Conditions: Hepatitis B Virus
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
A Pharmacokinetics study of Baraclude in a real world clinical setting in Japan.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Baraclude
Intervention descriptions: intervention 1: Specified dose on specified day

Protocol document:
Prot_000.pdf: 
Official Title of Study: 
A Clinical Study to Evaluate the Steady State Pharmacokinetics of Baraclude in Participants with 
Hepatitis B Virus Infection 
 
NCT Number: NCT03083821 
Document Date (Date in which document was last revised): 27-Mar-2017 


Page:
1
Protocol Number:
AI463528
IND Number:
NA
EX-US
Non-IND
EUDRACT Number:
NA
Date:
22-Feb-2017
Revised Date:
27-Mar-2017
Clinical Protocol AI463528
A Clinical Study to Evaluate the Steady State Pharmacokinetics of Baraclude in Participants with 
Hepatitis B Virus Infection
Revised Protocol Number: 01
Incorporates amendment(s) 01
Study Director
Medical Monitor
24-hr Emergency Telephone Number
USA: 
International: 
Japan: 
Bristol-Myers Squibb Research and Development
6-5-1 Nishi-Shinjuku, Shinjuku-ku,
Tokyo, 163-1328, Japan
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Revised Protocol No: 01
Date: 27-Mar-2017
2
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Revised Protocol No.: 01
Date: 27-Mar-2017
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 01
27-Mar-2017
Incorporates Amendment 01
Amendment 01
27-Mar-2017
Changes to Protocol include:

According to the regulation for non-registrational study 
in Japan, changed the word from "GCP" to "Ethical 
Guidelines for Medical and Health Research Involving 
Human Subjects".

Added some clarifications.
Original Protocol
22-Feb-2017
Not applicable
Approved
2.0
v
Approved
1.0
v


TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2. SCHEDULE OF ACTIVITIES................................................................................. 
3. INTRODUCTION .................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.2 Background ....................................................................................................... 
3.2.1 Pharmacology .......................................................................................... 
3.2.2 Toxicity ..................................................................................................... 
3.2.3 Preclinical Metabolism and Pharmacokinetics ....................................... 
3.2.4 Pharmacokinetics of Baraclude ............................................................... 
3.3 Benefit/Risk Assessment .................................................................................. 
4. OBJECTIVES AND ENDPOINTS .......................................................................... 
5. STUDY DESIGN...................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
5.4 Scientific Rationale for Study Design............................................................... 
5.5 Justification for Dose ........................................................................................ 
6. STUDY POPULATION ........................................................................................... 
6.1 Inclusion Criteria .............................................................................................. 
6.2 Exclusion Criteria ............................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
6.4 Screen Failures .................................................................................................. 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
7. TREATMENT .......................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modification ......................................................................................... 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
7.6 Treatment Compliance ...................................................................................... 
7.7 Concomitant Therapy........................................................................................ 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.8 Treatment After the End of the Study ............................................................... 
8. DISCONTINUATION CRITERIA .......................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Post Study Treatment Study Follow-up.................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up ............................................................................................. 
9. STUDY ASSESSMENTS AND PROCEDURES .................................................... 
1
3
4
6
9
11
12
12
12
12
12
13
13
14
14
14
15
15
15
15
15
15
15
16
17
18
18
18
19
19
19
19
19
20
20
20
20
21
21
21
22
22
22
22
Clinical Protocol
BMS-200475
AI463528
Entecavir
Revised Protocol No.: 01
Date: 27-Mar-2017
4
Approved
2.0
v
Approved
1.0
v


9.1 Efficacy Assessments ........................................................................................ 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.8 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Clinical Safety Laboratory Assessments .................................................. 
9.4.2 Imaging Safety Assessment ...................................................................... 
9.5 Pharmacokinetics .............................................................................................. 
9.6 Pharmacodynamics ........................................................................................... 
9.7 Pharmacogenomics ........................................................................................... 
9.8 Biomarkers ........................................................................................................ 
9.8.1 Additional Research Collection ............................................................... 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
10. STATISTICAL CONSIDERATIONS ................................................................... 
10.1 Sample Size Determination ............................................................................. 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.3 Pharmacokinetic Analyses ..................................................................... 
11. REFERENCES ....................................................................................................... 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 5 DIAGNOSTIC CRITERIA FOR DRUG AND ALCOHOL ABUSE .. 
23
23
23
24
24
24
25
25
26
26
26
26
26
26
26
27
27
27
27
27
28
28
28
28
28
28
28
29
32
33
39
48
52
56
Clinical Protocol
BMS-200475
AI463528
Entecavir
Revised Protocol No.: 01
Date: 27-Mar-2017
5
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
1
SYNOPSIS
Protocol Title: A Clinical Study to Evaluate the Steady State Pharmacokinetics of Baraclude
in Participants with Hepatitis B Virus Infection
Study Phase: IV (post-marketing)
Rationale:
While pharmacokinetics of Baraclude® has been investigated in the global HBV clinical trial 
population, pharmacokinetic (PK) information specifically for Japanese patients diagnosed with 
HBV infection has not been studied. Such pharmacokinetic information may provide a better 
understanding of Baraclude in a real-world clinical setting in Japan.
Study Population:
Inclusion Criteria
a) Participants with chronic hepatitis B (CHB) (excluding participants with a superinfection) 
who have been confirmed to have CHB by one of the following:
i)
Detectable Hepatitis B surface antigen (HBsAg) at screening and for at least 24 
weeks prior to screening or detectable HBsAg for < 24 weeks and negative for IgM core 
antibody and confirmation of chronic hepatitis on liver biopsy
ii)
Documentation of positive Hepatitis e antigen (HBeAg) status at screening and at 
least once 4 weeks prior to screening
b) Participants whose condition is stable in the investigator’s judgement
c) Participants who are being treated with 0.5 mg daily of Baraclude for a minimum of 
10 consecutive days prior to the study enrollment
d) Creatinine clearance is > 50 mL/min
Exclusion Criteria
a) Lamivudine-refractory participants
b) Any significant, acute illness or chronic medical illness that is  not stable and/or untreated
c) Current or recent (within 3 months of Baraclude administration) gastrointestinal disease 
that could impact upon the absorption of study drug
d) Any gastrointestinal surgery that could impact upon the absorption of study drug
e) Inability to be venipunctured and/or tolerate venous access
Objectives and Endpoints:
Objective
Endpoint
Primary
Revised Protocol No.: 01
Date: 27-Mar-2017
6
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Objective
Endpoint

to evaluate the steady state of Baraclude 
pharmacokinetics in HBV-infected participants

pharmacokinetic parameter values derived from 
plasma concentration versus time data using 
non-compartmental methods 
Secondary

