Conditions: Chronic Hepatitis B Virus, Pediatric
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 180
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the safety and efficacy of entecavir in pediatric patients with chronic hepatitis B virus infection

Detailed description:

Arms:
arm 1: Participants received entecavir, 0.015 mg/kg up to 0.5 mg, once daily, for 96 to 144 weeks, depending on response arm 2: Participants received placebo, 0 mg, once daily, for 48 to 96 weeks, depending on response

Interventions: intervention 1: Entecavir intervention 2: Placebo
Intervention descriptions: intervention 1: Tablets/oral solution, 0.015 mg/kg up to 0.5 mg, administered orally, once daily, for 96 to144 weeks, depending on response intervention 2: Tablets/oral solution, 0 mg, administered orally, once daily, for 48 to 96 weeks, depending on response

Protocol document:
Prot_001.pdf: 
Page:
1
Protocol Number:
AI463189
IND Number:
52,196
Ex-US
Non-IND
EUDRACT Number
2009-016357-17
Date:
26-Jan-2010
Revised Date:
04-Sep-2012
Clinical Protocol AI463189
A Comparative Study of the Antiviral Efficacy and Safety of Entecavir (ETV) versus 
Placebo in Pediatric Subjects with Chronic Hepatitis B Virus (HBV) Infection who are 
HBeAg-Positive
Revised Protocol Number: 02
Incorporates Administrative Letters 1 and 2, and Amendment 05
Study Director/Central Medical Monitor
Peter Ackerman, MD 
24-hr Emergency Telephone Number
USA: 1-866-470-2267
International: +1-248-844-7390
Bristol-Myers Squibb Research and Development
5 Research Parkway
Wallingford, CT 06492
This protocol contains information that is confidential and proprietary to 
Bristol-Myers Squibb
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.
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Revised Protocol No.: 02
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Date: 04-Sep-2012
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 02
04-Sep-2012
Incorporates Amendment 05.
Amendment 05
04-Sep-2012
Address the potential safety issues associated with extreme 
elevations of ALT (serum ALT > 1,000 U/L or > 20x ULN and 
clinical or laboratory findings suggestive of liver dysfunction) 
due to acute exacerbation of CHB by providing emergency 
access to open-label study ETV (“rescue open-label ETV”) for 
subjects who cannot access acceptable alternative anti-HBV 
therapy.
1)
Specify that rescue open-label ETV would be provided by the 
sponsor at the request of a primary investigator and approval of 
the Central Medical Monitor; 
2)
Specify that rescue therapy provided by the sponsor would be 
open-label ETV only, and would be provided for up to 
96 consecutive weeks;
3)
Specify that the management of extreme elevations of ALT are 
at the discretion of the primary investigator;
4)
Clarify that non-serious adverse events should be documented 
for all LTFU subjects receiving rescue open-label ETV;
5)
Change the duration of study to, “5 years, or until the last study 
subject treated with rescue open-label ETV for an extreme 
elevation of ALT completes 48-weeks of off-treatment 
follow-up; whichever is later”;
6)
Specify that on-treatment efficacy endpoints are based on 
double-blind or open-label ETV therapy, and therefore exclude 
rescue open-label ETV:
7)
Modify Figure 5.3.2.1 to provide guidance to investigators 
managing significant elevations of ALT due to acute 
exacerbation of CHB.
Administrative 
Letter 2
11-Jan-2012
Change in Central Medical Monitor.
Administrative
Letter 1
02-May-2011
Open-label tablet bottles have a 2-panel label on them, rather than a 
1-panel label.
Revised 
Protocol 01
23-Sep-2010
Incorporates Amendment 02.
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Document
Date of Issue
Summary of Change
Amendment 02
23-Sep-2010
1)
Augment the number of randomized subjects from 123 to 180
and increase the estimated number of participating study centers;
2)
Change the entry ALT entry criteria from 1.3 to 1.5 x upper 
limit of normal (ULN), increase the minimum time span 
between the 2 pre-randomization ALT measurements from 4 to 
8 weeks, and exclude other reasons for elevated ALT;
3)
Specify the early unblinding and mechanism for doing so if 
subjects demonstrate significant worsening of HBV clinical 
symptoms or increases in ALT;
4)
Specify additional analyses that will be conducted as key 
secondary and exploratory endpoints;
5)
Modify the blood volume collected at some visits due to 
minimum fill volume requirements of available specimen 
collection tubes;
6)
Summarize the plan for PK/PD analyses that will integrate 
Studies AI463028 and AI463189.
Original 
Protocol
26-Jan-2010
Not applicable.
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SYNOPSIS
Clinical Protocol AI463189
Title of Study: Protocol AI463189: A Comparative Study of the Antiviral Efficacy and Safety of Entecavir 
(ETV) versus Placebo in Pediatric Subjects with Chronic Hepatitis B Virus (HBV) Infection who are 
HBeAg-Positive
Estimated Number of Study Centers and Countries/Regions: Approximately 50 centers in North 
America, South America, Asia, and Europe.
Study Phase: 3
Research Hypothesis: ETV will have superior antiviral activity compared to placebo in pediatric patients 
(2 to < 18 years of age) with HBeAg-positive chronic hepatitis B (CHB) who are naive to nucleoside and 
nucleotide antiviral agents.
Primary Objective: To compare the proportion of subjects in each treatment group who achieve a 
combination of HBV DNA suppression and HBeAg seroconversion (undetectable HBeAg AND detectable 
anti-HBe antibodies) at Week 48. 
Study Design: This is a comparative, randomized, double-blinded, placebo-control, multicenter study, 
assessing the efficacy and safety of ETV in pediatric subjects with chronic HBV infection who are 
HBeAg-positive and nucleos[t]ide naive. Chronic HBV-infected children and adolescents from 2 to 
< 18 years of age will be enrolled. Subjects will be randomized 2:1 to ETV or placebo for a maximum of 
96 weeks, with the primary endpoint at Week 48. The randomization will be stratified by age group (2 to 
6 yrs; > 6 to 12 yrs; > 12 to < 18 yrs). At Week 52 an assessment of HBeAg seroconversion 
(undetectable HBeAg and presence of anti-HBe antibodies) shall be performed based on Week 48 serology 
results; subjects achieving HBeAg seroconversion will continue blinded study treatment through Week 96, 
and subjects without HBeAg seroconversion will be switched to open-label ETV. Thereafter, assessment of 
HBeAg seroconversion shall be conducted at study Weeks 100 and 148 during the open-label treatment.
Study subjects who achieve HBeAg seroconversion during open-label ETV at the respective assessment 
time points shall receive up to an additional 48 weeks of study treatment for consolidation; open-label ETV 
may therefore be continued up to Week 144 in ETV randomized subjects and Week 192 for Placebo
randomized subjects. All randomized study subjects who do not achieve HBeAg seroconversion will 
receive a maximum of 96 weeks of study ETV therapy. After concluding the blinded or open-label phase of 
the study, all subjects will be followed in an observational long-term follow up phase until they complete a 
total of 5 years of study participation from the start of blinded treatment. 
A subject who experiences an extreme elevation of ALT due to acute exacerbation of CHB may be eligible 
to receive rescue open-label ETV from the study’s sponsor at the request of their principal investigator and 
after discussion and approval by the BMS Central Medical Monitor, for up to 96 consecutive weeks, in an 
effort to optimize patient safety. Rescue open-label ETV will be limited to those subjects who do not have 
access to acceptable alternative anti-HBV therapy. Upon completion of rescue open-label ETV, subjects 
will remain on study until they complete a total of 5 years of study participation from the start of blinded 
treatment or 48 weeks beyond the completion of rescue open-label ETV; whichever is later.
Duration of Study: 5 years, or until the last study subject treated with rescue open-label ETV for an 
extreme elevation of ALT due to acute exacerbation of CHB completes 48-weeks of off-treatment 
follow-up; whichever is later. 
Revised Protocol No.: 02
Date: 04-Sep-2012
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Number of Subjects per Group: Approximately 180 total [randomized 2:1 to ETV (120) and Placebo 
(60)]; the target enrollment will be 30 subjects for each age group, with a minimum requirement of 
18 subjects.
Study Population: Male and female patients 2 to < 18 years of age with a history of chronic HBV infection 
(defined as HBsAg positive at the Screening visit and on at least one other occasion 24 weeks prior). All 
subjects must be nucleos[t]ide naive (< 12 weeks of prior therapy with any nucleos[t]ide antiviral agent 
with activity against hepatitis B virus and no anti-HBV treatment within 24 weeks of screening); have 
detectable HBeAg AND no detectable anti-HBe antibodies; have active viral replication and biochemical 
evidence of active hepatitis with compensated liver function.
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with 
Investigational Product(s): ETV dosing at 0.015 mg/kg/day up to a maximum dose of 0.5 mg/day using 
oral solution or tablets. During the treatment period, ETV dosing will be for a maximum of 144 weeks. 
Placebo (reference therapy) dosing with oral solution or tablets will be for a maximum of 96 weeks. A 
subject who experiences an extreme elevation of ALT due to acute exacerbation of CHB may be provided 
with rescue open-label ETV for up to 96 consecutive weeks at investigator’s discretion and after discussion 
and approval by the BMS Central Medical Monitor. Rescue open-label ETV will be limited to those 
subjects who do not have access to acceptable alternative anti-HBV therapy.
Study Assessments and Primary Endpoints: 
To test the study hypothesis, the primary endpoint of the analysis will be the proportion of subjects who 
achieve the composite of: 1) HBV DNA < 50 IU/mL (approximately 300 copies/mL) using the Roche 
COBASTaqMan HBV Test for use with the High Pure System (HPS) assay; and 2) HBeAg 
seroconversion (undetectable HBeAg AND detectable anti-HBe antibodies) at Week 48.
Key Secondary Endpoints:
Proportion of subjects with HBV DNA < 50 IU/mL at Week 48; Proportion of subjects with HBV DNA 
< LOQ (29 IU/mL) at Week 48; Proportion of subjects with serum ALT 1 ULN at Week 48; Proportion 
of subjects with HBe seroconversion at Week 48; and Proportion of subjects who achieved sustained 
HBeAg seroconversion during off-treatment follow-up among subjects who achieved HBe seroconversion 
(undetectable HBeAg and presence of anti-HBe antibodies) at end of treatment.
Other Secondary Endpoints:
The number and percent of subjects with adverse events (including palatability issues), serious adverse 
events, discontinuations due to adverse events, and HBV disease progression through Week 48; proportion 
of subjects who maintained HBeAg seroconversion at Week 96 (end of blinded therapy) among subjects 
who achieved HBeAg seroconversion at Week 48; and Histological analysis among subjects with available 
liver biopsy.
Statistical Methods:
Sample Size determination:
One hundred and twenty-three (123) subjects (randomized 2:1 to ETV versus placebo) will provide 90% 
power to show superiority of ETV versus placebo assuming a response rate for the primary endpoint HBV 
DNA by PCR < 50 IU/mL (approximately 300 copies/mL) and HBeAg seroconversion of 20% for ETV 
and 1% for the placebo arm. A two-sided significance level of 0.05 will be used. Subjects who discontinue 
from study prior to Week 48 or have missing Week 48 measurement at Week 48 will be considered as 
failures at Week 48. This sample size will also fulfill the requirement that the ETV integrated pediatric 
safety database has at least 100 pediatric patients who have received ETV for at least 48 weeks; this 
database will be comprised of subjects currently enrolled in study AI463028 and from this study 
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(AI463189). The size of the overall study population has been augmented to 180 randomized subjects in 
order to meet the requirement of a Health Authority.
Methods:
The primary and key secondary analyses will be based on treated subjects (modified intention-to-treat 
[ITT]). For the analysis of the primary and key secondary endpoints at Week 48, subjects who discontinue 
from study prior to Week 48 or have missing Week 48 measurements will be considered failures at 
Week 48 (Non-completer = Failure). Sensitivity analyses will be performed in order to account for possible 
effects of early discontinuation, in which subjects who discontinue from study prior to Week 48 or have 
missing Week 48 measurements are excluded (Non completer = Missing). Treatment comparisons for the 
primary 
endpoint 
and 
key 
secondary 
endpoints 
will 
be 
stratified 
by 
age 
group 
using 
Cochran-Mantel-Haenszel (CMH) weights and NC=F. The difference in proportions (ETV - placebo), 
p-value, and 95% Confidence Interval (CI) will be presented. ETV will be considered superior to placebo if 
the p-value is < 0.05. The CI for the differences in proportions will be based on the normal approximation 
to the binomial distribution. On-treatment efficacy endpoints are assessed based on double-blind or open-
label ETV therapy, and therefore exclude rescue open-label ETV during long-term follow-up.
Serious adverse events and deaths will be reported for enrolled subjects. Other safety analyses will be based 
on treated subjects. Discontinuations due to adverse events will be summarized. Adverse events will be 
reported by severity and relationship to study medication. Laboratory abnormalities will be summarized.
Pharmacokinetic samples will be collected at specified times to further evaluate and characterize the 
pharmacokinetics of ETV in pediatric subjects. The PK data collected in the study will be combined with 
the PK data collected in the pediatric
study AI463028 to help develop a population 
pharmacokinetic/pharmacodynamic model in pediatric nucleos[t]ide naive subjects.
There will be an external data monitoring committee (DMC) for this study.
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TABLE OF CONTENTS 
 
 
TITLE PAGE .........................................................................
DOCUMENT HISTORY ........................................................
SYNOPSIS ............................................................................
TABLE OF CONTENTS ........................................................
1 
 ....................
.
1.5 Overall Risk/Benefit Assessment ...............................
2 STUDY OBJECTIVES ........................................................
2.1 Primary Objective .......................................................
2.2 Secondary Objectives .................................................
3 ETHICAL CONSIDERATIONS ..........................................
3.1 Good Clinical Practice ................................................
3.2 Institutional Review Board/Independent Ethics 
Committee ....................................................................
3.3 Informed Consent .......................................................
4 INVESTIGATIONAL PLAN.................................................
4.1 Study Design and Duration .........................................
4.1.1 Subject Management Decisions .......................................
4.1.2 Subjects Experiencing Significant Elevations Of ALT 
Due To Acute Exacerbation of CHB .....................................
4.2 Study Population .........................................................
4.2.1 Inclusion Criteria ...............................................................
4.2.2 Exclusion Criteria .............................................................
4.2.3 Discontinuation of Subjects from Treatment ....................
4.3 Data Monitoring Committee ........................................
5 TREATMENTS ...................................................................
5.1 Study Treatment .........................................................
5.1.1 Investigational Product .....................................................
5.1.2 Noninvestigational Product ...............................................
5.1.3 Identification .....................................................................
1
2
4
7
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5.1.4 Packaging and Labeling of Drug ......................................
5.1.5 Handling and Dispensing .................................................
5.2 Method of Assigning Subjects to a Treatment ............
5.3 Selection and Timing of Dose for Each Subject .........
5.3.1 Dose Modifications ...........................................................
5.3.2 Other Guidance ................................................................
5.3.2.1 Study Subject Management for ALT Elevations or 
Hepatic Clinical Events ....................................................
5.3.2.2 Management of Laboratory Abnormalities and 
Clinical Events Using Modified Toxicity Grading 
System. ...........................................................................
5.4 Blinding/Unblinding .....................................................
5.5 Concomitant Treatments ............................................
5.5.1 Prohibited and/or Restricted Treatments .........................
5.5.2 Other Restrictions and Precautions .................................
5.6 Treatment Compliance ...............................................
6 STUDY ASSESSMENTS AND PROCEDURES ................
6.1 Flow Chart/Time and Events Schedule ......................
6.2 Study Materials ...........................................................
6.3 Safety Assessments ...................................................
6.3.1 Vital Signs, Physical Examination, and Targeted 
Physical Examination ...........................................................
6.3.2 Adverse Event Monitoring ................................................
6.3.3 Medication Assessments ..................................................
6.4 Efficacy Assessments .................................................
6.4.1 Primary Efficacy Assessment ...........................................
6.4.2 Secondary Efficacy Assessments ....................................
6.5 Pharmacokinetic Assessments ...................................
6.5.1 Pharmacokinetics: Blood Collection and Processing .......
6.5.2 Pharmacokinetic Sample Shipment .................................
6.6 Pharmacodynamics Assessments ..............................
6.7 Pharmacogenomic/Pharmacogenetic Assessments ..
6.8 Outcomes Research Assessments ............................
6.9 Other Assessments ....................................................
6.9.1 Laboratory Test Assessments ..........................................
6.9.2 Genotypic Analysis for Drug Resistance ..........................
7 ADVERSE EVENTS ...........................................................
7.1 Definitions ...................................................................
7.1.1 Serious Adverse Events ...................................................
37
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42
44
45
46
46
47
47
49
49
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7.1.2 Nonserious Adverse Events .............................................
7.2 Assignment of Adverse Event Intensity and 
Relationship to Study Drug ...........................................
7.3 Collection and Reporting ............................................
7.3.1 Serious Adverse Events ...................................................
7.3.2 Handling of Expedited Safety Reports .............................
7.3.3 Nonserious Adverse Events .............................................
7.4 Laboratory Test Abnormalities ....................................
7.5 Overdose ....................................................................
7.6 Pregnancy ...................................................................
7.6.1 Requirements for Pregnancy Testing ...............................
7.6.2 Reporting of Pregnancy ....................................................
7.6.3 Specific Information Related to ETV and Pregnancy .......
7.7 Other Safety Considerations .......................................
8 STATISTICAL CONSIDERATIONS ...................................
8.1 Sample Size Determination ........................................
8.2 Populations for Analyses ............................................
8.3 Endpoint Definitions ....................................................
8.4 Analyses .....................................................................
8.4.1 Demographics and Baseline Characteristics ...................
8.4.2 Safety Analyses ................................................................
8.4.3 Efficacy Analyses .............................................................
8.4.4 Pharmacokinetic Analyses ...............................................
8.4.5 Pharmacodynamic Analyses ............................................
8.4.6 Pharmacogenomic Analyses ............................................
8.4.7 Outcomes Research Analyses .........................................
8.4.8 Other Analyses .................................................................
8.5 Interim Analyses .........................................................
9 ADMINISTRATIVE SECTION ............................................
9.1 Compliance .................................................................
9.1.1 Compliance with the Protocol and Protocol Revisions .....
9.1.2 Monitoring .........................................................................
9.1.3 Investigational Site Training .............................................
9.2 Records Retention ......................................................
9.2.1 Case Report Forms ..........................................................
9.2.2 Study Drug Records .........................................................
9.3 Destruction and Return of Study Drug ........................
9.3.1 Destruction of Study Drug ................................................
9.3.2 Return of Study Drug ........................................................
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9.4 Publications ................................................................
10 GLOSSARY OF TERMS ..................................................
11 LIST OF ABBREVIATIONS .............................................
APPENDIX 1 ADDITIONAL ETHICAL 
CONSIDERATIONS .........................................................
APPENDIX 2 DAIDS TOXICITY GRADES ...........................
 
