Clinical Laboratory Tests/Assessments
In addition to the PK blood samples that will be collected, blood samples will be collected 
pre-dose as outlined in the schedule of assessments, Table 6-1 and Table 6-2 for the following 
laboratory analyses:
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, MCV, and 
Coagulation Panel (PT, PTT, and INR).
Chemistry: Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline phosphatase, Creatinine, Total Bilirubin (reflex to Direct Bilirubin), Glucose, 
Total Protein, Bicarbonate, BUN, Calcium, Chloride, Phosphorus, Magnesium, Potassium,
Sodium, and FibroTest®.

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Thyroid-stimulating hormone (TSH)
Haemoglobin A1C (HbA1c)
Virological Tests: Serologies for HCV, HBV and HIV. HCV RNA will be measured using 
COBAS® AmpliPrep/COBAS® TaqMan® HCV Test. HCV genotype and subtype will be 
determined using the Siemens VERSANTHCV Genotype INNO-LiPA 2.0 Assay. Gilead 
reserves the right to use alternate assays for HCV RNA and HCV genotype should the above 
assays become unavailable or are not definitive.
Viral RNA Sequencing/Phenotyping plasma samples will be collected to confirm virologic 
breakthrough. Untested samples may be archived.
IL28B genotype will be determined by polymerase chain reaction (PCR) amplification of the 
SNP, rs12979860, with sequence specific forward and reverse primers and allele specific 
fluorescently labeled TaqMan® MGB probes. Gilead reserves the rights to use an alternate assay 
for IL28B determination should the above assay become unavailable.
Pregnancy Tests: All females of childbearing potential will have serum or urine pregnancy 
testing every 4 weeks during the dosing period and for a minimum of 6 months following the last 
dose of RBV. If required by local regulations, additional pregnancy tests may be collected. In the 
event of a positive urine pregnancy result, subjects will be instructed to stop study drugs 
immediately and return to the clinic as soon as possible for a serum pregnancy test.
Pregnancy tests must be completed for all females of childbearing potential (see Appendix 2
for definition) as specified in Table 6-1 and Table 6-2. When feasible for subjects, a urine 
pregnancy test may also be taken. During post treatment of the study, subject will be contacted 
by telephone monthly to confirm that the serum or urine pregnancy testing has been performed 
post-treatment during non-clinic visits. Alternatively, if required by local regulations or preferred 
by the investigator or subject, the subject may return to the clinic for urine or serum pregnancy 
tests post treatment.
6.5.8.
Adverse Events/Concomitant Medications/Protocol Restrictions
Evaluation for adverse events, review of concomitant medications, and review of protocol 
restrictions will occur at the times shown in the schedule of assessments Table 6-1 and
Table 6-2. See Section 7 for more information regarding adverse events and Section 5 for more 
information about concomitant medications.
6.6.
Pharmacokinetic (PK) Assessments
Subjects will be instructed to take their SOF or LDV/SOF dose on the day prior to clinic visits, 
20-28 hours before the clinic visit. On the day of clinic visits, subjects should bring their 
medication with them to the clinic and take their dose after the trough PK sample is collected, or 
after the predose intensive PK sample is taken.
The exact time of the dose taken prior to collection of the PK sample and the exact time the PK 
sample is drawn will be recorded on the appropriate eCRF.

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Intensive PK Assessments:
Cohorts 1 and 2:
Serial plasma PK samples will be collected on week 2 and 12 at the following timepoints:

0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours post-dose. 
Cohort 3:
Serial blood samples will be collected once either on week 2 OR 4 (per investigator discretion) at 
the following timepoints:

0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours post-dose.
Plasma concentrations of SOF and its metabolites and LDV will be determined and PK 
parameters will be estimated as appropriate. Plasma concentrations of RBV may be determined, 
as applicable.
Trough PK Assessments:
Trough PK plasma samples for analyses of SOF, its metabolites, RBV and LDV concentrations 
will be collected at all other on treatment visits beginning at the Week 1 visit as applicable.
PK Parameters for SOF, its metabolites, LDV and RBV will be estimated as appropriate. 
6.7.
Early Termination (ET)/Unscheduled Visit
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. The 
assessments at the unscheduled visits are at the investigator’s discretion. At all unscheduled 
visits initiated for the purpose of confirming virologic failure a Viral RNA 
Sequencing/Phenotyping Sample must be collected. 
The Sponsor (e.g. Medical Monitor and Clinical Program Manager)/CRO must be informed, as 
soon as possible, when a subject prematurely discontinues treatment. The primary reason for 
premature treatment discontinuation must be provided to the Sponsor/CRO.
If a subject discontinues treatment early for any reason then the following assessments for the 
Early Termination (ET) Visit must be performed: 