Not applicable

Not applicable.
Overall Design:
This is an open label, single-dose, steady state pharmacokinetics (PK) study of Baraclude in
Japanese HBV-infected participants. Participants will undergo a screening evaluation to determine 
eligibility within 21 days prior to administration of study drug. Participants will be admitted into 
the clinical site prior to study drug administration. On this day (Day 1), Baraclude will be 
administered, and breakfast will be provided 2 hours after administration. 
Participants will remain at the clinical site for approximately 2 days following administration of 
the single dose of study medication. The initial time of dose administration will be called “0” hour. 
At the time of dosing, 240 mL of water will be administered to the participants with the dose. 
PK samples will be taken as described in the Schedule of Activities. 
The study design schematic is presented in Table below. 
Physical examinations, vital sign measurements, and clinical laboratory evaluations will be 
performed at screening. Blood samples will be collected for up to 24 hours after study drug 
administration for pharmacokinetic (PK) analysis. Participants will be closely monitored for 
adverse events throughout the study.
Number of Participants: 
Approximately 8 participants will be enrolled. 
Treatment Arms and Duration:
Participants will take 1 dose of 0.5 mg Baraclude in the clinic facility on Day 1. The local marketed 
Baraclude will be used as study treatment in this study. Approximately 2 days after Baraclude
administration, participants will leave the clinical site if they have not experienced any adverse 
events or are in a condition to be released according to the investigator’s clinical judgement. The 
approximate duration of this study is 2 days plus up to 3 weeks for the screening period.
Study Schematic
Day -21 or Later
Day 1
Day 2
Screening and Enrollment
Laboratory assessments
Treatment with Baraclude
PK Assessments
PK Assessment 
Study discharge 
Revised Protocol No.: 01
Date: 27-Mar-2017
7
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Study treatment: 
Study Drug for AI463528
Medication 
Potency 
IP/Non-IP 
Baraclude
0.5 mg
IP
Revised Protocol No.: 01
Date: 27-Mar-2017
8
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
2.
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (AI463528)
Procedure
Screening 
Day -21
Visit
Notes
Eligibility Assessments
Informed Consent
X
A participant is considered enrolled only when a protocol-specific informed consent is 
signed.
Inclusion/Exclusion Criteria
X
Medical History
X
Include any toxicities or allergy related to previous treatments.
Safety Assessments
Physical Examination (PE)
X
If the screening PE is performed within 24 hours prior to dosing on Day 1, then a single 
exam may count as both the screening and pre-dose evaluation.
Physical Measurements
X
Includes height, weight, and BMI.
Vital Signs
X
Includes body temperature, respiratory rate, seated blood pressure, and heart rate. Blood 
pressure and heart rate should be measured after the participant has been resting quietly 
for at least 5 minutes. Consider alternate position(s) for vital sign collection.
Concomitant Medication Use
X
Electrocardiogram (ECGs)
X
ECGs should be recorded after the participant has been supine for at least 5 minutes.
Laboratory Tests
Serology
X
Includes hepatitis C antibody, HIV-1 and -2 antibody, and CrCl.
Pregnancy Test
X
For WOCBP only. Urine or serum.
Serum creatinine
X
Adverse Event Reporting
Monitor for Serious Adverse Events
All SAEs must be collected from the date of participant’s written consent until 30 days 
after discontinuation of dosing or participant’s participation in the study if the last 
scheduled visit occurs at a later time
Revised Protocol No.: 01
Date: 27-Mar-2017
9
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Table 2-2:
On Treatment Procedural Outline(AI463528)
Procedure
Day 1
Study Discharge
Notes
Safety Assessments
Physical 
Examination (PE)
X
Physical 
Measurements 
X
Weight only
Vital Signs
X
Includes body temperature, respiratory rate, and seated blood 
pressure, and heart rate. Blood pressure and heart rate should 
be measured after the participant has been resting quietly for 
at least 5 minutes. Consider alternate position(s) for vital 
sign collection.
Concomitant 
Medication Use
X
Adverse Event 
Reporting
Monitor for Adverse 
Events and Serious 
Adverse Events
X
X
See note in screening procedures.
Pharmacokinetic 
(PK) Assessments
Serial Blood PK 
Sampling
X
X
See Section 9.5.
Clinical Drug 
Supplies
Study Drug 
Administration
X
Supplied by the participant.
Abbreviations: D=Day
Revised Protocol No.: 01
Date: 27-Mar-2017
10
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
3.
INTRODUCTION
Chronic infection with Hepatitis B Virus (HBV) is a cause of substantial morbidity and mortality, 
around the world. Approximately 350 to 400 million people worldwide have chronic hepatitis B 
(CHB) infection,1,2 and over 1 million people die each year from complications of cirrhosis and 
primary hepatocellular carcinoma (HCC).3
HBV genomic sequences have been classified into at least eight genotypes (A through H) based 
on a divergence of 8% or more over the complete nucleotide sequence.4,5 These genotypes vary 
worldwide and have distinct geographic distributions.6,7,8 Japanese patients with chronic HBV 
infection often have genotypes B and C9 whereas those with acute infection are more likely to 
have genotype A.10,11 In addition, studies suggest that acute infection with HBV genotype A may 
be associated with an increased risk of progression to persistent infection.12
Chronic intrahepatic replication of HBV also appears to be a critical event in the pathogenesis of 
liver injury, and results in an ongoing cascade of inflammation, injury, and repair. This recurring 
inflammatory cycle leads to scarring (fibrosis), progression to cirrhosis, and to dysregulation of 
hepatocyte regeneration with the potential for HCC. 
Intrahepatic replication of the virus appears to be a critical factor in HBV disease progression. A
meta-analysis of epidemiology studies concluded that the risk for HCC increased 20-fold for 
individuals who were hepatitis B surface antigen (HBsAg)-positive compared with those who were 
HBsAg-negative.13 Another study found that, compared to HBsAg-negative controls, the relative 
risk for HCC was 9.6 in HBsAg-positive patients and 60.2 in those who were also 
HBeAg-positive.14 These data suggest that optimal anti-HBV therapy would provide sustained 
inhibition of viral replication, leading to improved clinical outcomes. A direct link between 
antiviral therapy and clinical outcome was established in a 32-month study in which continuous 
treatment with lamivudine (LVD) approximately halved the rate of hepatic decompensation and 
reduced the risk of HCC among patients with CHB infection and advanced fibrosis or cirrhosis at 
baseline.15
Approved therapies for CHB infection include interferon alfa, peginterferon alfa-2a,16 LVD,17
adefovir dipivoxil (ADV),18 Baraclude(entecavir), telbivudine (LdT), and tenofovir disoproxyl 
fumarate (TDF). 19
The recombinant alfa interferons act primarily as endogenous 
immunomodulatory agents and also have intrinsic antiviral effects. Interferon is administered by 
injection and is frequently associated with fever, flu-like symptoms, neutropenia, and depression. 
Lamivudine, ADV, LdT, TDF, and Baraclude are nucleoside analogs (NAs) that directly inhibit 
viral replication. Lamivudine is well tolerated, but efficacy is limited by resistance, which develops 
at a rate of 15% to 25% during the first year of treatment and up to 70% after 4 years of treatment.20
The emergence of lamivudine-resistant (LVDr) virus is usually associated with renewed HBV 
replication and a subsequent reduction in clinical efficacy.21 Among subjects with pre-existing 
LVDr, rates of ADV resistance (ADVr) are reported to be 18% after 1 year and 25% after 2 years 
Revised Protocol No.: 01
Date: 27-Mar-2017
11
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
of therapy.22,23 Adefovir therapy is associated with a potential risk of nephrotoxicity.18 The 
efficacy of LdT was demonstrated in Phase 3 controlled study of nucleoside-naive subjects with 
HBeAg-positive or HBeAg-negative HBV infection. Genotypic analysis detected amino acid 
substitutions associated with virologic failure in 49 of 103 HBeAg-positive subjects and 12 of 12 
HBeAg-negative subjects after ≥ 16 weeks of treatment.19 Tenofovir is approved for the treatment 
of CHB based on the results of 2 Phase 3 controlled studies in HBeAg-positive and 
HBeAg-negative subjects.24
Overall, based on the efficacy and safety results of Phase 2/3 studies of Baraclude vs LVD, a Phase 
3b study of Baraclude vs ADV in CHB patients with compensated liver disease, and a Phase 3b 
study of Baraclude vs ADV in patients with decompensated liver disease, as well as pediatric 
studies, Baraclude is an important treatment option among available oral HBV therapies
3.1
Study Rationale
While pharmacokinetics of Baraclude has been investigated in the global HBV clinical trial 
population, pharmacokinetic (PK) information specifically for Japanese patients diagnosed with 
HBV infection has not been studied. Such pharmacokinetic information may provide a better
understanding of Baraclude in a real world clinical setting in Japan.
3.2
Background
3.2.1
Pharmacology
For physical/chemical and pharmaceutical properties and formulation, refer to the Investigator 
Brochure Section 3.25
3.2.2
Toxicity
Dose-related systemic exposures to Baraclude were established after multiple doses in nonclinical 
toxicology species. Mean steady-state exposures in toxicology studies 3 months in duration were 
up to 2,500 times greater than the mean steady-state exposure in humans at 1.0 mg.
3.2.3
Preclinical Metabolism and Pharmacokinetics
Mechanism of Action
Baraclude is efficiently phosphorylated to entecavir (ETV)-TP by cellular nucleoside kinases. By 
competing directly with the natural substrate, dGTP, ETV-TP functionally inhibits all 3 activities 
of the viral polymerase: (1) priming of the HBV polymerase; (2) reverse transcription negative 
strand DNA synthesis; and (3) DNA polymerase activity responsible for positive strand DNA 
synthesis.
Entecavir-triphosphate has > 15-fold and > 30-fold potency than the active phosphorylated forms 
of LVD and ADV, respectively, in inhibiting polymerization.26
Revised Protocol No.: 01
Date: 27-Mar-2017
12
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
In Vitro Antiviral Activity
Baraclude inhibited HBV DNA synthesis (EC50) at a concentration of 0.004 μM in human HepG2 
cells transfected with wild-type HBV. The median EC50 value for Baraclude against LVDr HBV 
(rtM204V, rtL180M) was 0.026 μM (range 0.010-0.059 M).27,28,29,30
3.2.4
Pharmacokinetics of Baraclude
In healthy subjects, Baraclude was rapidly absorbed, with peak plasma concentrations occurring 
between 0.5 and 1.5 hours. There was a dose-proportionate increase in peak plasma concentration 
(Cmax) and area under concentration-time curve (AUC) values following multiple doses ranging 
from 0.1 to 1 mg. Steady-state was achieved after 6-10 days of once daily (QD) dosing with 
approximately 2-fold accumulation. Maximum observed concentration and trough plasma 
concentration at steady state were 4.2 and 0.3 ng/mL, respectively, for a 0.5-mg dose, and 8.2 and 
0.5 ng/mL, respectively, for a 1 mg dose. In healthy subjects, the bioavailability of the tablet was 
100% relative to the oral solution. The oral solution and tablet may be used interchangeably.31,32,33
Oral administration of Baraclude 0.5 mg with a standard high-fat meal (945 kcal, 54.6 g fat) or a 
light meal (379 kcal, 8.2 g fat) resulted in a minimal delay in absorption (1-1.5 hour fed vs 
0.75 hour fasted), a decrease in Cmax of 44% to 46%, and a decrease in AUC of 18% to 20%.34,35
The estimated volume of distribution for Baraclude was in excess of total body water, suggesting 
that it has good penetration into tissues. Protein binding to human serum protein in vitro was 
approximately 13%.31,33,36
Baraclude is not a substrate, inhibitor, or inducer of the cytochrome P-450 (CYP450) enzyme 
system. Following administration of 14C-ETV in humans and rats, no oxidative or acetylated 
metabolites and minor amounts of Phase 2 metabolites (glucuronide and sulfate conjugates) were 
observed.33,37,38,39,40 After reaching peak levels, Baraclude plasma concentrations decreased in a 
bi-exponential manner with a terminal elimination half-life of approximately 128-149 hours. The 
observed drug accumulation index is approximately 2-fold with daily dosing, suggesting an 
effective accumulation half-life of about 24 hours.31,33
Baraclude is predominantly eliminated by the kidney, with urinary recovery of unchanged drug at 
steady-state ranging from 62% to 73% of the dose. Renal clearance is independent of dose and 
ranges between 360 and 471 mL/min suggesting that Baraclude undergoes both glomerular 
filtration and net tubular secretion.31,33
3.3
Benefit/Risk Assessment
Baraclude has been approved for the treatment of HBV in Japan since 2006. Participants in this 
study routinely take Baraclude as part of their daily medication for the management of HBV; 
therefore, there is no additional risk. In this study, participants will experience 12 venipunctures 
for blood draws for screening assessments and PK assessments. There is a small risk of infection 
with each venipuncture. The data collected from this study will add to the understanding of 
real-world use of Baraclude in HBV Participants in Japan. 
Revised Protocol No.: 01
Date: 27-Mar-2017
13
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
4.
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary