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Extreme elevations of ALT associated with severe acute exacerbations of CHB may 
represent a critical scenario with the potential for serious hepatic injury and even 
death.28,29,30,31 Prior studies among adults have demonstrated significant benefit to the 
rapid introduction of nucleos(t)ide analogue therapy in such circumstances. 32,33
1.4.1
Dose Selection / Pharmacokinetics
The dose selection for this study is based on PK data from Study AI463028.34 AI463028 
demonstrated that the dose of 0.015mg/kg resulted in adequate exposures of ETV in the 
three different age groups of nucleoside naive subjects tested (2 yrs to 6 yrs; > 6 yrs to 
12 yrs; > 12 yrs to 18 yrs). The ETV exposures across all the age groups were 
comparable to historical PK data obtained at the dose of 0.5 mg daily in nucleoside naive 
adults enrolled in study AI463017; 35 a Phase 2 population pharmacokinetic/
pharmacodynamic (PK/PD) assessment in adults with chronic HBV infection.
The primary objective of Study AI463028 was to determine the doses of ETV in children 
and adolescents that produced drug exposures comparable to those observed in adults 
given the 0.5 mg and 1.0 mg doses in nucleoside naive (LVD-naive) and LVD refractory 
subjects respectively. For LVD-naive subjects, a dose of 0.015 mg/kg was selected by 
scaling the adult dose to the dose in children on the basis of body surface area. For 
LVD-naive subjects, an adult 0.5 mg dose scaled to approximately 0.29 mg/m2 which 
extrapolated to 0.013 mg/kg in a young child of normal height and weight, therefore, a 
dose of 0.015 mg/kg was selected for testing in LVD-naive subjects. The target exposure 
selected for the study was based on achieving a geometric mean steady-state plasma 
AUC similar to the median AUC that was observed in the Phase 2 population 
pharmacokinetic/pharmacodynamic (PK/PD) assessment (Study AI463017). That
analysis resulted in a median plasma AUC of 18.7 ng∙h/mL for adult subjects receiving a 
0.5 mg dose. The targeted median exposure for the pediatric population was anticipated 
to be between 13.1 and 24.3 ng∙h/mL, well within the AUC range where efficacy was 
demonstrated in the adult Phase 2 trials. Furthermore, the PK/PD analysis demonstrated 
that AUC was predictive of efficacy, and an AUC of 2.22 ng∙h/mL resulted in 90% of the 
maximal antiviral effect in the adult Phase 2 clinical trials, indicating that the targeted 
exposure in Study AI463028 should provide an efficacious exposure for the pediatric 
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1.5
Overall Risk/Benefit Assessment
The overall clinical safety profile of ETV is benign and comparable to that for LVD. The 
safety experience from Phase 3 clinical trials in adults reflects 1 to 2 years of ETV 
treatment in a broad range of patients with chronic HBV infection. This experience 
includes nucleoside-naïve and LVD-refractory patients, and those with HBeAg-positive 
as well as HBeAg-negative disease. The most common adverse events that may have 
been related to treatment with ETV were headache, fatigue, dizziness, nausea, increased 
liver enzymes, increased pancreas enzymes, upper abdominal pain and dyspepsia. Other 
common adverse events were diarrhea, vomiting, insomnia as well as sleepiness. These 
events were generally of mild to moderate severity and they occurred at similar rates for 
ETV as for LVD. Like all other available treatments for chronic HBV, exacerbations of 
hepatitis have been observed both during treatment with ETV and during post-treatment 
follow-up observation.37,38 The long-term studies with extended dosing through 5 years, 
and the post-marketing experience with ETV both remain consistent with this overall 
profile.
Given its favorable clinical safety profile, the risk assessment for ETV is primarily 
concerned with specific findings from the pre-clinical
evaluation. In rodent 
carcinogenicity studies using lifetime dosing, ETV was associated with statistically 
increased rates of tumors for both mice and rats with 2 distinct patterns observed. First, a 
specific pattern of lung tumor development was observed only in mice and at low 
exposure multiples (ranging between 4 and 5 times the exposure in humans at 0.5 mg 
daily, or between 2 and 3 times the exposure in humans at the 1.0 mg dose, depending on 
whether the multiples are calculated in relation to patients or healthy subjects 
respectively). Second, multiple tumor types occurred in both mice and rats, but only after 
lifetime exposure at high exposure multiples.37,38 The results of investigative studies 
suggest that lung tumors observed in mice at low exposure multiples result from unique 
effects of ETV on the mouse lung; whereas tumors in rodents occurring only at high 
doses/exposures may result from biochemical actions that are likely to demonstrate a 
biological threshold (eg, are not expected to occur below a threshold dose). Observed 
malignancy rates for ETV- and LVD-treated patients from the ETV development 
program (1755 ETV patients observed for a mean of 77.6 weeks, including a mean 
treatment duration of 60.4 weeks; 1160 LVD patients observed for a mean of 71.6 weeks, 
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including a mean treatment duration of 59.5 weeks) are comparable across the 
2 treatment groups and these rates fall within the expected range for malignancies based 
on epidemiologic studies in populations with chronic HBV infection.39
Additional analysis of malignancy rates for subjects enrolled in three ETV rollover 
studies (AI463049, AI463050, and AI463901) is conducted annually; the observation 
time for this analysis is restricted to time spent in the rollover studies. Subjects in the 
rollover studies may have been treated with LVD or ADV in prior protocols before 
entering the rollover studies (AI463049, -050, and -901) or with any commercially 
available anti-HBV therapy during the rollover study (AI463049); thus a comparison of 
malignancy rates by treatment arm is not possible. In the most current report of the 
analysis of malignancy rates from the rollover studies, a total of 1955 subjects (prior ETV
n = 1193; prior LVD/ADV n = 762) were observed over 7053.5 person years of 
observation (prior ETV group = 4034.9; Prior LVD/ADV group = 3018.6). The results 
were within the expected rates for malignancies based upon epidemiological studies in 
the reference populations of chronic HBV infected persons.40
Thus there is no early safety signal for an increased rate of cancers as a result of 
treatment with ETV. Nevertheless, the number of ETV-treated patients and the duration 
of follow-up in the development program to date remain limited, and therefore the 
long-term risk of malignancy remains unknown. Exposure to other nucleoside/nucleotide 
analogues (including some for which animal carcinogenicity studies were positive) has 
not been associated with an increased incidence of tumors in humans. The data that 
address this issue are limited and derive primarily from long-term follow up studies of 
neonatal zidovudine exposure.41,42
Although HIV/HBV co-infected subjects are excluded from enrolling in this study, there 
is a potential risk that subjects enrolled may acquire new HIV infection during the course 
of the study. From subsequent observations during post marketing clinical experience, 
ETV use for HBV therapy in HIV/HBV co-infected persons who were not concurrently 
receiving anti-retroviral therapy has been documented to select for the M184V reverse 
transcriptase substitution, which confers resistance to anti-retroviral drugs such as LVD 
and emtricitabine (FTC). ETV is therefore not recommended for use in HIV/HBV 
co-infected persons who are not concurrently receiving effective anti-retroviral therapy. 
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Any subject who develops new HIV infection during participation in the study is 
therefore at risk for the development of HIV nucleoside/nucleotide resistance if they are 
not concurrently receiving effective anti-retroviral therapy while on ETV. This potential 
risk to patients is minimized by the fact that the protocol excludes HIV infected persons 
from enrollment and HIV serologies will be tested every 48 weeks while on study 
treatment. Additionally, the protocol strongly recommends that investigators consider 
HIV serologies for any subject in the observational long-term follow-up phase of the 
study that they decide to maintain on any anti-HBV therapy.
The clinical benefit of ETV derives from its potent activity against HBV. In the 
worldwide ETV development program, ETV was consistently superior to LVD across 
specific virologic, histologic, and biochemical endpoints. ETV was comparable to LVD 
for serologic endpoints. In addition, the resistance profile of ETV is favorable and is of 
particular note for nucleoside-naive patients among whom the cumulative probability of 
genotypic ETV-resistance remains low at 1.2% through 5 years of continuous ETV 
treatment. Small studies of adult patients with severe acute exacerbation of CHB have 
suggested that early initiation of nucleos(t)ide therapy, including ETV, is beneficial.32,33
Taken together, these clinical benefits of ETV represent an important treatment advance 
for patients with chronic HBV infection. In weighing the overall risk/benefit, it must be 
noted that HBV is a human carcinogen and causes HCC;43 chronic HBV infection is 
associated with a 30- to 148-fold higher relative risk for HCC compared with the 
background rate in uninfected individuals.44 Among those with cirrhosis at baseline, 
antiviral therapy with LVD has now been shown to delay the progression to 
decompensated disease and to delay or prevent HCC,45 a finding consistent with the 
known pathophysiology of this tumor. Thus, there is a rationale to predict that the 
superiority of ETV over LVD in well established 48-week efficacy endpoints may be 
associated with superior long-term benefit, potentially including long-term benefit with 
respect to HCC.
This study will have external oversight which will ensure the well-being of study 
participants. An external data monitoring committee (DMC) will provide review and 
input surrounding the benefit risk assessment throughout the duration of the study. The 
DMC shall act as an advisor to the sponsor and have responsibility for safeguarding the 
patients’ interests. The DMC shall bring any safety concerns to the attention of the 
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sponsor so that the sponsor can review the data and prepare appropriate communications 
to the Regulatory Authorities.
In summary, chronic HBV infection carries with it the risk for serious morbidity and 
mortality related to the long-term risks for progression to cirrhosis and its complications, 
including HCC. Treatment of CHB with ETV results in demonstrable clinical benefit, 
which must be weighed against the potential risk posed by the rodent carcinogenicity 
data. The relevance of the animal carcinogenicity findings with respect to the long term 
risk of human malignancy is unknown. A full evaluation of the currently available data 
leads to a favorable benefit-risk assessment in which the proven benefit of ETV
outweighs the unknown risk. Importantly, this assessment remains on-going and will be 
re-evaluated on a regular basis as further clinical data (including a large 10-year 
observational study) become available.
2
STUDY OBJECTIVES
This protocol is being developed at a time when reporting of HBV DNA has just 
concluded the transition from copies/mL to IU/mL. Though the use of HBV DNA 
categories based on IU/mL has now become a universal standard, it not inconceivable 
that some local labs may not have made the transition. In this protocol, the cutoff for the 
HBV DNA component of the primary endpoint is established as 50 IU/mL 
(291 copies/mL); however, the cutoff for the enrollment criteria is based on copies/mL 
and a conversion table for guiding the conversion between copies/mL and IU/mL can be 
found in Section 6.9.1.
2.1
Primary Objective
To compare the proportion of subjects in each treatment group who achieve a 
combination of HBV DNA suppression and HBeAg seroconversion (undetectable 
HBeAg AND detectable anti-HBe antibodies) at Week 48.
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2.2
Secondary Objectives

Assess the serologic response rates (defined as HBsAg loss and/or seroconversion; 
and HBeAg loss and/or seroconversion) including durability of response off 
treatment; 

Assess the virological response rates;

Assess the biochemical response rates;

Assess ETV resistance rates;

Evaluate the long-term safety of ETV use in pediatric patients.
3
ETHICAL CONSIDERATIONS
3.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as 
defined by the International Conference on Harmonisation (ICH) and in accordance with 
the ethical principles underlying European Union Directive 2001/20/EC and the United 
States Code of Federal Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to 
initiation of the study.
All potential serious breaches must be reported to BMS 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.
Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective task(s).
This study will not use the services of study personnel where sanctions have been 
invoked or where there has been scientific misconduct or fraud (eg, loss of medical 
licensure, debarment).
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Systems with procedures that assure the quality of every aspect of the study will be 
implemented.
3.2
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, subject recruitment 
materials/process (eg, advertisements), and any other written information to be provided 
to subjects. The investigator or sponsor 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 or sponsor should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures.
3.3
Informed Consent
Investigators must ensure that subjects, or, in those situations where consent cannot be
given by subjects, their legally acceptable representatives, are clearly and fully informed 
about the purpose, potential risks, and other critical issues regarding clinical studies in 
which they volunteer to participate. Freely given written informed consent must be 
obtained from every subject or, in those situations where consent cannot be given by 
subjects, their legally acceptable representative, prior to clinical study participation, 
including informed consent for any screening procedures conducted to establish subject
eligibility for the study.
The rights, safety, and well-being of the study subjects are the most important 
considerations and should prevail over interests of science and society.
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 
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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.
Appendix 1 contains BMS procedures on obtaining informed consent from subjects, or, 
in those situations where consent cannot be given by subjects, their legally acceptable 
representative prior to participating in a clinical study. Procedures are described for all 
subjects, including those who are unable to give informed consent. The relevant 
procedures must be used whenever they are applicable (see subject selection criteria in 
Sections 4.2.1 and 4.2.2).
4
INVESTIGATIONAL PLAN
4.1
Study Design and Duration
This is a comparative, randomized, double-blinded, placebo-control, multicenter study, 
assessing the efficacy and safety of oral ETV in pediatric subjects with chronic HBV 
infection who are HBeAg-positive and nucleos[t]ide naive (< 12 weeks of prior therapy 
with any nucleos[t]ide antiviral agent with activity against hepatitis B virus). Chronic
HBV-infected children and adolescents from 2 to < 18 years of age will be enrolled. 
Approximately 180 subjects will be randomized 2:1 to ETV or placebo (PLB) for a 
maximum of 96 weeks of blinded therapy, with the analysis of the primary endpoint at 
Week 48 to be conducted for the first 123 treated subjects. The randomization will be 
stratified by age group (2 to 6 yrs; > 6 to 12 yrs; > 12 to < 18 yrs). To ensure 
adequate representation, the target enrollment will be 30 subjects for each age group,
with a minimum requirement of 18 subjects. At Week 52 an assessment of HBeAg 
seroconversion shall be performed based on Week 48 serology results.
At the 
Week 52 assessment, all subjects who achieve HBeAg seroconversion will remain on 
blinded therapy through Week 96; subjects without HBeAg seroconversion will be 
switched to open-label ETV. Thereafter, assessment of HBeAg seroconversion shall be 
conducted at study Weeks 100 and 148 during the open-label treatment. Study subjects 
who achieve HBeAg seroconversion during open-label ETV at the respective assessment 
time points shall receive up to an additional 48 weeks of study treatment for 
consolidation. Open-label ETV may therefore be continued up to Week 144 in ETV 
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randomized subjects and Week 192 for placebo randomized subjects. All randomized 
study subjects who do not achieve HBeAg seroconversion will receive a maximum of 
96 weeks of study ETV therapy (Figure 4.1).
After completing the blinded treatment or the open-label phase, all subjects will be 
followed in an observational long-term follow up (LTFU) phase until they complete a 
total of 5 years of study participation from the start of blinded treatment.
A subject who experiences an extreme elevation of ALT due to acute exacerbation of 
CHB is eligible to receive rescue open-label ETV from the study’s sponsor at the request 
of their principal investigator and after discussion and approval by the BMS Central 
Medical Monitor, for up to 96 consecutive weeks, in an effort to optimize patient safety. 
Rescue open-label study ETV will be limited to those subjects who do not have access to 
acceptable alternative anti-HBV therapy. Upon completion of rescue open-label ETV, 
subjects will remain on study until they complete a total of 5 years of study participation 
from the start of blinded treatment or 48 weeks beyond the completion of rescue 
open-label ETV; whichever is later.  
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Figure 4.1:
AI463189 Study Schema
Randomization to ETV or PLB (2:1). Stratification by age group with target enrollment of 
30 subjects; minimum requirement of 18 subjects
At Week 52 assessment of HBeAg status based upon Week 48 results
No HBeAg seroconversion
No HBeAg seroconversion; go to 
open label ETV
At Week 100 assessment 
of HBeAg status based 
upon Week 96 results
Observational Long-Term Follow-Up (LTFU) to complete
264 weeks (5 years) from start of blinded therapy or 48 weeks beyond the completion of rescue 
open-label ETV initiated for the purpose of treating an extreme elevation of ALT due to acute 
exacerbation of CHB; whichever is later
PLB randomized 
continue open label 
ETV 
At Week 148 assessment 
of HBeAg status based 
upon Week 144 results
HBeAg seroconversion; continue 
blinded therapy for consolidation 
to Week 96 and STOP
ETV randomized 
No HBeAg 
seroconversion 
HBeAg seroconversion continue 
open label ETV for consolidation 
to Week 192 and STOP
HBeAg seroconversion 
continue open label ETV for 
consolidation to Week 144 
and STOP
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The total duration of the study will be 264 weeks (5 years) or 48 weeks beyond the 
completion of rescue open-label ETV initiated for the purpose of treating an extreme 
elevation of ALT due to acute exacerbation of CHB; whichever is later; the end of the 
study is defined as the date of the last follow-up visit for the last subject treated. Study 
visits will occur at screening, Baseline, Weeks 4, 8, 12, and then every 12 weeks during 
study treatment. Additional ‘On Treatment’ visits to modify or discontinue study drug 
based on HBeAg assessments will occur at Weeks 52, 100, and 148, if needed. At 
selected sites, a subset of up to 9 treated subjects in each age cohort will have 4 plasma 
specimens collected for semi-intense pharmacokinetic assessments during a single visit 
between study Day 14 and Week 4. Once in the observational LTFU phase, study visits 
will occur at Weeks 6, 12, and then every 12 weeks until completion of a total of 
264 weeks of ‘on-study follow-up’ or 48 weeks beyond the completion of rescue 
open-label ETV initiated for the purpose of treating an extreme elevation of ALT due to 
acute exacerbation of CHB; whichever is later. 
4.1.1
Subject Management Decisions
Assessment of HBeAg seroconversion will be done, as needed, at Study Weeks:

52 (based upon Week 48 result); 

100 (based upon Week 96 result); and 

148 (based upon Week 144 result).
The investigators shall conduct the assessment of HBeAg response status at the 
assessment time points; this will be cross checked centrally by the BMS Medical 
Monitor/Protocol Manager. Subjects achieving HBeAg seroconversion shall initiate 
consolidation therapy for an additional 48 weeks as follows:

At Week 52 (consolidation using blinded therapy to Week 96; 48 weeks counting 
from Week 48)

At Week 100 (consolidation using open-label ETV to Week 144; 48 weeks counting 
from Week 96)

At Week 148 (consolidation using open-label ETV to Week 192; 48 weeks counting 
from Week 144)
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Subjects who achieve HBeAg seroconversion and revert back to HBeAg-positivity or 
develop HBeAg-negative CHB shall be managed as follows:

Any subject who achieves HBeAg seroconversion by the Week 48 assessment and 
reverts to HBeAg-positive status before reaching Week 96 will be treated with 
open-label ETV until study Week 144, and then will stop study therapy and proceed 
to the LTFU phase;

Any subject who achieves HBeAg seroconversion after the Week 48 assessment, who 
reverts back to HBeAg-positive status shall stop study treatment, if applicable, and be 
treated at the discretion of the investigator in consultation with the BMS Medical 
Monitor. 