Perform complete physical examination

Obtain body weight

Obtain vital signs

Assessment of AEs and concomitant medications

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• 
Pregnancy prevention counseling 
• 
Obtain blood samples for: 
-
Hematology & Chemistiy 
-
Coagulation (PT, PTT, and INR) 
-
HCVRNA 
-
Viral Sequencing I Phenotyping Sample 
-
TroughPK 
-
Semm pregnancy test (females of childbearing potential only) 
Final 
Amendment3 
• 
Review study dmg adherence with subject including recording the date and time of the 
subject's last dose of study dmg prior to the PK draw (subject should retum all study dmgs at 
this visit) 
All subjects will attend the 4-Week Post-Treatment Visit. 
6.8. 
Post-Treatment Assessments 
Subjects with HCV RNA < LLOQ at the 4-Week Post-Treatment Visit will attend the 12-Week 
Post-Treatment Visit. 
Subjects with HCV RNA ~ LLOQ do not need to retum for additional visits and they will be 
tenninated early from the study. 
Subjects with HCV RNA < LLOQ at the Post-Treatment Week 12 Visit will retum at the 
post-u·eatment Week 24 Visit. 
6.9. 
Optional Samples for Pharmacogenetic Testing 
PPD 
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6.10.
Archived Plasma Sample
Archive plasma samples will be collected at the study visits, indicated in Table 6-1 and 
Table 6-2. Archive plasma samples are being collected for possible additional analyses, 
including but not limited to, study drug or metabolite measurements, viral load, safety/efficacy 
assessments, HCV gene sequencing, HCV resistance testing and other possible predictors of 
response as determined by Gilead.
In the event of a subject’s death or loss of competence, the subject’s specimens and data will 
continue to be used as part of the future biomarker research.
If a subject wishes to withdraw the testing of his or her specimens for future research, the 
investigator must inform the Gilead Sciences Medical Monitor in writing of the subject’s wishes.
6.11.
Blood Storage
Archived plasma samples will be collected for future testing. These samples will be frozen and 
stored. The stored plasma samples may be used by the Sponsor or its research partner for future 
clinical laboratory testing to provide additional clinical data. At the conclusion of this study, 
these samples may be retained in storage by Gilead Sciences, Inc. at its research partner facility 
for a period up to 10 years.

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7.
ADVERSE EVENTS 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 pharmaceutical product, which does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. AEs may also include pre- or post-treatment complications that 
occur as a result of protocol specified procedures, lack of efficacy, 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).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
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
The severity grading of AEs will be assessed as Grade 1, 2, 3, or 4 using the GSI Grading Scale 
for Severity of Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated 
with laboratory abnormalities, the event should be graded on the basis of the clinical severity in 
the context of the underlying conditions; this may or may not be in agreement with the grading 
of the laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication until 30 days after last administration of study IMP, all 
AEs, regardless of cause or relationship, must be reported to the CRF/eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of 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 
CRF/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 IMP, 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 IMP, he/she should promptly document and report 
the event to Gilead DSPH

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/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:
+1-650-522-5477
safety_fc@gilead.com

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
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. 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.
Stopping Rules for Toxicity
Subjects who meet any of the following criteria should be instructed to immediately stop all 
study drugs and return for an Early Termination Visit:

Confirmed elevation of ALT and/or AST > 5× Day 1 or nadir, confirmed by immediate 
repeat testing

Confirmed elevation of ALT > 3× Day 1 and total bilirubin > 2 × ULN

Confirmed elevation of ALT >15 x ULN

Any Grade 3 or greater rash associated with constitutional symptoms

Any Grade 4 event assessed as related to treatment 

Echocardiogram demonstrating left ventricular ejection fraction ≤40%
7.5.2.
Sofosbuvir (SOF) or LDV/SOF 
Administration of SOF or LDV/SOF may be discontinued due to a clinical or laboratory event.  
There is no option for sofosbuvir or LDV/SOF dose reduction. In the event that SOF is stopped, 
RBV should also be discontinued. 

