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 
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 
HCV-Infected Subjects with Renal Insufficiency 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404, USA 
106,739 
2013-002897-30 
Hepatitis C Vims Infection 
GS-US-3 34-0154 
Name: 
Telephone: 
Fax: 
E-mail: 
PPD 
PPD 
PPD 
t-'t-'U 
Original: 
11 July 2013 
Amendment 1: 
05 September 2013 
Amendment 2: 
20 Febmmy 2014 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmiiculm·ly unpublished data, is the prope1iy or 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 Bom·d or Independent Ethics Committee. The inf01mation is 
only to be used by you in connection with authorized clinical studies of the investigational 
dmg described in the protocol. You will not disclose any of the infonnation to others without 
written authorization from Gilead Sciences, Inc., except to the extent necessmy to obtain 
inf01med consent from those persons to whom the dmg may be administered. 

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TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................................................................2
LIST OF IN-TEXT TABLES.................................................................................................................................4
PROTOCOL SYNOPSIS .......................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................10
1.
INTRODUCTION .......................................................................................................................................13
1.1.
Background.....................................................................................................................................13
1.2.
Sofosbuvir (formerly GS-7977)......................................................................................................13
1.3.
Ribavirin (RBV)..............................................................................................................................13
1.4.
Rationale for the Current Study ......................................................................................................14
1.5.
Rationale for SOF Dose Selection ..................................................................................................15
1.6.
Rationale for RBV Dose Selection .................................................................................................16
2.
OBJECTIVES..............................................................................................................................................17
3.
STUDY DESIGN ........................................................................................................................................18
3.1.
Treatment Plan and Regimen..........................................................................................................18
3.2.
Visit Schedule .................................................................................................................................18
3.3.
Virologic Response-Based Stopping Criteria..................................................................................19
3.3.1.
Cardiac Function-Based Stopping Criterion .................................................................19
3.4.
Treatment Discontinuation Criteria.................................................................................................19
3.5.
Registry Studies ..............................................................................................................................20
3.5.1.
Sequence Registry Study...............................................................................................20
3.5.2.
SVR Registry Study ......................................................................................................20
4.
SUBJECT POPULATION...........................................................................................................................21
4.1.
Number of Subjects and Subject Selection .....................................................................................21
4.2.
Inclusion Criteria ............................................................................................................................21
4.3.
Exclusion Criteria ...........................................................................................................................22
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ....................................................................................25
5.1.
Sofosbuvir (SOF) ............................................................................................................................25
5.1.1.
Formulation...................................................................................................................25
5.1.2.
Packaging and Labeling ................................................................................................25
5.1.3.
Storage and Handling....................................................................................................25
5.1.4.
Sofosbuvir (SOF) Dosage and Administration..............................................................26
5.2.
Ribavirin (RBV)..............................................................................................................................26
5.2.1.
Formulation...................................................................................................................26
5.2.2.
Packaging and Labeling ................................................................................................26
5.2.3.
Storage and Handling....................................................................................................26
5.2.4.
RBV Dosage and Administration..................................................................................27
5.3.
Co-administration of Sofosbuvir (SOF) and Ribavirin (RBV) .......................................................27
5.4.
Study Drug Compliance..................................................................................................................27
5.5.
Dispensing and Accountability of Study Drugs..............................................................................27
5.6.
Study Drug Return or Disposal.......................................................................................................28
5.7.
Concomitant Medications ...............................................................................................................28
5.7.1.
Medications Associated with QT Prolongation.............................................................29
5.7.2.
Hematopoietic Growth Factors .....................................................................................31