Subjects who develop HBeAg-negative CHB (absence of HBeAg, presence of 
anti-HBe antibodies, active viral replication [HBV DNA by PCR assay 
10,000 copies/mL] and biochemical or histological evidence of hepatitis) shall be 
managed at the discretion of the investigator in consultation with the BMS Medical 
Monitor.
Study treatment (ETV and placebo) shall be provided during the blinded and open-label 
study treatment phases. Rescue open-label ETV shall be provided to subjects who 
experience extreme elevations of ALT due to acute exacerbations of CHB upon 
investigator request and approval by the Central Medical Monitor (see section 4.1.2).  
Anti-HBV treatment of study subjects during LTFU shall be at the discretion of the 
treating clinicians and may include marketed or investigational products. In the event that 
a subject in LTFU develops an extreme elevation of ALT due to acute exacerbation of 
CHB, rescue open-label study ETV will be made available upon investigator request and 
after discussion and approval by the BMS Central Medical Monitor (see section 4.1.2). If 
ETV is initiated during the LTFU phase, HIV testing and monitoring is strongly 
recommended as ETV is not recommended in subjects co-infected with HIV and HBV 
unless the subject is also receiving effective anti-retroviral therapy. For subjects initiated 
on other anti-HBV treatment during LTFU, investigators should evaluate the need for 
HIV testing based upon standard of care and the product label for the selected agent.
At the end of the on study treatment phase, the sponsor will not continue to supply study 
drug to subjects/investigators unless the sponsor chooses to extend the study. The only 
exception is for subjects started on rescue open-label ETV as a consequence of an
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extreme elevation of ALT due to acute exacerbation of CHB (see section 4.1.2). The 
investigator should ensure that the subject receives appropriate standard of care to treat 
the condition under study, if necessary. 
4.1.2
Subjects Experiencing Significant Elevations Of ALT Due To 
Acute Exacerbation of CHB
A subject who experiences an extreme elevation of ALT due to acute exacerbation of 
CHB should be carefully managed at the discretion of the primary investigator. 
Additional laboratory testing and frequent clinical evaluations are recommended 
(See Figure 5.3.2.1).

An extreme elevation of ALT due to acute exacerbation of CHB is defined as:

a serum ALT > 1,000 U/L, 
OR 

an elevation in serum ALT > 20x ULN WITH associated clinical or laboratory 
findings suggestive of hepatic dysfunction,

Upon investigator request and after discussion and approval by the BMS Central 
Medical Monitor:

A subject who experiences an extreme elevation of ALT due to acute 
exacerbation of CHB will be provided access to rescue open-label ETV. 
The choice of anti-HBV therapy to be used to treat an extreme elevation of ALT due to 
acute exacerbation of CHB remains at the discretion of the investigator. Only open-label
ETV will be provided by the sponsor, and will be limited to those subjects who do not 
have access to acceptable alternative anti-HBV therapy. Subjects started on rescue 
open-label ETV will be provided the drug for up to 96 consecutive weeks. Upon 
completion of the rescue open-label ETV course, subjects will remain on study as part of 
the LTFU phase until they complete a total of 5 years of study participation from the start 
of blinded treatment or 48 weeks beyond the completion of rescue open-label ETV; 
whichever is later. During this time, subjects may be treated with alternative anti-HBV 
therapy at the discretion of their primary investigator. The sponsor reserves the right to 
terminate access to rescue open-label ETV if any of the following occur: a) the study is 
terminated due to safety concerns; b) the subject can obtain medication from a 
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government sponsored or private health program; or c) therapeutic alternatives become 
available in the local market.
Specific decisions regarding the management of an extreme elevation of ALT due to 
acute exacerbation of CHB remain at the discretion of the subject’s primary investigator
but access to rescue open-label ETV must be discussed with and approved by the BMS 
Central Medical Monitor.
4.2
Study Population
For entry into the study, the following criteria MUST be met.
4.2.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Freely given informed consent must be obtained prior to clinical trial 
participation, including informed consent for any screening procedures conducted 
to establish subject eligibility for the trial. Minor’s parents or legally acceptable 
representatives must give fully informed written consent. Assent should be 
obtained when the minor is judged to be of an age of reason (see Appendix 1);
2) Target Population
a) History of CHB infection defined as HBsAg-positive at the Screening visit and on 
at least one other occasion 24 weeks prior to screening;
b) Detectable HBeAg AND no detectable anti-HBe antibodies at screening and at 
least once 4 weeks prior to screening;
c) Serum ALT 1.5 to < 10 x ULN at screening and at least on one other occasion 
within 8 to 24 weeks prior to screening;
d) HBV DNA by PCR 105 copies/mL at screening and evidence of the presence of 
HBV DNA at least once 4 weeks prior to screening;
3) Age and Sex
a) Male and females, 2 to <18 years of age.
Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy throughout the study and for up to 6 weeks after 
the last dose of investigational product in such a manner that the risk of pregnancy 
is minimized. 
WOCBP include any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, 
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or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined 
as: 

Amenorrhea 12 consecutive months without another cause or 

For women with irregular menstrual periods and on hormone replacement 
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level 
> 35 mIU/mL
Women who are using oral contraceptives, other hormonal contraceptives 
(vaginal products, skin patches, or implanted or injectable products), or 
mechanical products such as an intrauterine device or barrier methods 
(diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing 
abstinence or where their partner is sterile (eg, vasectomy) should be considered 
to be of childbearing potential.
WOCBP must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) at screening AND within 
72 hours prior to the start of investigational product.
4.2.2
Exclusion Criteria
1) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to avoid 
pregnancy for the entire study period and for up to 6 weeks after the last dose of 
investigational product;
b) WOCBP using a prohibited contraceptive method. At this time there are no 
known contraindicated contraceptives to entecavir;4
c) Women who are pregnant or breastfeeding;
d) Women with a positive pregnancy test on enrollment or prior to investigational 
product administration;
e) Sexually active fertile men not using effective birth control if their partners are 
WOCBP;
2) Target Disease Exceptions 
a) Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) 
or hepatitis D virus (HDV);
b) Other forms of acute and chronic conditions which may cause increased ALT as 
determined by the investigators (eg, acute viral illness, Wilson Disease, other 
metabolic disorders, autoimmune hepatitis, alcoholic liver disease);
c) Liver transplant recipients;
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3) Medical History and Concurrent Diseases
a) Current evidence of, or history of variceal bleeding, hepatic encephalopathy, or 
ascites requiring diuretics or paracentesis or evidence of these on physical 
examination performed for this study;
b) Current evidence of, or history of pancreatitis;
c) Received 
bone 
marrow 
or 
organ 
transplant 
or
therapy 
with 
an 
immunomodulatory, cytotoxic, or systemic corticosteroid therapies within 
2 months of enrollment;
d) Evidence of current pre-malignant lesions and malignancies including HCC; (to 
be excluded by screening and evaluation practices standard in the country of 
enrollment);
e) Other serious medical conditions that might preclude completion of this study;
4) Physical and Laboratory Test Findings
a) Hemoglobin < 10.0 g/dL;
b) Platelet count < 70,000/mm3
;
c) Inadequate renal function with estimated glomerular filtration rate of 
< 50 mL/min/1.73m2 (using the Schwartz formula; [k * Ht]/Cr)
d) Total serum bilirubin > 2.5 mg/dL (> 42.75 mol/L); 
e) INR > 1.5; 
f)
Serum albumin < 3.0 g/dL (< 30 g/L); 
g) Alpha Fetoprotein 50 ng/mL;
5) Allergies and Adverse Drug Reactions
a) Known allergy to nucleoside analogues;
6) Prohibited Treatments and/or Therapies
a) 12 weeks of prior therapy with any nucleoside or nucleotide antiviral agent with 
activity against hepatitis B virus (including but not limited to adefovir, tenofovir, 
famciclovir, clevudine, lamivudine, telbivudine, or emtricitabine);
b) Therapy with interferon alpha, thymosin alpha or any nucleos[t]ide antiviral agent 
with activity against hepatitis B virus within 24 weeks of screening;
c) Any prior therapy with ETV;
d) Any use of illegal drugs OR use of alcoholic beverages which in the investigator’s 
opinion is sufficient to prevent adequate compliance with study procedures or 
increase the risk pancreatitis or hepatotoxicty;
e) Concomitant medications which may cause immunosuppression, nephrotoxicity 
or hepatotoxicity or affect renal excretion or hepatic metabolism are not 
permitted; 
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f)
Concomitant use of Traditional Chinese Medicines or other herbal products 
purported to have antiviral activity or intended for use in improving/protecting 
liver function;
g) During the treatment phase of the study, a subject may not be coenrolled in 
another clinical trial where an investigational drug is administered;
7) Other Exclusion Criteria
a) Unable to tolerate oral medication;
b) Children that are currently breastfeeding, or those who were breastfed while their 
mother received LVD; maternal LVD treatment during pregnancy;
c) Prisoners or subjects who are involuntarily incarcerated;
d) Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness.
A liver biopsy prior to the start of study medication is optional. If a biopsy has been 
performed prior to randomization, then histological results will be collected; likewise, 
results from any subsequent on-study biopsies will be collected.
Subjects may be rescreened twice (for a total of three screens) if it can be reasonably 
expected that study criteria will be met. However, beyond this, subjects should be 
reevaluated only after consultation with the study team.
Eligibility criteria for this study have been carefully considered to ensure the safety of the 
study subjects and to ensure that the results of the study can be used. It is imperative that 
subjects fully meet all eligibility criteria.
4.2.3
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and noninvestigational product at 
the discretion of the investigator) for any of the following reasons:

Withdrawal of informed consent (subject’s decision to withdraw for any reason)

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 subject

Pregnancy (see Section 7.6.2)

Termination of the study by Bristol-Myers Squibb (BMS)
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
Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness

