A Phase 1, Open-Label, Multiple Dose Study to Evaluate the Pharmacokinetics of Entospletinib in Subjects With Normal and Impaired Hepatic Function
Phase: PHASE1
Conditions: Oncology
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1, Open-Label, Multiple Dose Study to Evaluate the 
Pharmacokinetics of Entospletinib in Subjects with Normal and 
Impaired Hepatic Function
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND No.:
EudraCT Number:
ClinicalTrials.gov 
Identifier:
116416
2016-003266-98
NCT02521376
Indication:
Oncology
Protocol ID:
GS-US-339-1631
Gilead Sciences Medical 
Monitor
Name:
Telephone:
Fax:
Mobile:
Protocol Version/Date:
Original:
28 July 2015
Amendment 1:
16 October 2015
Amendment 2:
01 July 2016
Amendment 3:
26 August 2016
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol.
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD

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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................13
1.
INTRODUCTION ..............................................................................................................................................16
1.1.
Background ............................................................................................................................................16
1.2.
Entospletinib (ENTO, GS-9973)............................................................................................................16
1.2.1.
General Information .............................................................................................................16
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................16
1.2.3.
Clinical Trials of Entospletinib ............................................................................................17
1.3.
Rationale for the Current Study .............................................................................................................18
1.3.1.
Rationale for the Dose Selection..........................................................................................20
1.4.
Compliance ............................................................................................................................................20
2.
OBJECTIVES.....................................................................................................................................................21
3.
STUDY DESIGN................................................................................................................................................22
3.1.
Study Design..........................................................................................................................................22
3.2.
Study Drug Administration ....................................................................................................................24
3.3.
Clinic Confinement ................................................................................................................................24
3.4.
Pharmacokinetic Assessments................................................................................................................24
3.4.1.
Plasma Pharmacokinetic Collection.....................................................................................25
3.5.
Safety Assessments ................................................................................................................................25
3.6.
Genetic Testing ......................................................................................................................................25
4.
SUBJECT POPULATION..................................................................................................................................26
4.1.
Number of Subjects and Subject Selection ............................................................................................26
4.2.
Inclusion Criteria....................................................................................................................................26
4.2.1.
All Subjects (Healthy Control Subjects and Subjects with Hepatic 
Impairment)..........................................................................................................................26
4.2.2.
Subjects with Impaired Hepatic Function ............................................................................27
4.2.3.
Healthy Matched Controlled Subjects..................................................................................28
4.3.
Exclusion Criteria...................................................................................................................................29
4.3.1.
All Subjects ..........................................................................................................................29
4.3.2.
Subjects with Impaired Hepatic Function ............................................................................31
4.3.3.
Healthy Matched Controlled Subjects..................................................................................31
5.
STUDY DRUGS.................................................................................................................................................33
5.1.
Randomization and Blinding..................................................................................................................33
5.2.
Description and Handling of Entospletinib............................................................................................33
5.2.1.
Formulation..........................................................................................................................33
5.2.2.
Packaging and Labeling .......................................................................................................33
5.2.3.
Storage and Handling...........................................................................................................34
5.3.
Dosage and Administration of Study Drug ............................................................................................34
5.4.
Fasting and Meals ..................................................................................................................................34
5.5.
Dispensing, Accountability, and Disposal or Return of Study Drug......................................................35
5.6.
Concomitant Medications and Other Protocol Restrictions ...................................................................35

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5.6.1.
Concomitant Medications.....................................................................................................35
5.6.2.
Other Protocol Restrictions ..................................................................................................36
6.
STUDY PROCEDURES ....................................................................................................................................38
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................38
6.2.
Pretreatment Assessments......................................................................................................................41
6.2.1.
Screening Visit .....................................................................................................................41
6.2.2.
Admission Assessments .......................................................................................................41
6.3.
Check-In Assessments ...........................................................................................................................42
6.4.
Treatment Assessments..........................................................................................................................42
6.5.
Posttreatment Assessments ....................................................................................................................42
6.6.
Assessments for Premature Discontinuation from Study.......................................................................42
6.7.
Criteria for Discontinuation of Study Drug............................................................................................43
6.8.
Pharmacokinetic Assessments................................................................................................................43
6.8.1.
Plasma PK Collection...........................................................................................................43
6.9.
Safety Assessments ................................................................................................................................43
6.9.1.
Electrocardiogram Assessment ............................................................................................44
6.9.2.
Physical Examination...........................................................................................................44
6.9.3.
Vital Signs............................................................................................................................44
6.9.4.
Body Mass Index..................................................................................................................44
6.9.5.
Clinical Laboratory Tests/Assessments................................................................................45
6.9.6.
Creatinine Clearance ............................................................................................................45
6.9.7.
Adverse Events/Concomitant Medications/Protocol Restrictions........................................45
6.10.
Genetic Testing ......................................................................................................................................45
6.11.
Sample Storage.......................................................................................................................................46
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................47
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................47
7.1.1.
Adverse Events.....................................................................................................................47
7.1.2.
Serious Adverse Events........................................................................................................47
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................48
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................48
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................48
7.2.2.
Assessment of Severity ........................................................................................................49
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................49
7.3.1.
Requirements for collection prior to study drug initiation: ..................................................49
7.4.
Gilead Reporting Requirements.............................................................................................................51
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................51
7.6.
Toxicity Management ............................................................................................................................52
7.7.
Special Situations Reports......................................................................................................................52
7.7.1.
Definitions of Special Situations..........................................................................................52
7.7.2.
Instructions for Reporting Special Situations.......................................................................53
8.
STATISTICAL CONSIDERATIONS................................................................................................................55
8.1.
Analysis Objectives and Endpoints........................................................................................................55
8.1.1.
Analysis Objectives..............................................................................................................55
8.1.2.
Primary Endpoint .................................................................................................................55
8.1.3.
Secondary Endpoint .............................................................................................................55
8.2.
Analysis Conventions.............................................................................................................................55
8.2.1.
Analysis Sets ........................................................................................................................55
8.3.
Data Handling Conventions ...................................................................................................................56

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8.4.
Demographic Data and Baseline Characteristics ...................................................................................56
8.5.
Safety Analysis.......................................................................................................................................56
8.5.1.
Extent of Exposure...............................................................................................................56
8.5.2.
Adverse Events.....................................................................................................................56
8.5.3.
Laboratory Evaluations ........................................................................................................56
8.5.4.
Other Safety Evaluations......................................................................................................57
8.6.
Pharmacokinetic Analysis......................................................................................................................57
8.7.
Sample Size............................................................................................................................................57
9.
RESPONSIBILITIES..........................................................................................................................................59
9.1.
Investigator Responsibilities ..................................................................................................................59
9.1.1.
Good Clinical Practice..........................................................................................................59
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (EC) 
Review and Approval...........................................................................................................59
9.1.3.
Informed Consent.................................................................................................................59
9.1.4.
Confidentiality......................................................................................................................60
9.1.5.
Study Files and Retention of Records ..................................................................................60
9.1.6.
Case Report Forms...............................................................................................................61
9.1.7.
Study Drug Accountability and Return ................................................................................62
9.1.8.
Inspections............................................................................................................................62
9.1.9.
Protocol Compliance............................................................................................................62
9.2.
Sponsor Responsibilities ........................................................................................................................63
9.2.1.
Protocol Modifications.........................................................................................................63
9.2.2.
Study Report.........................................................................................................................63
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................63
9.3.1.
Payment Reporting...............................................................................................................63
9.3.2.
Access to Information for Monitoring..................................................................................63
9.3.3.
Access to Information for Auditing or Inspections ..............................................................63
9.3.4.
Study Discontinuation..........................................................................................................64
10.
REFERENCES ...................................................................................................................................................65
11.
APPENDICES ....................................................................................................................................................66
Appendix 1.
Investigator Signature Page....................................................................................................67
Appendix 2.
Management of Clinical and Laboratory Adverse Events......................................................68
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................69
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............71
Appendix 5.
Child -Pugh-Turcotte Score....................................................................................................92

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LIST OF IN-TEXT TABLES
Table 6-1.
Schedule of Assessments – All Cohorts .................................................................................39
LIST OF IN-TEXT FIGURES
Figure 3-1.
High Level Study Schema......................................................................................................23
Figure 3-2.
Study Schema – All Cohorts ..................................................................................................24

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 1, Open-Label, Multiple Dose Study to Evaluate the 
Pharmacokinetics of Entospletinib in Subjects with Normal and 
Impaired Hepatic Function
IND Number:
EudraCT Number:
116416
Not Applicable
Study Centers 
Planned:
Multiple centers in the United States, New Zealand, and Germany
Objectives:
The primary objective of this study is as follows:

To evaluate the pharmacokinetics of Entospletinib (ENTO) and/or 
its metabolites (if applicable) in subjects with impaired hepatic 
function (stratified by smoking status, as appropriate) relative to 
matched, healthy controls
The secondary objectives of this study are as follows:

To evaluate the safety and tolerability of administration of ENTO 
in subjects with normal and impaired hepatic function

To evaluate the potential impact of smoking on the PK of ENTO 
in subjects with moderate hepatic impairment
Study Design:
Phase 1, open-label, parallel-group, adaptive, multiple dose study
Number of Subjects 
Planned:
A minimum of 40 subjects and a maximum of 80 subjects total. 
Cohort 1 (Moderate Hepatic Impairment) initial cohort
Up to 40 subjects: 20 with moderate hepatic impairment (10 smokers
[at least 8 evaluable] and 10 non-smokers [at least 8 evaluable]), 
20 matched healthy controls (at least 8 evaluable healthy controls 
matched to smokers with moderate impairment, and at least 
8 evaluable healthy controls matched to non-smokers with moderate 
hepatic impairment).
Adaptive Cohort 2 (Severe Hepatic Impairment) 
Up to 20 subjects: 10 with severe impairment, up to 10 matched 
healthy controls, for 8 evaluable subjects per group. Data from 
healthy subjects in previous cohort who are an appropriate match for 
a severe hepatic impairment subject may be used.

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Adaptive Cohort 3 (Mild Hepatic Impairment)
Up to 20 subjects: 10 with mild impairment, up to 10 matched healthy 
controls, for 8 evaluable subjects per group. Data from healthy 
subjects in previous cohort who are an appropriate match for a mild 
impairment subject may be used.
The 90% CIs will be examined to determine if a meaningful change 
(≥ 2-fold mean difference from matched controls) in the exposures of 
ENTO and/or metabolite (if applicable) is identified which would be 
clinically interpreted. A decision to enroll subjects in adaptive 
Cohort 2 (Severe Hepatic Impairment) and/or adaptive Cohort 3 
(Mild Hepatic Impairment) will be enrolled as determined by safety
(treatment-emergent AEs, treatment-emergent laboratory 
abnormalities, vital signs, safety ECGs) and/or PK data from Cohort 1
(Moderate Hepatic Impairment). Specifically, Cohort 2 will be
initiated if supported by safety (treatment-emergent AEs, treatment-
emergent laboratory abnormalities, vital signs, safety ECGs) and PK 
findings from subjects in Cohort 1. Cohort 3 will be enrolled if a 
clinically meaningful change (≥ 2-fold mean difference from matched 
healthy controls) in the exposures of ENTO and/or metabolite (if 
applicable) exposure is identified in non-smoking hepatic impairment 
subjects in Cohort 1.
Target Population:
Male and non-pregnant, non-lactating females subjects aged
≥18 years, with varying degrees of hepatic impairment and matched 
healthy controls. Those with hepatic impairment will be categorized 
based upon the Child-Pugh-Turcotte (CPT) classification system for 
hepatic impairment (CPT Class A, B, or C) as recommended by the 
United States Food and Drug Administration (FDA) and international 
guidance documents. Within the CPT system, subjects will be 
assigned to Class A, B, or C based on a cumulative score evaluating 
the presence and severity of hyperbilirubinemia, hypoalbuminemia, 
prolongation of international normalized ratio (INR) for coagulation 
time, ascites, and hepatic encephalopathy. Designations of hepatic
impairment will be assigned as follows:

Class A (mild): CPT score 5-6

Class B (moderate): CPT score 7-9

Class C (severe): CPT score 10-15
The control group will consist of matched healthy subjects with 
normal hepatic function.
Cohort 1 enrollment of hepatic impairment subjects will be an 
approximate even distribution of subjects who are active cigarette 
smokers (at least 10 cigarettes/day) and subjects who are current 

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non-smokers (no use of tobacco, nicotine-containing or 
THC-containing products within the last 14 days). Hepatic 
impairment subjects enrolled in adaptive Cohorts 2 and 3 will be
current non-smokers (no use of tobacco, nicotine-containing or 
THC-containing products within the last 14 days).
Duration of Dosing:
5 days 
Study Duration:
20 days 
Main Eligibility 
Criteria:
Eligible subjects will be male and non-pregnant, non-lactating female 
subjects, aged ≥18 years, 18 BMI 40, with either impaired 
hepatic function of CPT classification A, B, or C or with normal 
hepatic function. Hepatic impairment must have been stable during 
the 3 months (90 days) prior to study drug administration. 
Each subject in the control group will be matched to a subject with 
impaired hepatic function by age (± 10 years), gender, and body mass 
index (± 20%). 
Subjects with use of moderate or strong CYP3A or CYP2C9 
inducers, or strong CYP2C9 inhibitors within 2 weeks prior to study 
drug administration will be excluded since these agents may affect the 
PK of ENTO. Subjects with use of proton pump inhibitors within 
1 week prior to study drug administration will be excluded.
Study Procedures/
Frequency:
Following completion of Screening and Day -1 assessments, eligible 
subjects will be enrolled in Cohort 1 (followed by Cohorts 2 and/or 
3 pending PK/Safety review) and receive multiple doses of 100 mg 
twice a day (BID) ENTO (1 00 mg tablet) starting on Day 1.
When feasible, dosing in a matched control subject with normal 
hepatic function will occur after the subject with impaired hepatic 
function has completed the PK assessments, except if data exist from 
a subject with normal hepatic function in a previous cohort, this will 
be used instead of enrolling an additional normal healthy control 
subject as permitted in adaptive Cohorts 2 and 3.
Subjects in adaptive Cohort 2 (Severe Hepatic Impairment) and/or 
adaptive Cohort 3 (Mild Hepatic Impairment) will be enrolled as 
determined by safety and/or PK data from Cohort 1 (Moderate 
Hepatic Impairment). Specifically, Cohort 2 will be initiated if 
supported by safety and PK findings from the non-smoking hepatic 
impairment subjects and matching, healthy control subjects  in Cohort 
1. Cohort 3 will be enrolled if a clinically meaningful change 
(≥2-fold mean difference from matched healthy controls) in the 
exposures of ENTO and/or metabolite (if applicable) exposure is 
identified in non-smoking hepatic impairment subjects in Cohort 1.
(Refer to Section 8.7, Sample Size)

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Study Visits and Confinement
Eligible subjects will be confined to the study center beginning 
Day -1 until the completion of assessments on Day 9. Subjects will 
return for an in-clinic follow-up visit 14 (±1) days after the last dose 
of study drug (i.e., Day 19).
Study Drug Administration
All study treatments will be administered at approximately the same 
time each day with 240 mL of water following an overnight fast 
(no food or drinks except water, for at least 8 hours).
When ENTO is administered twice a day, the evening dose of ENTO 
will be administered approximately 12 hours after the AM dose. 
Subjects should continue fasting for 2 hours post AM dose and 
2 hours before and 2 hours after the PM dose.
Only the AM dose of ENTO will be given on Day 5.
On the days of intensive pharmacokinetic sampling, study treatments 
will be administered in the morning following an overnight fast 
(no food or drinks except water, for at least 8 hours). Subjects will 
continue to fast until after collection of the 4-hour pharmacokinetic 
samples, relative to study drug dosing.
Additionally, subjects will be restricted from water consumption 
1 hour before until 2 hours after dosing, except for the 240 mL given 
with the study treatment.
Pharmacokinetic Assessments
Serial blood samples will be collected relative to the AM dose on the 
following days and timepoints for ENTO and/or metabolites 
(if applicable).
Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (pre-PM dose) 
hours postdose
Day 5: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 
84, and 96 hours postdose
Trough Sampling: Days 2 and 4: 0 (pre-AM dose, at approximately 
the same time each day)
Plasma concentrations for ENTO and/or its metabolites (if applicable) 
will be determined and PK parameters evaluated. Protein binding of 
ENTO and/or its metabolites (if applicable), may be assessed at their 
Tmax time point(s) as well as another later time point.
An additional Trough PK sample will be collected at the follow-up 
visit for assessing plasma concentrations for ENTO and/or its 
metabolites (if applicable).

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Safety Assessments
Complete physical exam: Screening and at the follow-up visit or the 
Early Termination visit (if applicable)
Symptom driven physical exam: Day -1, Day 3, Day 7, and prior to 
discharge on Day 9
Vital signs (blood pressure, pulse, respiration rate, and temperature):
Screening, Day -1, Day3, Day 7, prior to discharge on Day 9, at the 
follow-up visit, and at the early termination visit, if applicable.
Clinical laboratory tests (hematology, blood chemistry, and 
urinalysis):  Screening, Day -1, Day 7, prior to discharge on Day 9, at 
the follow-up visit, and at the early termination visit, if applicable.
Urine Drug and Alcohol Assessments: Screening, Day -1, Day 5, 
prior to discharge on Day 9, at the follow-up visit, and at the early 
termination visit, if applicable.
12-lead ECG: Screening, Day -1, Day 3, Day 7, prior to discharge on 
Day 9, at the follow-up visit, and at the early termination visit, if 
applicable.
Serum Pregnancy Test (women of childbearing potential only):
Screening, Day -1, Day 4, prior to discharge on Day 9, at the 
follow-up visit, and at the early termination visit, if applicable.
Serology Test (HBV, HCV, HIV): Screening
FSH testing (females of childbearing potential only): Screening
Other Assessments
Height: Screening
Weight: Screening, Day -1
Assessment of adverse events and concomitant medications will 
continue throughout the study. 
Genetic Testing
A separate, mandatory blood specimen will be collected for the 
extraction of deoxyribonucleic acid (DNA) for genotyping to identify 
polymorphisms of drug metabolizing enzymes (such as CYP2C9, 
CYP3A4/5, CYP1A2 and UGT1A1) and transporters (such as 
OATP 1B1/3, P-gp, BCRP and MATE1) to optimize the therapeutic 
strategy for ENTO. This sample should be collected on Day -1, 
before administration of the first dose of study drug, but may be 
collected at any time during clinic confinement.

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Test Product, Dose, 
and Mode of 
Administration:
ENTO 100 mg [1 100 mg tablet] twice a day
Reference Therapy, 
Dose, and Mode of 
Administration:
Not applicable
Criteria for 
Evaluation:
Safety:
Safety will be evaluated by assessment of periodic physical
examinations including vital sign and 12-lead ECGs performed at
various time points during the study, by the documentation of adverse 
events, and by intervention with concomitant medications.
Efficacy:
Not applicable
Pharmacokinetics:
The following plasma pharmacokinetic parameters will be calculated: 
Cmax, Tmax, Clast, Tlast, z, AUClast, AUCinf, %AUCexp, T½, CL/F, and 
Vz/F, and as appropriate, AUCtau, Ctau.
Statistical Methods:
Pharmacokinetic parameters for ENTO and/or its metabolites
(if applicable) will be listed and summarized by hepatic function 
group (normal or CPT Class A, B, or C) and smoking status (Cohort 1 
only) using descriptive statistics (e.g., sample size, arithmetic mean, 
geometric mean, % coefficient of variation, standard deviation, 
median, minimum, an maximum). An analysis of variance 
appropriate for a parallel design will be fit to the natural 
logarithm-transformed pharmacokinetic parameters (AUC and Cmax). 
The 90% confidence intervals (CIs) will be constructed for the least-
squares geometric mean (GLSM) ratios of pharmacokinetic 
parameters for ENTO and/or its metabolite (if applicable), in groups 
of subjects with hepatic impairment (for Cohort 1 only, stratified by 
smoking status) versus the appropriate group of matched, healthy
controls.
Protein binding of ENTO and/or its metabolites (if applicable) at their 
Tmax and another later time point will be summarized by hepatic 
function group and smoking status (Cohort 1 only) using descriptive 
statistics (if applicable).
Safety data will be listed by subject and summarized by hepatic 
function groups, and frequency of event/abnormality or descriptive 
statistical summaries, as appropriate.
A sample size of 8 evaluable subjects per hepatic function group (for 
Cohort 1, it is 8 evaluable subjects per hepatic function group within 

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each smoking status group) will provide a ≥89% probability for the 
90% CI for the GLSM ratio of pharmacokinetic parameters (AUC or 
Cmax) for ENTO in the hepatic impairment/dysfunction group(s) 
versus the appropriate group of matched, healthy controls, to be 
within limits of 50% to 200%. The calculation assumes an expected
ratio of geometric means of 1.0 in pharmacokinetic parameters and 
inter-subject standard deviation of 0.455 for the natural 
logarithm-transformed pharmacokinetic parameters for ENTO. The 
assumption is based on the data obtained from a prior clinical study of 
ENTO (Study GS-US-339-0111).
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
AE
adverse event
ALL
acute lymphoid leukemia
AML
acute myeloid leukemia
ALT
alanine aminotransferase
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the ENTO concentration versus time curve
AUC0-last
area under the plasma concentration-time curve from time 0 to the last 
measurable concentration
AUCinf
area under the plasma/serum/PBMC concentration versus time curve 
extrapolated to infinite time, calculated as AUC0-last + (Clast/λz)
AUCtau
area under the plasma/serum/PBMC concentration versus time curve over the 
dosing interval
BID
twice a day
BLQ
below limit of quantification
BMI
body mass index
BUN
blood urea nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatine kinase
CLL
chronic lymphocytic leukemia
CL/F
apparent oral clearance
Clast
last observed quantifiable serum/plasma/PBMC concentration of the drug
Cmax
maximum observed ENTOconcentration of drug
CPK
creatine phosphokinase
CPT
Child-Pugh-Turcotte
CrCl
creatinine clearance
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CSR
clinical study report
CTA
clinical trial application
Ctau
observed drug concentration at the end of the dosing interval
CV
coefficient of variation
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health

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EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form(s)
EDC
electronic data capture
ENTO
entospetenib
eSAE
electronic serious adverse event
ET
early termination
EU
European Union
FDA
(United States) Food and Drug Administration
FSH
follicle stimulating hormone
FU
follow up
GCP
Good Clinical Practice (Guidelines)
Gilead
Gilead Sciences, Inc.
GLSM
geometric least square mean
HBV
hepatitis B virus
HCV
hepatitis C virus
HDPE
high density polyethylene
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
IB
investigator’s brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ID
Identification
IND
Investigational New Drug (Application)
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
LLT
lower-level term
LLOQ
lower-limit of quantitation
LOEL
lowest observable effect level
MedDRA
Medical Dictionary for Regulatory Activities
NDA
New Drug Application
NHL
non-Hodgkin lymphoma
NOEL
no observable effect level
OTC
over the counter
PD
pharmacodynamics
PI
principal investigator
PI3K
phosphatidylinositol 3-kinase
PK
pharmacokinetic(s)