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6.
STUDY PROCEDURES .............................................................................................................................32
6.1.
Subject Enrollment and Treatment Assignment..............................................................................32
6.2.
Pretreatment Assessments...............................................................................................................36
6.2.1.
Screening Visit..............................................................................................................36
6.2.2.
Medical History.............................................................................................................36
6.3.
Day 1 Assessments..........................................................................................................................37
6.3.1.
Dosing Diary.................................................................................................................37
6.4.
Treatment Assessments...................................................................................................................37
6.5.
Safety Assessments.........................................................................................................................37
6.5.1.
Safety ECGs..................................................................................................................37
6.5.2.
Safety echocardiograms ................................................................................................38
6.5.3.
Physical Examination....................................................................................................38
6.5.4.
Vital Signs.....................................................................................................................38
6.5.5.
BMI...............................................................................................................................38
6.5.6.
Creatinine Clearance .....................................................................................................38
6.5.7.
Clinical Laboratory Tests/Assessments.........................................................................39
6.5.8.
Adverse Events/ Concomitant Medications/ Protocol Restrictions...............................40
6.6.
Pharmacokinetic (PK) Assessments................................................................................................40
6.7.
Early Termination (ET)/Unscheduled Visit ....................................................................................41
6.8.
Post-Treatment Assessments...........................................................................................................42
6.9.
Optional Samples for Pharmacogenetic Testing .............................................................................42
6.10.
Archived Plasma Sample ................................................................................................................42
6.11.
Blood Storage..................................................................................................................................42
7.
ADVERSE EVENTS MANAGEMENT.....................................................................................................43
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events..........................43
7.1.1.
Adverse Events..............................................................................................................43
7.1.2.
Serious Adverse Events.................................................................................................43
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events..............................................................44
7.2.
Assessment of Adverse Events and Serious Adverse Events..........................................................44
7.2.1.
Assessment of Causality for Study Drugs and Procedures............................................45
7.2.2.
Assessment of Severity .................................................................................................45
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead................................................................................................................45
7.4.
Gilead Reporting Requirements......................................................................................................47
7.5.
Toxicity Management .....................................................................................................................47
7.5.1.
Stopping Rules for Toxicity..........................................................................................47
7.5.2.
Sofosbuvir (SOF) ..........................................................................................................48
7.5.3.
Ribavirin (RBV)............................................................................................................48
7.6.
Special Situations Reports ..............................................................................................................48
7.6.1.
Definitions of Special Situations...................................................................................48
7.6.2.
Instructions for Reporting Special Situations................................................................49
8.
STATISTICAL CONSIDERATIONS.........................................................................................................51
8.1.
Analysis Objectives and Endpoints.................................................................................................51
8.1.1.
Analysis Objectives.......................................................................................................51
8.1.2.
Primary Endpoint ..........................................................................................................51
8.1.3.
Secondary Endpoint ......................................................................................................52
8.1.4.
Other Endpoints of Interest ...........................................................................................52
8.2.
Analysis Conventions .....................................................................................................................52
8.2.1.
Analysis Sets.................................................................................................................52
8.2.2.
Data Handling Conventions ..........................................................................................53

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8.2.3.
Interim Analysis............................................................................................................54
8.3.
Demographic Data and Baseline Characteristics ............................................................................54
8.4.
Efficacy Analysis............................................................................................................................54
8.4.1.
Primary Analysis...........................................................................................................54
8.4.2.
Secondary Analysis.......................................................................................................54
8.5.
Safety Analysis ...............................................................................................................................55
8.5.1.
Extent of Exposure........................................................................................................55
8.5.2.
Adverse Events..............................................................................................................55
8.5.3.
Laboratory Evaluations .................................................................................................56
8.6.
Pharmacokinetic Analysis...............................................................................................................56
8.7.
Stopping Rules for Individual Groups ............................................................................................57
8.8.
Sample Size.....................................................................................................................................57
8.9.
Data Monitoring Committee ...........................................................................................................57
9.
RESPONSIBILITIES ..................................................................................................................................58
9.1.
Investigator Responsibilities ...........................................................................................................58
9.1.1.
Good Clinical Practice ..................................................................................................58
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) Approval..............................................................................................................58
9.1.3.
Informed Consent..........................................................................................................59
9.1.4.
Confidentiality ..............................................................................................................59
9.1.5.
Study Files and Retention of Records...........................................................................59
9.1.6.
Case Report Forms........................................................................................................61
9.1.7.
Drug Accountability......................................................................................................61
9.1.8.
Inspections ....................................................................................................................61
9.1.9.
Protocol Compliance.....................................................................................................62
9.2.
Sponsor Responsibilities.................................................................................................................62
9.2.1.
Protocol Modifications..................................................................................................62
9.2.2.
Study Report and Publications ......................................................................................62
9.3.
Joint Investigator/Sponsor Responsibilities ....................................................................................62
9.3.1.
Access to Information for Monitoring...........................................................................62
9.3.2.
Access to Information for Auditing or Inspections .......................................................63
9.3.3.
Study Discontinuation...................................................................................................63
10.
REFERENCES ............................................................................................................................................64
11.
APPENDICES .............................................................................................................................................66
Appendix 1.
Investigator Signature Page...........................................................................................67
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements ..................................................................68
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities .............................................................................................70
LIST OF IN-TEXT TABLES
Table 6-1.
Schedule of Assessments ..............................................................................................33