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7.5.3.
Ribavirin (RBV)
Dose reduction or interruption of RBV due to toxicity should be performed based on the clinical 
experience of the Investigator. RBV may be temporarily discontinued due to toxicity without 
stopping SOF. However, if RBV is permanently discontinued due to toxicity, SOF should also be 
discontinued.
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.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure to 
the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
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 all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the Gilead DSPH using the pregnancy report form within 
24 hours of becoming aware of the pregnancy. Refer to Section 7.3 and the eCRF completion 
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The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.3 and 7.4. 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: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy 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 
+1 650 522-5477 or email Safety_FC@gilead.com. 
Clinical staff should also report any relevant pregnancies to the Ribavirin Pregnancy Registry 
at 1-800-593-2214 (see also http://www.ribavirinpregnancyregistry.com).
Refer to Appendix 2 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of 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 eCRF completion guidelines for full instructions on the mechanism 
of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.

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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y objectives of this study are as follows: 
Final 
Amendment3 
• 
To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks as assessed by review of the accumulated safety data 
in each treatment mm 
• 
To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks and LDV/SOF for 12 weeks measured by the prop01iion of subjects with renal 
insufficiency who have achieved a sustained viral response 12 weeks after treatment 
discontinuation (SVR12) in each treatment ann 
• 
To evaluate the steady state phmmacokinetics ofSOF and its metabolites and LDV upon 
dosing SOF 200 mg or 400 mg or LDV/SOF in subjects with renal insufficiency 
The secondmy objectives ofthis study m·e as follows: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR at 
4 and 24 weeks after discontinuation of treatment (SVR4 and SVR24) 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF and LDV during and after treatment 
discontinuation 
The explorat01y objective of this study is: 
PPO 
8.1.2. 
Primary Endpoint 
The prima1y safety endpoints include incidences of AEs, laborat01y, 12-lead ECG, and vital sign 
abn01malities. 
The prima1y PK endpoints are pm·ameters AUCtau, Cmax, and Ctau for analytes SOF, its 
metabolites, LDV and RBV as applicable. 
The prima1y efficacy endpoint is SVR12 (HCV RNA < LLOQ 12 weeks after discontinuation 
of therapy). 
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8.1.3.
Secondary Endpoint
Secondary PK endpoints are parameters AUClast, Clast, Tmax, Tlast, λz, and t1/2 for analytes SOF, its 
metabolites, LDV and RBV as applicable.
Secondary efficacy endpoints include the proportion of subjects with SVR4 and SVR24, the 
proportion of subjects with virologic failure including viral breakthrough and relapse.
8.1.4.
Other Endpoints of Interest
Additional efficacy evaluations may include HCV RNA change from baseline; ALT 
normalization, andviral kinetic parameters.
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 drugs in this study include SOF, RBV and LDV/SOF. Last dose of study drug refers to 
the last dose of any of the study drugs in a treatment group and 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.
All analyses will be presented by treatment cohort. Subjects who receive study drug other than 
that to which they were assigned will be analyzed according to the study drug received.
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The analysis set for antiviral activity analyses will be the Full Analysis Set (FAS) which includes 
subjects who were enrolled and received at least one dose of study drug. 
8.2.1.2.
Safety
The primary analysis set for safety analyses will be the Safety Analysis Set which includes
subjects who received at least one dose of study drug.
Treatment-emergent data will be analyzed and defined as data collected from the first dose of 
study drug through the date of the last dose of study drug plus 30 days.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all subjects who are enrolled and have received at least one dose 
of study drug and for whom PK concentration data of interested analytes (SOF, its metabolites,
LDV or RBV) are available. The PK analysis set will be used for analyses of general PK.

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8.2.2.
Data Handling Conventions
Missing data can have an impact upon the interpretation of the trial data. In general, values for 
missing data will not be imputed. 
For the analysis of post-baseline categorical efficacy endpoints, if a data point is missing and is 
immediately preceded and followed in time by values that are deemed successes, then the 
missing data point will be termed a success; otherwise the data point will be termed a failure.
Any subject with missing data due to premature discontinuation of the study medication will be 
considered a failure at the time points on, or following, the date of discontinuation. If no HCV 
RNA values are obtained after the last dose of study medication, the subject will be considered a 
treatment failure for the SVR endpoints. 
Where appropriate, safety data for subjects that did not complete the study will be included in 
summary statistics. For example,

If a subject received study medication, the subject will be included in a summary of adverse 
events according to the treatment received; otherwise, if the subject is not dosed then they 
will be excluded from the summary.