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PT
preferred term
PT
prothrombin time
Q1
first quartile
Q3
third quartile
QT
electrocardiographic interval between the beginning of the Q wave and 
termination of the T wave representing the time for both ventricular 
depolarization and repolarization to occur
QTcF
QT interval corrected for heart rate using the Fridericia formulation
RA
rheumatoid arthritis
SADR
serious adverse drug reaction
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SD
standard deviation
SOC
System Organ Class
SOP
standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SYK
spleen tyrosine kinase
TEAE
treatment-emergent adverse event
THC
Tetrahydrocannabinol
Tlast
time (observed time point) of Clast
Tmax
the time (observed time point) of Cmax
T1/2
an estimate of the terminal elimination half-life of the drug in ENTO calculated 
by dividing the natural log of 2 by the terminal elimination rate constant (λz)
US
United States
Vz/F
apparent volume of distribution of the drug
λz
terminal elimination rate constant; estimated by linear regression of the terminal 
elimination phase of the log serum/plasma/PBMC concentration versus time 
curve of the drug

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1.
INTRODUCTION
1.1.
Background
Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily 
expressed in cells of hematopoietic lineage and is an important mediator of immunoreceptor 
signaling in macrophages, neutrophils, mast cells, and B cells. SYK contains 2 adjacent Src 
Homology 2 (SH2) domains that bind to immunoreceptor tyrosine-based activation motifs 
(ITAMs) to autophosphorylate and activate the enzyme. This allows SYK to phosphorylate its 
specific substrates, including other enzymes and adaptor proteins, orchestrating a complex series 
of cellular responses such as cell proliferation, differentiation, survival, and phagocytosis in 
these cells.
Recent studies have suggested a role for the dysregulation of SYK in B-cell malignancies. SYK 
is expressed in B cells and is essentially involved in multiple signal transduction pathways 
downstream of the B-cell receptor (BCR). In this process, SYK trans-autophosphorylates and 
activates effector molecules such as phospholipase C gamma (PLCγ), phosphatidylinositol 
3-kinase (PI3K), and mitogen-activated protein kinase (MAPK), and their associated signaling 
pathways, to induce an array of B-cell responses, including: proliferation, survival, 
differentiation, and apoptosis. Inhibition of BCR-mediated SYK activity is therefore an attractive 
therapeutic target for hematopoietic B-cell malignancies where SYK inhibition could inhibit the 
proliferation and survival of malignant B cells.
1.2.
Entospletinib (ENTO, GS-9973)
The generic name of GS-9973 is entospletinib (ENTO).
1.2.1.
General Information
Entospletinib (ENTO) is a potent and highly selective inhibitor of SYK, orally bioavailable and 
is being developed for the treatment of hematologic malignancies. Entospletinib is currently in a 
Phase 2 clinical trial in subjects with acute myeloid leukemia (AML)/acute lymphoid leukemia 
(ALL)/chronic lymphocytic leukemia (CLL)/non-Hodgkin lymphoma (NHL).
Further information is available in the Investigator’s Brochure (IB) for GS-9973.
1.2.2.
Preclinical Pharmacology and Toxicology
ENTO was evaluated in a standard battery of safety pharmacology studies to assess potential 
effects on central nervous, cardiovascular, and respiratory systems. ENTO had no effect on 
central nervous and respiratory system parameters evaluated in rats. In a cardiovascular safety
pharmacology study in dogs, small increases in heart rate (up to a 25% increase) were observed 
in male dogs given ENTO at 15, 50, or 150 mg/kg. While the higher heart rates were considered 
ENTO-related, the relevance of these changes to humans is not known. Due to the observed 
increases in heart rate, a NOEL was not identified and the lowest observed effect level (LOEL) 
was 15-mg/kg. ENTO had no effect on ECGs or arterial blood pressure values at oral doses up to 
150 mg/kg, the highest dose tested. Consistent with the lack of effect on ECG parameters, ENTO
has no meaningful effect on the human-ether-a-go-go related gene (hERG), indicating that 
ENTO would not be expected to induce clinical QT prolongation. 

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The toxicity of ENTO has been characterized in animal genotoxicity, embryo-fetal reproductive 
toxicity, and phototoxicity studies. Recently published data demonstrated that species-specific GI 
toxicity and lymphoid changes, similar to that which was observed following ENTO
administration to dogs, can occur in dogs but not rats, cynomolgus monkeys, or humans treated 
with p38 map kinase and MAP kinase activated protein kinase-2 (MK2) small molecule kinase 
inhibitors that inhibit pathways that overlap with SYK signaling pathways {Morris et al 2010}. 
Oral administration of ENTO to rats for up to 26 weeks or cynomolgus monkeys for up to 
39 weeks showed no evidence of GI toxicity or lymphoid changes at exposures which 
overlapped with or exceeded those that resulted in acute toxicity in dogs. Furthermore, ENTO
has been previously investigated in healthy human subjects at doses up to 1200 mg twice a day 
for 7 days and in subjects with RA at doses up to 900 mg  for 26 days and no evidence of GI or 
lymphoid toxicity was observed in these clinical studies. Therefore, the relevance of these 
findings to humans is not known.
ENTO inhibits uridine disphosphate glucuronosyltransferase 1A1 (UGT1A1) with an IC50 of 
2 μM. This enzyme is involved in glucuronidation of bilirubin, and inhibitors of UGT1A1 have 
the potential to produce increased levels of total and indirect (unconjugated) bilirubin in the 
circulation {Zhang et al 2005}. 
ENTO is considered non-genotoxic and administration of ENTO did not result in skin reactions 
indicative of phototoxicity in mice.
Administration of ENTO to pregnant female rats and rabbits from implantation to the closure of 
the hard palate (International Conference on Harmonisation [ICH] Harmonised Tripartite 
Guideline stages C to D) resulted in dose-dependent developmental findings including increased 
incidence of early and late fetal resorptions and reduced fetal weights, and delays in ossification 
of the forelimb phalanges (rats and rabbits) and metacarpals (rabbits only). These fetal findings 
occurred at ENTO doses that caused maternal toxicity as demonstrated in both studies by 
dose-dependent decreases in body weight gain and/or body weight loss and decreased food 
consumption of the dams. Maternal toxicity was also demonstrated in these studies at doses that 
did not result in developmental findings.
1.2.3.
Clinical Trials of Entospletinib
Positive results have been reported from a Phase 2 clinical trial with the putative SYK inhibitor 
fostamatinib showing objective anti-tumor responses in CLL and NHL subjects. {Friedberg et al 
2010} These responses occurred despite off target toxicities that limited drug exposure. 
Entospletinib is a highly selective inhibitor of SYK and hence has the potential for an improved 
efficacy and tolerability profile in subjects with hematologic malignancies.
To date, 8 clinical studies have been initiated with ENTO including a total of 486 subjects 
(including 304 healthy subjects, 7 subjects with rheumatoid arthritis (RA), 80 subjects with 
chronic lymphocytic leukemia (CLL), 95 subjects with non-Hodgkins lymphoma (NHL); 
26 subjects receiving placebo) in Phase 1 and Phase 2 clinical studies. Of the 460 subjects 
receiving ENTO in these studies, ENTO has generally been well tolerated.

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Entospletinib is being evaluated in an ongoing Phase 2 clinical trial in subjects with relapsed or 
refractory CLL/NHL, and aPhase 1b/2 clinical trial in subjects with entospletinib monotherapy 
and in combination with chemotherapy in subjects with AML and ALL.
ENTO given at doses up to 1200 mg twice a day (2400 mg/day) for 7 days was well tolerated in 
healthy human subjects, and doses of up to 900 mg twice a day (1800 mg/day) given in 
combination with methotrexate were well tolerated for 26 days in subjects with RA and at 
800 mg BID (1600 mg/day) was well tolerated in subjects with relapsed or refractory CLL/NHL 
for a median duration of exposure for 15 weeks. 
Treatment emergent adverse events (AEs) that were commonly reported across the studies 
included headache, somnolence, and GI symptoms (nausea and abdominal pain), all of which 
were mild and reversible. ENTO administered for 26 days at a dose of 900 mg twice a day was 
well tolerated by subjects with RA on stable doses of methotrexate. This dose and treatment 
schedule produced levels of drug exposure similar to what we expect in subjects with 
hematologic malignancies receiving doses of ENTO at 800 mg twice a day.
Increased transaminases were noted in some subjects observed approximately 2 weeks after 
completion of study drug. In the cohort of subjects with RA, 2 subjects had elevated 
transaminases, which were also observed after completion of study drug. One subject with RA 
had elevated AST/ALT concurrent with bronchopneumonia while the other was diagnosed with 
acute hepatitis.
ENTO is expected to produce asymptomatic and transient elevations of unconjugated (indirect) 
bilirubin due to inhibition of UGT1A1. Eight of 178 healthy subjects treated developed 
asymptomatic indirect bilirubin elevations (6 Grade 1, 1 Grade 2, and 1 Grade 3) that resolved 
following discontinuation of the drug. Three of 7 subjects with RA who received ENTO for 
26 days developed asymptomatic indirect bilirubin elevations (2 Grade 1 and 1 Grade 3) which 
improved despite continued dosing.
Common AEs from an on-going Phase 2 study evaluating chronic administration of entospletinib 
monotherapy in 186 subjects with hematologic malignancies are fatigue (53.2%), 
nausea (45.2%), diarrhea (38.7%), decreased appetite (24.7%), constipation (23.7%), 
cough (21.0%), and headache (21.0%) as of 21 November 2014. 
1.3.
Rationale for the Current Study
Hepatic disease may alter absorption, disposition, and elimination of drugs resulting in 
pharmacokinetic and subsequently pharmacodynamic changes. Available data indicate a hepatic 
role in the disposition of ENTO. Hence, the objective of this study is to investigate potential 
alterations in the pharmacokinetics, pharmacodynamics, and safety of ENTO (and/or its 
metabolites, if applicable) in the context of hepatic insufficiency. The data from this study will 
directly inform dosing recommendations for patients who have liver dysfunction. 

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This study will be conducted in an adaptive manner. The initial subjects to be enrolled will have 
moderate (Child-Pugh Classification B {Pugh et al 1973}) hepatic functional impairment; data 
from these subjects will be compared to matched subjects with normal hepatic function. Based 
upon adequate safety and assessment of the pharmacokinetics in these subjects with moderate 
hepatic impairment (CPT Class B), the study will subsequently evaluate subjects with mild 
(CPT Class A) and/or severe (CPT Class C) hepatic impairment. The planned, staged approach 
of this study design is consistent with recommendations included in the FDA Guidance for 
Industry entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, 
Data Analysis, and Impact on Dosing and Labeling” {U.S. Department of Health and Human 
Services Food and Drug Administration Center for Drug Evaluation and Research (CDER); Center for 
Biologics Evaluation and Research (CBER) 2003}. Such a design enhances subject safety by 
minimizing the potential for exposing subjects to supratherapeutic exposures of ENTO and/or its 
metabolites (if applicable). Specifically, the study will first generate pharmacokinetic and safety 
data in the setting of moderate hepatic impairment where adequate numbers of subjects with 
stable hepatic dysfunction are available and are suitable for evaluation in a Phase 1 study. 
Results obtained from these subjects with moderate impairment are also likely to yield 
determinative data that indicate either, a) the lack of an effect of moderate hepatic impairment, 
thus obviating the need for evaluation in subjects with mild disease or, alternatively, 
b) the potential for large changes in the exposure of ENTO in the setting of end-organ 
dysfunction that may provide evidence for a need for caution with respect to an evaluation in the 
setting of severe hepatic dysfunction.
In vitro studies indicate that ENTO is primarily metabolized by CYP2C9, and to a lesser extent 
by CYP3A and CYP1A2. Use of nicotine-containing or THC-containing products may induce 
CYP1A2, which has the potential to affect ENTO metabolism. Due to lower observed ENTO 
exposure in smokers in Cohort 1, enrollment in Cohort 1 has been expanded to enroll 10 smokers 
with moderate hepatic impairment (for 8 evaluable) and appropriate matched healthy controls, in 
order to further investigate the impact of smoking on ENTO PK. To avoid the potentially 
confounding effect of smoking on the assessment of hepatic impairment on ENTO PK, 
additional non-smoking subjects with moderate hepatic impairment will also be enrolled in 
Cohort 1 (10 enrolled for 8 evaluable, and appropriate healthy, matched controls). In Cohorts 2 
and 3, only non-smoking subjects with hepatic impairment will be enrolled so that an accurate 
assessment of the effect of hepatic impairment on ENTO PK can be made, without the 
potentially confounding effect of smoking. 
The trial will enroll subjects with chronically impaired hepatic function and healthy controls, 
matched for body mass index, age, and sex. This study will proceed in a staggered fashion. 
Dosing of subjects with mild and/or severe hepatic impairment will occur only after the review 
of safety and PK from smoking and non-smoking subjects with moderate hepatic impairment.
Specifically, Cohort 2 will be initiated if supported by safety and PK findings from subjects in 
Cohort 1. Cohort 3 will be enrolled if a clinically meaningful change (≥ 2-fold mean difference 
from matched healthy controls) in the exposures of ENTO and/or metabolite (if applicable) 
exposure is identified in non-smoking hepatic impairment subjects in Cohort 1.