to evaluate the steady state of Baraclude 
pharmacokinetics in HBV-infected participants

pharmacokinetic parameter values derived from 
plasma concentration versus time data using 
non-compartmental methods 
Secondary

Not applicable. 

Not applicable
Tertiary/Exploratory

Not applicable

Not applicable
5.
STUDY DESIGN
5.1
Overall Design
This is an open-label, single-dose, steady state pharmacokinetics (PK) study of Baraclude in 
Japanese HBV participants. Participants will undergo a screening evaluation to determine 
eligibility within 21 days prior to administration of study drug. Participants will be admitted into 
the clinical site prior to study drug administration. On this day (Day 1), Baraclude will be 
administered, and breakfast will be provided 2 hours after administration. 
Participants will remain at the clinical site for approximately 2 days following administration of 
the single dose of study medication. The initial time of dose administration will be called “0” hour. 
At the time of dosing, 240 mL of water will be administered to the participants with the dose. 
Participants will take 1 dose of 0.5 mg Baraclude in the clinic facility on Day 1. The local marketed 
Baraclude will be used as study treatment in this study. PK samples will be taken as described in 
Table 9.5-1. Approximately 2 days after Baraclude administration, participants will leave the 
clinical site if they have not experienced any adverse events or are in a condition to be released 
according to the investigator’s clinical judgement. The approximate duration of this study is 2 days
and up to 3 weeks for the screening period.
Participants are asked to take Baraclude once daily at the same time in the day (eg, 9:00AM) for 
10 days before entering the clinical site.
The study design schematic is presented in Table 5.1-1.
Table 5.1-1:
Study Schematic
Day -21 or Later
Day 1
Day 2
Screening and Enrollment
Laboratory assessments
Treatment with Baraclude
PK Assessments
PK Assessment 
Study discharge 
Revised Protocol No.: 01
Date: 27-Mar-2017
14
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Physical examinations, vital sign measurements, and clinical laboratory evaluations will be 
performed at screening. Blood samples will be collected for up to 24 hours after study drug 
administration for pharmacokinetic (PK) analysis. Approximately 30 mL of blood will be drawn 
from each participant for screening assessments (8 mL) and PK assessments (22 mL) during the 
study. Participants will be closely monitored for adverse events throughout the study.
5.1.1
Data Monitoring Committee and Other External Committees
Not applicable.
5.2
Number of Participants
Approximately 8 participants will be enrolled. 
5.3
End of Study Definition
The start of the trial is defined as the first participant’s first visit. End of trial is defined as the last 
participant’s last visit. Study completion is defined as the final date on which data for the primary 
endpoint was or is expected to be collected, if this is not the same.
5.4
Scientific Rationale for Study Design
The endpoints selected for this study are to determine the steady state pharmacokinetics of 
Baraclude when Baraclude is administered to real-world HBV-infected participants in Japan.
Participants enrolled in this study are expected to achieve steady state prior to the start of the study; 
therefore, a single dose of Baraclude will provide the necessary information to assess the primary 
objective. 
5.5
Justification for Dose
The dose selected for this study is 0.5 mg of Baraclude, based on current prescribing information 
in the label.
6.
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Informed consent forms voluntarily signed by participants including consent for 
screening procedures to confirm eligibility shall be obtained prior to their enrollment in 
the study
2) Type of Participant and Target Disease Characteristics
a) Participants with chronic hepatitis B (CHB) (excluding participants with a superinfection) 
who have been confirmed to have CHB by one of the following:
i)
Detectable HBsAg at screening and for at least 24 weeks prior to screening or 
detectable HBsAg for < 24 weeks and negative for IgM core antibody and confirmation 
of chronic hepatitis on liver biopsy
ii) Documentation of positive Hepatitis e antigen (HBeAg) status at screening and at least 
once 4 weeks prior to screening
Revised Protocol No.: 01
Date: 27-Mar-2017
15
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
b) Participants whose condition is stable in the investigator’s judgement
c) Participants who are being treated with 0.5 mg daily Baraclude for a minimum of 10
consecutive days prior to the study enrollment
d) Creatinine clearance is > 50 mL/min
e) Body mass index (BMI) of 18.5 to 30 kg/m2 (BMI = body weight [kg]/height [m]2)
3) Age and Reproductive Status
a) Males and Females, ages 20 or age of majority to 70 years, inclusive
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) during the 
screening period.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study treatment(s), 
Baraclude, plus 5 half-lives of study treatment Baraclude (5 days) plus 30 days (duration 
of ovulatory cycle) for a total of 35 days post-treatment completion
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 4) for the duration of treatment with study 
treatment(s), Baraclude, plus 5 half-lives of the study treatment (5 days) plus 90 days 
(duration of sperm turnover) for a total of 95 days post-treatment completion. In addition, 
male participants must be willing to refrain from sperm donation during this time. 
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception, (Appendix 4 
which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) Lamivudine-refractory participants
b) Any significant, acute illness or chronic medical illness that is not stable and/or untreated
c) Current or recent (within 3 months of Baraclude administration) gastrointestinal disease 
that could impact upon the absorption of study drug
d) Any major surgery within 4 weeks of study drug administration
e) Any gastrointestinal surgery that could impact upon the absorption of study drug
f)
Donation of blood to a blood bank or in a clinical study (except a screening visit) within 
4 weeks of study drug administration (within 2 weeks for plasma only)
g) Blood transfusion within 4 weeks of study drug administration
h) Inability to tolerate oral medication
Revised Protocol No.: 01
Date: 27-Mar-2017
16
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
i)
Inability to be venipunctured and/or tolerate venous access
j)
Smoking more than 10 cigarettes per day
k) Recent (within 6 months of study drug administration) drug or alcohol abuse as defined in 
DSM IV, Diagnostic Criteria for Drug and Alcohol Abuse (Appendix 5)
l)
Any other sound medical, psychiatric and/or social reason as determined by the investigator
2) Prior/Concomitant Therapy
a) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7,
Concomitant Therapy.
3) Physical and Laboratory Test Findings
a) Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs, ECG or clinical laboratory determinations beyond what 
is consistent with the target population
b) Any of the following on 12-lead electrocardiogram (ECG) prior to study drug 
administration, confirmed by repeat
i)
PR 210 msec
ii) QRS 120 msec
iii) QT 500 msec
iv) QTcF 450 msec
c) Positive blood screen for hepatitis C antibody or HIV-1 and -2 antibody 
4) Allergies and Adverse Drug Reaction
a) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity)
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Inability to comply with restrictions as listed in Section 6.3, Lifestyle Restrictions
d) Discretion of the investigator 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
1) Participants are to refrain from strenuous exercise, contact sports, and sunbathing from at least 
1 day prior to the day of study dosing until study discharge.
2) Participants are not permitted to consume alcohol-containing beverages from 3 days prior to 
the day of study dosing until study discharge.
3) Participants are not permitted to smoke while residing at the clinical facility. 
Revised Protocol No.: 01
Date: 27-Mar-2017
17
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
4) Participants are required to remain in the clinical facility at least 24 hours after dosing during 
or until furloughed. 
5) Participants may not drink water one hour before and after study drug administration except 
with dosing. Water may be consumed ad libitum at other times. 
6) Participants are required to fast (nothing to eat or drink except water) for 10 hours prior until 
2 hours after study drug administration. 
7) Participants should maintain an upright (seated or standing) position for at least 4 hours 
post-dose.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study does not permit the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure.
Retesting of laboratory parameters and/or other assessments during the Screening or Lead-in 
period will not be permitted (this does not include parameters that require a confirmatory result). 
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
7.
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation
Study 
treatment
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial. 

Study required premedication

Other drugs administered as part of the study that are critical to claims of efficacy (eg, 
background therapy, rescue medications)

If specific criteria are required for treatment in a given phase of the study (eg extension phase), 
provide detailed criteria in this section

Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
Revised Protocol No.: 01
Date: 27-Mar-2017
18
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products.
7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
Baraclude
0.5 mg
1 dose at 9:00 am of 
Day 1 (30 minutes)
oral
The local marketed Baraclude will be used as study treatment in this study.
Restrictions related to food and fluid intake are described in Section 6.3.
7.2
Method of Treatment Assignment
Enrolled participants, including those not dosed, will be assigned sequential participant numbers 
starting with 00001 (eg, 00001, 00002, 00003.... 00010). Those enrolled participants meeting 
inclusion and exclusion criteria will be eligible to be dosed and undergo PK sampling.
7.3
Blinding
Not applicable.
7.4
Dosage Modification
Participants will receive a single dose of Baraclude 0.5 mg. No dose modifications are permitted 
during the conduct of the study or for 10 days prior to Day 1. 
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
Revised Protocol No.: 01
Date: 27-Mar-2017
19
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).

Further guidance and information for final disposition of unused study treatment are provided 
in Appendix 2 
7.5.1
Retained Samples for Bioavailability / Bioequivalence
Not applicable. 
7.6
Treatment Compliance
Study drug will be administered in the clinical facility. After administration of Baraclude, a mouth 
check will be performed to verify that the participant has swallowed the dose.
7.7
Concomitant Therapy
Please follow guidance on concomitant therapy in the Japanese package insert. 
7.7.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to study drug administration in the study are 
described below. Medications taken within 4 weeks prior to study drug administration must be 
recorded on the CRF.
1) Exposure to any investigational drug or placebo within 4 weeks of study drug administration. 
2) Use of any prescription drugs or over-the-counter acid controllers within 4 weeks prior to study 
drug administration except those medications cleared by the BMS medical monitor.
3) Use of any other drugs, including over-the-counter medications and herbal preparations, within 
1 week prior to study drug administration except those medications cleared by the BMS 
medical monitor.
4) There should be no changes to the medications and/or dosages of those medications used to 
manage chronic illnesses for 10 days prior to Day 1 and during Day 1. 
No concomitant medications (prescription, over-the-counter or herbal) are to be administered 
during study unless they are prescribed for treatment of specific clinical events. Any concomitant 
therapies must be recorded on the CRF.
The investigator should contact and confirm agreement with the BMS medical monitor (and 
acknowledgement from the contract research organization medical monitor) prior to the 
administration of any concomitant medications.
Revised Protocol No.: 01
Date: 27-Mar-2017
20
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
7.8
Treatment After the End of the Study
At the end of the study/Period (approximately 2 days), BMS will not continue to provide BMS 
supplied study treatment to participants/investigators unless BMS chooses to extend the study. The 
investigator should ensure that the participant receives appropriate standard of care to treat the 
condition under study.
8.
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the
discretion of the investigator) for any of the following reasons:

Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a normal healthy female participant becomes pregnant 
during a clinical trial, the study treatment must be discontinued immediately. In most cases, the 
study treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Please call the BMS Medical Monitor within 24 hours of 
awareness of the pregnancy. If the investigator determines a possible favorable benefit/risk ratio 
that warrants continuation of study treatment, a discussion between the investigator and the BMS 
Medical Monitor/designee must occur.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
Revised Protocol No.: 01
Date: 27-Mar-2017
21
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
8.1.1
Post Study Treatment Study Follow-up
Participants who discontinue study treatment may continue to be followed.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 

Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.