If safety laboratory results for a subject are missing for any reason at a time point, the subject 
will be excluded from the calculation of summary statistics for that time point. If the subject 
is missing a predose value, then the subject will be excluded from the calculation of summary 
statistics for the predose value and the change from predose values.
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pretreatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities.
Values for missing vital signs data will not be imputed; however, a missing baseline result will 
be replaced with a screening result, if available.
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for 
calculation of summary statistics for the actual HCV RNA values and the change from baseline 
values by study visit. The reported values will be provided in the HCV RNA listing.
For selected analyses of early time point data, HCV RNA data (IU/mL) may be transformed to 
the logarithmic (base 10) scale (log10 IU/mL).
PK concentration values below the lower limit of quantitation (BLQ) will be treated as zero for 
determination of summary and order statistics. Individual values that are BLQ will be presented 
as “BLQ” in the concentration data listing. For the presentation of summary and order statistics, 
if at least 1 subject has a concentration value BLQ for the time point, then the minimum value 
will be displayed as “BLQ.” If more than 50% of the subjects have a concentration data value 

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BLQ for the time point, then the minimum and median values will be displayed as “BLQ.” If 
more than 75% of the subjects have a concentration data value of BLQ for a given time point, 
then the minimum. 1st quartile [q1], median, and 3rd quartile [Q3] values will be displayed as 
“BLQ.” If all subjects have concentration data values BLQ for the time point, then all order 
statistics (minimum, first quartile [Q1], median, third quartile [Q3], maximum) will be displayed 
as “BLQ”.
Exposure parameters that are selected for statistical analysis will be natural log-transformed. 
Concentration values that are BLQ will be excluded for any ratio or natural log-transformed 
statistical analysis.
8.2.3.
Interim Analysis
Interim analyses will be performed to support external multidisciplinary data monitoring 
committee meetings (Section 8.9).
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized using standard descriptive 
methods by treatment cohort.
Demographic data will include sex, self-identified race/ethnicity, and age.
Baseline characteristic data will include body weight/body mass index, HCV RNA level 
(log10 IU/mL), IL28B genotype, baseline ALT level, creatinine clearance estimated by 
Cockcroft-Gault, and additional endpoints as necessary.
8.4.
Efficacy Analysis
8.4.1.
Primary Analysis
The primary efficacy endpoint is SVR12 in the FAS population. The primary analysis will be 
performed after all enrolled subjects have been followed through 12 weeks post-treatment or 
discontinued from study.
A point estimate with a 2-sided 95% exact confidence interval (CI) using the exact binomial 
distribution (Clopper-Pearson method) will be constructed for the SVR12 rate by treatment 
cohort.
No statistical hypothesis testing will be performed.
8.4.2.
Secondary Analysis
The proportion of subjects with HCV RNA below the LLOQ over time (including SVR12) will 
be presented by treatment cohort in tabular and graphical form. 
Descriptive summaries and listings will be provided for additional efficacy evaluations including 
the proportion of subjects who experience virologic failure, ALT normalization, serum HCV 
RNA actual values and change from baseline. 

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Details on efficacy analyses will be described in the statistical analysis plan (SAP). 
8.5. 
Safety Analysis 
Safety will be evaluated by assessment of clinical laborat01y tests, physical examinations, vital 
signs measmements, at various time points dming the study, and by the documentation of AEs. 
All safety data collected on or after the first dose of study dmg adminisu·ation up to 30 days after 
the last dose of study dmg will be summarized according to the study dmg received. Safety 
endpoints will be summarized as the number (prop01tion) of subjects with events or 
abnonnalities for categorical data or as an 8-number summaty (n, mean, standard deviation, 
minimum, Ql, median, Q3, maximum) for continuous data. 
8.5.1. 
Extent of Exposure 
A subject's extent of exposme to study dmg will be generated from the study dmg 
adminisu·ation page of the CRF. Exposme data will be summarized by u·eatment coh01t . 
8.5.2. 
Adverse Events 
Clinical and laborat01y AEs will be coded using the Medical Dictionruy for Regulat01y 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Tetm (HLGT), 
High-Level Tetm (HLT), Prefened Tetm (PT), and Lower-Level Tetm (LLT) will be attached to 
the clinical database. 
Events will be summarized on the basis of the date of onset for the event. A u·eatlnent-emergent 
adverse event will be defined as any new or worsening adverse event that begins on or after the 
date of first dose of study dmg up to the date of last dose of study dmg plus 30 days. 
Summaries (number and percentage of subjects) ofu·eatlnent-emergent adverse events 
(by SOC and prefen ed te1m) will be provided by u·eatlnent coh01t: 
• 
All AEs, 
• 
All study dmg-related AEs, 
• 
Combined Grade 2, 3 and 4 AEs, 
• 
Combined Grade 3 and 4 AEs, 
• 
Combined Grade 2, 3 and 4 study dmg-related AEs, 
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
Combined Grade 3 and 4 study drug-related AEs,