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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 HCV-Infected 
Subjects with Renal Insufficiency
IND Number:
Eudra CT Number:
106,739
2013-002897-30
Study Centers 
Planned:
Multiple sites in New Zealand, Europe, North America and South 
America
Number of Subjects 
Planned:
Approximately 40 subjects
Target Population:
Adults with chronic renal insufficiency and HCV infection
Treatment Duration:
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 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 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 upon dosing SOF 200 mg or 400 mg in subjects
with renal insufficiency 
The secondary objectives of this study are:

To evaluate the proportion 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 during 
and after treatment discontinuation

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Study Design: 
Registry Studies: 
CONFIDENTIAL 
The explorat01y objective of this study is: 
This study will have 2 pmis. 
Final 
Amendment2 
Pmi 1 will enroll approximately 20 subjects with severe renal 
insufficiency. 
• 
10 subjects will receive SOF 200 mg QD + RBV 200 mg QD 
for 24 weeks. 
• 
Following review of safety, efficacy and PK data through 
post-tr·eatrnent Week 4 of the Pmi 1 SOF 200 mg group, 
10 additional subjects will receive SOF 400 mg QD + RBV 
200 mg QD for 24 weeks. 
Pmi 2 will enroll approximately 20 subjects on dialysis following 
review of safety, efficacy and PK data through post-tr·eatrnent 
Week 4 of Pmi 1 SOF 400 mg group. 
• 
10 subjects will receive SOF 200 mg QD + RBV 200 mg QD 
for 24 weeks. 
• 
Following review of safety, efficacy and PK data through 
post-tr·eatrnent Week 4 of the Pmi 2 SOF 200 mg group, 
10 additional subjects will receive SOF 400 mg QD + RBV 
200 mg QD for 24 weeks. 
Sequence Registry Study 
Subjects who do not achieve SVR will be eligible for enrollment in 
the Sequence Registry Study where available and approved. The 
pmpose of the Sequence Registry Study will be to monitor the 
persistence of resistant mutations for up to 3 yem·s. The Sequence 
Registry Study is described in a sepm·ate protocol 
(GS-US-248-0123). 
SVR Registry Study 
All subjects who achieve SVR will be eligible for enrollment in the 
SVR Registry Study where available and approved. The pmpose of 
the SVR Registry Study will be to evaluate dmability of SVR for 
up to 3 yem·s post-tr·eat:Inent. The SVR Regisby Study is described 
in a sepm·ate protocol (GS-US-248-0122). 
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Diagnosis and Main 
Eligibility Criteria:
Adults (≥ 18 years) with chronic genotype 1 or genotype 3 HCV 
infection. Reference Sections 4.2 and 4.3 for detailed Inclusion and 
Exclusion criteria.
Study Procedures/
Frequency:
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, 16, 20 and 24 and at Post-Treatment 
Weeks 4, 12, and 24. Screening assessments will include physical 
examination, height, weight, vital signs, 12-lead ECG, 
echocardiogram, concomitant medications, safety laboratory tests, 
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
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.
Plasma concentrations of SOF and its metabolites 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 
and RBV concentrations will be collected at all other on treatment 
visits beginning at the Week 1 visit.
PK Parameters for SOF, its metabolites, and RBV will be 
estimated as appropriate. 

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Test Product, Dose, 
and Mode of 
Administration: 
Optional Genetic Sample Collection 
PPD 
Archived Plasma Sample 
Final 
Amendment2 
Archive plasma samples are being collected for possible additional 
analyses, including but not limited to, study dmg or metabolite 
measurements, viral load, safety/efficacy assessments, HCV gene 
sequencing, HCV resistance testing and other possible predictors 
of response as detennined by Gilead. 
Sofosbuvir is manufactured as 100 mg and 400 mg tablets for oral 
administration. Subjects enrolled 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 enrolled to take the 
400 mg dose will take 1x400 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 administration by 
Gilead Sciences. Subjects will take 1 x 200 mg tablet in the 
moming with SOF and with food. 
Reference Therapy: 
None 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
PK: 
CONFIDENTIAL 
AEs will be collected through 4 weeks post-treatment. Safety labs 
and SAEs will be collected throughout the study. Safety will be 
evaluated by assessment of clinical laborat01y tests, ECG, 
echocardiogram, periodic physical examinations including vital 
signs at various time points during the study, and by the 
documentation of adverse events. 
Efficacy will be evaluated using scheduled assessments of HCV 
RNA perf01m ed using CO BAS® AmpliPrep/COBAS® TaqMan® 
HCV Test. 
Plasma PK parameters will be calculated for sofosbuvir and its 
metabolites GS-566500 and GS-331007 and RBV, as applicable. 
Examples are AUCiast, AUCtau, Cmax, Clast, Ctau, and t112. 
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Statistical Methods:
Safety data will be listed by subject and summarized by treatment 
in each renal function subgroup (study part) 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 and study part using 
descriptive statistics for each analyte (SOF, GS-566500, 
GS-331007, and RBV, as appropriate). 
In the efficacy analysis, no statistical hypothesis testing will be 
performed and no formal inference will be made on 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 and study part. 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 and visit in each study part 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 40 (i.e., 10 enrolled to obtain 
8 evaluable for each dose level group in each study part) 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 
dL
Deciliter
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
Electrocardiogram
eCRF
Electronic case report form(s)
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
HBV
Hepatitis B virus
HCV
Hepatitis C virus