Subjects who develop HIV infection after starting the study.
Study treatment should always be withdrawn in a manner that will maintain subject 
safety. Subjects who discontinue study treatment must be followed on study for 
observation, regardless of the reason for stopping study drug.
All subjects who discontinue should comply with protocol specified follow-up 
procedures as outlined in Section 6. The only exception to this requirement is when a 
subject withdraws consent for all study procedures or loses the ability to consent freely
(ie, is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or 
physical illness).
If a subject was withdrawn before completing the study, the reason for withdrawal must 
be entered on the appropriate case report form (CRF) page.
4.3
Data Monitoring Committee
There will be a data monitoring committee (DMC) for this study. The DMC shall have 
access to partially unblinded data (coded treatment assignments) on at least an annual 
basis, including but not limited to following: the frequency and spectrum of serious 
adverse events; Grades 3 to 4 laboratory abnormalities; occurrence of malignancies; and 
other select adverse events of interest. The DMC shall have the right to request full 
unblinding of the data (codes will be decoded to reveal actual treatment assignments).
The DMC shall act as an advisor to the sponsor and have responsibility for safeguarding 
the patients’ interests. The DMC shall bring any safety concerns to the attention of the 
sponsor so that the sponsor can review the data and prepare appropriate communications 
to the Regulatory Authorities. A separate charter shall be developed for the DMC; this 
will describe the membership and activities of the DMC.
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5
TREATMENTS
5.1
Study Treatment
All protocol-specified investigational and noninvestigational products are considered 
study drug. 
5.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some 
regions, is defined as follows:
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) in a way different from the authorized 
form, or used for an unauthorized indication, or when used to gain further information 
about the authorized form.
In this protocol, investigational product(s) is/are: entecavir (BMS-200475) 0.5 mg tablets, 
matching placebo tablets, entecavir oral solution, and matching placebo solution.
5.1.2
Noninvestigational Product
Other medications used in the study as support or escape medication for preventative, 
diagnostic, or therapeutic reasons, as components of the standard of care for a given 
diagnosis, are considered noninvestigational products.
In this protocol, noninvestigational product(s) is/are: not applicable.
5.1.3
Identification
ETV tablets and oral solution, and relevant placebo will be provided by Bristol-Myers 
Squibb. The ETV 0.05 mg/mL oral solution and placebo will be supplied as a 
ready-to-use, orange-flavored, clear, colorless to pale yellow, solution in a 260-mL bottle 
containing 210 mL of solution.
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5.1.4
Packaging and Labeling of Drug
Double-Blind Phase
Entecavir 0.5 mg and matching placebo tablets will be packaged into bottles containing 
30 tablets each. Each bottle will be labeled with a 1-panel blinded label with at least the 
following information: protocol number (or stem number), container number, batch 
number, quantity of tablets, dosing directions, and storage conditions.
Entecavir oral solution and matching placebo will be in 260 mL bottles (containing 
210 mL oral solution) and be labeled with a 1-panel blinded label with at least the 
following information: protocol number (or stem number), container number, batch 
number, quantity of oral solution, dosing directions, and storage conditions. Each bottle 
of oral solution will be housed in a carton containing a plastic dosing syringe and adapter.
Each carton will be labeled with a 1-panel label containing at least the following 
information: protocol number (or stem number), container number, batch number, dosing 
directions, and storage conditions.
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Open-Label Phase and Rescue Open-Label ETV
Entecavir 0.5 mg tablets will be packaged into bottles containing 30 tablets each. Each 
bottle will be labeled with a 2-panel open label with at least the following information:
protocol number (or stem number), container number, batch number, drug name and 
potency, quantity of tablets, dosing directions, and storage conditions.
Entecavir oral solution will be in 260 mL bottles (containing 210 mL oral solution) and
be labeled with a 1-panel open label with at least the following information: protocol 
number (or stem number), container number, batch number, drug name and potency, 
quantity of oral solution, dosing directions, and storage conditions. Each bottle of oral 
solution will be housed in a carton containing a plastic dosing syringe and adapter. Each 
carton will be labeled with a 1-panel open label containing at least the following 
information: protocol number (or stem number), container number, product name and 
potency, batch number, dosing directions, and storage conditions.
5.1.5
Handling and Dispensing
Study drug supplied by the sponsor or sourced by the investigator should be stored in a 
secure area according to local regulations. It is the responsibility of the investigator to 
ensure that study drug is only dispensed to study subjects. The study drug must be 
dispensed only from official study sites by authorized personnel according to local 
regulations.
The investigator should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the 
sponsor. Entecavir 0.5 mg and matching placebo tablets should be stored at 15 - 25C in 
a tightly closed container. Entecavir oral solution and matching placebo should be stored 
at 15 - 25C, protected from light and freezing. Materials will be provided to assist in the 
accurate measuring the dispensation of ETV and placebo oral solution.
If concerns regarding the quality or appearance of the study drug arise, do not dispense 
the study drug and contact the sponsor immediately.
Please refer to Section 9.2.2 for information on study drug record retention and 9.3 for 
destruction and return instructions.
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5.2
Method of Assigning Subjects to a Treatment
At the start of the screening period, the investigative staff will call the Randomization 
Center designated by the sponsor to register the subject and to obtain a subject number or 
patient identification number (PID). For subjects who meet the protocol defined 
eligibility criteria during screening, the investigative staff will again call the 
Randomization Center for the subject to be randomized into a blinded treatment 
assignment based on the subject’s age at the time of randomization. The subject will be 
assigned bottle numbers according to the randomization scheme. For each study visit, the 
site will need to call the Randomization Center for container assignments. Details will be 
provided.
A randomized blocked design stratified by age group (2 to 6 yrs; > 6 to 12 yrs; 
> 12 to < 18 yrs) will be used. The target enrollment will be 30 subjects for each age 
group, with a minimum requirement of 18 subjects. It is important that the investigative 
staff reconfirm the subject’s willingness to continue in the study prior to randomizing the 
subject.
Randomization should occur within 6 weeks after the screening evaluation. 
5.3
Selection and Timing of Dose for Each Subject
Study medication MUST be initiated within 72 hours of randomization. 
On Day 1, after all Day 1 procedures have been performed, eligible subjects will start 
study medication once daily. Study medication should be taken at approximately the 
same time each day. Study medication should be taken on an empty stomach (2 hours 
before OR 2 hours after food); therefore it is suggested that subjects take their study 
medication at bedtime or very early in the morning. Subjects participating in the 
semi-intense PK assessment should take study medication in the morning from Day 1 
until the PK specimens are collected at a single visit between Day 14 and Week 4. On the 
day of the semi-intense PK assessment, subjects should take study medication, on an 
empty stomach, in the clinic under direct observation. Subjects who have completed the 
semi-intense PK assessments are permitted to take study medication at bedtime.
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Note: The Summary of Product Characteristics (SmPC) for Baracludeand product 
inserts in some other countries, state that ETV may be taken “with or without” food in 
treatment naive subjects. This labeling reflects a regulatory assessment of the 
pharmacokinetic/pharmacodynamic data for ETV. In developing this study, BMS has 
chosen to standardize study conduct worldwide using the approach that ETV should be 
taken on an empty stomach.
During the blinded treatment phase, ETV or the relevant placebo will be dosed once 
daily, as shown in Table 5.3
Table 5.3:
Study Medication Dosing Table
Body Weight (kg)a
Body Weight (lbs)
Dose Final
(mL, per 0.015 mg/kg)b
10.0 - 10.8
22.1 - 23.8
3.0
10.9 - 12.4
24.0 - 27.3
3.5
12.5 - 14.1
27.6 - 31.1
4.0
14.2 - 15.8
31.3 - 34.8
4.5
15.9 - 17.4
35.1 - 38.4
5.0
17.5 - 19.1
38.6 - 42.1
5.5
19.2 - 20.8
42.3 - 45.9
6.0
20.9 - 22.5
46.1 - 49.6
6.5
22.6 - 24.1
49.8 - 53.1
7.0
24.2 - 25.8
53.4 - 56.9
7.5
25.9 - 27.5
57.1 - 60.6
8.0
27.6 - 29.1
60.9 - 64.2
8.5
29.2 - 30.8
64.4 - 67.9
9.0
30.9 - 32.5
68.1 - 71.7
9.5
32.6 - 33.0
71.9 - 72.8
10.0
a If weight in pounds (lb) is not included in the table, use the closest higher body weight (lb.) in the table 
for study medication dose. The ETV dose is calculated as follows:
weight (kg) x 0.015 mg/Kg = weight (Kg) x 0.3 mL/Kg = mL solution.
0.05 mg/mL
Round to the nearest 0.5 mL.
b Children with body weight > 32.6 kg (71.9 lb) should receive 10.0 mL of oral solution or the tablet 
formulation (0.5 mg) of the study medication.
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Clinical Protocol
During the open-label phase, ETV shall be dosed once daily at 0.015 mg/kg and should 
follow the dosing scheme in Table 5.3.
The need for further anti-HBV treatment of study subjects during the LTFU shall be 
determined by the investigator. The choice of therapy is at the discretion of the 
investigator and may include marketed or investigational products. In the event that a 
subject is treated with rescue open-label ETV as a result of an extreme elevation of ALT 
due to the acute exacerbation of CHB, as defined in Section 4.1.2, ETV shall be dosed 
once daily at 0.015 mg/kg up to 0.5mg/day and should follow the dosing scheme in 
Table 5.3.
If ETV is initiated during the LTFU phase, HIV testing and monitoring is strongly 
recommended as ETV is not recommended in subjects co-infected with HIV and HBV 
unless the subject is also receiving effective anti-retroviral therapy. For subjects initiated 
on other anti-HBV treatment during LTFU, investigators should evaluate the need for 
HIV testing based upon standard of care and the product label for the selected agent.
5.3.1
Dose Modifications
ETV is a nucleoside analogue that is primarily cleared by the kidneys. In patients with 
renal impairment, the apparent clearance of entecavir decreases as creatinine clearance 
decreases. In the unlikely event that a subject develops inadequate renal function while 
on study (estimated glomerular filtration rate of < 50 mL/min/1.73 m2), the 
recommendation for dose reduction will follow the established approach used in studies 
of adult CHB patients. Table 5.3.1 shows the recommendation for dose reduction based 
upon estimated glomerular filtration rate (GFR).
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Table 5.3.1:
Recommended Dosing of ETV in Subjects Who Develop 
Renal Impairment on Study
Estimated GFR
Usual Dose
(0.015 mg/kg/day up to a maximum of 0.5 mg/daily)a
50
Usual Dose
30 to < 50
Dose reduction by 50 % OR Usual dose every 48 hours
10 to < 30
Dose reduction by 70 % OR Usual dose every 72 hours
< 10/hemodialysis/ CAPDb
Dose reduction by 90 % OR Usual dose every 7 days
a For doses less than 0.5 mg daily, the oral solution is recommended.
b Subjects receiving ETV on the day of hemodialysis should receive ETV after the session.
5.3.2
Other Guidance
5.3.2.1
Study Subject Management for ALT Elevations or Hepatic Clinical 
Events
Acute exacerbation of hepatitis B (ALT > 2 x baseline AND > 10 x ULN) and hepatic 
clinical events may represent a critical scenario with the potential for serious hepatic 
injury and death. Guidelines for managing these events can be found in Figures 5.3.2.1.
Should an event as described occur, a blood sample for HBV DNA determination using a 
sensitive PCR technique should be obtained and sent to the central laboratory for this 
study. If results are needed urgently for patient management decisions, a sample should 
be also drawn and concurrently sent to a local laboratory for assessment. An unscheduled 
visit laboratory kit should be used for the HBV DNA sample if it is collected at a time 
that is not required by the protocol. Non-HBV related potential causes of worsening 
hepatitis also need to be considered (hepatitis A, C, D, concomitant medications, etc).
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Figure 5.3.2.1:
Management of Significant Elevations of Serum ALT Due to 
the Acute Exacerbation of Chronic Hepatitis B
Subjects with ALT > 2 x baseline and > 10 x ULN but 20x 
ULN
Subjects with serum ALT > 
1,000 U/L, or > 20x ULN 
and clinical or laboratory 
findings suggestive of liver 
dysfunction 1,2,5
IF subject 
WITHOUT clinical or 
laboratory findings suggestive of 
liver dysfunction1,2
THEN
• Monitor subject closely until 
ALT is significantly improved
_______________
IF ALT elevation persists
THEN
• Continue to monitor ALT and 
liver function parameters 
closely
• Consider alternative causes of 
acute hepatitis
• Consider consultation with 
BMS Medical Monitor
IF subject 
WITH clinical or laboratory findings 
suggestive of liver dysfunction1,2
OR
Investigator has serious concerns 
regarding the subject’s safety
THEN
• Consider immediate medical 
evaluation
• Consider consultation with BMS 
Medical Monitor3
• Confirm lab results (preferably within 
24 hours) 4
-
Check AST/ALT, Total bilirubin. 
PT/INR, Albumin, Lactate, HBV 
serologies, and HBV DNA level
• Continue to monitor subject closely 
until ALT significantly improved and
liver function parameters are stable
• Consider alternative causes of acute 
hepatitis
• Perform immediate medical 
evaluation
• Consider consultation with BMS 
Medical Monitor
• Consider early initiation of anti-
HBV therapy 
• Confirm lab results (preferably 
within 24-hours) 4
-
Check AST/ALT, Total 
bilirubin. PT/INR, Albumin, 
Lactate, HBV serologies, and 
HBV DNA level
• Continue to monitor subject closely 
until ALT significantly improved 
and liver function parameters are 
stable
• Consider alternative causes of 
acute hepatitis
1 Clinical manifestations suggestive of hepatic complications include but are not limited to: Ascites, Hepatic 
encephalopathy, Increasing nausea, vomiting, or abdominal pain, Jaundice, Variceal bleeding, etc.
2 Laboratory findings that may be suggestive of evolving liver dysfunction include but are not limited to: 
Increasing INR, Total bilirubin, or Serum lactate levels, or Declining serum albumin values.
3Subjects experiencing acute exacerbation of CHB resulting in ALT flare WITH clinical or laboratory findings 
suggestive of liver dysfunction or other serious safety concern may be eligible for rescue open-label ETV as 
determined on a case-by-case basis following consultation with the BMS Central Medical Monitor.
4 Labs may be processed by local or central laboratory. An unscheduled visit laboratory kit should be used if 
labs are collected at a time that is not required by the protocol.
5Subjects placed on rescue open-label ETV will be immediately placed into the study’s LTFU phase. Protocol 
visits should be scheduled as described in Section 6.1. Patients who are provided rescue open-label ETV to treat 
an extreme elevation of ALT due to acute exacerbation of CHB should undergo additional non-protocol visits 
and assessments at the discretion of the managing investigator. See section 4.1.2.
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5.3.2.2
Management of Laboratory Abnormalities and Clinical Events 
Using Modified Toxicity Grading System.
If a subject develops a non-hepatic laboratory toxicity during the study, Table 5.3.2.2A 
provides guidance pending a full medical evaluation for the underlying etiology of the 
abnormality. The medical monitor should be consulted for the following laboratory 
abnormalities: 
Table 5.3.2.2A:
Management of Laboratory Toxicities and Clinical Events 
using DAIDS Toxicity Grading System
Laboratory Test
Alert Value
Lipase
> 5 times ULN (Grade 4)
ALT or AST
> 2 X baseline and > 10 x ULN (Grade 4) (see Figure 5.3.2.1)
Total Bilirubin 
2 mg/dL increase from baseline and > ULN
INR
> 1.5 (Grade 2) and an increase in the INR 0.5 from baseline
Serum Albumin
Decrease 1 g/dL from baseline and < 3 g/dL
Plasma lactatea
Elevated: 3 mmol/L (27 mg/dL)
a The Central Medical Monitor must be informed
If a subject develops certain specified clinical events during the study, Table 5.3.2.2B 
provides guidance pending a full medical evaluation for the underlying etiology of the 
event. Study drug should be interrupted and the medical monitor consulted for the 
following clinical events:
Table 5.3.2.2B:
Clinical Events Requiring Interruption of Study Drug
Grade & Events
Dose Modifications
All Grades: Pancreatitis, Acute Allergic Reaction (if 
it appears related to study drug), Lactic Acidosis
Interrupt study medication and inform
BMS Medical Monitor
Grade 2: Shortness of breath, bronchospasm if 
associated with evidence of allergic reaction due to 
study drug
Interrupt study medication and inform
BMS Medical Monitor
Grade 3: Hypotension if associated with evidence of 
allergic reaction due to study drug
Interrupt study medication and inform
BMS Medical Monitor
Grade 4: All Clinical Events
Interrupt study medication and inform
BMS Medical Monitor
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Clinical Protocol
All subjects who discontinue study medication, regardless of the reason off study, are to 
be followed to complete 5 years on study.
5.4
Blinding/Unblinding
The subject, investigator and Bristol-Myers Squibb personnel involved in the conduct of 
the study will be blinded to treatment assignment. Designated staff of Bristol-Myers 
Squibb pharmacokinetics and modeling departments, as well as personnel from the 
central and analytical laboratories, will be unblinded to treatment assignments in order to 
minimize unnecessary analysis of samples from subjects receiving placebo.
A pharmacist at Bristol-Myers Squibb not involved in the study design, assessment, or 
analyses will be given access to the treatment codes to permit efficient drug distribution.
The treatment codes will be maintained in a password-protected file which cannot be 
accessed by the study personnel or subjects. 
HBV DNA results from Day 1 through Week 96 will be blinded to the investigator. Any 
subject who has achieved HBeAg seroconversion by Week 96 shall remain blinded to 
their randomized treatment assignment except in the event of a change in clinical status 
for which knowledge of the randomized arm is critical to subject management. Subjects 
who have not yet achieved HBeAg seroconversion by Week 96 will be unblinded on an 
individual basis, as needed in order to determine their further management.
Blinding is critical to the integrity of this clinical study. However, in the event of a 
medical emergency or pregnancy in an individual subject, in which knowledge of the 
investigational product is critical to the subject's management, the blind for that 
subject may be broken by the treating physician. The primary emergency treatment arm 
unblinding method is through the IVRS. 
In the event that a subject develops an ALT flare and/or other HBV clinical symptoms, 
the investigator should consult with the study medical monitor on a case by case basis. If 
knowledge of the subject’s HBV DNA is deemed necessary for further clinical 
management, as in a case of an extreme elevation of ALT due to acute exacerbation of 
CHB, that subject’s HBV DNA values will be unblinded; subsequent unblinding of the 
treatment assignment may or may not be necessary.
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Before breaking the blind of an individual subject's treatment, the investigator should 
have determined that the information is necessary, ie, that it will alter the subject's 
immediate management. In many cases, particularly when the emergency is clearly not 
investigational product-related, the problem may be properly managed by assuming that 
the subject is receiving active product without the need for unblinding. 
The DMC will be able to review unblinded HBV DNA results for individual subjects, 
and will inform BMS of the need to unblind data for individual subjects as appropriate; in 
that event the investigator will be able to make individual management decisions based 
on the unblinded HBV DNA.
5.5
Concomitant Treatments 
5.5.1
Prohibited and/or Restricted Treatments
Subjects should be on stable doses of other medications for at least four weeks prior to 
first dose of study medication. If the subject is on chronic medications, a consistent 
dosing schedule should be maintained for the duration of the study.
In general, concomitant medications which may cause nephrotoxicity (including 
long-term treatment with immunosuppressive drugs); hepatotoxicity; affect renal 
excretion or hepatic metabolism; and agents with activity against hepatitis B are not 
permitted in this study (see Exclusion Criteria Section 4.2.2, number 6).
Examples of these potentially nephrotoxic or hepatotoxic agents are: amphotericin B; 
aminoglycosides; foscarnet; systemic corticosteroids; 
cyclosporin; 
azathioprine; 
carbamazepine; disulfiram; isoniazid; rifampin (rifampicin); diclofenac; troglitazone; 
trovofloxacin. Should a subject develop a medical need for short term therapy with any of 
these agents (2 weeks), such an agent may be used; longer term therapy while on study 
should be discussed with the central BMS Medical Monitor.
Examples of agents with anti HBV activity include: interferon alpha, thymosin alpha; any 
nucleos[t]ide antiviral agent with activity against hepatitis B virus (including but not 
limited to adefovir, tenofovir, famciclovir, clevudine, lamivudine, telbivudine, or 
emtricitabine); and mycophenolate mofetil.
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Traditional Chinese medicines and other herbal products with purported antiviral activity 
or intended to improve/protect liver function are prohibited during this study and must be 
discontinued at the time of enrollment.
During the on study treatment phase, the subject may not be co-enrolled in another 
clinical trial where an investigational drug is administered.
An assessment of concomitant medication use will be performed at each on study 
treatment visit.
5.5.2
Other Restrictions and Precautions
Restrictions: Female subjects of childbearing potential should take measures to avoid 
pregnancy both during dosing and for 6 weeks after study medication has been 
discontinued. Male subjects should also be advised to practice barrier contraception or 
abstinence during the dosing period and for at least 6 weeks after dosing.
Precautions: If the subject is on chronic medications, a consistent dosing schedule is 
recommended for the duration of this study when medically possible.
5.6
Treatment Compliance
Assessment of study medication will be performed at each clinical evaluation visit. The 
subject should be instructed to bring all unused study medication in the original bottle to 
each visit. Partially used bottles of study medication can be returned to the subject, and 
dosing should continue from the in-use container until it has been emptied. The dates and 
number of solution/tablets dispensed and returned must be recorded in the source 
documents for compliance and accountability purposes.
The subject’s caregiver will be provided with a diary card to record study medication and 
meal times preceding the semi-intense and sparse PK sampling.
Any interruptions in dosing (start and stop dates) or missed doses due to concurrent 
illness or toxicity will be recorded on the CRF.
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Clinical Protocol
Subject adherence with treatment regimens should be evaluated by the site at every visit 
through direct interviews with the subject’s caregiver. Counseling for reinforcement of 
dosing instructions and importance of compliance should be provided as needed.
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6
STUDY ASSESSMENTS AND PROCEDURES
6.1
Flow Chart/Time and Events Schedule 
Table 6.1:
Flow Chart for Protocol AI463189
Procedure
Screening
6 Weeks prior 
to 
Randomization
Randomize
Initiate study 
drug (Day 1) 
within 
72 hours
On Study Treatment
Weeks 4, 8, 12 3 days, 
and every 12 weeks 5 
days up to end of study 
drug dosing
Weeks 52, 
100 and 148 
10 days
(if needed)a
End of 
Treatment
(Scheduled 
or Early)
Observational LTFUb
Weeks 6, 12, and every 
12 weeks 5 days
Up to 264 weeks total 
study participation
[or 48 weeks beyond 
completion of rescue open-
label ETV used for treatment 
of an extreme elevation of 
ALT due to acute 
exacerbation of CHB; 
whichever is later]
Protocol 
Section
Eligibility Assessments
Informed Consent
X
3.3
Inclusion/Exclusion Criteria
X
4.2
Medical & anti HBV historyc
X
4.2
HCV, HDV serology (1 mL)
X
6.9
Alpha Fetoprotein (1 mL)
X
6.9
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Table 6.1:
Flow Chart for Protocol AI463189
Procedure
Screening
6 Weeks prior 
to 
Randomization
Randomize
Initiate study 
drug (Day 1) 
within 
72 hours
On Study Treatment
Weeks 4, 8, 12 3 days, 
and every 12 weeks 5 
days up to end of study 
drug dosing
Weeks 52, 
100 and 148 
10 days
(if needed)a
End of 
Treatment
(Scheduled 
or Early)
Observational LTFUb
Weeks 6, 12, and every 
12 weeks 5 days
Up to 264 weeks total 
study participation
[or 48 weeks beyond 
completion of rescue open-
label ETV used for treatment 
of an extreme elevation of 
ALT due to acute 
exacerbation of CHB; 
whichever is later]
Protocol 
Section
Safety Assessments
Physical Examination
X
X
6.3
Targeted Physical Examination 
(including neurologic 
assessment)
X
X
Xd, 
6.3
Vital Signs including height, 
and weight
X
X
X
X
X
6.3
Tanner Stage Assessment
X
Week 24 and every 24 
weeks
X
Week 24 and every 
24 weeks
App 3
Pretreatment Events 
Assessment
X
6.3
Adverse Events Assessment
X
X
Xe
6.3
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Table 6.1:
Flow Chart for Protocol AI463189
Procedure
Screening
6 Weeks prior 
to 
Randomization
Randomize
Initiate study 
drug (Day 1) 
within 
72 hours
On Study Treatment
Weeks 4, 8, 12 3 days, 
and every 12 weeks 5 
days up to end of study 
drug dosing
Weeks 52, 
100 and 148 
10 days
(if needed)a
End of 
Treatment
(Scheduled 
or Early)
Observational LTFUb
Weeks 6, 12, and every 
12 weeks 5 days
Up to 264 weeks total 
study participation
[or 48 weeks beyond 
completion of rescue open-
label ETV used for treatment 
of an extreme elevation of 
ALT due to acute 
exacerbation of CHB; 
whichever is later]
Protocol 
Section
Serious Adverse Events 
Assessment
X
X
X
X
X
6.3
Concomitant Medication Use
X
X
X
X
5.5
Use of anti-HBV therapies
X
5.5
Assess HBV related diagnoses
X
7.3
Hematology, Chemistry
(4 - 5.5 mL)f
X
X
X
X
X
6.9
INR (1.8 mL)
X
X
Week 24 and every 24 
weeks
X
Week 24 and every 24 
weeks
6.9
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Table 6.1:
Flow Chart for Protocol AI463189
Procedure
Screening
6 Weeks prior 
to 
Randomization
Randomize
Initiate study 
drug (Day 1) 
within 
72 hours
On Study Treatment
Weeks 4, 8, 12 3 days, 
and every 12 weeks 5 
days up to end of study 
drug dosing
Weeks 52, 
100 and 148 
10 days
(if needed)a
End of 
Treatment
(Scheduled 
or Early)
Observational LTFUb
Weeks 6, 12, and every 
12 weeks 5 days
Up to 264 weeks total 
study participation
[or 48 weeks beyond 
completion of rescue open-
label ETV used for treatment 
of an extreme elevation of 
ALT due to acute 
exacerbation of CHB; 
whichever is later]
Protocol 
Section
HIV Serology (1 mL)
X
Weeks 48, 96 and 144g
X
Weeks 48 and 96 after 
initiation of rescue open-
label ETVd
6.9
Pregnancy Testh
X
X
X
X
Xi
7.6
Efficacy Assessments
Hepatitis B serologies (1 mL)
X
X
Week 12 and every 12 
weeks
X
Week 24 and every 24 
weeks
6.9
HBV DNA PCR (2 mL)
X
X
Week 4, Week 12 and 
every 12 weeks
X
Weeks 6, 12, 24, and 
every 24 weeks
6.9
HBV Genotype (HBV 
subtype) (2 mL)
X
6.9
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Table 6.1:
Flow Chart for Protocol AI463189
Procedure
Screening
6 Weeks prior 
to 
Randomization
Randomize
Initiate study 
drug (Day 1) 
within 
72 hours
On Study Treatment
Weeks 4, 8, 12 3 days, 
and every 12 weeks 5 
days up to end of study 
drug dosing
Weeks 52, 
100 and 148 
10 days
(if needed)a
End of 
Treatment
(Scheduled 
or Early)
Observational LTFUb
Weeks 6, 12, and every 
12 weeks 5 days
Up to 264 weeks total 
study participation
[or 48 weeks beyond 
completion of rescue open-
label ETV used for treatment 
of an extreme elevation of 
ALT due to acute 
exacerbation of CHB; 
whichever is later]
Protocol 
Section
Specimens for Resistance 
Testing (3 mL)
X
Week 48, 96, 144j
X
6.9
Other Assessments
Sparse PK (2 ml)k
Weeks 4, 12, 24, 48
Semi-intense PK (8 ml)l
Week 4
Clinical Drug Supplies
Dispense Study Medication
X
X
X
Xd
5.2
Assessment of Study 
Medication Use
X
X
X
Xd
5.6
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a Assessments of seroconversion will be made based on serology results at Weeks 48, 96, and 144. Study drug will be modified, continued, or discontinued 
according to the study schema (Section 4.1).
b Only protocol required visits and assessments are mentioned. Subjects placed on rescue open-label ETV to treat an extreme elevation of ALT due to acute 
exacerbation of CHB should undergo additional non-protocol visits and assessments at investigator discretion.   
c Histological results will be documented for subjects who have had a prior liver biopsy.
d For subjects receiving rescue open-label ETV to treat an extreme elevation of ALT due to acute exacerbation of CHB only.
e Adverse events should be recorded at week 6 for all subjects enrolled in LTFU, and at each visit for subjects receiving rescue open-label ETV.
f Volume of blood to be collected may vary based on available specimen collection tubes.
g While on study treatment.
h WOCBP only. Additional home pregnancy testing will be required in between study visits starting from Week 18 and every 12 weeks thereafter while on 
study treatment.
i
All subjects enrolled in LTFU should undergo pregnancy testing at week 6. Subjects receiving rescue open-label ETV should be tested every 6 weeks during 
treatment and 6 weeks after the last dose of study medication (home pregnancy tests should be used in between study visits).
j
For subjects still on study ETV only (Section 6.9.2).
k Sparse PK assessments will be conducted in all subjects. Four samples, each drawn as a single sample, will be collected during study visits at Weeks 4 (except 
for subjects participating in the semi-intense PK assessment), 12, 24, and 48.
l
Semi-intense PK assessments will be conducted at selected sites in a subset of up to 9 treated subjects in each age cohort at the Week 4 visit. For convenience, 
this PK assessment may be performed on any single day between Day 14 and Week 4 (Section 6.5).
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6.2
Study Materials
The sponsor will provide a copy of the ETV (BMS-200475) IB and any relevant safety 
addendum, protocol and any amendments to the protocol, instructions for completing 
case report forms (CRFs; both electronic and paper), Investigator Manual from the 
central laboratory and serious adverse event (SAE) and pregnancy forms, etc. Materials 
will be provided to assist in the accurate measuring and dispensation of ETV/PLB
solution. Diary cards will be provided to help record any interruptions in dosing, as well 
as dosing and meal time information required for the PK assessments. 
6.3
Safety Assessments
Only data for the procedures and assessments specified in this protocol should be 
submitted to BMS on a case report form. Additional procedures and assessments may be 
performed as part of standard of care; however, data for these assessments should remain 
in the subject’s medical record and should not be provided to BMS, unless specifically 
requested by the sponsor.
6.3.1
Vital Signs, Physical Examination, and Targeted Physical 
Examination
The schedule of vital signs (seated Blood Pressure and Pulse Rate, full and targeted 
physical examinations) is provided in Section 6.1 (Flow Chart/ Time and Events 
Schedule). Targeted physical exam includes assessment of neurological system, heart, 
lungs, and abdomen.
6.3.2
Adverse Event Monitoring
Subjects will be closely monitored throughout the study for adverse events. Subjects who 
have study medication completed or discontinued permanently must be followed for the 
full 5 years of the study. 
During the dosing phase, palatability issues with respect to the oral solution (placebo or 
active drug) should be reported as Adverse Events.
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During the observational long-term follow up phase, Adverse Events related to the 
administration or discontinuation of study drug should be documented for subjects that 
are not receiving commercially available anti-HBV therapy. Serious Adverse Events and 
HBV-related diagnoses should be reported during the long-term follow up phase, 
regardless of whether or not the subjects are receiving commercially available anti-HBV 
therapy.
6.3.3
Medication Assessments
Medications taken within one month prior to study participation and while on study 
treatment will be reported. During the LTFU phase, anti-HBV medications will be 
reported.
6.4
Efficacy Assessments
Only data for the procedures and assessments specified in this protocol should be 
submitted to BMS on a case report form. Additional procedures and assessments may be 
performed as part of standard of care; however, data for these assessments should remain 
in the subject’s medical record and should not be provided to BMS, unless specifically 
requested by the sponsor.
6.4.1
Primary Efficacy Assessment
The schedule of the primary efficacy endpoint assessment, HBV DNA assay, and 
hepatitis B e antigen serology, is provided in Section 6.1, Flow Chart/Time and Events 
Schedule, Table 6.1.
6.4.2
Secondary Efficacy Assessments
The schedule of the secondary efficacy endpoint assessments, HBV DNA assay, hepatitis 
B serologies, and ALT is provided in Section 6.1, Flow Chart/Time and Events Schedule, 
Table 6.1.
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6.5
Pharmacokinetic Assessments
Table 6.5A lists the sparse PK sampling schedule for all subjects for the assessment of 
ETV. For each subject a single sparse sample will be collected during Weeks 4, 12, 24,
and 48. 
In addition, a semi-intense PK assessment will be conducted at selected sites, in a subset 
of up to 9 treated subjects in each age cohort. Subjects providing informed consent for 
this PK assessment will have one pre-dose and three post-dose samples drawn during a 
single visit scheduled between Day 14 and Week 4 as listed in Table 6.5B.
Table 6.5A:
All Subjects - Sparse PK Sampling Schedule
PK Sample Schedule
Sample No.
Time Relative to Dosing
Week 4 Visit*
1
Anytime between 1 - 24 hours after dosing
Week 12 Visit
2
Anytime between 1 - 24 hours after dosing
Week 24 Visit
3
Anytime between 1 - 24 hours after dosing
Week 48 Visit
4
Anytime between 1 - 24 hours after dosing
* The Week 4 sparse PK sample is not required for subjects participating in the Week 4 semi-intense PK 
assessment 
Table 6.5B:
Subset of Subjects - Semi-intense PK Sampling Schedule
PK Sample Schedule
Sample No.
Time Relative to Dosing
Single visit between Day 14 and Week 4
1
immediately pre-dose
2
1.0 hours after dosing
3
2.0 hours after dosing
4
4.0 hours after dosing
Subjects will be directed to take their medication at the same time every day, at least 
2 hours before or 2 hours after meals. The date and time of the last dose of study drug and 
the time of the nearest meals relative to the last study drug dose taken before sample 
collection should be recorded on the CRF. For each sample, the date and time of sample 
collection will be recorded.
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In the subset of subjects who consent to the semi-intense PK assessments, study drug 
must be taken each day in the morning, at least 2 hours before or 2 hours after meals. On 
the day of the semi-intense PK assessment, subjects should take study medication, on an 
empty stomach, in the clinic under direct observation. The time of the meals relative to 
the PK dose will be recorded. Once the semi-intense PK assessment has been completed, 
evening dosing may begin.
6.5.1
Pharmacokinetics: Blood Collection and Processing
Tables 6.5A and 6.5B list the sampling schedule to be followed for the assessment of 
plasma pharmacokinetics. 
Blood (2.0 mL per sample) will be collected by direct venipuncture or from an indwelling 
catheter (for semi-intense PK assessments). Each blood sample is to be collected into a 
labeled tube containing EDTA (K2 or K3 EDTA) as the anticoagulant. Immediately after 
collection, the tube should be gently inverted several times to completely mix the 
anticoagulant and placed on ice. Within 60 minutes of collection, each sample should be 
centrifuged for 10 minutes at ~1000 x g in a refrigerated centrifuge (~ 5C) to separate 
the cellular elements from plasma. The use of a chilled rotor head (~ 5C) in a centrifuge 
at room temperature is permitted. The separated plasma sample should be transferred to a 
labeled screw-capped polypropylene tube and stored upright and frozen at or 
below -20C until shipped frozen on dry ice to the designated laboratory.
6.5.2
Pharmacokinetic Sample Shipment
The plasma samples are to be shipped by express courier with enough dry ice to maintain 
the samples in a frozen state until received by the Central Laboratory. Requisition slips 
supplied by the Central Laboratory are to be completed and included with each shipment. 
Do not ship to arrive over weekends or holidays. The addressee is to be notified of the air 
bill number in advance of the shipment via telephone or fax. Additional shipping 
instructions will be provided to investigators at the time of study initiation. The Central 
Laboratory will ship the samples to an analytical laboratory designated by Bristol-Myers 
Squibb. Plasma samples will be analyzed using a validated assay for ETV.
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6.6
Pharmacodynamics Assessments
Not applicable.
6.7
Pharmacogenomic/Pharmacogenetic Assessments
Not applicable.
6.8
Outcomes Research Assessments
Not applicable.
6.9
Other Assessments 
6.9.1
Laboratory Test Assessments
A central laboratory will be used for all testing. All serum and plasma samples, including 
back-up samples, will be stored by the Central Laboratory. The following testing may be 
performed retrospectively on any stored serum or plasma samples which have been 
obtained during conduct of the study: analysis for HBV resistance to study therapy and 
analysis for exploratory markers of HBV disease that could be influenced by study 
therapy but which have not previously been assessed. Laboratory test kits and a manual 
will be provided by the Central Laboratory designated by the Sponsor.
HBV DNA results from the Central Laboratory will be provided in both copies/mL and 
IU/mL. For the Roche COBASTaqMan - HPS assay, the conversion factor is 
5.82 copies = 1 IU. Table 6.9.1 is provided to assist in interpretation of results.
Table 6.9.1:
Copies/IU Conversion Table for COBAS TaqMan - HPS Assay
Copies/mL (rounded to nearest copy)
IU/mL (reported to 2 decimal places)
28
4.8
50
8.6
58
10: Lower Limit of Detection (LLD) 
169
29: Lower Limit of Linearity
300
51.5
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Table 6.9.1:
Copies/IU Conversion Table for COBAS TaqMan - HPS Assay
Copies/mL (rounded to nearest copy)
IU/mL (reported to 2 decimal places)
1000 (103)
172
10,000 (104)
1,720
100,000 (105)
17,200
1,000,000 (106)
172,000
10,000,000 (107)
1,720,000
100,000,000 (108)
17,200,000
* Conversion Factor: 5.82 copies = 1 IU
Required laboratory tests include the following:
Hematology:

hemoglobin;

white blood cell count with differential (including neutrophil count);

platelet count;

INR.
Chemistries:

albumin;

AST;

ALT;

total bilirubin;

creatinine;

urea nitrogen (BUN) or urea;

serum lipase;

electrolytes (Na+, K+, Cl-);

glucose;

alpha fetoprotein (AFP).
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Serologies: 

hepatitis B surface antigen;

hepatitis B surface antibody;

hepatitis B e antigen;

anti-hepatitis B e antibody;

anti-hepatitis C antibody;

anti-hepatitis D antibody;

HIV antibody.
Pregnancy test: 

urine or serum pregnancy test.
Other:

HBV DNA by COBASTaqMan- HPS assay;

HBV Genotype (eg, genotype A, B, C, D etc, or mixed).
Refer to Section 6.1 for details regarding at what visits the tests are required.
6.9.2
Genotypic Analysis for Drug Resistance
Blood samples shall be collected at Day 1 (prior to first study dose), Weeks 48; 96; 144; 
192 for subjects on study treatment, and at the last on study treatment visit. These 
samples will be stored for possible HBV resistance testing.
Genotyping of HBV polymerase will be performed using the Trugene assay on stored 
specimens from:
1) All subjects who have received at least 12 weeks of continuous ETV treatment 
(blinded or open-label) immediately prior to and continuing through the Week 48, 96, 
144, 192, or last on study treatment visit, and who have HBV DNA (50 IU/mL) at 
the specified analysis visit;
2) All subjects with a confirmed rise in HBV DNA of 1 log10 after achieving nadir on 
treatment as well as the subjects whose HBV DNA increases to 50 IU/mL after 
having achieved a value < 50 IU/mL. (Note: if such increase in DNA level occurs
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between analysis visits, the collected specimen will be tested in addition to any 
evaluable specimens at the specified analysis visit as described in item 1 above), 
and/or
3) On a case by case basis after consultation with the BMS Central Medical Monitor.
A Central Laboratory designated by the sponsor will be used for genotypic analysis.
7
ADVERSE EVENTS
7.1
Definitions
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a pre-existing medical condition in a patient or clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product.
7.1.1
Serious Adverse Events
A serious AE (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject 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 for exceptions)

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 subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are not 
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limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.
Suspected transmission of an infectious agent (eg, any organism, virus or infectious 
particle, pathogenic or non-pathogenic) via the study drug is an SAE and must be 
reported accordingly.
Although overdose and cancer are not always serious by regulatory definition, these 
events should be reported on an SAE form and sent to BMS in an expedited manner.
All pregnancies, regardless of outcome, must be reported to the sponsor on a Pregnancy 
Surveillance Form, not an SAE form (see Section 7.6).
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 "important medical event" or event life 
threatening)

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 (eg, routine colonoscopy)

medical/surgical admission for purpose other than remedying ill health state and 
was 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 (eg, lack of housing, 
economic inadequacy, care-giver respite, family circumstances, administrative)
7.1.2
Nonserious Adverse Events
All AEs that are not classified as serious.
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7.2
Assignment of Adverse Event Intensity and 
Relationship to Study Drug
The following categories and definitions of intensity as determined by a physician should 
be used for all BMS clinical study AEs:

Mild (Grade 1) - Awareness of event but easily tolerated

Moderate (Grade 2) - Discomfort enough to cause some interference with usual 
activity

Severe (Grade 3) - Inability to carry out usual activity

Very Severe (Grade 4) - Debilitating, significantly incapacitates subject despite 
symptomatic therapy
Refer to Appendix 2 for the Division of AIDS (DAIDS) Adult and Pediatric Toxicity 
Grading System.
The following categories and definitions of causal relationship to study drug as 
determined by a physician should be used for all BMS clinical study AEs:

Related: There is a reasonable causal relationship to study drug administration and the 
AE