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1.3.1.
Rationale for the Dose Selection
A therapeutic dose of ENTO 400 mg twice a day is being evaluated in the Phase 2 program in 
subjects with CLL (Study 339-0102). Safety results from clinical studies to date indicate that 
ENTO is well tolerated when administered to healthy subjects at 400 mg BID. In this study, a 
lower dose of ENTO (100 mg) compared to therapeutic dose will be used to evaluate the effect 
of hepatic insufficiency on the PK, PD and safety of ENTO (and/or its metabolites, if applicable) 
to allow for a potential increase in ENTO exposures due to impaired hepatic metabolism.
ENTO exhibited non-linear PK (i.e. time and dose dependency in pharmacokinetic parameters) 
in Phase 1 studies. Per the FDA’s recommendation {U.S. Department of Health and Human 
Services Food and Drug Administration Center for Drug Evaluation and Research (CDER); Center 
for Biologics Evaluation and Research (CBER) 2003}, a multiple dose hepatic impairment study is 
desirable when the drug or an active metabolite is known to exhibit nonlinear or time dependent 
PK. Therefore, the current study involves administration of ENTO 100 mg BID for 5 days.
1.4.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.

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2.
OBJECTIVES
The primary objective of this study is as follows:

To evaluate the pharmacokinetics of Entospletinib (ENTO) and/or its metabolites (if 
applicable) in subjects with impaired hepatic function (stratified by smoking status, as 
appropriate) relative to matched, healthy controls
The secondary objectives of this study are as follows:

To evaluate the safety and tolerability of administration of ENTO in subjects with normal 
and impaired hepatic function

To evaluate the potential impact of smoking on the PK of ENTO in subjects with moderate 
hepatic impairment

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3.
STUDY DESIGN
3.1.
Study Design
This protocol describes an open-label, parallel-group, adaptive, multiple-dose, Phase 1 study 
evaluating the pharmacokinetics of ENTO and/or its metabolites (if applicable), in subjects with 
impaired hepatic function relative to matched, healthy controls.  
This study will enroll a minimum of 40 and a maximum of 80 subjects using an adaptive study 
design that includes up to 3 enrolled cohorts of subjects with hepatic impairment as well as 
matched healthy controls. Eligible subjects will be male and nonpregnant, nonlactating female 
subjects, aged ≥18 years, 18 BMI 40, with either impaired hepatic function of CPT 
classification A, B, or C or with normal hepatic function. Each subject in the control group will 
be matched to a subject with impaired hepatic function by age (± 10 years), gender, and body 
mass index (± 20%).
When feasible, dosing in a matched control subject with normal hepatic function will occur after 
the subject with impaired hepatic function has completed the PK assessments, except if data exist 
from a subject with normal hepatic function in a previous cohort, this will be used instead of 
enrolling an additional normal healthy control subject, as permitted in adaptive Cohorts 2 and 3.
Cohort 1 enrollment of hepatic impairment subjects will be an approximate even distribution of 
subjects who are active cigarette smokers (at least 10 cigarettes/day) and subjects who are 
current non-smokers (no use of tobacco, nicotine-containing or THC-containing products within 
the last 14 days). Hepatic impairment subjects enrolled in adaptive Cohorts 2 and 3 will be 
current non-smokers (no use of tobacco, nicotine-containing or THC-containing products within 
the last 14 days).
Based on safety and/or PK results from the non-smoking subjects with moderate hepatic 
impairment and matching, healthy controls (Cohort 1), subjects with severe hepatic impairment 
(Cohort 2) and/or mild hepatic impairment (Cohort 3) will be enrolled as follows:

Cohort 1 (CPT Class B, Moderate Hepatic Impairment)
Up to 40 subjects total:
20 with moderate impairment, (10 smokers ]at least 8 evaluable] and 10 non-smokers ]at 
least 8 evaluable]), 20 matched healthy controls (at least 8 evaluable healthy controls 
matched to smokers with moderate impairment, and at least 8 evaluable healthy controls 
matched to non-smokers with moderate impairment).

Adaptive Cohort 2 (CPT Class C, Severe Hepatic Impairment)
Up to 20 subjects: 
10 with severe impairment, up to 10 matched healthy controls if none of the healthy subjects 
from a previous cohort is an appropriate match for a severe impairment subject, for 
8 evaluable per group. 

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
Adaptive Cohort 3 (CPT Class A, Mild Hepatic Impairment)
Up to 20 subjects: 
10 subjects with mild impairment, up to 10 matched healthy control subjects if none of the 
healthy subjects from a previous cohort is an appropriate match for a mild impairment 
subject, for 8 evaluable per group 
The 90% CIs will be examined to determine if a meaningful change (≥ 2-fold mean difference 
from matched controls) in the exposures of ENTO and/or metabolite (if applicable) is identified
which would be clinically interpreted. A decision to enroll subjects in adaptive Cohort 2 (Severe 
Hepatic Impairment) and/or adaptive Cohort 3 (Mild Hepatic Impairment) will be enrolled as 
determined by safety (treatment-emergent AEs, treatment-emergent laboratory abnormalities, 
vital signs, safety ECGs) and/or PK data from non-smoking moderate hepatic impairment
subjects and matching, healthy controls in Cohort 1. Specifically, Cohort 2 will be initiated if 
supported by safety (treatment-emergent AEs, treatment-emergent laboratory abnormalities, vital 
signs, safety ECGs) and PK findings from non-smoking subjects and healthy, matched cotrols in
Cohort 1. Cohort 3 will be enrolled if a clinically meaningful change (≥ 2-fold mean difference 
from matched healthy controls) in the exposures of ENTO and/or metabolite (if applicable) 
exposure is identified in non-smoking hepatic impairment subjects in Cohort 1..
An overview of the study design is shown below in Figure 3-1
Figure 3-1.
High Level Study Schema

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The study schema for all subjects is shown in Figure 3-2
Figure 3-2.
Study Schema – All Cohorts 
3.2.
Study Drug Administration
Following completion of Screening and Day -1 assessments, eligible subjects will be enrolled in 
1 of 3 cohorts and receive multiple doses of 100 mg twice a day (BID) ENTO (1 00 mg 
tablet) in the fasted state starting on Day 1 for 5 days.
Please refer to Section 5.3 for additional information for study drug dosage and administration.
3.3.
Clinic Confinement
Following completion of Screening and Day -1 assessments, eligible subjects will be confined to 
the study center starting on Day -1 until completion of assessments on Day 9.  Subjects will be 
required to return for an in-clinic follow-up visit 14 (±1) days after the last dose of study drug
(ie, Day 19).
3.4.
Pharmacokinetic Assessments
Pharmacokinetic assessments will occur on assigned study days as outlined in Table 6-1 and 
Section 6.7.

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3.4.1.
Plasma Pharmacokinetic Collection
Plasma concentrations of Entospletinib and/or its major metabolite (if applicable) will be 
determined and PK parameters estimated. PK of other metabolites (if applicable) of 
Entospletinib may be explored.
3.5.
Safety Assessments
Safety assessments will be performed through the study as outlined in Table 6-1 Section 6.9.
3.6.
Genetic Testing
A blood sample for genetic sampling will be taken in the study as outlined in Table 6-1
Section 6.10.
A separate, mandatory blood specimen will be collected for the extraction of DNA for 
genotyping to identify polymorphisms of drug metabolizing enzymes (such as CYP2C9, 
CYP3A4/5, CYP1A2 and UGT1A1) and transporters (such as OATP 1B1/3, P-gp, BCRP and 
MATE1) to optimize the therapeutic strategy for ENTO. This sample should be collected on 
Day -1, before administration of the first dose of study drug, but may be collected at any time 
during clinic confinement.

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
A minimum of 40 and a maximum of 80 unique subjects will be enrolled in the study, with an 
approximate even distribution of male and nonpregnant, nonlactating female subjects 18 years of 
age or older, with varying degrees of hepatic impairment and matched healthy controls will be 
enrolled. Replacement subjects may be enrolled if fewer than 16 evaluable subjects (8 per group) 
complete the study in any cohort. Replacement subjects will not be enrolled for subjects who 
discontinue the study due to treatment-related toxicity.
Cohort 1 enrollment of hepatic impairment subjects will be an approximate even distribution of 
subjects who are active cigarette smokers (at least 10 cigarettes/day) and subjects who are 
current non-smokers (no use of tobacco, nicotine-containing or THC-containing products within 
at least 14 days prior to study drug dosing). Hepatic impairment subjects enrolled in adaptive 
Cohorts 2 and 3 will be current non-smokers (no use of tobacco, nicotine-containing or 
THC-containing products within at least 14 days prior to study drug dosing).
All subjects will be categorized by the Child-Pugh-Turcotte (CPT) classification system 
(Appendix 5) for hepatic impairment as recommended by the United States Food and Drug 
Administration (FDA) and international guidance documents. Within the CPT system, subjects 
will be assigned to Class A, B, or C (CPT Class A, B, or C) based on a cumulative score 
evaluating the presence and severity of hyperbilirubinemia, hypoalbuminemia, prolongation of 
internationalized normalized ratio (INR) for coagulation time, ascites, and hepatic 
encephalopathy. Designations of hepatic impairment will be assigned as follows:

Class A (mild): CPT score 5-6

Class B (moderate): CPT score 7-9

Class C (severe): CPT score 10-15
Based on CPT classification, subjects with hepatic impairment and healthy matched controls will 
be enrolled as described in Section 6.1. The control group will consist of matched healthy 
subjects with normal hepatic function. Each subject in the control group will be matched to a 
subject with impaired hepatic function by age (± 10 years), gender, and body mass index 
(± 20%).
4.2.
Inclusion Criteria
4.2.1.
All Subjects (Healthy Control Subjects and Subjects with Hepatic 
Impairment)
All subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study.
1) Have the ability to understand and sign a written informed consent form (ICF), which must 
be obtained prior to initiation of study procedures

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2) Must be ≥18 years of age at Screening
3) Have a calculated body mass index (BMI) from 18 to 40 kg/m2, inclusive, at study Screening.
4) Have a creatinine clearance (CrCl) 50 mL/min (using the Cockcroft-Gault method 
{Cockcroft et al 1976}) based on serum creatinine and actual body weight as measured at 
Screening ie.,
Male:
(140 – age in years) (wt in kg) CrCl (mL/min)
72 (serum creatinine in mg/dL)
Female:
(140 – age in years) (wt in kg) 0.85 CrCl (mL/min)
72 (serum creatinine in mg/dL)
5) Females of childbearing potential (as defined in Appendix 3) must have a negative serum 
pregnancy test at Screening and clinic admission.
6) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 3.
7) Male subjects must refrain from sperm donation from clinic admission, throughout the study 
period, and continuing for at least 90 days following the last dose of study drug.
8) Subjects must refrain from blood donation from clinic admission, throughout the study 
period, and continuing for at least 30 days following the last dose of study drug.
9) Have either a normal 12-lead electrocardiogram (ECG) or one with abnormalities that are 
considered clinically insignificant by the investigator.
10) Must be willing and able to comply with all study requirements.
4.2.2.
Subjects with Impaired Hepatic Function
Subjects with mild, moderate, or severe hepatic impairment must also meet the following 
additional inclusion criteria to be eligible for participation in this study:
11) Aside from hepatic insufficiency, the subject must, in the opinion of the Investigator, be 
sufficiently healthy for study participation based upon medical history, physical examination, 
vital signs, and screening laboratory evaluations.
12) Must have diagnosis of chronic (> 6 months), stable hepatic impairment with no clinically 
significant changes within 3 months (90 days) prior to study drug administration (Day 1).
13) Must meet all of the following laboratory parameters at Screening:

ALT value 10 ULN

AST value 10 ULN

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
Absolute neutrophil count 1,000/mm3

Platelets 25,000/mm3

Hemoglobin 9 g/dL

α-fetoprotein 50 ng/mL
14) Subjects with severe hepatic impairment must have a score on the Child-Pugh-Turcotte scale 
of 10-15 at Screening. If a subject’s score changes during the course of the study, the score at 
Screening will be used for classification.
15) Subjects with moderate hepatic impairment must have a score on the Child-Pugh-Turcotte 
scale of 7-9 at Screening. If a subject’s score changes during the course of the study, the 
score at Screening will be used for classification.
16) Subjects with mild hepatic impairment must have a score on the Child-Pugh-Turcotte scale 
of 5-6 at Screening. If a subject’s score changes during the course of the study, the score at 
Screening will be used for classification.
17) Subjects in Cohort 1: Non-smoking hepatic impairment subjects must have no use of 
tobacco, nicotine-containing, or THC-containing products within at least 14 days prior to 
study drug dosing, and cannot smoke or use these products during the study. Smoking 
hepatic impairment subjects must have smoked ≥10 cigarettes/day for at least 30 days and 
plan to continue smoking ≥10 cigarettes/day during the study.
18) Subjects in adaptive Cohorts 2 and 3: Must be current non-smokers (no use of tobacco,
nicotine-containing, or THC-containing products within the last 14 days prior to study drug 
dosing, and cannot smoke or use these products during the study).
4.2.3.
Healthy Matched Controlled Subjects
Healthy matched control subjects must also meet the following additional inclusion criteria to be 
eligible for participation in this study:
1) Must, in the opinion of the Investigator, be in good health based upon medical history, 
physical examination, vital signs, and screening laboratory evaluations.
2) Must meet all of the following laboratory parameters at Screening:

INR 1 ULN

Albumin 1 LLN

Total bilirubin 1 ULN

AST value 1 ULN

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
ALT value 1 ULN 

Alkaline phosphatase 1 ULN

α-fetoprotein 1 ULN

Negative Hepatitis B surface antigen (HBsAg)

Negative Hepatitis B core (HBc) antibody 

Negative HCV antibody

Screening laboratory evaluations (hematology, fasting lipids, chemistry, and urinalysis) must 
be within the normal range unless the results have been determined by the investigator to 
have no clinical significance.
4.3.
Exclusion Criteria
4.3.1.
All Subjects 
Any subjects who meet any of the following exclusion criteria are not to be enrolled in this 
study.
1) Pregnant or lactating subjects
2) Have received any investigational compound within 30 days prior to study dosing
3) Concurrent participation in another therapeutic clinical trial
4) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance or subject safety
5) A positive test result for human immunodeficiency virus (HIV-1/HIV-2) antibody, 
hepatitis B (HBV) surface antigen  or current HCV infection (exclude all subjects who test 
positive (reactive) for HCV antibody with repeat test HCV RNA detected)
6) Have poor venous access that limits phlebotomy
7) History of having donated blood within 56 days prior to check in (Day-1).
8) History of having donated plasma within 7 days prior to check in (Day -1).
9) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation.
10) Currently registered on an organ transplantation list.
11) History of bleeding from esophageal varices within 90 days prior to check in (Day-1).

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12) Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic 
agents within 3 months prior to Screening or expected to receive these agents during the 
study (eg., corticosteroids, immunoglobulins, and other immune- or cytokine-based 
therapies)
13) Significant serious skin disease, such as but not limited to rash, food allergy, eczema, 
psoriasis, or urticaria
14) Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatotoxicity)
15) Known hypersensitivity to the study drugs, their metabolites (if applicable), or to formulation 
excipients (see Section 5.2.1)
16) Significant cardiac disease (including history of myocardial infarction based on ECG and/or 
clinical history, any history of ventricular tachycardia, congestive heart failure, or dilated 
cardiomyopathy with left ventricular ejection fraction <40%), a family history of  Long QT 
Syndrome, or unexplained death in an otherwise healthy individual between the ages of 1 and 
30 years.
17) Presence or history of cardiovascular disease, cardiomyopathy, and/or clinically significant 
cardiac conduction abnormalities. 
18) Syncope, palpitations, or unexplained dizziness
19) Implanted defibrillator or pacemaker.
20) Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid 
hypersecretory conditions requiring prolonged (>6 months) medical treatment.
21) Medical or surgical treatment that permanently alters gastric absorption (eg, gastric or 
intestinal surgery). A history of cholecystectomy is not exclusionary. 
22) Subjects with use of moderate or strong CYP3A or CYP2C9 inducers, or strong CYP2C9 
inhibitors within 2 weeks prior to study drug administration will be excluded. Subjects with 
use of proton pump inhibitors within 1 week prior to study drug administration will be 
excluded. (Please see Section 5.6.1 for excluded Concomitant Medications)
23) Are unable to comply with study requirements or are otherwise believed, by the study 
investigator, to be inappropriate for study participation for any reason. 

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4.3.2.
Subjects with Impaired Hepatic Function
Subjects with mild, moderate, or severe hepatic impairment meeting any of the following 
additional exclusion criteria are not to be enrolled in this study:
1) Aside from hepatic insufficiency, serious or active medical or psychiatric illness that, in the 
opinion of the Investigator, would interfere with subject treatment, assessment, or 
compliance with the protocol. This would include renal, cardiac, hematological, unstable 
hepatic, pulmonary (including chronic asthma), endocrine (eg, diabetes), central nervous, 
gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), 
immunodeficiency disorders, active infection, or malignancy that are clinically significant or 
requiring treatment.
2) Requires paracentesis > 1 time per month.
3) Subjects with hepatic impairment with co-morbid diseases requiring medication(s) must be 
taking the medication(s) without a clinically significant change in dose of con-meds for 
co-morbid diseases for > 3 months prior to screening.
4) Smoking Subjects in Cohort 1: Recent significant changes in smoking habits or the use of 
nicotine or nicotine containing products (ie, initiation, substantial increase or decrease or 
cessation of use) for at least 14 days prior to study drug dosing, or anticipated significant 
changes in smoking habits or the use of nicotine or nicotine containing products during the 
course of the study through the follow-up visit.
5) Positive test for drugs of abuse, including alcohol at Screening or on Day -1/check-in
(Positive THC screen allowed for subjects in states/countries that have legalized THC 
containing substances)
All concomitant medications including over-the-counter and herbal products must be 
approved by the Investigator and Medical Monitor prior to study enrollment and study 
drug administration.
4.3.3.
Healthy Matched Controlled Subjects
Healthy matched controlled subjects meeting any of the following additional exclusion criteria 
are not to be enrolled in this study:
1) Serious or active medical or psychiatric illness that, in the opinion of the Investigator, would 
interfere with subject treatment, assessment, or compliance with the protocol. This would 
include renal, cardiac, hematological, hepatic, pulmonary (including chronic asthma), 
endocrine (eg, diabetes), central nervous, gastrointestinal (including an ulcer), vascular, 
metabolic (thyroid disorders, adrenal disease), immunodeficiency disorders, active infection, 
or malignancy that are clinically significant or requiring treatment.
2) History of liver disease.

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3) Have taken any prescription medications or over-the-counter medications, including herbal 
products, within 28 days prior to start of study drug dosing, with the exception of vitamins 
and/or acetaminophen and/or ibuprofen
4) Positive test for drugs of abuse, including alcohol at Screening or on Day -1/check-in
5) Subjects will be required to refrain from the use of nicotine, nicotine-containing products
(including cigarette smoking) or THC-containing products for at least 14 days prior to first 
dose of study drug, and during the course of the study through the follow-up visit

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5.
STUDY DRUGS
5.1.
Randomization and Blinding
This is an open-label, non-randomized study.
It is the responsibility of the Investigator to ensure that the subject is eligible for the study prior 
to enrollment. Subjects will be assigned a Screening number at the time of consent.
A minimum of 40 and a maximum of 80 male and non-pregnant, non-lactating female subjects 
with either impaired hepatic function of CPT classification A, B, or C or with normal hepatic 
function will be enrolled to 1 of the 3 cohorts as described in Section 6.1.  
Study drug will be dispensed by the study pharmacist in an open-label fashion to the subjects. 
All Screening and check-in (Day -1) tests and procedures must be completed prior to the 
administration of the first dose of study drug on Day 1. Once a subject number has been assigned 
to a subject, it will not be reassigned to another subject. If necessary, replacement subjects may 
be enrolled after discussion and approval from Sponsor. A new unique subject number will be 
assigned to the replacement subject. 
A subject number schema will be provided to the study center by the Sponsor. Once eligibility is 
confirmed in consultation with the Sponsor, a subject number will be assigned by the Sponsor.
5.2.
Description and Handling of Entospletinib
5.2.1.
Formulation
Study drug entospletinib (ENTO, GS-9973) is available as 100 mg strength tablets. The tablets 
contain ENTO spray-dried dispersion (SDD) and commonly used excipients including mannitol, 
poloxamer 188, crospovidone, silicon dioxide, microcrystalline cellulose, magnesium stearate, 
polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and FD&C blue #2 aluminum 
lake. ENTO SDD consists of ENTO, methanesulfonic acid, and hypromellose. The 100 mg 
ENTO tablets are blue, capsule-shaped, plain-faced, film-coated blue tablets.
5.2.2.
Packaging and Labeling
ENTO 100 mg tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 60 tablets, silica gel desiccant and polyester packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed and aluminum-faced liner. 
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.

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5.2.3.
Storage and Handling
ENTO should be stored at a controlled room temperature of 25°C (77°F); excursions are 
permitted from 15°C to 30°C (59°F to 86°F). Storage conditions are specified on the label.  Until 
dispensed to the subjects, all bottles of study drugs should be stored in a securely locked area, 
accessible only to authorized site personnel.
To ensure the stability and proper identification, study drugs should not be stored in a container 
other than the container in which they were 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.
5.3.
Dosage and Administration of Study Drug
Following completion of Screening and Day -1 assessments, eligible subjects will be enrolled in 
1 of 3 cohorts and receive multiple doses of 100 mg twice a day (BID) ENTO 
(1 x 00 mg tablet) starting on Day 1 in the fasted state.
When feasible, dosing in a control subject with normal hepatic function will occur after the 
matched subject with impaired hepatic function has completed the PK assessments, except for 
control subjects that were already matched to a subject with impaired hepatic function in a 
previous cohort, as permitted in adaptive Cohorts 2 and 3.
Subjects in adaptive Cohort 2 (Severe Hepatic Impairment) and/or adaptive Cohort 3 (Mild 
Hepatic Impairment) will be enrolled as determined by safety and/or PK data non-smoking 
subjects and healthy, matching controls in Cohort 1 (Moderate Hepatic Impairment). 
Specifically, Cohort 2 will be initiated if supported by safety and PK findings from 
non-smoking hepatic impairment subjects and matching, healthy control subjects in 
Cohort 1.. Cohort 3 will be enrolled if a clinically meaningful change (≥ 2-fold mean difference 
from matched healthy controls) in the exposures of ENTO and/or metabolite (if applicable) 
exposure is identified in non-smoking hepatic impairment subjects in Cohort 1.
5.4.
Fasting and Meals
All study treatments will be administered at approximately the same time each day with 240 mL 
of water following an overnight fast (no food or drinks except water, for at least 8 hours).
When ENTO is administered twice a day, the evening dose of ENTO will be administered 
approximately 12 hours after the AM dose. Subjects should continue fasting for 2 hours post AM 
dose and 2 hours before and 2 hours after the PM dose. Only the AM dose of ENTO will be 
given on Day 5.
On the days of intensive pharmacokinetic sampling, study treatments will be administered in the 
morning following an overnight fast (no food or drinks except water, for at least 8 hours). 
Subjects will continue to fast until after collection of the 4-hour pharmacokinetic samples, 