The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.

In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up

All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.

Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.

If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.

If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 

The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.

If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and timing are summarized in the Schedule of Activities. 

Protocol waivers or exemptions are not allowed.
Revised Protocol No.: 01
Date: 27-Mar-2017
22
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir

All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.

Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
9.1
Efficacy Assessments
Not applicable. 
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment until 
30 days after discontinuation, at the time points specified in the Schedule of Activities (Section 2). 
Nonserious AE information should also be collected from the start of a placebo lead-in period or 
other observational period intended to establish a baseline status for the participants.
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the participant’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures.
All SAEs must be collected that occur during the screening period and within 30 days of 
discontinuation of dosing.
Revised Protocol No.: 01
Date: 27-Mar-2017
23
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.

Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section.

All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 

The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.)
9.2.3
Follow-up of AEs and SAEs

Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section Appendix 3).

Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.

All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Revised Protocol No.: 01
Date: 27-Mar-2017
24
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3
Start In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for participant safety). Please call the BMS Medical Monitor within 
24 hours of awareness of the pregnancy.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted

Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
Revised Protocol No.: 01
Date: 27-Mar-2017
25
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
9.2.7
Potential Drug Induced Liver Injury (DILI)
Specific criteria for identifying potential DILI have not been identified for this protocol. Standard 
medical practice in identifying and monitoring hepatic issues should be followed.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 9.2).
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
9.4.1
Clinical Safety Laboratory Assessments