All AEs that caused permanent discontinuation from study drug,

All AEs that caused change in dose or temporary interruption of study drug,

All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized (n, mean, SD, minimum, Q1, median, Q3, 
maximum) by study visit along with corresponding change from baseline.
Graded laboratory abnormalities will be defined using the laboratory toxicity grading scheme 
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 at any 
time post-baseline up to the date of last dose of study drug plus 30 days will be summarized by 
treatment cohort. 
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pretreatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities. Thus, any post-baseline graded abnormality 
(i.e., at least Grade 1) will be considered treatment emergent.
All laboratory abnormalities will be included in the listings of laboratory data.
8.6.
Pharmacokinetic Analysis
Plasma concentrations of the study drug over time will be listed and summarized using 
descriptive statistics. PK parameters (e.g., AUCtau, Cmax, and Ctau) will be listed and summarized 
for study drug (i.e., SOF and its metabolites, LDV and RBV) using descriptive statistics 
(e.g., sample size, arithmetic mean, geometric mean, % coefficient of variation [%CV], SD, 
minimum, Q1, median, Q3, maximum). 
8.7.
Stopping Rules for Individual Groups
There are no predetermined futility criteria which would require enrollment to be halted or 
treatment discontinued.

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8.8.
Sample Size
Due to the exploratory nature of this study, no formal power or sample size calculations were 
performed to determine treatment group size. The total sample size of 30 is largely based on 
feasibility.
8.9.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety, efficacy, and PK data for each cohort of the study 
before proceeding to the next. Specifically, all of the data through post-treatment week 4 from 
the SOF 200 mg group (Cohort 1) will be reviewed before screening, enrollment and dosing for 
the SOF 400 mg group (Cohort 2). A similar review and initiation process will occur between  
SOF 400 mg (Cohort 2) and LDV/SOF dose group (Cohort 3), with review of safety and PK data 
through Week 12 from Cohort 2 prior to initiating Cohort 3. The DMC will provide 
recommendations to Gilead whether the nature, frequency, and severity of adverse effects 
associated with study treatment warrant the early termination of the study in the best interests of 
the participants, whether the study should continue as planned, or the study should continue with 
modifications. The DMC may also provide recommendations as needed regarding the need for 
additional meetings or an alternative meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.

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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) 
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 or IEC. The investigator will not begin any study subject activities 
until approval from the IRB or 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 or IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB or 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 each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 

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investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or
local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB 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. Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in the 

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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.
Drug Accountability
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. Documentation of GSI review and approval of the 
site’s approved SOP will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs 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 Sciences. All protocol modifications must be submitted to the Competent 
Authorities, IRB or IEC in accordance with local requirements. Approval must be obtained 
before changes can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be
prepared in certain cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.

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9.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or audits 
of the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
9.3.3.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.

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10.
REFERENCES
2202
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41.
12557
Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. 
Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 
weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of 
chronic infection with hepatitis C virus. International Hepatitis Interventional 
Therapy Group (IHIT). Lancet 1998;352 (9138):1426-32.
12558
McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et 
al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for 
chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 
1998;339 (21):1485-92.
15572
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: January 2010.
15668
Copegus 200mg and 400mg Film-coated Tablets. Summary of Product 
Characteristics. Roche Products Limited, Welwyn Garden City, United Kingdom. 
Revised: March 2010.
19705
Esteban JI, Sauleda S, Quer J. The changing epidemiology of hepatitis C virus 
infection in Europe. J Hepatol 2008;48 (1):148-62.
23275
Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. 
Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J 
Med 2013;368 (1):34-44.
24149
COPEGUS® (ribavirin, USP) TABLETS. US Prescribing Information. Roche 
Laboratories Inc., Nutley, NJ. Revised: February 2013.
24713
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, 
Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients 
without treatment options. N Engl J Med 2013;368 (20):1867-77.
24715
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et 
al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J 
Med 2013;368 (20):1878-87.
27832
Gilead Sciences Limited. SOVALDI 400 mg film-coated tablets. Summary of 
Product Characteristics.  County Cork Ireland. January 2014.  2014:

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31179
Gilead Sciences Inc. HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use. 
US Prescribing Information.  Foster City, CA October 2014:
32081
Gilead Sciences Inc. SOVALDI® (sofosbuvir) tablets, for oral use. US 
Prescribing Information.  Foster City, CA. November 2014:

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

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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2b, Open-Label Study of200 mg or 400 mg Sofosbuvir+RBV for 24 Weeks in 
Genotype 1 or 3 and Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination (FDC) Tablet 
for 12 weeks in Genotype 1 or 4 HCY-lnfected Subjects with Renal Insufficiency 
GS-US-334-0154, Amendment 3, 23 February 2015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
0~u gv-C{..,.I{ t - ~ 
~< f 
f.I-1.P 
Theo Sarif, MD (Printed) 
Medical Monitor 
Date 
Z.viC 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 75 
23 February 2015 

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Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Background
For Cohorts 1 and 2
Ribavirin is contraindicated in pregnancy as significant teratogenic and embryocidal effects have 
been demonstrated in all animal species tested. Pregnancy must be excluded before the start of 
treatment with study drugs and prevented thereafter by reliable contraceptive methods. 
Pregnancy tests will be performed regularly throughout this study. Furthermore, RBV is known 
to accumulate intracellularly where it is cleared slowly, and is also excreted in semen. Therefore, 
extreme care must be taken to avoid pregnancy during RBV therapy and for up to 6 months 
following completion of treatment (7 months for males). Please refer to the latest version of the 
product insert for additional information. 
Non-clinical toxicity studies of SOF demonstrated no adverse effect on fertility or embryo-fetal 
development. However, there are no clinical studies of SOF in pregnant women. Please refer to 
the latest version of the investigator’s brochure for additional information. 
For Cohort 3
Non-clinical toxicity studies of LDV/SOF demonstrated no adverse effect on embryo-fetal 
development. However, there are no clinical studies of LDV/SOF in pregnant women Please 
refer to the latest version of the Investigator’s Brochure for additional information.
2) Definition of Female of Childbearing Potential and Contraceptive Requirements for 
Female Subjects (and their male partners)
Women 54 years of age with cessation for ≥ 12 months of previously occurring menses, or 
women of any age who have had a hysterectomy, or have had both ovaries removed, or have had 
medically documented ovarian failure will be considered to be of non-childbearing potential. 
Women < 54 years of age (including those with amenorrhea of any duration) who have not had a 
hysterectomy, and have not had both ovaries removed, and have not had medically documented 
ovarian failure will be considered to be of childbearing potential. 
Women of childbearing potential must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test on the Day 1 visit prior to enrollment. They must also agree to one 
of the following from 3 weeks prior to Day 1 until 6 months after last dose of RBV
(Cohorts 1 and 2) or until 30 days after the last dose of study drug in the absence of RBV 
(Cohort 3):

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
Complete abstinence from intercourse. Abstinence is an acceptable method of contraception 
only when it is in line with the subject's preferred and usual lifestyle. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom, from the date of Screening until 
6 months after the last dose of RBV (Cohorts 1 and 2) or 30 days after last dose of study drug 
in the absence of RBV (Cohort 3): 
intrauterine device (IUD) with a failure rate of < 1% per year
female barrier method: cervical cap or diaphragm with spermicidal agent
tubal sterilization
vasectomy in male partner
implants of levonorgestrel
injectable progesterone
oral contraceptives (either combined or progesterone only)
contraceptive vaginal ring 
transdermal contraceptive patch
3) Contraceptive Requirements for Male Subjects (and their female partners)
All male study participants must agree to consistently and correctly use a condom from 
Baseline until 7 months after the last dose of RBV (Cohorts 1 and 2) or until 90 days after 
administration of the last dose of study drug in the absence of RBV (Cohort 3). If their female 
partner is of childbearing potential (as defined above), their female partner must use 1 of the 
methods of birth control listed above from the date of Screening until 7 months after last dose of 
RBV (Cohorts 1 and 2) or until 90 days after administration of the last dose of study drug in the 
absence of RBV (Cohort 3).
Male subjects must agree to refrain from sperm donation for at least 7 months after the last dose 
of RBV (Cohorts 1 and 2) or for at least 90 days after the last dose of study drug in the absence 
of RBV (Cohort 3).

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4) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 6 months (7 months for partners of male subjects) of 
last RBV dose or within 30 days (90 days for partners of male subjects) of last LDV/SOF dose.
Subjects who become pregnant or who suspect that they are pregnant must report the information 
to the investigator and discontinue study drug immediately. Subjects whose partner has become 
pregnant or suspects she is pregnant must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.6.2.

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Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18 June 2012
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L

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

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

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

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

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.14 mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric > 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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