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relative to study drug dosing. Additionally, subjects will be restricted from water consumption
1 hour before until 2 hours after dosing, except for the 240 mL given with the study treatment.
All meals and/or snacks given to subjects during their stay in the clinical study facility will be 
standardized for all subjects and should be similar in calorie and fat content and taken at 
approximately the same time each day. All meals provided must be approved by the Sponsor.
Components of meals (eg, margarine, jelly, bread) should be given to subjects in individual 
portions (eg, 1 tablespoon) per the approved meal schedule. The provision of meal components 
in bulk (eg, a jar of jelly for subjects to share) should not be practiced. All meals should be given 
at approximately the same time each day (eg, 07:30, 12:00, and 18:00).
5.5.
Dispensing, Accountability, and Disposal or Return of Study Drug
The Investigator (or designee, eg, study center pharmacist) will acknowledge receipt of the study 
drug (after reviewing the shipment’s content and condition) from Gilead (or designee). The 
Investigator will maintain an accurate inventory of all study drug(s). Each dose of the study 
drug(s) administered at the study center will be administered by qualified study center staff. The 
dose of study drug(s) administered to subjects in the clinic under the supervision of staff will be 
accurately recorded on the Study Drug Accountability Form provided by Gilead (or on 
equivalent documentation maintained by the study center), which indicates the date and quantity 
of each dosage formulation dispensed to individual subjects.
Gilead recommends that used and unused study drug supplies, including empty containers, be 
returned to the shipping facility from which it came or Gilead Sciences for destruction following 
drug accountability and drug inventory reconciliation.
If returning drug supplies to the shipping facility from which it came or to Gilead Sciences is not 
possible, the monitor will evaluate the site’s SOP for study drug disposal/destruction in order to 
ensure that it complies with Gilead’s requirements. At the end of the study, following final drug 
inventory reconciliation by the monitor, the study site will dispose of and/or destroy all unused 
study drug supplies, including empty containers, according to these procedures. 
5.6.
Concomitant Medications and Other Protocol Restrictions
5.6.1.
Concomitant Medications 
The following medications are excluded while subjects are participating in the study:
For subjects with normal hepatic function:

Any prescription medications and over-the-counter medications including herbal products 
and antacids with the exception of vitamins, and/or acetaminophen and/or ibuprofen. 
However, the short term use of topical hydrocortisone cream or AD ointment to treat minor 
skin irritation due to ECG leads will be allowed. If a subject requires use of a disallowed 
medication, a request for such use must be reviewed by the Sponsor and if approved, subjects 
may continue to participate in the study.

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For all subjects:

Any and all illegal or illicit drug use, including use of prescription drugs outside the care of 
the prescribing physician.

Subjects may not be taking rifaximin within 7 days prior to baseline (Day -1) or during the 
study. Rifaximin is a substrate of P-gp, OATP1B1 and OATP1B3; in a clinical DDI study 
with cyclosporine (an inhibitor of these transporters), a 124-fold increase in rifaximin 
exposure was observed. ENTO is an inhibitor of P-gp, OATP1B1 and OATP1B3 and a
similar DDI with rifaximin may occur. Rifaximin exposures are also significantly increased 
in subjects with mild, moderate and severe hepatic impairment. Further, rifaximin activates 
PXR at higher exposures leading to induction of drug metabolizing enzymes, therefore the 
use of rifaximin in this study may significantly confound the evaluation of the effect of 
hepatic impairment on ENTO PK.
Subjects with hepatic impairment:

Subjects with hepatic impairment with co-morbid diseases requiring medication(s) must be 
taking the medication(s) without a clinically significant change in dose for > 3 months prior 
to screening. 

The use of moderate or strong CYP3A or CYP2C9 inducers, or strong CYP2C9 inhibitors 
within 2 weeks prior to study drug administration and during the study is prohibited. The use 
of proton pump inhibitors within 1 week prior to study drug administration and during the 
study is prohibited.

All concomitant medications must be approved by the medical monitor (or the clinical 
pharmacologist) prior to enrollment.
5.6.2.
Other Protocol Restrictions

Subjects will be required to refrain from the consumption of food and beverages containing 
alcohol products 72 hours prior to the first dose of study drug and during the course of the 
study through the follow-up visit.

Subjects will be required to refrain from the use of nicotine or nicotine-containing products
and THC-containing products for at least 14 days prior to first dose of study drug, and during 
the course of the study through the follow-up visit. This restriction does not apply to smoking 
hepatic impairment subjects enrolled in Cohort 1. 

Subjects will be required to refrain from consumption of grapefruit juice, grapefruits, and 
Seville orange juice 72 hours prior to the first dose of study drug and during the course of the 
study through the follow-up visit.

While confined at the study center, tea, coffee, chocolate, and other foods and beverages 
containing caffeine and other methyl xanthines will be prohibited on each dosing day. At all 
other times, caffeine-containing beverages and foodstuffs may be served or withheld in 
accordance with normal study center practice. Caffeine-containing beverages and foodstuffs 
will not be restricted while subjects are outside of the clinic.

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
Subjects will be encouraged to avoid strenuous or prolonged exercise, as well as saunas, 
steambaths, and sunbathing or other prolonged UV exposure, eg, in a tanning salon, from the 
Screening evaluation until completion of the follow-up visit, as these activities are known to 
affect certain clinical laboratory test parameters, (eg, creatine kinase (CPK)) and will provide 
false indicators of a potentially treatment-related toxicity. 
Upon every admission to the clinic, each subject will be questioned as to their compliance with 
the above protocol restrictions. If a subject is unable to comply with any of the restrictions 
described above, the subject’s continued participation in the study will be reevaluated by the 
Investigator in consultation with the Sponsor.

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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are detailed below.
Any deviation from protocol procedures should be noted in the subject’s clinical chart and 
appropriate CRFs / eCRFs. In addition, the Sponsor should be promptly notified of any protocol 
deviations. 
The study center will not initiate dosing until:

The Institutional Review Board (IRB)/Ethics Committee (EC)/other applicable regulatory 
agencies have reviewed and approved the study and the informed consent document;

All requested regulatory documents have been submitted to and approved by Gilead;

A Master Services Agreement and/or Study Agreement is executed;

The study initiation meeting has been conducted by Gilead (or designee).
The initiation meeting will include but is not limited to a review of the protocol, the IB, study 
drugs, and Investigator responsibilities.
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific, IRB/EC-approved Informed Consent Forms (ICF), is required before initiating 
the screening process. 
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 continue to remain eligible throughout the study.
Once informed consent has been obtained, all screening and admission tests and procedures have 
been assessed, and study eligibility has been confirmed, subjects will be enrolled to receive study 
drug on Day 1.
Subjects will receive the study treatments as described in Section 5.3.

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Table 6-1.
Schedule of Assessments – All Cohorts
Study Procedure
Screena
Day -1
Days 1 
and 5
Days 2
and 4
Day 3
Days 6 
and 8
Day 7
Day 9b
Day 19 (±1) 
FUc
ETd
Written Informed 
Consent
X
Medical History 
X
Complete Physical 
Exam
X
X
X
Symptom-Driven 
Physical Examinatione
X
X
X
X
Height 
X
Weight 
X
X
Vital Signsf
X
X
X
X
X
X
X
HIV-1/HIV-2, HBV, 
and HCV Serology
X
Hematologyg
X
X
X
X
X
X
Serum Chemistryh
X
X
X
X
X
X
Genotype Testing for 
Enzymes and 
Transporters
Xp
Urinalysis 
X
X
X
X
X
X
Serum Pregnancy Testi
X
X
Xn
X
X
X
FSH testingi
X
Urine and Alcohol 
Drug Screen 
X
X
Xo
X
X
X
12-Lead ECG
X
X
X
X
X
X
X
Subject Enrollmentj
X

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Study Procedure
Screena
Day -1
Days 1 
and 5
Days 2
and 4
Day 3
Days 6 
and 8
Day 7
Day 9b
Day 19 (±1) 
FUc
ETd
Study Drug 
Administration
X
X
X
Intensive Plasma PKk
X
X
X
X
Trough PKl
Xl
X
Review Study 
Restrictions
Clinic Confinement
X
X
X
X
X
X
X
Review AEs & 
Concomitant 
Medicationsm
X
X
X
X
X
X
X
X
X
X
a
Prospective subjects should be screened no more than 28 days prior to administration of the first dose of study drugs.
b
Subjects will be discharged from the clinic on Day 9, following all morning assessments.
c
14 (±1) days after the last administration of study drug, all subjects will return to the clinic for a follow-up visit.
d
Assessments will be performed within 72 hours of early termination from the study.
e
Symptom-driven PE’s will be performed on Days -1, 3, 7, 9, during confinement as needed, and the follow-up visit.
f
Vital signs include blood pressure, pulse rate, respiration rate, and body temperature.
g
Hematology: INR, CBC with differential and platelet, neutrophil, and hemoglobin count.
h
Fasting serum chemistry: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, α-fetoprotein (at screening only), LDH, 
CPK, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, total cholesterol, HDL, LDL, and triglycerides, and 
amylase (reflex lipase testing is performed in subjects with total amylase > 1.5 x ULN).
i
Females of child-bearing potential only.
j
On Day -1, subjects will be enrolled.
k
Intensive PK sampling will occur relative to the morning dosing of ENTO at the following time points:
Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (pre-PM dose) hours postdose
Day 5: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 84, and 96 hours postdose
l
Trough PK sample is taken pre-morning dose on Days 2 and 4 at approximately the same time each day. An additional trough PK sample is taken at the Follow Up visit.
m
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any non-serious adverse events related to 
protocol-mandated procedures on the AE eCRF. All other untoward medical occurrences observed during the screening period, including exacerbation or changes in medical 
history are to be captured on the medical history CRF.  See Section 7 Adverse Events and Toxicity Management for additional details.
n
Day 4 only
o
Day 5 only
p
Day -1, before administration of the first dose of study drug, or at any time during clinic confinement.

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6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Prospective subjects should be screened no more than 28 days prior to administration of the first 
dose of study drug. If the subject does not begin the treatment phase within this 28-day window, 
all screening evaluation procedures must be repeated. Screening labs may be repeated once 
within 28 days prior to administration of study drug to rule out laboratory error.
Subjects should fast (no food or drink, except water), starting from midnight (00:00) or earlier, as 
appropriate, on the evening prior to the Screening visit to ensure an approximate 8-hour fast prior
to the fasted blood sample collection the next morning.
Written informed consent must be obtained from each subject before initiation of any screening 
procedure. After a subject has provided informed consent, the Investigator and other study 
personnel will determine if the subject is eligible for participation in the study. This assessment 
will include a review of the inclusion/exclusion criteria and completion of all screening 
procedures as outlined in Table 6-1 and described in the following text. 
Eligible subjects meeting all of the inclusion criteria and none of the exclusion criteria will be 
instructed on all protocol requirements, including the restrictions on concomitant medication 
usage and other substances as well as consumption of food or beverages containing alcohol, 
caffeine, or xanthine. Subjects will be asked to arrive at the study center on Day -1 for admission 
assessments.
From the time of obtaining informed consent through the first administration of study drug, 
record all SAEs, as well as any AE related to protocol-mandated procedures on the AE eCRF.  
All other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF.  
See Section 7 Adverse Events and Toxicity Management for additional details.
6.2.2.
Admission Assessments
6.2.2.1.
Admission
Subjects meeting all eligibility criteria following the screening evaluation will return to the clinic 
for admission assessments on Day -1. The admission evaluations and/or procedures are outlined 
in Table 6-1.
Prior to dosing on Day 1, the results of the clinical and laboratory evaluations (as described in 
Table 6-1) must be reviewed by the Investigator to confirm the continued eligibility of each 
subject to participate in the study. At the time of randomization, subjects will be assigned a 
sequential subject number as described in Section 5.1. Subjects will remain confined to the study 
clinic for the duration as described in Section 6.2.2.2 and Table 6-1.