Investigators must document their review of each laboratory safety report. Investigators must 
confirm the laboratory test results for participant’s eligibility. 
Results of clinical laboratory tests performed as part of screening must be available prior to dosing.
9.4.2
Imaging Safety Assessment
Not applicable.
9.5
Pharmacokinetics
Pharmacokinetics of Baraclude will be derived from plasma concentration versus time. The 
pharmacokinetic parameters to be assessed include:
Cmax
Maximum observed plasma concentration
Tmax
Time of maximum observed plasma concentration
Ctrough
Trough observed plasma (predose) concentration
C24
Observed plasma concentration at 24 hours postdose
AUC(TAU)
Area under the concentration-time curve in one dosing interval
CLT/F
Apparent total body clearance 
Table 9.5-1 lists the sampling schedule to be followed for the assessment of pharmacokinetics. 
Further details of blood collection and processing will be provided to the site in the procedure 
manual.
Individual participant pharmacokinetic parameter values will be derived by non-compartmental 
methods by a validated pharmacokinetic analysis program. Actual times will be used for the 
analyses.
Revised Protocol No.: 01
Date: 27-Mar-2017
26
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Table 9.5-1:
Pharmacokinetic Sampling Schedule for AI463528
Study Day of Sample 
Collection
Event
Time
(Relative To Baraclude Dose)
Hour: Min
1
predose
00:00
1
0.25
00:15
1
0.5
00:30
1
1.0
01:00
1
1.5
01:30
1
2
02:00
1
4
4:00
1
6
6:00
1
8
8:00
1
12
12:00
2
24
24:00
The plasma will be analyzed for Baraclude by a validated assay. 
In addition, plasma samples will be archived for potential metabolite analysis, if the need arises 
and to the extent possible.
Detailed instructions for the pharmacokinetic plasma collection, labeling, processing, storage, and 
shipping will be provided to the site in the procedure manual.
9.6
Pharmacodynamics
Not applicable. 
9.7
Pharmacogenomics
Not applicable.
9.8
Biomarkers
Not applicable.
9.8.1
Additional Research Collection
This protocol will not include sample collection and/or residual sample storage for additional 
research (AR).
9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
Revised Protocol No.: 01
Date: 27-Mar-2017
27
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
10.
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
This is an estimation study. A sample size of approximately 8 participants will provide two-sided 
95% confidence interval half-widths of 1.12, 8.93, and 136.63, respectively, for Cmax (ng/mL), 
AUC(TAU) (ng*h/mL), and CLT/F (mL/min) based on 80% coverage probability and historic 
standard deviations. These calculations are based on one-sample t-tests using historic standard 
deviations of 1.13, 9.03, and 138.1, respectively, for Cmax, AUC(TAU), and CLT/F, based on 
population PK modeling from participants with HBV following 14 days of oral 0.5 mg Baraclude
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled Participants
All participants who sign informed consent
Treated Participants
All participants who take at least 1 dose of study treatment.
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary endpoint.
10.3.1
Efficacy Analyses
Not applicable. 
10.3.2
Safety Analyses
Not applicable. 
10.3.3
Pharmacokinetic Analyses 
Individual pharmacokinetic parameter values will be derived from plasma concentration versus 
time using non-compartmental methods. Values will be summarized with univariate statistics (n, 
arithmetic mean, standard deviation, geometric mean, coefficient of variation, median, minimum, 
maximum). Parameters will include: Cmax, Ctrough, C24, Tmax, AUC(TAU), and CLT/F.
Revised Protocol No.: 01
Date: 27-Mar-2017
28
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
11.
REFERENCES
1
World Health Organization fact sheet WHO/204 hepatitis B. 2000.World Health Organization. 
Available at: www.who.org. Accessed 09 October 2003. 
2
Purcell RH. The discovery of the hepatitis viruses. Gastroenterology 1993;104:955-963.
3
Lee WM. Hepatitis B virus infection. New Engl J Med 1997;337:1733-1745.
4
Okamoto H, Tsuda F, Sakugawa H, Sastrosoewignjo RI, Imai M, Miyakawa Y, et al. Typing 
hepatitis B virus by homology in nucleotide sequence: comparison of surface antigen subtypes. 
J Gen Virol 1988; 69(Pt 10):2575-2583.
5
Norder H, Hammas B, Lofdahl S, Courouce AM, Magnius LO. Comparison of the amino acid 
sequences of nine different serotypes of hepatitis hepatitis B surface antigen and genomic 
classification of the corresponding hepatitis B virus strains. J Gen Virol 1992;73(Pt 5):1201-
1208.
6
Miyakawa Y, Mizokami M. Classifying hepatitis B virus genotypes. Intervirology 
2003;46:329-338.
7
Fung SK, Lok AS. Hepatitis B virus genotypes: do they play a role in the outcome of HBV 
infection? HEPATOLOGY 2004;40:790-792.
8
Fung SK, Lok AS. Hepatitis B virus genotypes: do they play a role in the outcome of HBV 
infection? HEPATOLOGY 2004;40:790-792.
9
Orito E, Ichida T, Sakugawa H, Sata M, Horiike N, Hino K, et al. Geographic distribution of 
hepatitis B virus (HBV) genotype in patients with chronic HBV infection in Japan. 
HEPATOLOGY 2001;34:590-594.
10 Matsuura K, Tanaka Y, Hige S, Yamada G, Murawaki Y, Komatsu M, et al. Distribution of 
hepatitis B virus genotypes among patients with chronic infection in Japan shifting toward an 
increase of genotype A. J Clin Microbiol 2009;47:1476-1483.
11 Ozasa A, Tanaka Y, Orito E, Sugiyama M, Kang JH, Hige S, et al. Influence of genotypes and 
precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. 
HEPATOLOGY 2006;44:326-334.
12 Ogawa M, Hasegawa K, Naritomi T, Torii N, Hayashi N. Clinical features and viral sequences 
of various genotypes of hepatitis B virus comparedamong patients with acute hepatitis B. 
Hepatol Res 2002;23: 167-177.
13 Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiologic studies on the combined 
effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer 
1998;75:347-354.
14 Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. 
N Engl J Med 2002;34(3):168-174.
Revised Protocol No.: 01
Date: 27-Mar-2017
29
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
15 Liaw Y-F, Sung J, Chow W, et al. for the Cirrhosis Asian LVD Multicentre Study Group. LVD 
for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-
1531.
16 Pegasys(Peginterferon alfa-2a) US package insert. Nutley, NJ: Hoffmann La-Roche Inc., 
2009.
17 Epivir-HBV(lamivudine) US package insert. Research Triangle Park, NC: GlaxoSmith 
Kline, 2009.
18 Hepsera(adefovir dipivoxil) US package insert. Foster City CA: Gilead, Sciences, revised 
May 2008.
19 Tyzeka(telbivudine) US package insert. Cambridge, MA: Indenix Pharmaceuticals, 2009.
20 Lai CL, Dienstag J, Schiff E, et al. Prevalence and clinical correlates of YMDD variants during 
lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis 2003;36:687-696.
21 Leung N. Clinical experience with LVD. Seminars in Liver Disease 2002;22(1):15-21.
22 Yeon J-E, Yoo W, Hong SP, et al. Resistance to adefovir dipivoxil (ADV) in lamividine-
resistant chronic hepatitis B patients treated with ADV. Gut online. Published on 04 February 
2006 as 10.1136/gut.2005.077099. Accessed 16 October 2006.
23 Lee Y-S, Suh DJ, Lim Y-S, et al. Increased risk of adefovir resistance in patients with 
lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir monotherapy. Hepatology 
2006;1385-1391.
24 Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir 
dipivoxil for chronic hepatitis B. N Engl J Med 2008;359:2442-2455.
25 Entecavir Investigator's Brochure. Version 17. May 2014. Bristol-Myers Squibb Research and 
Development: Princeton, NJ. Document Control No.: 
.