Not related: There is not a reasonable causal relationship to study drug administration 
and the AE
The expression "reasonable causal relationship" is meant to convey in general that there 
are facts (eg, evidence such as de-challenge/re-challenge) or other arguments to suggest a 
positive causal relationship. 
7.3
Collection and Reporting
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects 
should not be questioned regarding the specific occurrence of one or more AEs.)
If known, the diagnosis of the underlying illness or disorder should be recorded, rather 
than its individual symptoms. The following information should be captured for all AEs: 
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onset, duration, intensity, seriousness, relationship to study drug, action taken, and 
treatment required. If treatment for the AE was administered, it should be recorded on the 
appropriate CRF page. The investigator shall supply the sponsor and Ethics Committee 
with any additional requested information, notably for reported deaths of subjects.
Completion of supplemental CRFs may be requested for AEs and/or laboratory 
abnormalities that are reported/identified during the course of the study. 
7.3.1
Serious Adverse Events
Following the subject’s written consent to participate in the study, all SAEs must be 
collected, including those thought to be associated with protocol-specified procedures.
All SAEs must be collected that occur within 30 days of discontinuation of dosing or 
within 30 days of the last visit for screen failures. If applicable, SAEs must be collected 
that relate to any later protocol-specified procedure (eg, a follow-up skin biopsy). 
The investigator should notify BMS of any SAE occurring after these time periods that is 
believed to be related to study drug or protocol-specified procedure. 
Serious Adverse Events should be reported during the long-term follow up phase, 
regardless of whether or not the subjects are receiving commercially available anti-HBV 
therapy. Any medical event that the investigator considers to be "medically important" in 
the context of pediatric drug exposure (for example neurodevelopmental delay), may be 
reported as an SAE under the category "Important Medical Event." (see Section 7.1.1)
Serious adverse events, whether related or unrelated to study drug, must be recorded on 
the SAE page of the CRF and reported within 24 hours to BMS (or designee) to comply 
with regulatory requirements. An SAE report should be completed for any event where 
doubt exists regarding its status of seriousness.
All SAEs must be reported within 24 hours by confirmed facsimile transmission (fax) or 
scanned and reported via electronic mail. (Note: Follow-up SAE reports should include 
the same investigator term(s) initially reported.) In selected circumstances, the protocol 
may specify conditions that require additional telephone reporting. The SAE electronic 
CRF in the electronic data capture tool should not be used.
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If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy, or a 
complication of a study procedure), the relationship should be specified in the narrative 
section of the SAE page of the CRF.
If an ongoing SAE changes in its intensity or relationship to study drug, a follow-up SAE 
report should be sent within 24 hours to the sponsor. As follow-up information becomes 
available it should be sent within 24 hours using the same procedure used for transmitting 
the initial SAE report. All SAEs should be followed to resolution or stabilization.
SAE FACSIMILE TRANSMISSION:
For US Sites: Central Facsimile Station:
(609) 818-3804
Local Contact: To be provided after study initiation.
SAE Email Address: Worldwide.Safety@BMS.com
7.3.2
Handling of Expedited Safety Reports
In accordance with local regulations, BMS will notify investigators of all SAEs that are 
suspected (related to the investigational product) and unexpected (ie, not previously 
described in the Investigator Brochure). In the European Union (EU), an event meeting 
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these criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). 
Investigator notification of these events will be in the form of an expedited safety report 
(ESR). 
Other important findings which may be reported by the sponsor as an ESR include: 
increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack of 
efficacy that poses significant hazard to study subjects, clinically significant safety 
finding from a nonclinical (eg, animal) study, important safety recommendations from a 
study data monitoring committee, or sponsor decision to end or temporarily halt a clinical 
study for safety reasons.
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with 
the Investigator Brochure. Where required by local regulations or when there is a central 
IRB/IEC for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. When 
BMS has a written agreement with a local IRB/IEC, BMS will directly submit ESR(s). 
The investigator should also comply with the IRB/IEC procedures for reporting any other 
safety information. 
In addition, suspected serious adverse reactions (whether expected or unexpected) shall 
be reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate reports).
7.3.3
Nonserious Adverse Events
The collection of nonserious AE information should begin at initiation of study drug.
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 
subjects. During the long-term follow up phase, Adverse Events related to the 
administration or discontinuation of study drug should be documented for subjects that 
are not receiving commercially available anti-HBV therapy. Also during the LTFU 
phase, all adverse events should be documented in subjects receiving rescue open-label 
ETV.
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If an ongoing nonserious AE worsens in its intensity or its relationship to the study drug
changes, a new nonserious AE entry for the event should be completed. Nonserious AEs
should be followed to resolution or stabilization, or reported as SAEs if they become 
serious (see Section 7.3.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug, or those that are present at the end of study
treatment as appropriate.
All identified nonserious AEs must be recorded and described on the appropriate 
nonserious AE page of the CRF (paper or electronic).
7.4
Laboratory Test Abnormalities
All laboratory test values captured as part of the study should be recorded on the 
appropriate laboratory test results pages of the CRF, or be submitted electronically from a 
central laboratory. In addition, the following laboratory abnormalities should also be 
captured on the nonserious AE CRF page (paper or electronic) or SAE paper CRF page 
as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an
SAE

Any laboratory abnormality that required the subject to have study drug discontinued 
or interrupted

Any laboratory abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical, rather than the laboratory term would 
be used by the reporting investigator (eg, anemia versus low hemoglobin value).
7.5
Overdose
An overdose is defined as the accidental or intentional ingestion or infusion 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 7.3.1 for reporting details.)
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7.6
Pregnancy
Sexually active WOCBP must use an effective method of birth control during the course 
of the study, in a manner such that risk of failure is minimized (see Section 4.2.1 for the 
definition of WOCBP).
Before enrolling WOCBP in this clinical study, investigators must review the 
sponsor-provided information about study participation for WOCBP. The topics include 
the following:

General Information

Informed Consent Form

Pregnancy Prevention Information Sheet

Drug Interactions with Hormonal Contraceptives

Contraceptives in Current Use

Guidelines for the Follow-up of a Reported Pregnancy 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form documenting this discussion. 
7.6.1
Requirements for Pregnancy Testing
All WOCBP MUST have a negative pregnancy test within 72 hours as specified in 
Section 6.1 prior to receiving the investigational product. The minimum sensitivity of the 
pregnancy test must be 25 IU/L or equivalent units of HCG. If the pregnancy test is 
positive, the subject must not receive the investigational product and must not continue in 
the study.
Pregnancy testing must also be performed throughout the study as specified in 
Section 6.1 (see flow chart/time and events schedule) and the results of all pregnancy 
tests (positive or negative) recorded on the CRF or transferred electronically.
In addition, all WOCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (eg, missed or late menstrual period) at any time 
during study participation.
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7.6.2
Reporting of Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 6 half-lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety). The investigator must immediately 
notify the BMS medical monitor of this event, record the pregnancy on the Pregnancy 
Surveillance Form (not an SAE form). Initial information on a pregnancy must be 
reported immediately to BMS and the outcome information provided once the outcome is 
known. Completed Pregnancy Surveillance Forms must be forwarded to BMS according 
to SAE reporting procedures described in Section 7.3.1.
Protocol-required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. Follow-up 
information regarding the course of the pregnancy, including perinatal and neonatal 
outcome 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 the sponsor. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
7.6.3
Specific Information Related to ETV and Pregnancy
Entecavir is classified by the US Food and Drug Administration (FDA) as Pregnancy 
“Category C” (Animal reproduction studies have shown an adverse effect on the fetus 
and there are no adequate and well-controlled studies in pregnant women).
In studies in rats and rabbits, entecavir doses producing systemic drug exposure levels 
approximately 28 and 212 times those expected in humans at the highest recommended 
dose (1 mg/day) showed no embryotoxicity or maternal toxicity, respectively. At 
exposures 3100 times those in humans, maternal toxicity, embryo-fetal toxicity 
(resorptions), lower fetal body weights, tail and vertebral malformations, reduced 
ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs 
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were observed in rats. At exposures 833 times those in humans, embryo-fetal toxicity 
(resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were 
observed in rabbits. In the pre- and post-natal development assessment in rats, entecavir, 
at maternally toxic drug exposure levels > 94 times those achieved in humans at the 
highest recommended dose (1 mg/day), no adverse effects on offspring were seen.
There are no adequate and well-controlled studies in pregnant women. A full description 
of the cumulative knowledge of ETV experience in pregnant women can be found in the 
Investigator Brochure.10
7.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded on the appropriate 
nonserious AE page of the CRF (paper or electronic) or SAE paper CRF page.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
One hundred and twenty-three (123) subjects (randomized 2:1 to ETV vs placebo) in this 
study will provide 90% power to show superiority of ETV versus placebo assuming a 
response rate for the primary endpoint HBV DNA by PCR < 50 IU/mL (approximately 
300 copies/mL) and HBeAg seroconversion of 20% for ETV arm and 1% for placebo 
arm. A two-sided significance level of 0.05 will be used. Subjects who either discontinue 
from study treatment prior to Week 48 or have having missing Week 48 HBV DNA or 
HBeAg 
serology 
measurement 
will 
be 
considered 
as 
failures 
at 
Week 48 (Non-Completer = Failure). The efficacy estimate for ETV is derived from an 
analysis of the identical endpoint (HBV DNA by PCR < 300 copies/mL and HBeAg 
seroconversion) in the pivotal Phase 3 study of HBeAg-positive subjects, (AI463022). 
The efficacy estimate for the placebo arm is derived from evidence in the literature which 
shows that whereas spontaneous seroconversion occurs at a relatively high rate in 
children, viral replication remains detectable using sensitive PCR assays. The results of 
the Gilead Sciences’ pediatric CHB study (GS 518)13 support this estimate; 3 of 
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57 placebo treated subjects (5.3%) achieved HBeAg seroconversion, but only 1 of 
58 subjects (1.7%) achieved HBV DNA < 2.23 log copies/mL at Week 48.
This sample size will also fulfill the requirement that the ETV integrated pediatric safety 
database has at least 100 pediatric patients who have received ETV for at least 48 weeks; 
this database will be comprised of subjects currently enrolled in study AI463028 and 
from this study (AI463189). Currently 24 nucleoside naive subjects are enrolled in 
AI463028; all 24 would have had 48 weeks of safety data collection by the time study 
AI463189 reaches Week 48.
Based on the original planning for study AI463189, it is estimated that 175 subjects will 
be enrolled to have approximately 123 subjects randomized (approximately 30% screen 
failure rate). Randomization will be 2:1 (ETV 82: Placebo 41); assuming a 10% drop out 
rate per year and even enrollment for 2 calendar years, approximately 72 ETV 
randomized subjects will have 48 weeks of safety data by study Week 144. This brings to 
approximately 96 the number of subjects that will be included in the integrated safety 
database at the end of study Week 144.
Additional safety data will be contributed by placebo randomized subjects switching to 
open-label ETV by study Week 52. Because it is expected to take 2 calendar years to 
randomize 123 subjects, and assuming even enrollment over that time frame, the last 
placebo randomized subject will be completing Week 48 by study week 144. Assuming a 
10% drop out per year, 18 of the 20 subjects randomized to PLB during the first calendar 
year will reach Week 48 by study Week 96; 16 of these 18 will be switched to open-label 
ETV (assuming a 10% HBeAg seroconversion rate on the PLB arm). With a 10% drop 
out rate per year, 14 of these 16 will be completing 48 weeks of open-label ETV by study 
Week 144 and will be added to the integrated safety database. This will bring the number 
of patients in the integrated safety database to approximately 110 subjects with at least 
48 weeks of ETV exposure by study Week 144.
While the analysis of the primary endpoint is based on a randomized sample size of 123, 
the size of the overall study population has been augmented to 180 randomized subjects 
in order to meet the requirement of a health authority. Therefore the final safety dataset as 
described in the previous 2 paragraphs will also be augmented. The accrual of the first 
123 randomized subjects is expected to take 2 years. Thereafter, the enrollment will 
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remain open until 180 subjects are randomized. Additional re-analyses will be performed 
on the augmented population.
8.2
Populations for Analyses
The enrolled cohort will include all subjects who provide informed consent and are 
assigned a Subject Identification number (PID).

The enrolled cohort will be used in the analyses of all SAEs and deaths.
The treated cohort will include subjects who are randomized and received at least 1 dose 
of study regimen.

The treated cohort will be used in the analyses of the efficacy endpoints; exploratory 
endpoints; HBV disease progression; AEs; and growth assessment. 
Within the treated cohort, the primary cohort will be defined as at least the first 
123 subjects treated.

The primary cohort will be used for the primary endpoint analyses.
Some exploratory analyses will be based on 2 analysis cohorts, if not otherwise specified:

Subjects who achieve seroconversion at Week 48 on study treatment;

Subjects who do not achieve seroconversion at Week 48 on study treatment.
8.3
Endpoint Definitions
Primary Endpoint: 

The proportion of subjects who achieve: 1) HBV DNA < 50 IU/mL (approximately 
300 copies/mL) using the Roche COBASTaqMan HBV Test for use with the 
High Pure System (HPS) assay; and 2) HBeAg seroconversion (undetectable HBeAg 
AND detectable anti-HBe antibodies) at Week 48 of study treatment.
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Key Secondary Endpoints:

Proportion of subjects with HBV DNA < 50 IU/mL using the Roche COBAS
TaqMan HBV Test for use with the High Pure System (HPS) assay at Week 48;

Proportion of subjects with HBV DNA < LOQ (29 IU/mL) using the Roche 
COBASTaqMan HBV Test for use with the High Pure System (HPS) assay at 
Week 48; 

Proportion of subjects with serum ALT 1 ULN at Week 48;

Proportion of subjects with HBe seroconversion (undetectable HBeAg and presence 
of anti-HBe antibodies) at Week 48;

Proportion of subjects who achieved sustained HBeAg seroconversion during
off-treatment follow-up among subjects who achieved HBe seroconversion 
(undetectable HBeAg and presence of anti-HBe antibodies) at end of treatment.
Other Secondary Endpoints:

The number and percent of subjects with adverse events (including palatability 
issues), serious adverse events, discontinuations due to adverse events, and HBV 
disease progression through Week 48;

Proportion of subjects who maintained HBeAg seroconversion at Week 96 (end of 
blinded therapy) among subjects who achieved HBeAg seroconversion at Week 48;

Histological analysis among subjects with available liver  biopsy.
Exploratory Endpoints:

Proportion of subjects who achieve HBV DNA < 50 IU/mL using the Roche 
COBASTaqMan HBV Test for use with the High Pure System (HPS) assay and 
serum ALT 1 x ULN at Week 48 of treatment;

Proportion of subjects who achieve HBV DNA < LLD (10 IU/mL) using the Roche 
COBASTaqMan HBV Test for use with the High Pure System (HPS) assay at 
Week 48;

Proportion of subjects with HBsAg loss at Weeks 48 and 96 on study treatment;

Proportion of subjects with HBV DNA < 50 IU/mL using the Roche COBAS
TaqMan HBV Test for use with the High Pure System (HPS) assay at Week 96 on 
study treatment;

Proportion of subjects with ALT 1 × ULN at Week 96 on study treatment;

Proportion of subjects with HBeAg loss at Weeks 48 and 96 on study treatment;
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
Proportion of subjects with HBe seroconversion at Week 96 on study treatment;

Growth and development assessments: Height for age Z (HAZ) scores, Weight for 
age Z (WAZ) scores, and Tanner Stage annually while on study treatment and 
annually during the follow-up period;

Cumulative probability of resistance for all patients who ever received study ETV 
(blinded or open-label) at treatment weeks 48, 96 and 144 of ETV;

Subgroup analysis by age group, baseline ALT subpopulation (> 2 x ULN vs 
2 x ULN), geography, genotype, and route of transmission for Primary and Key 
secondary endpoints;

Subgroup analysis by age group , geography, genotype, and route of transmission for 
key 
safety 
endpoints 
including 
adverse 
events, 
serious 
adverse 
events, 
discontinuations due to adverse events, HBV disease progression or laboratory 
abnormalities.
The exploratory endpoints will be assessed for descriptive purposes and will be presented 
longitudinally every 48 weeks on treatment and during the follow-up period, unless 
otherwise specified.
8.4
Analyses
Binary variables will be summarized by counts and percentages. Comparisons of binary 
variables will be based on Cochran-Mantel-Haenszel (CMH) statistic stratified by age 
group. Confidence intervals (CI) for differences in proportions will be based on the 
normal approximation to the binomial distribution with unpooled proportions used in the 
computation of the standard error of the difference. The CI procedure will be used for 
both primary and secondary efficacy endpoints if applicable.
Continuous variables will be summarized with univariate statistics (eg, mean, median, 
standard deviation, minimum, and maximum).
8.4.1
Demographics and Baseline Characteristics
Baseline demography, HBV disease characteristics, prior anti-HBV (Interferon-; ADV 
and TDF) treatment status, and laboratory values will be summarized and tabulated.
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8.4.2
Safety Analyses
Serious adverse events and deaths will be reported for enrolled subjects regardless of 
treatment status. Discontinuations due to adverse events will be summarized. Other safety 
evaluations will be reported for Treated Subjects during the following study periods:
on-study treatment (from the start of dosing until end of dosing plus 5 days), and 
off-treatment follow-up (from the end of dosing plus 6 days until the start of alternative
anti-HBV therapy or the end of follow-up, whichever is earlier). Adverse events will be 
summarized by severity and relationship to study medication. Laboratory abnormalities 
will be summarized by modified Division of AIDS (DAIDS) or World Health 
Organization (WHO) grades (when pediatric specific DAIDS grading are not available). 
The events of HBV disease progression will be tabulated.
In addition, subgroup analysis by age group will be performed for adverse events, serious 
adverse events, discontinuations due to adverse events, HBV disease progression and
laboratory abnormalities.
8.4.3
Efficacy Analyses
The primary and key secondary analyses will be based on randomized and treated 
subjects (modified intention-to-treat [ITT]). For the analysis of the primary and the key 
secondary endpoints at Week 48, subjects who discontinue from study prior to 
Week 48 or have missing measurement at Week 48 will be considered as failures at 
Week 48 (Non-completer = Failure). Sensitivity analyses will be performed in order to 
account for possible effects of early discontinuation, in which subjects who discontinue 
from study prior to Week 48 or have missing Week 48 measurements are excluded 
(Non completer = Missing). Treatment comparison for the primary endpoint and key 
secondary 
endpoints 
will 
be 
performed 
stratified 
by
age 
group 
using 
Cochran-Mantel-Haenszel 
(CMH) 
weights. 
The 
difference 
in 
proportions 
(ETV - placebo), p-value, and 95% Confidence Interval (CI) will be presented. ETV will 
be considered superior to placebo if the p-value is < 0.05. The CI for the differences in 
proportions will be based on the normal approximation to the binomial distribution. A 
two-stage testing procedure will be employed for testing the primary and key secondary 
endpoints. In the first stage, the test for primary endpoint will be performed. Provided test 
result of the primary endpoint is significant (the p-value < 0.05), the second stage tests of 
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the key secondary endpoints will be conducted. Because the test for the key secondary 
endpoint will be conducted only if the test for the primary endpoint is successful, 
significance levels will not be adjusted for the first stage testing. All tests for treatment 
comparison will be two-sided at a significance level of 0.05. In addition, treatment 
comparisons for the primary endpoint and key secondary endpoints will be performed 
within each age group. Subgroup analysis by age group will be exploratory.
For exploratory efficacy endpoints, subjects who discontinue from study prior to the 
analysis week or have missing analysis week measurements will be excluded 
(Non completer = Missing). The difference in proportions along with its 95% CI will be 
presented.
Genotypic resistance to ETV will be described.
8.4.4
Pharmacokinetic Analyses
Pharmacokinetic data collected in this study will be combined with data obtained from 
the pediatric study AI463028 to develop a Population PK/PD model which will be 
reported in a separate report. The population PK model will be used to provide estimates 
of steady state AUC which will be compared to the target exposure in adults. The median 
target exposure in adults of 18.7 ng∙h/mL was determined based on a Phase 2 PK/PD 
assessment, and is reported in study AI463017. The PK/PD analysis demonstrated that 
AUC was predictive of efficacy, and an AUC of 2.22 ng∙h/mL resulted in 90% of the 
maximal antiviral effect in the adult Phase 2 clinical trials. An exposure-response 
assessment in pediatric patients will be explored if supported by the data from study 
AI463189. 
In addition to the population PK analysis described above, PK parameters from the 
intense sampling in the PK subset in Study AI463189 will be compared to the PK 
parameters from Study AI463028, and also combined with the intense PK data obtained 
in Study AI463028 to compare this exposure to the adult exposure in adults from Study 
AI463017. This will allow better estimation of PK parameters and variability.
8.4.5
Pharmacodynamic Analyses
Not applicable.
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8.4.6
Pharmacogenomic Analyses
Not applicable.
8.4.7
Outcomes Research Analyses
Not applicable.
8.4.8
Other Analyses
Growth assessment: Height for age Z (HAZ) scores; Weight for age (WAZ) scores, and 
Tanner Stage scores will be summarized longitudinally by treatment group.
8.5
Interim Analyses
The primary analysis will evaluate safety and antiviral activity when the primary cohort 
has been treated for 48 weeks. Additional analyses will be performed when all subjects 
have reached Week 48, and when all subjects have completed study treatment. The final 
analysis will be conducted when the last randomized subjects completes the observational 
LTFU phase.
Additional analyses may be conducted at unscheduled intervals to support regulatory 
questions/interactions; and at the request of the DMC. 
9
ADMINISTRATIVE SECTION
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the 
protocol must be discussed with, and be prepared by, BMS. The investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment, except where necessary 
to eliminate an immediate hazard(s) to study subjects. Any significant deviation must be 
documented in the CRF.
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If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) 
prior to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation 
or change will be submitted to:

IRB/IEC for review and approval/favorable opinion

Bristol-Myers Squibb

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) 
must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (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 an administrative letter, investigators must inform their IRB(s)/IEC(s). 
9.1.2
Monitoring
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.
In addition, the study may be evaluated by BMS 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 BMS.
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9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study 
initiation. Training topics will include but are not limited to: GCP, AE reporting, study 
details and procedure, study documentation, informed consent, and enrollment of 
WOCBP.
For sites using the BMS electronic data capture tool, each individual making entries 
and/or corrections on electronic CRFs must meet BMS training requirements and must 
only access the BMS electronic data capture tool using the unique user account provided 
by the sponsor. User accounts are not to be shared or reassigned to other individuals.
For electronic CRFs, corrections are made through the BMS electronic data capture tool 
that generates an automated audit trail including date and timestamp, full name of the 
person making the correction and original entry. The system also prompts the user to 
document reason for change that is also maintained in the audit trail.
Each individual electronically signing electronic CRFs must meet BMS training 
requirements and must only access the BMS electronic data capture tool using the unique 
user account provided by the sponsor. User accounts are not to be shared or reassigned to 
other individuals.
9.2
Records Retention
The investigator must retain study drug (those supplied by the sponsor or sourced by the 
investigator) disposition records, copies of CRFs (or electronic files), and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by the sponsor, whichever is longer. 
The investigator must contact BMS prior to destroying any records associated with the 
study.
BMS will notify the investigator 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, IRB). Notice 
of such transfer will be given in writing to BMS.
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9.2.1
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 reported on the CRF
that are derived from source documents must be consistent with the source documents or 
the discrepancies must be explained. 
For sites using the BMS 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 Pregnancy Surveillance Form. Spaces may be left blank only in those 
circumstances permitted by study-specific CRF completion guidelines provided by the
sponsor.
Paper CRFs must be completed legibly in ink. Subjects are to be identified by birth date 
and subject number, if applicable. All requested information must be entered on the CRF 
in the spaces provided. If an item is not available or is not applicable, it must be 
documented as such; do not leave a space blank.
Electronic data transfer is acceptable.
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. 
For paper CRFs, a correction must be made by striking through the incorrect entry with a 
single line and entering the correct information adjacent to the incorrect entry. The 
correction must be dated, initialed and explained (if necessary) by the person making the 
correction and must not obscure the original entry.
The completed CRF, including any paper SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by a qualified physician who is an investigator or 
subinvestigator. For electronic CRFs, review and approval/signature is completed 
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electronically through the BMS electronic data capture tool. The investigator must retain 
a copy of the CRFs including records of the changes and corrections.
9.2.2
Study Drug Records
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by the sponsor) is maintained at each study site 
where study drug is inventoried and disposed. 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 ID number or batch number and use date

dates and initials of person responsible for the inventory /entry/ movement of each
study drug

amount dispensed to and returned by each subject, including unique subject 
identifiers

amount transferred to another area/site for dispensing or storage

non-study disposition (eg, lost, wasted, broken)

amount returned to the sponsor

amount destroyed at study site, if applicable

retain samples sent to third party for bioavailability/bioequivalence, if applicable
The sponsor will provide forms to facilitate inventory control if the staff at the 
investigational site does not have an established system that meets these requirements.
9.3
Destruction and Return of Study Drug
9.3.1
Destruction of Study Drug
If study drugs (those supplied by the sponsor or sourced by the investigator) are to be 
destroyed on site, it is the investigator’s responsibility to ensure that arrangements have 
been made for the disposal, procedures for proper disposal have been established 
according to applicable regulations, guidelines and institutional procedures, and 
appropriate records of the disposal have been documented. The unused study drugs can 
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only be destroyed after being inspected and reconciled by the responsible BMS Study 
Monitor.
9.3.2
Return of Study Drug
Upon completion or termination of the study, all unused and/or partially used study drug 
that was supplied by the sponsor must be returned to BMS.
All study drug returned to BMS must be accompanied by the appropriate documentation 
and be clearly identified by protocol number and study site number on the outermost 
shipping container. Returned supplies should be in the original containers (eg, patient kits 
that have clinical labels attached). Empty containers should not be returned to BMS. It is 
the investigator’s responsibility to arrange for disposal of all empty containers, 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 return of unused study drug, those that were supplied by 
the sponsor, should be arranged by the responsible Study Monitor. 
9.4
Publications
The data collected during this study are confidential and proprietary to the sponsor. Any 
publications or abstracts arising from this study require approval by the sponsor prior to 
publication or presentation and must adhere to the sponsor’s publication requirements as 
set forth in the approved clinical trial agreement (CTA). All draft publications, including 
abstracts or detailed summaries of any proposed presentations, must be submitted to the 
sponsor at the earliest practicable time for review, but at any event not less than 30 days 
before submission or presentation unless otherwise set forth in the CTA. Sponsor shall 
have the right to delete any confidential or proprietary information contained in any 
proposed presentation or abstract and may delay publication for up to 60 days for 
purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the
investigator or the sponsor as related to the 
investigational product
Expedited Safety Report
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (ie, not previously described in the 
Investigator Brochure), or that could be associated with 
the study procedures. 
SUSAR
Suspected, Unexpected, Serious Adverse Reaction as 
termed by the European Clinical Trial Directive 
(2001/20/EC). 
Unexpected Adverse 
Reaction
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved 
investigational product)
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11
LIST OF ABBREVIATIONS
Term
Definition
AASLD
American Association for the Study of Liver Diseases
ADV
Adefovir
AE
Adverse event
AFP
Alpha-feto protein
Alk Phos
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the plasma-concentration time curve
bDNA
Branched DNA hybridization assay
BID
Twice daily
BMS
Bristol-Myers Squibb
BUN
Blood urea nitrogen
CAPD
Continuous Ambulatory Peritoneal Dialysis
cccDNA
Covalently closed circular DNA
CHB
Chronic Hepatitis B
CI
Confidence Interval
Cl-
Chloride
CLcr
Creatinine Clearance
CNS
Central Nervous System
CRF
Case Report Form
CT
Computerized Tomography
CTA
Clinical Trial Agreement
CV
Coefficient of Variation
DAIDS
Division of AIDS
D/C
Discontinue
DMC
Data Monitoring Committee
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Term
Definition
DNA
Deoxyribonucleic acid
EAP
Early Access Program
EC50
Effective concentration for inhibition of 50% of isolates
ESR
Expedited Safety Report
ETV
Entecavir
FDA
U.S. Food and Drug Administration
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HBV
Hepatitis B virus
HBeAb
Hepatitis B e antibody
HBeAg
Hepatitis B e antigen
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HCC
Hepatocellular Carcinoma
HCG
Human Chorionic Gonadotropin
HCV
Hepatitis C virus
HDV
Hepatitis D Virus
HIV
Human immunodeficiency virus
HPS
High Pure System
HRT
Hormone Replacement Therapy
IB
Investigator Brochure
ICH
International Conference on Harmonization
IC50
Concentration which inhibits 50% of the reaction
IEC
Independent Ethics Committee
Interferon-
Interferon Alpha
IND
Investigational New Drug
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Term
Definition
INR
International Normalization Ratio
IRB
Institutional Review Board
ITT
Intention To Treat
IU
International Units
K+
Potassium
Kg
Kilogram
KFDA
Korean Food and Drug Administration
LC/MS/MS
Liquid Chromotography - tandem mass spectrometry
LLD
lower limit of detection
LLL
lower Limit of Linearity
LOCF
Last Observation Carried Forward
LOQ
Limit of Quantification
LTFU
Long Term Follow Up
LVD
Lamivudine
MEq/mL
Mega genome equivalents per milliliter; 1 MEq/mL = 1 
million copies/mL
mg
Milligram
mL
Milliliter
Na+
Sodium
nM
Nanomolar
NR
Non-responder
Nucleos[t]ide
Nucleoside and Nucleotide
PCR
Polymerase Chain Reaction
PDR
Protocol Defined Response
PID
Subject/Patient Identification Number
pg/mL
Picograms per milliliter
PD
Pharmacodynamic
PK
Pharmacokinetic
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Term
Definition
PLB
Placebo
PO
By mouth
SAE
Serious adverse event
SD
Standard Deviation
SmPC
Summary of Product Characteristics
TDF
Tenofovir
ULN
Upper Limit of Normal
USPI
United States Product Insert
mol
Micromoles
vs
Versus
WOCBP
Women of childbearing potential
Wt
Weight
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APPENDIX 1
ADDITIONAL ETHICAL CONSIDERATIONS
1
INFORMED CONSENT PROCEDURES
BMS will provide the investigator with an appropriate (ie, 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.
The consent form must also include a statement that BMS and regulatory authorities have 
direct access to subject records. Prior to the beginning of the study, the investigator must 
have the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects.
The investigator must provide the subject, or, in those situations where consent cannot be 
given by subjects, their legally acceptable representative with a copy of the consent form 
and written information about the study in the language in which the subject is most 
proficient. The language must be non-technical and easily understood. The investigator 
should allow time necessary for subject or subject's legally acceptable representative to 
inquire about the details of the study, then informed consent must be signed and 
personally dated by the subject or the subject's legally acceptable representative and by 
the person who conducted the informed consent discussion. The subject or legally 
acceptable representative should receive a copy of the signed informed consent and any 
other written information provided to study subjects prior to subject's participation in the
study.
1.1
Subjects Unable to Give Written Informed Consent
1.1.1
Minors
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. (In the event that 
the parents or legal guardians are unable to read, then an impartial witness should be 
present during the entire informed consent discussion). Whenever feasible, minors who 
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are judged to be of an age of reason must also give their written assent by signing and 
dating the completed informed consent. All local laws, rules and regulations regarding 
informed consent of minors must be followed.
1.1.2
Subjects Experiencing Acute Events or Emergencies
A legally acceptable representative or legal guardian must provide informed consent 
when consent of the subject is not possible prior to clinical study participation, eg, for 
subjects experiencing an acute medical event such as myocardial infarction or stroke. 
Informed consent of the subject must additionally be obtained if they become capable of 
making and communicating their informed consent during the clinical study. All local 
laws, rules and regulations regarding informed consent of adult subjects incapable of 
giving informed consent must be followed.
1.1.3
Mentally Impaired or Incapacitated Subjects
Investigators (or whoever required by local regulations) should determine whether or not 
a mentally impaired or incapacitated subject is capable of giving informed consent and 
should sign a statement to that effect. If the subject is deemed mentally competent to give 
informed consent, the investigator should follow standard procedures. If the subject is 
deemed not to be mentally competent to give informed consent, a fully informed legal 
guardian or legally acceptable representative can be asked to give consent for, or on 
behalf of, the subject. All local laws, rules and regulations regarding informed consent of 
mentally impaired or incapacitated subjects must be followed.
Patients who are involuntarily hospitalized because of mental illness must not be enrolled 
in clinical studies
1.1.4
Other Circumstances
Subjects who are imprisoned or involuntarily detained for treatment of either a 
psychiatric or physical (eg, infectious disease) illness must not be enrolled in clinical
studies. 
In circumstances where a subject’s only access to treatment is through enrollment in a 
clinical study, eg, for subjects in developing countries with limited resources or for 
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subjects with no marketed treatment options, the investigator must take special care to 
explain the potential risks and benefits associated with the study and ensure that the 
subject is giving informed consent.
When a subject may be in a dependent relationship with the investigator, a well-informed 
physician who is not engaged in the clinical study and is completely independent of the 
relationship between the subject and investigator should obtain the subject’s informed 
consent.
1.1.5
Illiterate Subjects
If the subject, or, in those situations where consent cannot be given by the subject, their
legally acceptable representative is unable to read, a reliable and independent witness 
should be present during the entire informed consent discussion. The choice of the 
witness must not breach the subject’s rights to confidentiality. A reliable independent 
witness is defined as one not affiliated with the institution or engaged in the investigation. 
A family member or acquaintance is an appropriate independent witness. After the 
subject or legally acceptable representative orally consents and has signed, if capable, the 
witness should sign and personally date the consent form attesting that the information is 
accurate and that the subject, or, in those situations where consent cannot be given by 
subjects, their legally acceptable representative has fully understood the content of the 
informed consent agreement and is giving true informed consent.  
1.2
Update of Informed Consent
The informed consent and any other information provided to subjects, or, in those 
situations where consent cannot be given by subjects, the subject's legally acceptable 
representative, should be revised whenever important new information becomes available 
that is relevant to the subject's consent, and should receive IRB/IEC approval/favorable 
opinion prior to use. The investigator, or a person designated by the investigator should 
fully inform the subject or the subject's legally acceptable representative of all pertinent 
aspects of the study and of any new information relevant to the subject's willingness to 
continue participation in the study. This communication should be documented. 
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During a subject's participation in the study, any updates to the consent form and any 
updates to the written information will be provided to the subject.
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APPENDIX 2
DAIDS TOXICITY GRADES
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SAP_000.pdf: 
Official Title of Study: 
A COMPARATIVE STUDY OF THE ANTIVIRAL EFFICACY AND SAFETY OF 
ENTECAVIR (ETV) VERSUS PLACEBO IN PEDIATRIC SUBJECTS WITH CHRONIC 
HEPATITIS B VIRUS (HBV) INFECTION WHO ARE HBEAG-POSITIVE 
 
NCT Number: NCT01079806 
Document Date (Date in which document was last revised): December 5, 2016 