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
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
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
QD
once daily (use only in tables)
QTcF
QT interval corrected using Fridericia’s formula
RBC
Red blood cell count 
RBV
Ribavirin
RNA
ribonucleic acid
RVR
rapid virologic response 
SADR
Serious adverse drug reaction

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
SAE
serious adverse event
SD
Standard deviation
SOC
Standard of Care
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
Sustained Virologic Response
tmax
The time (observed time point) of Cmax
TND
Target not detected
TSH
Thyroid stimulating hormone
t½
An estimate of the 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}.
Standard of care for genotype 1 HCV infection involves 24-48 weeks of an HCV protease 
inhibitor in combination with pegylated interferon-alfa (PEG)+ribavirin (RBV). The 
recommended first-line treatment for subjects with genotype 2 or genotype 3 chronic 
hepatitis C is PEG+ RBV for 24 weeks {13693}, {17940}. There are minimal data regarding 
the optimal regimen for patients with severe renal disease (e.g., Cr clearance<30 mL/min) or 
end stage renal disease on maintenance hemodialysis. Interferon monotherapy for 48 weeks 
which provides an SVR rate of approximately 40% in clinical trials is often deemed the 
treatment of choice. Due to the side effects and lengthy duration of current treatment, there is 
substantial need for a short, simple, interferon-free regimen, particularly in patients who are 
more susceptible to drug toxicities, such as those with renal insufficiency. 
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 {27503}, {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 

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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.
1.4.
Rationale for the Current Study
This study will evaluate the safety, efficacy and pharmacokinetics of treatment with 
SOF+RBV for 24 weeks in subjects with chronic genotype 1 or 3 HCV infection and severe 
renal impairment.
Liver disease caused by HCV causes significant morbidity and mortality among patients with 
end-stage renal disease, particularly those treated with dialysis. Although treatment for 
chronic HCV has evolved over the last decade resulting in response rates of approximately 
70%, treatment with PEG and RBV is not recommended in ESRD patients {24913}. 
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.
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 

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dose in the current study (Section 1.6), 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.
1.5.
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.  
Part 1 of this study will evaluate the safety, efficacy and pharmacokinetics of 2 doses of 
sofosbuvir in subjects with severe renal impairment; the reduced dose of 200 mg sofosbuvir 
is expected to provide sofosbuvir systemic exposures that are comparable to the 400 mg dose 
in subjects with normal renal function and GS-331007 exposures that are approximately 
2.2-fold above those observed in subjects with normal renal function at the 400 mg dose.
Safety, efficacy and pharmacokinetic data from the 200 mg and then the 400 mg dose of 
sofosbuvir in Part 1 will inform the initiation of Part 2.  In Part 2, the safety, efficacy and 
pharmacokinetics of SOF at a dose of 200 mg and then 400 mg will be evaluated in subjects 
with End Stage Renal Disease (ESRD) on dialysis.  In study P7977-0915, exposure (AUCinf) 
of sofosbuvir and GS-331007, were 1.6 fold and 14 to 22-fold higher respectively in subjects 
with ESRD compared to matched controls with normal renal function.  Dose reduction of 
sofosbuvir to mitigate increased GS-331007 exposure in subjects with ESRD may result in 
suboptimal sofosbuvir exposure.  As such, in this patient population with a high unmet 
medical need, to balance both safety and efficacy, the 200 mg and 400 mg dose will be 
evaluated in Part 2 in subjects with ESRD.

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1.6.
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 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 2-part stepwise design will 
allow a full review of the risk/benefit of both doses and treatment arms in patients with Cr 
clearance <30 mL/min before proceeding to the cohort of patients on dialysis who are 
predicted to have higher SOF and GS-331007 exposures. 
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 
and end stage renal disease.