26 Inhibition of human hepatitis B virus replication in cultured human liver cells by BMS-200475. 
Bristol-Myers Squibb Company; 1996. Document Control No. 
.
27 Innaimo S, Seifer M, Bisacchi G, et al. Identification of BMS-200475 as a potent and selective 
inhibitor of hepatitis B virus. Antimicrob Agents Chemother 1997;41:1444-1448.
28 Metabolic studies on entecavir (BMS-200475) in hepatocytes:II. Phosphorylation at 
nanomolar labeling concentrations.Bristol-Myers Squibb Company; 2000. Document Control 
No
.
29 Assessment of in vitro mitochondrial toxicity of entecavir and other hepatitis B virus antivirals 
in 15-day cultures of human hepG2 hepatoma cells. Bristol-Myers Squibb Company; 2006. 
Document Control No. 
.
30 Tenney DJ, Levine SM, Rose RE, et al. Clinical emergence of entecavir-resistant hepatitis B 
virus requires additional substitutions in virus already resistant to lamivudine. Antimicrob 
Agents Chemother 2004;48:3498-3507.
Revised Protocol No.: 01
Date: 27-Mar-2017
30
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
31 Study AI463033: Placebo-controlled ascending multipledose study to evaluate the safety and 
pharmacokinetics of entecavir in healthy subjects. Final study report. Bristol-Myers Squibb 
Company; 2003. Document Control No. 
. 
32 Study AI463035: Bioequivalence study of entecavir oral solution relative to entecavir tablet in 
healthy subjects. Final study report. Bristol-Myers Squibb Company; 2004, Document Control 
No. 
.
33 Entecavir summary of clinical pharmacology studies. Bristol-Myers Squibb Research and 
Development; 2004. Document Control No. 
. 
34 Study AI463058: Open-label, sequential design, drug interaction study of entecavir and 
lamivudine in healthy subjects. Clinical study report. Bristol-Myers Squibb Company; 2004. 
Document Control No. 
.
35 Study AI463016: Effect of a high fat meal and a light meal on the pharmacokinetics of 
entecavir in healthy subjects. Final study report. Bristol-Myers Squibb Company; 2003. 
Document Control No. 
.
36 In vitro determination of mouse, rat, dog, monkey, and human serum protein binding and/or 
red blood cell distribution of [14C]-entecavir. Bristol-Myers Squibb Company; 1999. 
Document Control No. 
.
37 Inhibition of the catalytic activities of cDNA-expressed human cytochrome P4502B6, 
cytochrome P4502C9, cytochrome P4502C19, cytochrome P4502D6, cytochrome P4502E1, 
and cytochrome P4503A4 by the test substance entecavir. Bristol-Myers Squibb Company; 
2003. Document Control No. 
.
38 Study XT033016: In vitro evaluation of entecavir as an inducer of cytochrome P450 expression 
in cultured human hepatocytes. Study report. Xenotech, LLC, Lenexa, KS. June 2004. 
Document Control No. 
.
39 Study AI463031: Metabolism of entecavir in humans. Final study report. Bristol-Myers Squibb 
Company; 2004. Document Control No. 
.
40 Biotransformation profiles of orally administered [14C]-entecavir (BMS- 200475) in plasma,
urine, feces, liver, and lung of mice and in liver and lung of rats. Bristol-Myers Squibb 
Company; 2001. Document Control No. 
Revised Protocol No.: 01
Date: 27-Mar-2017
31
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
12
APPENDICES
Revised Protocol No.: 01
Date: 27-Mar-2017
32
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
AI
accumulation index
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
%BE
percent biliary excretion
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BRt
Total amount recovered in bile
%BRt
Total percent of administered dose recovered in bile
BUN
blood urea nitrogen
Revised Protocol No.: 01
Date: 27-Mar-2017
33
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Term
Definition
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CLD
Dialysate clearance of drug from plasma/serum
CLNR
nonrenal clearance
CLR
renal clearance
CLT
total body clearance
CLT/F (or CLT)
apparent total body clearance
CLT/F/fu or 
CLT/fu
Apparent clearance of free drug or clearance of free if (if IV)
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
minimum observed concentration
CNS
Central nervous system
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
Revised Protocol No.: 01
Date: 27-Mar-2017
34
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Term
Definition
D/C
discontinue
dL
deciliter
DMC
Data monitoring committee
DRt
Total amount recovered in dialysate
%DRt
Total percent of administered dose recovered in dialysate
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
EA
extent of absorption
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
electroencephalogram
eg
exempli gratia (for example)
FDA
Food and Drug Administration
FI
fluctuation Index ([Cmax-Ctau)/Cavg])
FRt
total amount recovered in feces
FSH
follicle stimulating hormone
fu
fraction of unbound drug
g
gram
GC
gas chromatography
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
ICD
International Classification of Diseases
Revised Protocol No.: 01
Date: 27-Mar-2017
35
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Term
Definition
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
kg
kilogram
L
liter
LAM
Lactation amenorrhea method
LC
liquid chromatography
LDH
lactate dehydrogenase
ln
natural logarithm
Lz_Start
The time point starting the log-linear elimination phase defining the 
terminal half life
Lz_End
The time point ending the log-linear elimination phase defining the 
terminal half life
Lz_N
Number of time points in the log-linear elimination phase defining the 
terminal half life
mg
milligram
Mg++
magnesium
MIC
minimum inhibitory concentration
min
minute
mL
milliliter
mmHg
millimeters of mercury
MR
medical research
MR_AUC(0-T)
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for 
molecular weight
MR_AUC(INF)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for 
molecular weight
Revised Protocol No.: 01
Date: 27-Mar-2017
36
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Term
Definition
MR_AUC(TAU)
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for 
molecular weight
MR_Cmax
Ratio of metabolite Cmax to parent Cmax, corrected for molecular 
weight
MR_Ctau
Ratio of metabolite Ctau to parent Ctau, corrected for molecular weight
MRT
mean residence time
MS
mass spectrometry
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
pAUCe
Extrapolated partial AUC from last quantifiable concentration to infinity
Pb
percent of bound drug
PD
pharmacodynamics
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PT
prothrombin time
PTT
partial thromboplastin time
Pu
percent of unbound drug
QC
quality control
QD, qd
quaque die, once daily
R2
coefficient of determination
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
SOP
Standard Operating Procedures
t
temperature
Revised Protocol No.: 01
Date: 27-Mar-2017
37
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Term
Definition
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
T-HALF
Half life
T-HALFeff_AUC
Effective elimination half life that explains the degree of AUC 
accumulation observed
T-HALFeff_Cmax
Effective elimination half life that explains the degree of Cmax 
accumulation observed)
TID, tid
ter in die, three times a day
Tmax, TMAX
time of maximum observed concentration
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
UR
urinary recovery
%UR
percent urinary recovery
URt
total amount recovered in urine
%URt
total percent of administered dose recovered in urine
UV
ultraviolet
Vss/F (or Vss)
apparent volume of distribution at steady state
Vz
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
W
washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
x g
times gravity
Revised Protocol No.: 01
Date: 27-Mar-2017
38
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GUIDELINES FOR MEDICAL AND HEALTH RESEARCH
This study will be conducted in accordance with:

Ethical Guidelines for Medical and Health Research Involving Human Subjects

applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant
recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
Revised Protocol No.: 01
Date: 27-Mar-2017
39
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:

IRB/IEC for 

Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (i.e., Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:

Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 

Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
Revised Protocol No.: 01
Date: 27-Mar-2017
40
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir

Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
For minors, according to local legislation, one or both parents or a legally acceptable representative 
must be informed of the study procedures and must sign the informed consent form approved for 
the study prior to clinical study participation. The explicit wish of a minor, who is capable of 
forming an opinion and assessing this information to refuse participation in, or to be withdrawn 
from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent.
Subjects unable to give their written consent (eg, stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this participant become capable, he or she should personally sign and 
date the consent form as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be considered 
by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
Revised Protocol No.: 01
Date: 27-Mar-2017
41
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
Revised Protocol No.: 01
Date: 27-Mar-2017
42
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:

amount received and placed in storage 
area

amount currently in storage area

label identification number or batch 
number

amount dispensed to and returned by each 
participant, including unique participant
identifiers

amount transferred to another area/site for 
dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if 
applicable

amount returned to BMS

retain samples for 
bioavailability/bioequivalence, if 
applicable 

dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study drug integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.   
These records should include:

label identification number or batch 
number 

amount dispensed to and returned by each 
participant, including unique participant
identifiers

dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
Revised Protocol No.: 01
Date: 27-Mar-2017
43
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively.  If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable .Certain CRF pages and/or electronic files may serve as the source 
documents:
Revised Protocol No.: 01
Date: 27-Mar-2017
44
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety, 
or to meet local regulations (eg, cytotoxics or 
biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
Revised Protocol No.: 01
Date: 27-Mar-2017
45
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Participant recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or country)

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Revised Protocol No.: 01
Date: 27-Mar-2017
46
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA.
Revised Protocol No.: 01
Date: 27-Mar-2017
47
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study drug.
Revised Protocol No.: 01
Date: 27-Mar-2017
48
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Revised Protocol No.: 01
Date: 27-Mar-2017
49
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 9.2.5
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal
relationship between study drug 
administration and the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, the SAE report must be updated and submitted within 24 
hours to BMS (or designee) using the same procedure used for transmitting the initial SAE 
report.
All SAEs must be followed to resolution or stabilization.
Revised Protocol No.: 01
Date: 27-Mar-2017
50
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
REPORTING OF SAES TO SPONSOR OR DESIGNEE

SAEs, whether related or not related to study drug, and pregnancies must be reported 
to BMS (or designee) within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy 
Surveillance Form (electronic or paper forms).

The preferred method for SAE data reporting collection is through the eCRF.

The paper SAE/pregnancy surveillance forms are only intended as a back-up option 
when the eCRF system is not functioning.

In this case, the paper forms are to be transmitted via email or confirmed facsimile 
(fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission 
is the required method for reporting. In the event the electronic system is unavailable for 
transmission, paper forms must be used and submitted immediately. When paper forms are 
used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
Revised Protocol No.: 01
Date: 27-Mar-2017
51
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
Revised Protocol No.: 01
Date: 27-Mar-2017
52
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 days days/weeks after the end of 
study treatment, plus 30 days
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulationb 

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
Revised Protocol No.: 01
Date: 27-Mar-2017
53
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly.

Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal(coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.

Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.

Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 5 days after the end of treatment plus an additional 90 days.
Revised Protocol No.: 01
Date: 27-Mar-2017
54
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir

Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 5 days after the end of 
treatment in the male participant.

Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 5 days after the end of treatment.

Refrain from donating sperm for the duration of the study treatment and until 5 days after the 
end of treatment plus an additional 90 days.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
Revised Protocol No.: 01
Date: 27-Mar-2017
55
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
APPENDIX 5
DIAGNOSTIC CRITERIA FOR DRUG AND ALCOHOL ABUSE
The following is taken from DSM-IV:
Diagnostic Criteria for Psychoactive Substance Dependence
A maladaptive pattern of substance use, leading to clinically significant impairment or distress as 
manifested by three (or more) of the following, occurring at any time in the same 12-month 
period:
1) Tolerance, as defined by either of the following:
a) A need for markedly increased amounts of the substance to achieve intoxication or 
desired effect,
b) Markedly diminished effect with continued use of the same amount of the substance.
2) Withdrawal, as manifested by either of the following:
a) The characteristic withdrawal syndrome for the substance,
b) The same (or closely related) substance is taken to relieve or avoid withdrawal 
symptoms.
3) The substance is often taken in larger amounts or over a longer period than was intended.
4) There is a persistent desire or unsuccessful efforts to cut down or control substance use.
5) A great deal of time is spent in activities necessary to obtain the substance (eg, visiting 
multiple doctors or driving long distances), use the substance (eg, chain-smoking) or recover 
from its effects.
6) Important social, occupational or recreational activities are given up or reduced because of 
substance use.
7) The substance use is continued despite knowledge of having a persistent or recurring 
physical or psychological problem that is likely to have been caused or exacerbated by the 
substance (eg, current cocaine use despite recognition of cocaine-induce depression, or 
continued drinking despite recognition that an ulcer was made worse by alcohol 
consumption.)
Criteria for Severity of Psychoactive Substance Dependence:
Mild:  Few, if any, symptoms in excess of those required to make the diagnosis, and the 
symptoms result in no more than mild impairment in occupational functioning or in usual social 
activities or relationships with others.
Moderate:  Symptoms or functional impairment between “mild” and “severe”.
Severe:  Many symptoms in excess of those required to make the diagnosis, and the symptoms 
markedly interfere with occupational functioning or with usual social activities or relationships 
with others.
In Partial Remission:  During the past six months, some use of the substance and some 
symptoms of dependence.
Revised Protocol No.: 01
Date: 27-Mar-2017
56
Approved
2.0
v
Approved
1.0
v