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6.2.2.2.
Clinic Confinement
Eligible subjects will be confined to the study center beginning Day -1 until the completion of 
assessments on Day 9. Subjects will return for an in-clinic follow-up visit 14 (±1) days after the
last dose of study drug (i.e., Day 19).
6.3.
Check-In Assessments
Subjects meeting all eligibility criteria following the screening evaluation will return to the clinic 
for admission assessments. The admission evaluations and/or procedures are outlined in 
Table 6-1. Subjects should be instructed to fast (no food or drink, except water) for 8 hours prior 
to admission on Day -1, to ensure an approximate 8-hour fast prior to the fasted blood sample 
collection.
Prior to dosing on Day 1, the results of the clinical and laboratory evaluations (as described in
Section 4.1) must be reviewed by the Investigator to confirm the continued eligibility of each 
subject to participate in the study. The decision to exclude a subject following that review will 
be made by the Investigator, in consultation with the Sponsor.
Upon confirmation of eligibility, subjects will be assigned a sequential subject number as 
described in Section 5.1. Subjects will remain confined to the clinic for the study as described in 
Section 3.3 and Table 6-1.
6.4.
Treatment Assessments
Study procedures and assessments are outlined in Table 6-1.
6.5.
Posttreatment Assessments
All subjects will be instructed to return to the clinic within 14 (± 1) days after the last dose of 
study drug for follow-up assessments as outlined in Table 6-1.
6.6.
Assessments for Premature Discontinuation from Study
If a subject discontinues study treatment dosing (see Section 6.7), for example as a result of an 
AE, every attempt should be made to keep the subject in the study and continue to perform the 
required study-related follow-up procedures. If this is not possible or acceptable to the subject or 
Investigator, the subject may be withdrawn from the study. Evaluations indicating abnormal 
results believed to be possibly or probably related to study treatment at the ET visit should be 
repeated weekly or as often as deemed appropriate by the Investigator until the abnormality 
resolves, returns to baseline visit levels, or is otherwise explained.
If the subject discontinues prematurely from the study, the ET evaluations and/or procedures 
outlined in Table 6-1 should be performed within 72 hours of permanently discontinuing the 
study drug.

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6.7.
Criteria for Discontinuation of Study Drug 
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the Investigator, affect assessments of 
clinical status to a significant degree

Unacceptable toxicity, as defined in the toxicity management section of the protocol, or
toxicity that, in the judgment of the Investigator, compromises the ability to continue 
study-specific procedures or is considered not to be in the subject’s best interest

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study (Refer to Appendix 4)

Investigator discretion

Discontinuation of the study at the request of Gilead, regulatory agency, or an IRB/EC
6.8.
Pharmacokinetic Assessments
6.8.1.
Plasma PK Collection
Plasma concentrations for ENTO and/or its metabolites (if applicable) will be determined and 
PK parameters evaluated. Protein binding of ENTO and/or its metabolites (if applicable), may be 
assessed at their Tmax time point(s) as well as another later time point.
Intensive PK sampling will occur relative to the morning dose of ENTO at the following time 
points:
Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 (pre-PM dose) hours postdose  
Day 5: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 84, and 96 hours postdose
Trough Sampling: Days 2 and 4: 0 (pre-AM dose, at approximately the same time each day)
An additional PK sample will be collected at the Day 19 Follow-Up visit.
6.9.
Safety Assessments
Safety will be evaluated throughout the study. Refer to Table 6-1 for a schedule of assessments.

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6.9.1.
Electrocardiogram Assessment
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 should be no environmental distractions (eg., TV, radio, conversation, etc.) while the 
subjects are resting prior to and during the recordings. Electrocardiograms will be recorded using 
the site’s standard ECG equipment. All ECGs will be obtained using instruments that analyze 
data using the same algorithms and produce the same data for interpretation. Electrode placement 
will be performed according to the method of Wilson, Goldberger, and Einthoven with a check 
to confirm that the aVR lead is not inverted.
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 pretreatment ECGs. ECG interval 
measurements output by the machine will be used for bedside safety monitoring.
Collection of additional ECGs for routine safety monitoring at additional time points or days is at 
the discretion of the Investigator based on GCP.
6.9.2.
Physical Examination
Physical examinations conducted throughout the study will be a complete physical examination 
or a symptom-directed physical examination, as outlined in Table 6-1. The complete physical 
examination conducted at Screening will also include the following assessments:

Review medical history, including history of allergies, and history of prior and current use of 
nicotine or nicotine-containing products, history of alcohol and illegal drug use; and history 
of prior (within 30 days, or within 3 months for systemic steroids, immunosuppressant 
therapies, or chemotherapeutic agents) and current medication use.
6.9.3.
Vital Signs
Vital sign measurements include blood pressure, pulse, respiration rate, and temperature and will 
occur throughout the study and will be recorded as outlined in Table 6-1. Vital signs (systolic 
blood pressure, diastolic blood pressure, respiration rate, temperature and heart rate) should be 
taken once subjects have been seated or in the supine position for a minimum of approximately 
5 minutes. Subject position for measurement should be kept consistent throughout the study.  
Vital signs should be assessed prior to study drug administration. Refer to Table 6-1 for vital 
signs collection time points.
6.9.4.
Body Mass Index
Height and weight will be collected at Screening for calculation of BMI for inclusion criteria.

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6.9.5.
Clinical Laboratory Tests/Assessments
Blood and urine samples for safety evaluations will be collected throughout the study as outlined 
in Table 6-1.
6.9.5.1.
Blood Sampling
Blood samples will be collected for the following laboratory analyses:

Hematology: INR, CBC with differential and platelet, neutrophil, and hemoglobin count.

Serum chemistry (fasting): alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, α-fetoprotein (at screening only), LDH, CPK, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, magnesium, 
potassium, sodium, uric acid, total cholesterol, HDL, LDL, and triglycerides, and amylase 
(reflex lipase testing is performed in subjects with total amylase > 1.5 x ULN).

Serum pregnancy test (females of childbearing potential only)

FSH (females only)

HIV, HBV, and HCV testing (Screening only)

Genotyping for drug metabolizing enzymes and transporters (Day -1 only, or any day during 
clinic confinement)
6.9.5.2.
Urine Samples
Urine samples will be collected for urinalysis and urine alcohol and drug screening assessments.
6.9.6.
Creatinine Clearance
Weight will be collected at Screening and upon admission to calculate creatinine clearance 
(using the Cockcroft-Gault method) for inclusion criteria.
6.9.7.
Adverse Events/Concomitant Medications/Protocol Restrictions
Evaluation for AEs, review of concomitant medications, and review of protocol restrictions will 
occur at the times shown in Table 6-1. See Section 7 for more information regarding AEs and 
Sections 4.3 and Section 5.6.1 for more information about concomitant medications.
6.10.
Genetic Testing
A blood sample for genetic sampling will be taken in the study as outlined in Table 6-1.
A separate, mandatory blood specimen will be collected for the extraction of DNA for 
genotyping to identify polymorphisms of drug metabolizing enzymes (such as CYP2C9, 

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CYP3A4/5, CYP1A2 and UGT1A1) and transporters (such as OATP 1B1/3, P-gp, BCRP and 
MATE1) to optimize the therapeutic strategy for ENTO. This sample should be collected on 
Day -1, before administration of the first dose of study drug, but may be collected at any time 
during clinic confinement.
6.11.
Sample Storage
 
 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
product, which does not necessarily have a causal relationship with the treatment. An AE can
therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product. 
AEs may also include pre- or post treatment complications that occur as a result of protocol 
specified procedures, 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 AE and must be reported.

Preexisting 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 (eg., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7.1.)

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 preexisting and should be documented on the medical history CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to study drug 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, ECG, x-rays, vital signs) that are associated with 
signs and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE 
or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased 
hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The Investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, preexisting condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the study drug.

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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity
AE severity should be recorded and graded according to the CTCAE Grading Scale for Severity 
of Adverse Events and Laboratory Abnormalities (Appendix 4). For adverse events 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.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead 
7.3.1.
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and AE related to 
protocol-mandated procedures.
7.3.1.1.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of study drug must be reported to the CRF/eCRF database 
as instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
7.3.1.2.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 

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CRF/eCRF database and Gilead DSPH as instructed. This also includes any SAEs resulting from 
protocol-associated procedures performed after informed consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported.
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period, 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of study drug, he/she should promptly document and 
report the event to Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

At the time of study start, SAEs will be reported using a paper serious AE reporting form. 
During the study conduct, sites may transition to an electronic SAE (eSAE) system. Gilead 
will notify sites in writing and provide training and account information prior to 
implementing an eSAE system.
7.3.1.3.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the SAE report form and submitted by faxing or emailing the 
report form within 24 hours of the investigator’s knowledge of the event to the attention of 
Gilead DSPH or to the designated CRO.
Gilead DSPH: 
Fax 
Email: 
7.3.1.4.
Electronic Serious Adverse Event (eSAE) Reporting Process 

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper SAE reporting form and submit 
within 24 hours to: Email: 
 and Fax: 

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.
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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 IB or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (eg, clinical chemistry, hematology, and urinalysis) that require medical or surgical 
intervention or lead to investigational medicinal product interruption 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 respectively. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (ie, anemia) not the laboratory result (ie, decreased 
hemoglobin).
Severity should be recorded and graded according to the GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 4). 

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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.
7.6.
Toxicity Management 
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead Sciences Medical Monitor or designee. Whether or not considered treatment-related, 
all subjects experiencing AEs must be monitored periodically until symptoms subside, any 
abnormal laboratory values have resolved or returned to baseline levels or they are considered
irreversible, or until there is a satisfactory explanation for the changes observed.
Clinical events and clinically significant laboratory abnormalities will be graded according to the 
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities (Appendix 4).
Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing as soon as practical to do so, and preferably within 3 calendar days after receipt of the 
original test results.

Any questions regarding toxicity management should be directed to the Gilead Medical 
Monitor.
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of AEs associated with product complaints, and pregnancy reports regardless of an associated 
AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  

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7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy. 
Refer to section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email:
 and Fax: 
 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to or Gilead DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH, 
fax number
 or email 
 
Refer to Appendix 3 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study drug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
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Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary analysis objective of this study is to evaluate the PK of ENTO and/or its metabolites 
(if applicable) in subjects with impaired hepatic function (stratified by smoking status, as 
appropriate) relative to matched, healthy controls
The secondary objectives of this study are as follows:

To evaluate the safety and tolerability of administration of ENTO in subjects with normal 
and impaired hepatic function

To evaluate the potential impact of smoking on the PK of ENTO in subjects with moderate 
hepatic impairment
8.1.2.
Primary Endpoint
The primary endpoints are the PK parameters AUC and Cmax of ENTO and/or its metabolites
(if applicable).
8.1.3.
Secondary Endpoint
The secondary endpoints are the incidences of adverse events and laboratory abnormalities.
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
PK Analysis Set
The PK analysis set will include all enrolled/randomized subjects who received at least 1 dose of 
study drug (ENTO) and had at least 1 non-missing PK concentration data reported by PK lab for 
each respective analyte. This is the primary analysis set for PK summaries.
8.2.1.2.
Safety Analysis Set
The safety analysis set will include all enrolled subjects who received at least 1 dose of study 
drug. This is the primary analysis set for safety summaries.
8.2.1.3.
All Enrolled Analysis Set
The all enrolled analysis set will include all subjects who were enrolled into the study. This is the 
primary analysis set for safety listings.