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2. 
OBJECTIVES 
The prima1y objectives of this study are: 
Final 
Amendment2 
• 
To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 weeks as assessed by review of the accumulated safety data in each treatment ann 
• 
To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV) for 
24 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 rum 
• 
To evaluate the steady state phrumacokinetics of SOF and its metabolites upon dosing 
SOF 200 mg or 400 mg 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 during and after treatment 
discontinuation 
The explorat01y objective of this study is: 
IT 
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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 in chronic renal insufficiency and HCV infection subjects with 
genotype 1 or genotype 3 HCV infection, including those with compensated cirrhosis.
This study will have 2 parts. 
Part 1 will enroll approximately 20 subjects with severe renal insufficiency. 

10 subjects will receive SOF 200 mg QD + RBV 200 mg QD for 24 weeks.

Following review of safety, efficacy and PK data through post-treatment Week 4 of the 
Part 1 SOF 200 mg group, 10 additional subjects will receive SOF 400 mg QD + RBV 
200 mg QD for 24 weeks.
Part 2 will enroll approximately 20 subjects on dialysis following review of safety, efficacy 
and PK data through post-treatment Week 4 of Part 1 SOF 400 mg group.  

10 subjects will receive SOF 200 mg QD + RBV 200 mg QD for 24 weeks.

Following review of safety, efficacy and PK data through post-treatment Week 4 of the 
Part 2 SOF 200 mg group, 10 additional subjects will receive SOF 400 mg QD + RBV 
200 mg QD for 24 weeks.
3.1.
Treatment Plan and Regimen
In Part 1, following screening procedures and Day 1 assessments, eligible subjects will 
receive either SOF 200 mg or 400 mg QD + RBV 200 mg QD for 24 weeks.
In Part 2, following screening procedures and Day 1 assessments, eligible subjects receive 
either SOF 200 mg or 400 mg QD + RBV 200 mg QD for 24 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.
3.3.1.
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 3.4.

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 24-week treatment duration will 
complete an Early Termination Visit (Section 6.7).

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3.5.
Registry Studies
3.5.1.
Sequence Registry Study
Subjects who do not achieve SVR will be eligible for enrollment in the Sequence Registry 
Study where available and approved. The purpose of the Sequence Registry Study will be to 
monitor the persistence of resistant mutations for up to 3 years. The Sequence Registry Study 
is described in a separate protocol (GS-US-248-0123).
3.5.2.
SVR Registry Study
All subjects who achieve SVR will be eligible for enrollment in the SVR Registry Study
where available and approved. The purpose of the SVR Registry Study will be to evaluate 
durability of SVR for up to 3 years post-treatment. The SVR Registry Study is described in a 
separate protocol (GS-US-248-0122).

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 40 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 or 3 as determined at Screening
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 x 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). For Part 1 subjects, CLcr  
≤30 mL/min and not on dialysis, and for Part 2 subjects,on dialysis 
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 x 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.
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 the HCV NS5B polymerase

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3) Prior null response to PEG+RBV therapy 
4) Male with pregnant female partner
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.
10) History of clinically significant hemoglobinopathy
11) History of porphyria
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 
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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 5.7 within 
21 days of the Day 1 visit
22) Known hypersensitivity to RBV, 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 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.

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Sufficient quantities of SOF tablets to complete the entire study will be shipped to the 
investigator or qualified designee from Gilead Sciences Materials & Logistics (or its 
designee).
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.

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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.
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.
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.
5.5.
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 

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end of the study, all unused study drugs (both bulk and individual subject returns) will be 
returned to a location designated by Gilead Sciences.
5.6.
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, 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.
5.7.
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.
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

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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.
5.7.1.
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
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)

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QT Prolonging Medication Class
Known or Strongly Suspected to cause 
QT Prolongation
Weaker Association with 
QT Prolongation
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
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.
5.7.2.
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 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
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 
Sample
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. In Part 2 (ESRD 
subjects on dialysis), the Week 2 and 12 visits (intensive PK assessments) must be conducted the same number of days after the previous dialysis session.
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.