Clinical Protocol
AI463528
BMS-200475
Entecavir
In Full Remission:  During the past six months, either no use of the substance, or use of the 
substance and no symptoms of dependence.
Diagnostic Criteria for Psychoactive Substance Abuse
A. A maladaptive pattern of psychoactive substance use, leading to clinically significant 
impairment or distress as manifested by one (or more) of the following, occurring at any time 
in the same 12-month period:
1. Recurrent substance use resulting in a failure to fulfill major role obligations at work, 
school, or home (eg, repeated absences or poor work performance related to substance 
use; substance-related absences, suspensions, or expulsions from school, neglect of 
children or household).
2. Recurrent substance use in situations in which it is physically hazardous (eg, driving an 
automobile or operating a machine when impaired by substance use).
3. Recurrent substance-related legal problems (eg, arrests for substance-related disorderly 
conduct).
4. Continued substance use despite having persistent or recurrent social or interpersonal 
problems caused or exacerbated by the effects of the substance (eg, arguments with 
spouse about consequences of intoxication, physical fights).
B. The symptoms have never met the criteria for substance dependence for this class of 
substance.
Revised Protocol No.: 01
Date: 27-Mar-2017
57
Approved
2.0
v
Approved
1.0
v

SAP_001.pdf: 
Preflight Summary Report for: ai463528-csr-app-16-1-9-statplan-v1-Redacted_Redacted.pdf
Profile: Convert to PDF/A-1b (Processed pages 1 to 16)
Processed by careyd1, Date: 12/18/2018 3:08 PM
Fixups
Prepare annotations for PDF/A-1 (64 objects)
Convert to PDF/A-1b (2 objects)
Force blend color space to sRGB (16 objects)
Remove document structure compression (2 objects)
Compress all uncompressed objects using lossless ZIP compression (1 object)
Recompress LZW as ZIP (1 object)
Fix font encoding (CIDSet) (10 objects)
Insert CMap for CID fonts (10 objects)
Remove unnecessary transparency groups (16 objects)
Repair invalid bookmark hierarchies (1 object)
Results (Summary)
No problems found
Document information
File name: "ai463528-csr-app-16-1-9-statplan-v1-Redacted_Redacted.pdf"
Path: "C:\Users\careyd1\Documents\CSR Studies\AI463\AI463-528"
PDF version number: "1.7"
File size (MB): 2.02
Created: "12/18/2018 3:08 PM"
Modified: "12/18/2018 3:08 PM"
Trapping: "Unknown"
Number of plates: 4
Names of plates: "(Cyan) (Magenta) (Yellow) (Black) "
Environment
Preflight, 11.0.20 (121)
Acrobat version: 11.023
Operating system: Microsoft Windows   (Build 9200)


 
 
  
  
   
    
  
 
 
 
  
  
  
   
  
 
 
 
 
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


  
 
 
 
 
  
  
  
   
 
    
 
 
 
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


  
 
 
  
 
 
 
 
  
  
 
  
 
 
 
  
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
    
 
 
  
  
  
  
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
  
 
 
   
  
 
  
  
 
 
  
 
  
 
  
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
   
  
  
 
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


  
 
 
  
  
 
 
  
 
 
 
 
  
 
 
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


  
 
 
  
  
 
 
  
 
 
  
 
  
 
  
 
 
 
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


  
 
 
    
 
   
 
 
   
 
 
  
  
   
 
 
 
 
  
 
 
  
   
  
 
   
    
 
   
  
  
  
  
  
 
     
   
 
  
  
    
    
  
   
     
 
   
    
 
  
  
  
     
    
  
  
   
  
 
 
  
   
  
    
   
 
   
   
  
  
  
     
  
 
  
   
  
   
 
   
 
  
  
      
    
 
    
  
  
   
  
       
 
 
      
    
 
   
  
  
  
      
     
 
 
 
  
  
  
  
   
 
  
  
  
   
    
  
  
 
 
 
   
 
    
  
  
 
 
 
  
 
  
    
  
  
 
  
   
  
  
    
      
    
 
 
 
   
  
 
   
  
 
  
  
 
  
 
 
 
 
 
 
 
   
    
  
  
 
 
 
  
 
    
 
 
 
  
 
   
    
  
  
   
  
  
    
 
   
 
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


  
 
 
 
 
  
  
   
   
 
   
   
   
 
 
  
         
 
  
  
  
  
   
   
  
  
   
   
  
  
 
  
   
 
    
  
  
 
  
  
  
 
  
  
  
   
  
 
  
        
 
  
       
 
  
  
  
 
 
 
  
  
 
  
    
   
   
 
 
  
   
 
  
  
 
  
 
  
   
 
  
   
 
 
    
 
  
   
  
  
 
  
  
  
 
 
 
  
  
  
   
  
   
 
 
   
 
  
    
    
  
   
   
 
  
 
  
  
   
  
     
 
  
  
      
   
  
   
  
 
    
  
  
  
  
   
   
  
  
 
   
  
 
 
   
   
 
   
 
    
  
  
  
  
    
  
   
 
  
   
 
 
   
  
  
  
 
  
  
 
 
  
 
   
  
    
   
   
 
  
 
 
  
  
 
   
   
  
 
   
 
  
  
   
  
  
    
    
  
 
 
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


  
 
 
     
  
    
   
  
    
  
 
   
   
   
  
  
   
   
 
    
  
 
   
   
 
 
 
  
  
 
 
    
   
  
  
  
 
   
  
   
   
   
  
     
 
 
  
 
 
 
   
  
 
  
  
 
  
 
   
   
 
  
    
   
  
 
   
   
 
 
  
  
 
 
  
 
 
 
   
   
    
   
  
 
 
     
   
     
 
  
    
  
  
   
 
   
   
 
 
   
  
  
  
  
 
  
  
  
  
  
  
 
   
 
  
  
  
 
  
 
  
   
  
  
  
  
  
  
  
 
    
    
 
 
 
  
  
  
  
 
   
    
   
  
    
  
    
   
  
 
  
    
  
      
  
   
 
  
  
       
  
  
    
  
  
 
 
  
  
   
   
 
  
   
  
  
  
  
   
  
  
   
 
   
   
 
 
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


  
 
 
 
 
  
  
   
  
 
   
   
  
  
 
  
  
   
 
  
 
   
  
   
   
  
   
 
 
 
 
 
    
     
  
  
  
  
  
 
  
  
  
  
   
  
   
 
 
 
 
  
  
  
 
 
 
  
  
   
  
  
 
   
   
    
     
     
 
 
  
   
  
    
    
    
  
   
 
    
   
    
  
  
 
 
    
  
 
 
  
     
  
    
    
    
    
 
  
 
  
 
 
   
 
 
   
 
  
  
  
  
  
  
    
    
     
   
 
 
   
   
   
  
 
    
  
  
 
   
  
  
    
  
 
          
  
  
 
    
 
  
 
   
    
 
   
 
   
 
   
   
 
 
  
  
  
 
 
 
 
   
  
    
  
   
  
  
 
  
   
   
  
  
  
 
 
  
  
  
  
  
   
   
  
   
  
    
    
  
   
  
  
  
  
      
      
  
 
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b


  
 
 
  
  
  
 
 
  
  
 
  
   
  
 
  
 
  
  
 
 
 
  
  
 
   
  
  
  
  
 
   
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
 
 
  
 
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b
All problems according to Preflight profile Convert to PDF/A-1b