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8.3.
Data Handling Conventions
For summary statistics, PK concentration values below the limit of quantitation (BLQ) will be 
treated as zero at predose and one-half of the lower limit of quantitation (LLOQ) for postdose 
timepoints, where LLOQ is corrected for the dilution factor (ie, reported dilution/dilution factor). 
Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed to the value of the lower or upper limit 
minus or plus one significant digit, respectively (eg, if the result of a continuous laboratory test is 
< 20, a value of 19 will be assigned; if the result of a continuous laboratory test is < 20.0, a value 
of 19.9 will be assigned).
Missing data can have an impact upon the interpretation of the trial data. As this study is of short 
duration, it is anticipated that missing data will be minimal. In general, values for missing data 
will not be imputed. However, a missing pretreatment laboratory result would be treated as 
normal (ie., no toxicity grade) for the laboratory abnormality summary.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized and descriptive statistics will be 
provided. 
8.5.
Safety Analysis
All safety data collected on or after the date that study drug was first administered up to the date 
of last dose of study drug plus 30 days will be listed and summarized using safety analysis set. 
8.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug data will be generated from the study drug 
administration page in eCRF. Exposure data will be listed.
8.5.2.
Adverse Events
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). System Organ Class (SOC), High-Level Group Term (HLGT), 
High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be attached to 
the clinical database.
Adverse event data will be listed by subject. Treatment-emergent AE (TEAE) and Serious TEAE 
will be summarized by system organ class and preferred term using the current version the 
Medical Dictionary for Regulatory Activities (MedDRA). 
8.5.3.
Laboratory Evaluations
Selected laboratory data (clinical chemistry and hematology) will be summarized using only 
observed data. Absolute values and change from predose at all scheduled time points will be 
summarized. 

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Laboratory abnormalities will be graded using GSI Grading Scale for Severity of Adverse Events 
and Laboratory Abnormalities (Appendix 4) for analysis purposes. 
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from predose at any time postdose up to the completion of study follow-up, 
will be summarized. If predose data are missing, then any graded abnormality (ie, at least a 
Grade 1) will be considered treatment emergent. 
Laboratory abnormalities that occur before the first dose of investigational medicinal product or 
after the completion of study follow-up will be included in a data listing.
8.5.4.
Other Safety Evaluations
ECG data will be summarized over time and presented in a listing.
Individual data for vital signs measurements will be listed by subject and summarized using 
incidence (frequencies) of events/ abnormalities or descriptive statistical summaries (eg, n, mean, 
SD, median, and range), as appropriate.
8.6.
Pharmacokinetic Analysis
Plasma concentrations of ENTO and/or its metabolites (if applicable) over sampling time will be 
listed and summarized by hepatic function group and smoking status (Cohort 1 only). 
Plasma concentrations of ENTO and/or its metabolites (if applicable) over time will be plotted in 
semi-logarithmic and linear formats as mean SD and as median (Q1, Q3). 
The PK parameters will be listed and summarized for ENTO and/or its metabolites
(if applicable) using descriptive statistics (e.g., sample size, arithmetic mean, geometric mean, 
% CV, SD, median, minimum, and maximum) by hepatic function group (normal or CPT 
Class A, B, or C) and smoking status (Cohort 1 only). 
A parametric (normal theory) ANOVA model appropriate for a parallel design will be fitted to 
the natural logarithmic transformation of PK parameters (AUCtau and Cmax) for ENTO and/or its 
metabolites (if applicable). The 90% CIs will be constructed for the GLSM ratios of PK 
parameters for ENTO and/or its metabolites (if applicable) in each hepatic impairment group 
versus the matched control (normal hepatic function) group (and for Cohort 1, stratified by 
smoking status). The 90% CIs will be examined to determine if the GLSM ratio is within limits 
of 50% to 200%.
ENTO percent protein binding will be summarized by hepatic function group and smoking status
(Cohort 1 only), and data for individual subjects will be presented in a listing (if applicable). 
8.7.
Sample Size
A sample size of 8 evaluable subjects per hepatic function group (for Cohort 1, it is 8 evaluable 
subjects per hepatic function group within each smoking status group) will provide a 

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≥89% probability for the 90% CI for the GLSM ratio of pharmacokinetic parameters (AUC or 
Cmax) for ENTO in the hepatic impairment/dysfunction group(s) versus the appropriate group of 
matched controls, to be within limits of 50% to 200%. The calculation assumes an expected ratio 
of geometric means of 1.0 in pharmacokinetic parameters and inter-subject standard deviation of 
0.455 for the natural logarithm-transformed pharmacokinetic parameters for ENTO. The 
assumption is based on the data obtained from a prior clinical study of ENTO (Study 
GS-US-339-0111).

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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, "Protection of Human Subjects", and 21 CFR, part 56, "Institutional Review Boards".
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 
"Financial Disclosure by Clinical Investigators", providing documentation of their financial 
interest or arrangements with Gilead, or proprietary interests in the study 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 (EC) 
Review and Approval
The investigator (or Sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/EC. The investigator will not begin any study subject activities until 
approval from the IRB/IEC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/EC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 

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investigator must use the most current IRB- or EC-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 EC or 
local requirements. 
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB/EC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions or in accordance 
with local regulations. NOTE: The investigator must keep a screening log showing codes, names, 
and addresses for all subjects screened and for all subjects enrolled in the trial. Subject data will 
be processed in accordance with all applicable regulations. Only subject initials or dummy
initials (in required regions), date of birth, another unique identifier (as allowed by local law),
and an identification code will be included for applicable regions.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the study drug, 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/EC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender). Only subject initials or dummy initials 
(in required regions), another unique identifier (as allowed by local law), and an 
identification code will be included for applicable regions

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
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 study drug, including dates of dispensing and 
return;

Record of all AEs and other safety parameters (start and end date, and including causality 
and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 

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safety data.  The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 
as described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (e.g. data entry error). At the conclusion of the trial, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.5.
9.1.7.
Study Drug Accountability and Return  
Gilead recommends that used and unused study drug supplies be returned to the shipping facility 
from which it came for eventual destruction. The study monitor will provide instructions for 
return. If return is not possible, the study monitor will evaluate each study center’s study drug
disposal procedures and provide appropriate instruction for destruction of unused study drug
supplies. If the site has an appropriate standard operating procedure (SOP) for drug destruction
as determined by Gilead QA, the site may destroy used (empty or partially empty) and unused 
study drug supplies in accordance with that site’s approved SOP. A copy of the site’s approved 
SOP will be obtained for central files. 
If study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the study drug. Upon study completion, 
copies of the study drug accountability records must be filed at the site. Another copy will be 
returned to Gilead.
The study monitor will review study drug supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRB/EC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.

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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/EC in 
accordance with local requirements and receive documented IRB/EC approval before 
modifications can be implemented.
9.2.2.
Study Report 
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. 
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.

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9.3.4.
Study Discontinuation
Both the Sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and ECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.

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10.
REFERENCES
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al. Inhibition of 
Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin 
lymphoma and chronic lymphocytic leukemia. Blood 2010;115 (13):2578-85.
Morris DL, O'Neil SP, Devraj RV, Portanova JP, Gilles RW, Gross CJ, et al. Acute lymphoid 
and gastrointestinal toxicity induced by selective p38alpha map kinase and map 
kinase-activated protein kinase-2 (MK2) inhibitors in the dog. Toxicol Pathol 
2010;38 (4):606-18.
Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg 1973;60 (8):646-9.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER); Center for Biologics Evaluation and Research 
(CBER). Guidance for Industry. Pharmacokinetics in Patients with Impaired 
Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and 
Labeling.  May, 2003.
Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG. In vitro inhibition of 
UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors 
and the relationship of this property to in vivo bilirubin glucuronidation. Drug 
Metab Dispos 2005;33 (11):1729-39.

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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Management of Clinical and Laboratory Adverse Events
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 5.
Child -Pugh-Turcotte Score

PPD
PPD
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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 1, Open-Label, Multiple Dose Study to Evaluate the Pharmacokinetics of Entospletinib 
in Subjects with Nonnal and Impaired Hepatic Function 
GS-US-339-1631 Protocol Amendment 3, 26 August 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 67 
26 August 2016 

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Appendix 2. 
Management of Clinical and Laboratory Adverse Events 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
May continue dosing at 
the discretion of the 
Investigator 
CONFIDENTIAL 
Grade 3 
(Severe) 
.. 
If confirmed, clinically 
significant and related to 
drug, discontinue dosing 
permanently and follow 
until a return to baseline or 
abnormality is otherwise 
explained 
-
Page 68 
I 
Grade 4 
(Possibly life-
Threatening) 
Repeat lab to 
confirm toxicity 
grade 
I 
If confirmed, non-significant or 
not related to study drug, 
dosing may continue ;;~t 
discretion of the Investigator 
26 August 2016 

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Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
ENTO is contraindicated in pregnancy as animal studies in rats and rabbits have shown that 
study drug is teratogenic. Pregnancy must be excluded before the start of treatment with study 
drug and prevented thereafter by reliable contraceptive methods. Pregnancy tests will be 
performed regularly throughout this study per Table 6-1. Please refer to the latest version of the 
investigator’s brochure for additional information.
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered to be fertile after the initiation 
of puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
ENTO is contraindicated in pregnancy as there is a strong suspicion of human 
teratogenicity/fetotoxicity in early pregnancy based on non-clinical data. In addition, ENTO has 
insufficient data to exclude the possibility of a clinically relevant interaction with hormonal 
contraception that results in reduced contraception efficacy; therefore, contraceptive steroids are 
not recommended as a contraceptive method either solely or as a part of a contraceptive regimen. 
Please refer to the latest version of the investigator’s brochure for additional information.
b) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must also not rely on hormone-containing contraceptives as a 
form of birth control during the study.  They must have a negative serum pregnancy test at 
Screening and a negative pregnancy test on the Baseline/Day -1 visit.  Pregnancy tests will be 
performed on the protocol-specified schedule thereafter.  Female subjects must agree to one of 

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the following methods to avoid pregnancy from Screening until 30 days from the last dose of 
ENTO:

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days from the last dose of ENTO.
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 90 days from the 
last dose of ENTO.  Additional contraception recommendations should also be considered if the 
female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
from the last dose of ENTO.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator.  Instructions for reporting pregnancy, partner pregnancy, and pregnancy 
outcome are outlined in Section 7.7.2.1.

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

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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN  to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
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
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
1 Month
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
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

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia (corrected for 
albumin if appropriate*)
Adult and Pediatric 7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.14 mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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/d
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
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake

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

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

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

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

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

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

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

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

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

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Appendix 5.
Child -Pugh-Turcotte Score
Child-Pugh dassification of severity of liver disease 
Parameter 
Points assigned 
1 
2 
3 
Ascites 
Absent 
Slight 
Moderate 
Bilirubin 
<2 mg/dl 
2-3 mg/dl (34.2 
>3 mg/dl 
(<34.2 
to 51.3 
(>5 1.3 
micromolfliter} 
micromoljliter) 
micromolfliter) 
Albumin 
>3.5 g/dl (35 
,2.8-3.5 g/dl (28 I <2.8 g/dl , <28 
gjliter) 
to 35 g/liter) 
gfliter) 
Prothrombin time 
Seconds over 
<4 
4-6 
I >6 
control 
INR 
<1.7 
1.7-2.3 
>2.3 
Encephalopathy 
None 
Grade 1-2 
Grade 3·4 
Modified Child-Pugh dasslflcatlon of the severity of liver disease 
according to the degree of asdtes, the plasma concentrations 
of bilirubin and albumin, the prothrombin time, and the degree 
of encephalopathy. A total score of 5· 6 is considered grade A 
(well-compensated disease); 7-9 Is grade 8 (significant 
functional compromise); and 10·15 Is grade C (decompensated 
disease). These grades correlate with one- and two-year 
patient survival: grade A - 100 and 85 percent; grade B - 80 
and 60 percent; and grade C - 45 and 35 percent.