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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.
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
— 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.
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
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. 
6.5.
Safety Assessments
Safety will be evaluated throughout the study. Refer to Table 6-1 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.
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.
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 

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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.  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.  For Part B, echocardiograms 
will be performed up to 36 hours following dialysis.
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. 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.
Blood pressure will be measured using the following standardized process:

Subject should sit for 5 minutes with feet flat on the floor and measurement arm 
supported so that the midpoint of the manometer cuff is at heart level;

Use a mercury sphygmomanometer or automatic blood pressure device with an 
appropriately sized cuff with the bladder centered over the brachial artery;

Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or 
to the nearest whole number on an automatic device.
6.5.5.
BMI
Height and weight will be collected at the times shown in the schedule of assessments 
Table 6-1.
BMI is calculated by the following equation.
BMI = weight (pounds) 703           or            weight in kilograms
   (height in inches)2                                (height in meters)2
6.5.6.
Creatinine Clearance
Creatinine clearance is calculated by the Cockcroft-Gault equation {2202} using ideal body 
weight (IBW). 

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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 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®.
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 

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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. 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. 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 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.
In Part 2 (ESRD subjects on dialysis), the Week 2 and 12 visits (intensive PK assessments) 
must be conducted the same number of days after the previous dialysis session.
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.
Intensive PK Assessments:
Intensive 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. 
Plasma concentrations of SOF and its metabolites will be determined and PK parameters will 
be estimated as appropriate. Plasma concentrations of RBV may be determined, if necessary.

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Trough PK Assessments:
Trough PK plasma samples for analyses of SOF, its metabolites and RBV concentrations will 
be collected at all other on treatment visits beginning at the Week 1 visit.
PK Parameters for SOF, its metabolites, 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

Pregnancy prevention counseling

Obtain blood samples for:
— Hematology & Chemistry
— Coagulation (PT, PTT, and INR)
— HCV RNA
— Viral Sequencing / Phenotyping Sample 
— Trough PK
— Serum pregnancy test (females of childbearing potential only)

Review study drug adherence with subject including recording the date and time of the 
subject’s last dose of study drug prior to the PK draw (subject should return all study 
drugs at this visit)
All subjects will attend the 4-Week Post-Treatment Visit.

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6.8. 
Post-Treatment Assessments 
Final 
Amendment2 
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-treatment Week 24 Visit. 
6.9. 
Optional Samples for Pharmacogenetic Testing 
PPD 
6.10. 
Archived Plasma Sample 
Archive plasma samples will be collected at the study visits, indicated in Table 6-1. Archive 
plasma samples are being collected for possible additional analyses, including but not limited 
to, study dmg 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 pmi of the future biomm·ker research. 
If a subject wishes to withdraw the testing of his or her specimens for future research, the 
investigator must inf01m 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 pminer for 
future clinical laborat01y 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 resem·ch 
pminer facility for a period up to 10 yem·s. 
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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

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
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

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 
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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.
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, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study IMP must be reported to the CRF/eCRF 
database as instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined 
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All SAEs, regardless of cause or relationship, that occms after the subject first consents to 
pmiicipate in the study (ie, signing the infonned consent) and throughout the dmation of the 
study, including the protocol-required post treatment follow-up period, must be reported to 
the CRF/eCRF database and Gilead Dmg Safety and Public Health (DSPH) as instructed. 
This also includes any SAEs resulting from protocol-associated procedmes perf01med after 
inf01med consent is signed. 
Any SAEs and deaths that occm after the post tr·eatment follow-up visit but within 30-days of 
the last dose of study IMP, regardless of causality, should also be rep01ied. 
Investigators m·e not obligated to actively seek SAEs after the protocol defined follow up 
period, however, if the investigator lemns of any SAEs that occm after study pmticipation 
has concluded and the event is deemed relevant to the use ofiMP, he/she should promptly 
document and rep01i 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. 
Electr·onic Serious Adverse Event ( eSAE) Rep01iing Process 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
inf01mation to Gilead DSPH within 24 homs of the investigator's knowledge of the 
event. Detailed instructions can be fmmd in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE infonnation electr·onically, ie, the 
eCRF database is not ftmctioning, record the SAE on the paper serious adverse event 
rep01iing f01m and submit within 24 homs to: 
Gilead DSPH: 
Fax: 
+ 1-650-522-5477 
E-mail: 
safety_ fc@gilead.com 
Gilead Sciences Medical 
Name: 
Luisa Stamm, MD, PhD 
Monitor: 
Phone: 
PPD 
Fax: 
PPD 
E-mail: 
1-'1-'U 
I 
• 
As soon as it is possible to do so, any SAE rep01ted via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been rep01ied via a paper fonn because the eCRF database has been 
locked, no ftnther action is necessaty. 
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
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and 
other documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate 
safety reports.

Any medications necessary for treatment of the SAE must be recorded onto the 
concomitant medication section of the subject’s CRF/eCRF and the event description 
section of the SAE form.
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 > 5x Day 1 or nadir, confirmed by immediate 
repeat testing

Confirmed elevation of ALT >3x Day 1 and total bilirubin >2 x ULN

Confirmed elevation of ALT >15 x ULN

Any Grade 3 or greater rash associated with constitutional symptoms

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
Any Grade 4 event assessed as related to treatment 

Echocardiogram demonstrating left ventricular ejection fraction ≤40%
7.5.2.
Sofosbuvir (SOF)
Administration of SOF may be discontinued due to a clinical or laboratory event.  In the 
event that SOF is stopped, RBV should also be discontinued. 
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 permanently discontinued due to toxicity 
without stopping SOF. 
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, and 
pregnancy reports regardless of an associated AE.  Also includes reports of adverse reactions 
in infants following exposure from breastfeeding, and reports of adverse reactions associated 
with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure 
to the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by 
a subject.
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.  

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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 guidelines for full instructions on the mechanism of pregnancy 
reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate 
a pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as 
an SAE. The underlying medical reason for this procedure should be recorded as the AE 
term.
A spontaneous abortion is always considered to be an SAE and will be reported as described 
in Sections 7.1.1 and 7.1.2 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 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 
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situation. These reports must consist of situations that involve study IMP, but do not apply to 
concomitant medications. Except for situations that result in AEs, special situations involving 
concomitant medications will not be reported. Any inappropriate use of 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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STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The prima1y objectives of this study are as follows: 
Final 
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• 
To evaluate the safety of SOF 200 mg or 400 mg + RBV for 24 weeks as assessed by 
review of the accumulated safety data in each treatment rum 
• 
To evaluate the efficacy of SOF 200 mg or 400 mg + RBV for 24 weeks measured by the 
prop01iion of subjects with renal insufficiency who have achieved a SVR12 after 
treatment discontinuation in each treatment ann 
• 
To evaluate the steady state PK of SOF and its metabolites upon dosing SOF 200 mg or 
400 mg in subjects with renal insufficiency 
The secondruy objectives of this study ru·e as follows: 
• 
To evaluate the prop01iion of subjects with renal insufficiency who attain SVR4 and 
SVR24 weeks after discontinuation of treatment 
• 
To evaluate the kinetics of plasma HCV RNA during and after treatment discontinuation 
• 
To evaluate the emergence of viral resistance to SOF during and after treatment 
discontinuation 
The explorat01y objective ofthis study is: 
PPO 
8.1.2. 
Primary Endpoint 
The prima1y safety endpoints include incidences of AEs, laborat01y, 12-lead ECG, and vital 
sign abn01m alities. 
The prima1y PK endpoints ru·e pru·ameters AUCtau, Cmax, and Ctau for analytes SOF, its 
metabolites, 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, 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; viral kinetic parameters, and the health related quality of life endpoints.
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 and RBV. 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 in each renal function subgroup (study part). 
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, 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 

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minimum value will be displayed as “BLQ.” If more than 50% of the subjects have a 
concentration data value BLQ for the time point, then the minimum and median values will 
be displayed as “BLQ.” If 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 in each study part.
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 
and study part.
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 and study part in tabular and graphical form. 

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Descriptive summaries and listings will be provided for additional efficacy evaluations 
including the prop01iion of subjects who experience virologic failme, ALT n01malization, 
semm HCV RNA actual values and change from baseline, other endpoints of interest 
including AL T nonnalization and health related quality of life endpoints. 
PD 
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 docmnentation 
ofAEs. 
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 (prop01iion) of subjects with events or 
abn01malities 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 and study 
pati. 
8.5.2. 
Adverse Events 
Clinical and laborat01y AEs will be coded using the Medical Dictionaty 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 smmnm·ized 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 tetm ) will be provided by u·eatlnent and study part: 
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
All AEs,

All study drug-related AEs,

Combined Grade 2, 3 and 4 AEs,

Combined Grade 3 and 4 AEs,

Combined Grade 2, 3 and 4 study drug-related AEs,

Combined Grade 3 and 4 study drug-related AEs,

All AEs that caused permanent discontinuation from study drug,

All AEs that caused change in dose or temporary interruption of study drug,

All SAEs (including death), and

All study drug-related SAEs
All AEs collected during the course of the study will be presented in data listings.
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 and study part. 
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, and RBV) using descriptive 

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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.
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 40 ( i.e., 10 enrolled to 
obtain 8 evaluable for each dose level group in each study part) 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 through post-
treatment week 4 for each part and dose of the study before proceeding to the next.
Specifically, all of the data from the Part 1 SOF 200 mg group will be reviewed before 
screening, enrollment and dosing will occur for the Part 1 SOF 400 mg group and the same 
review and initiation process will occur between Part 1 SOF 400 mg and Part 2 SOF 200 mg 
and also between Part 2 SOF 200 mg and Part 2 SOF 400 mg.   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.

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9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be 
appropriately signed and dated by the subject or the subject’s legally authorized 
representative and the person conducting the consent discussion, and also by an impartial 
witness if required by IRB or IEC or local requirements. The consent form will inform 
subjects about pharmacogenomic testing and sample retention, and their right to receive 
clinically relevant pharmacogenomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only subject initials, date of birth, 
another unique identifier (as allowed by local law) and an identification code will be 
recorded on any form or biological sample submitted to the Sponsor, IRB 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.

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

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9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. 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 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 QA, the site may destroy used (empty or partially 
empty) and unused IMP supplies in accordance with that site’s approved SOP. A copy of the 
site’s approved SOP will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the IMP. Upon study completion, 
copies of the IMP accountability records must be filed at the site. Another copy will be 
returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs or to regulatory authority or health 
authority inspectors.

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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Gilead 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.

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The monitor is responsible for routine review of the CRF/eCRF at regular intervals 
throughout the study to verify adherence to the protocol and the completeness, consistency, 
and accuracy of the data being entered on them. The monitor should have access to any 
subject records needed to verify the entries on the CRF/eCRF. The investigator agrees to 
cooperate with the monitor to ensure that any problems detected through any type of 
monitoring (central, on site) are resolved.
9.3.2.
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.
13693
Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and 
treatment of hepatitis C: an update. Hepatology 2009;49 (4):1335-74.
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.
17940
Craxi A. EASL clinical practice guidelines: management of hepatitis C virus 
infection, European association for the study of the liver. J Hepatol 2011;55:245-
64.
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.

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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.
24913
Abboud O, Becker G, Bellorin-Font E, Field M, Johnson R, Li PK, et al. KDIGO 
clinical practice guidelines on hepatitis C in chronic kidney disease acknowledged 
by ISN. Nature clinical practice 2008;4 (12):648-9.
27503
SOVALDI® (sofosbuvir) tablets, for oral use. US Prescribing Information. Gilead 
Sciences, Inc. Foster City, CA. December 2013.  
27832
Sovaldi 400 mg film-coated tablets. Summary of Product Characteristics. Gilead 
Sciences Limited. County Cork Ireland. January 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 HCV-lnfected Subjects with Renal Insufficiency 
GS-US-334-0154, Amendment 2, 20 February 2014 
This protocol bas been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
V1 
PrN A 8 42.-A-J t¥ A-rl-P Far 
Luisa Stamm, MD, PhD (Printed) LuLs. A 
Medical Monitor 
.S lAMM 
Date 
PPD 
Signature 
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 tbis 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. 
l 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 
CONFIDENT1AL 
Page67 
20 Febroary 2014 

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Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
11.1.1.
Background
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. 
11.1.2.
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:

Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted.
Or

Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom, from the date of Screening until 
6 months after the last dose of RBV: 
— intrauterine device (IUD) with a failure rate of < 1% per year
— female barrier method: cervical cap or diaphragm with spermicidal agent

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— tubal sterilization
— vasectomy in male partner
— implants of levonorgestrel
— injectable progesterone
— oral contraceptives (either combined or progesterone only)
— contraceptive vaginal ring 
— transdermal contraceptive patch
11.1.3.
Contraceptive Requirements for Male Subjects (and their female 
partners)
All male study participants must agree to consistently and correctly use a condom from 
Baseline until 7 months after the last dose of RBV. If their female partner is of childbearing 
potential (as defined above), their female partner must use 1 of the methods of birth control 
listed above from the date of Screening until 7 months after last dose of RBV.
Male subjects must agree to refrain from sperm donation for at least 7 months after the last
dose of RBV.
11.1.4.
Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any 
time during the study, or if they become pregnant within 6 months (7 months for 
partners of male subjects) of last RBV dose. Subjects who become pregnant or who 
suspect that they are pregnant must report the information to the investigator and 
discontinue study drug immediately. Subjects whose partner has become pregnant 
or suspects she is pregnant must report the information to the investigator. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined 
in Section 7.6.2. 

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

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

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

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

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Amendment 2
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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

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
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

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated

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

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

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

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Amendment 2
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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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Amendment 2
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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