STATISTICAL ANALYSIS PLAN FOR CSR
A COMPARATIVE STUDY OF THE ANTIVIRAL EFFICACY AND SAFETY OF 
ENTECAVIR (ETV) VERSUS PLACEBO IN PEDIATRIC SUBJECTS WITH CHRONIC 
HEPATITIS B VIRUS (HBV) INFECTION WHO ARE HBEAG-POSITIVE
PROTOCOL AI463-189
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Statistical Analysis Plan
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REVSION HISTORY
Version 
Number
Author(s)
Description
1.0
A. Thiry
Original version
2.0
A. Thiry
See SAP Amendment 1.
3.0
A. Thiry
See SAP Amendment 2.
4.0
A. Thiry
See SAP Amendment 3.
5.0
A. Thiry
See SAP Amendment 4.
6.0
A. Thiry
See SAP Amendment 5.
7.0
A. Thiry
See SAP Amendment 6.
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CSR ...........................................................................1
REVSION HISTORY .................................................................................................................2
TABLE OF CONTENTS............................................................................................................3
LIST OF TABLES......................................................................................................................5
2
STUDY DESCRIPTION ..........................................................................................7
2.1
Study Design ............................................................................................................7
2.2
Treatment Assignment..............................................................................................8
2.3
Blinding and Unblinding...........................................................................................8
2.4
Protocol Amendments...............................................................................................9
2.4.1
Amendment 1 (Country Specific - Brazil Only)..........................................................9
2.4.2
Amendment 2............................................................................................................9
2.4.3
Amendment 3 (Site Specific - Site -038).....................................................................9
2.4.4
Amendment 4 (Country Specific - India only)............................................................9
2.4.5
Amendment 5..........................................................................................................10
2.5
Data Monitoring Committee ...................................................................................10
3
OBJECTIVES ........................................................................................................10
3.1
Primary...................................................................................................................10
3.2
Secondary...............................................................................................................10
4
ENDPOINTS..........................................................................................................10
4.1
Primary Endpoint....................................................................................................10
4.2
Key Secondary Endpoints.......................................................................................11
4.3
Other Secondary Endpoints ....................................................................................11
4.5
PK Endpoints..........................................................................................................12
5
SAMPLE SIZE AND POWER...............................................................................12
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................13
6.1
Study Periods..........................................................................................................13
6.2
Treatment Regimens...............................................................................................13
6.3
Populations for Analyses ........................................................................................14
7
STATISTICAL ANALYSES..................................................................................15
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7.1
General Methods ....................................................................................................15
7.2
Study Conduct........................................................................................................16
7.3
Study Population ....................................................................................................16
7.3.1
Pre-Randomization Subject Status and Accrual Pattern..........................................16
7.3.2
Accounting for Patient Identification Number (PID) Assignments...........................16
7.3.3
Subject Disposition.................................................................................................17
7.3.4
Demographic and Other Baseline Characteristics ..................................................17
7.4
Extent of Exposure .................................................................................................18
7.4.1
Study Therapy.........................................................................................................18
7.4.2
Concomitant Medications.......................................................................................19
7.5
Efficacy..................................................................................................................19
7.5.1
Primary Efficacy Endpoint......................................................................................20
7.5.2
Key Secondary Endpoints .......................................................................................21
7.5.2.1
HBV DNA Below 50 IU/mL ....................................................................................21
7.5.2.2
ALT Normalization .................................................................................................21
7.5.2.3
HBV DNA Below LOQ............................................................................................21
7.5.2.4
HBeAg Seroconversion...........................................................................................21
7.5.2.5
Sustained HBeAg Seroconversion During Off-Treatment Follow-up .......................21
7.5.3
Other Year 1 Efficacy .............................................................................................22
7.5.3.1
Response Rates.......................................................................................................22
7.5.3.2
HBV DNA Reduction from Baseline........................................................................22
7.5.4
Year 2 Efficacy .......................................................................................................22
7.5.5
Year 3 Efficacy .......................................................................................................23
7.5.6
Year 4 Efficacy .......................................................................................................23
7.5.7
All ETV On-Treatment Efficacy ..............................................................................24
7.5.8
Efficacy During Off-Treatment Follow-up ..............................................................24
7.5.9
Histology................................................................................................................25
7.5.10
Genotypic Resistance..............................................................................................25
7.6
Safety.....................................................................................................................25
7.6.1
Deaths ....................................................................................................................26
7.6.2
Other Serious Adverse Events.................................................................................26
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................27
7.6.4
Other Significant Adverse Events............................................................................27
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7.6.4.1
Events of HBV Disease Progression .......................................................................27
7.6.4.2
Neoplasms and Pre-Malignant Lesions...................................................................27
7.6.5
Overall Adverse Events...........................................................................................28
7.6.6
Clinical Laboratory Evaluations.............................................................................29
7.6.6.1
Laboratory Abnormalities.......................................................................................29
7.6.6.2
Laboratory Tests over Time ....................................................................................30
7.6.7
Growth/Development Assessment ...........................................................................31
7.6.8
Results by Subgroups..............................................................................................32
7.7
Pharmacokinetic (PK) Analysis ..............................................................................32
8
CONVENTIONS....................................................................................................32
8.1
Missing, Unknown or Partial Dates.........................................................................32
8.2
Unknown Study Medication End Dates...................................................................32
8.3
Partial or Missing Safety Information .....................................................................33
8.4
Visit Week Windows..............................................................................................33
8.5
Baseline and EOD Measurements...........................................................................34
8.6
HBV DNA Below LOQ or LLD .............................................................................35
8.7
Multiple Measurements ..........................................................................................35
8.8
Indeterminate Serology Results...............................................................................35
8.9
Derived Dates.........................................................................................................35
8.10
Collapsed AEs and Exposure-Adjusted Incidence Rates .........................................37
8.11
Laboratory Test Conversion....................................................................................37
9
CONTENT OF REPORTS .....................................................................................38
APPENDIX 1
RELEVANT PROTOCOL DEVIATIONS.............................................40
LIST OF TABLES
Table 7.6.4.1-1:
Events of HBV Disease Progression.......................................................27
Table 7.6.4.2-1:
Selected Pre-Malignant Lesions..............................................................28
Table 8.4-1:
Visit Week Windows..............................................................................33
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2
STUDY DESCRIPTION
2.1
Study Design
This is a comparative, randomized, double-blinded, placebo-control, multicenter study, assessing 
the efficacy and safety of ETV in pediatric subjects with chronic HBV infection who are 
HBeAg-positive and nucleos[t]ide naive (< 12 weeks of prior therapy with any nucleos[t]ide 
antiviral agent with activity against hepatitis B virus). Chronic HBV-infected children and 
adolescents from 2 to < 18 years of age will be enrolled. Approximately 180 subjects will be 
randomized 2:1 to ETV or placebo (PBO) for a maximum of 96 weeks of blinded therapy, with 
the primary endpoint at Week 48 for the first 123 randomized subjects (the Primary Cohort). The 
randomization will be stratified by age group (≥ 2 to ≤ 6, > 6 to ≤ 12, > 12 to < 18 years). To 
ensure adequate representation, the target enrollment will be 30 subjects for each age group, with 
a minimum requirement of 18 subjects. At Week 52, an assessment of HBeAg seroconversion 
shall be performed based on Week 48 serology results. At the Week 52 assessment, all subjects 
who achieve HBeAg seroconversion will remain on blinded therapy through Week 96; subjects 
without HBeAg seroconversion will be switched to open-label ETV. Thereafter, assessment of 
HBeAg seroconversion shall be conducted at study Weeks 100 and 148 during the open label 
treatment. Study subjects who achieve HBeAg seroconversion during open label ETV at the 
respective assessment time points shall receive up to an additional 48 weeks of study treatment 
for consolidation (extended treatment to strengthen study drug effects). Open-label ETV may 
therefore be continued up to Week 144 in ETV randomized subjects and Week 192 for placebo 
randomized subjects. All randomized study subjects who do not achieve HBeAg seroconversion 
will receive a maximum of 96 weeks of study ETV therapy.
After completing the blinded treatment or the open-label phase, all subjects will be followed in 
an observational long-term follow up phase until they complete a total of 5 years of study 
participation from the start of blinded treatment.
The total duration of the study will be 264 weeks (5 years); the end of the study is defined as the 
date of the last follow-up visit. Study visits will occur at screening, Baseline, Weeks 4, 8, 12, and 
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then every 12 weeks during study treatment. Additional ‘On Treatment’ visits to modify or 
discontinue study drug based on HBeAg assessments will occur at Weeks 52, 100, and 148, if 
needed. At selected sites, a subset of up to 9 treated subjects in each age cohort will have 4 
plasma specimens collected for semi-intense pharmacokinetic assessments during a single visit 
between study Day 14 and Week 4. Once in the observational long-term follow-up phase, study 
visits will occur at Weeks 6, 12, and then every 12 weeks until completion of a total of 264 
weeks of “on-study follow-up”. 
2.2
Treatment Assignment
Eligible subjects will be randomized (2:1) to either ETV or PBO.
At the start of the screening period, the investigative staff will call the Randomization Center 
designated by the sponsor to register the subject and to obtain a subject number or patient 
identification number (PID). For subjects who meet the protocol defined eligibility criteria 
during screening, the investigative staff will again call the Randomization Center for the subject 
to be randomized into a blinded treatment assignment based on the subject’s age at the time of 
randomization. The subject will be assigned bottle numbers according to the randomization 
scheme. For each study visit, the site will need to call the Randomization Center for container 
assignments. 
A randomized block design stratified by age group will be used. The target enrollment will be 30 
subjects for each age group with a minimum requirement of 18 subjects to support the primary 
analysis for Primary Cohort.
2.3
Blinding and Unblinding
The subject, investigator and Bristol-Myers Squibb personnel involved in the conduct of the 
study will be blinded to treatment assignment. Designated staff of Bristol-Myers Squibb 
pharmacokinetics and modeling departments, as well as personnel from the central and analytical 
laboratories, will be unblinded to treatment assignments in order to minimize unnecessary 
analysis of samples from subjects receiving placebo.
A pharmacist at Bristol-Myers Squibb not involved in the study design, assessment, or analyses 
will be given access to the treatment codes to permit efficient drug distribution. The treatment 
codes will be maintained in a password-protected file which cannot be accessed by the study 
personnel or subjects. 
HBV DNA results from Day 1 through Week 96 will be blinded to the investigator. Any subject 
who has achieved HBeAg seroconversion by Week 96 shall remain blinded to their randomized 
treatment assignment except in the event of a change in clinical status for which knowledge of 
the randomized arm is critical to subject management. Subjects who have not yet achieved 
HBeAg seroconversion by Week 96 will be unblinded on an individual basis, as needed in order 
to determine their further management. Refer to Protocol Section 5.4 for more details on blinding 
and unblinding.
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2.4
Protocol Amendments
2.4.1
Amendment 1 (Country Specific - Brazil Only)
The purpose of this amendment is to incorporate changes requested by the Brazilian Research 
Ethics Commission (CONEP) regarding post study access to therapy. This country-specific 
amendment applies to all subjects enrolled in Brazil. 
2.4.2
Amendment 2 

The purpose of this amendment is to make the following changes to the protocol:

Augment the number of randomized subjects from 123 to 180 and increase the estimated 
number of participating study centers.

Change the entry ALT entry criteria from 1.3 to 1.5 x upper limit of normal (ULN), 
increase the minimum time span between the 2 pre-randomization ALT measurements from 
4 to 8 weeks, and exclude other reasons for elevated ALT.

Specify the early unblinding and mechanism for doing so if subjects demonstrate significant 
worsening of HBV clinical symptoms or increases in ALT. The role of the DMC in 
safeguarding subjects is clarified.

Specify additional analyses that will be conducted as key secondary and exploratory 
endpoints. 

Modify the blood volume collected at some visits due to minimum fill volume requirements 
of available specimen collection tubes.

Summarize the plan for PK/PD analyses that will integrate Studies AI463-028 and AI463-
189.

Add Tanner Stage assessment and analysis.
2.4.3
Amendment 3 (Site Specific - Site -038)
This amendment has been required by the Ethics Committee (EC) at Rambam Medical Center 
and it documents the standard of care practices that will take place for all patients prior to 
possible study enrollment at this site. Per the site’s usual standard of care, a liver biopsy will be 
performed for any patient with a pre-screening ALT > 3 x ULN. Based on the histological 
findings, those patients for whom possible randomization to PBO is judged not to be in their best 
interest, will not be consented and enrolled in study AI463-189. This site-specific amendment 
applies to the pre-enrollment practices at site -038 as requested by their EC. 
2.4.4
Amendment 4 (Country Specific - India only)
The purpose of this amendment is to restrict the age of study participants enrolled in this study at 
sites in India, as required by the Directorate General of Health Services in the Office of Drugs 
Controller General (India).  This amendment will document the modified inclusion criteria for 
India sites; restricting enrollment to male and female adolescents aged > 12 to < 18 years (oldest 
age group). 
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Sites in other participating countries will enroll subjects 2 to < 18 years of age. Therefore, the 
description of the age groups written in other sections of the protocol will not be modified in this 
amendment.
2.4.5
Amendment 5
The purpose of this amendment is to address the potential safety issues associated with extreme 
elevations of ALT due to acute exacerbation of CHB by providing emergency access to rescue 
open-label ETV for subjects who cannot access acceptable alternative anti-HBV therapy.
2.5
Data Monitoring Committee
There will be a data monitoring committee (DMC) for this study. The DMC shall have access to
unblinded data on at least an annual basis, including but not limited to following: the frequency 
and spectrum of serious adverse events; Grades 3 to 4 laboratory abnormalities; occurrence of 
malignancies; and other select adverse events of interest. The DMC shall act as an advisor to the 
sponsor and have responsibility for safeguarding the subjects’ interests. The DMC shall bring 
any safety concerns to the attention of the sponsor so that the sponsor can review the data and 
prepare appropriate communications to the Regulatory Authorities. A separate charter describes
the membership and activities of the DMC.
3
OBJECTIVES
3.1
Primary
To compare the proportion of subjects in each treatment group who achieve a combination of 
HBV DNA suppression and HBeAg seroconversion (undetectable HBeAg AND detectable anti-
HBe antibodies) at Week 48.
3.2
Secondary

Assess the serologic response rates (defined as HBsAg loss and/or seroconversion; and 
HBeAg loss and/or seroconversion) including durability of response off treatment; 

Assess the virological response rates;

Assess the biochemical response rates;

Assess ETV resistance rates;

Evaluate the long-term safety of ETV use in pediatric patients.
4
ENDPOINTS
4.1
Primary Endpoint 

The proportion of subjects who achieve: 1) HBV DNA < 50 IU/mL (approximately 300 
copies/mL) using the Roche COBASTaqMan HBV Test for use with the High Pure System 
(HPS) assay; and 2) HBeAg seroconversion (undetectable HBeAg AND detectable anti-HBe 
antibodies) at Week 48 of study treatment.
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4.2
Key Secondary Endpoints

Proportion of subjects with HBV DNA < 50 IU/mL using the Roche COBASTaqMan 
HBV Test for use with the High Pure System (HPS) assay at Week 48;

Proportion of subjects with serum ALT 1 ULN at Week 48;

Proportion of subjects with HBV DNA < limit of quantification (LOQ; 29 IU/mL) using the 
Roche COBASTaqMan HBV Test for use with the High Pure System (HPS) assay at Week 
48;

Proportion of subjects with HBeAg seroconversion (undetectable HBeAg and presence of 
anti-HBe antibodies) at Week 48;

Proportion of subjects who achieved sustained HBeAg seroconversion during off-treatment 
follow-up among subjects who achieved HBe seroconversion (undetectable HBeAg and 
presence of anti-HBe antibodies) at end of treatment.
4.3
Other Secondary Endpoints

The number and percent of subjects with adverse events (including palatability issues), 
serious adverse events (SAEs), discontinuations due to adverse events, and HBV disease 
progression through Week 48;

Proportions of subjects with HBeAg loss at Weeks 48 and 96;

Proportion of subjects with HBeAg seroconversion at Week 96;

Proportion of subjects who maintained HBeAg seroconversion at Week 96 (end of blinded
therapy) among subjects who achieved HBeAg seroconversion at Week 48;

Histological analysis among subjects with available liver biopsy.
 
 
 
 
 
 
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
 
 
 
 
4.5
PK Endpoints
PK parameters include Cmin, Cmax and Tmax.
5
SAMPLE SIZE AND POWER
One hundred and twenty-three (123) subjects (randomized 2:1 to ETV vs placebo) in this study 
provide 90% power to show superiority of ETV versus PBO assuming a response rate for the 
primary endpoint HBV DNA by PCR < 50 IU/mL (approximately 300 copies/mL) and HBeAg 
seroconversion of 20% for ETV and 1% for PBO. A two-sided significance level of 0.05 is used. 
Subjects who either discontinue from study treatment prior to Week 48 or have having missing 
Week 48 HBV DNA or HBeAg serology measurement are considered as failures at 
Week 48 (Non-Completer = Failure). The efficacy estimate for ETV is derived from an analysis 
of the identical endpoint (HBV DNA by PCR < 300 copies/mL and HBeAg seroconversion) in 
the pivotal Phase 3 study of HBeAg-positive subjects, (AI463022). The efficacy estimate for 
PBO is derived from evidence in the literature which shows that whereas spontaneous 
seroconversion occurs at a relatively high rate in children, viral replication remains detectable 
using sensitive PCR assays. The results of the Gilead Sciences’ pediatric CHB study (GS 518) 
support this estimate; 3 of 57 placebo treated subjects (5.3%) achieved HBeAg seroconversion, 
but only 1 of 58 subjects (1.7%) achieved HBV DNA < 2.23 log10 copies/mL at Week 48. 
This sample size also fulfills the requirement that the ETV integrated pediatric safety database 
has at least 100 pediatric subjects who have received ETV for at least 48 weeks; this database 
will be comprised of subjects currently enrolled in study AI463-028 and from this study (AI463-
189). 
Currently 24 nucleoside naive subjects are enrolled in AI463-028; all 24 would have had 48 
weeks of safety data collection by the time study AI463-189 reaches Week 48.
Based on the original planning for study AI463-189, it is estimated that 175 subjects will be 
enrolled to have approximately 123 subjects randomized (approximately 30% screen failure 
rate). Randomization is 2:1 (ETV 82: PBO 41); assuming a 10% drop out rate per year and even 
enrollment for 2 calendar years, approximately 72 ETV randomized subjects will have 48 weeks 
of safety data by study Week 144. This brings the number of subjects that will be included in the 
integrated safety database at the end of study Week 144 to approximately 96 subjects.
Additional safety data will be contributed by PBO randomized subjects switching to open label 
ETV at study Week 52. Because it is expected to take 2 calendar years to randomize 123 subjects 
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and assuming steady enrollment over that time frame, the last PBO randomized subject will be 
completing Week 48 by study week 144. Assuming a 10% drop out per year, 18 of the 20 
subjects randomized to PBO during the first calendar year will reach Week 48 by study Week 
96; 16 of these 18 will be switched to open label ETV (assuming a 10% HBeAg seroconversion 
rate on PBO). With a 10% drop out rate per year, 14 of these 16 will be completing 48 weeks of 
open label ETV by study Week 144 and will be added to the integrated safety database. This will 
bring the number of subjects in the integrated safety database with at least 48 weeks of ETV 
exposure after two years of enrollment to approximately 110 subjects. 
While the analysis of the primary endpoint is based on a randomized sample size of 123, the size 
of the overall study population has been augmented to 180 randomized subjects in order to meet 
the requirement of a health authority. Therefore the final safety dataset as described in the 
previous 2 paragraphs will also be augmented. The accrual of the first 123 randomized subjects 
is expected to take 2 years. Thereafter, the enrollment will remain open until 180 subjects are 
randomized. Additional re-analyses will be performed on the augmented population.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
Study periods for efficacy and safety analyses are defined as follows:

Pre-treatment period begins at the first visit until initiation of study therapy.

On-treatment period begins after the first day of study therapy and ends at the last dose of 
study therapy plus 5 days. 

ETV treatment period begins after the first day of active ETV and ends at the last dose of 
active ETV plus 5 days.

Off-treatment follow-up period begins on the last dose of study therapy plus 6 days and 
ends at the start of alternative anti-HBV therapy minus 1 day.

Long-term follow-up period begins on the last dose of study therapy plus 6 days until the 
end of the study.

Alternative ETV follow-up period begins on the later of the last dose of study therapy plus 
6 days and the start of alternative ETV therapy, until the end of the study.
Note that rescue open-label ETV is considered alternative anti-HBV therapy. See Section 8.9 for 
additional conventions.
6.2
Treatment Regimens
Treatment regimens are described in Protocol Section 5.1 as ETV treated subjects (ETV) given a 
starting dose of 0.015 mg/kg up to a maximum dose of 0.5 mg and PBO subjects.
Treatment regimens are defined as follows:
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
As-randomized refers to the treatment regimen assigned at randomization. Accrual and 
efficacy results are presented as-randomized.

As-treated refers to the actual treatment regimen received. Subjects who receive the incorrect 
study therapy for the entire period of treatment are grouped according to the treatment 
regimen associated with the incorrect study therapy. Otherwise, subjects are grouped 
according to their randomized treatment regimen. Subjects who never receive study therapy 
have missing as-treated treatment regimen. Results for subject disposition, demographics, 
baseline characteristics, safety, and PK parameters are presented as-treated. Furthermore, 
important safety events that occur while a subject is on an incorrect treatment regimen are 
specifically discussed in the text of the Clinical Study Report.
If a subject receives at least 1 dose of drug in the randomized regimen, then the as-randomized 
treatment regimen is equal to the as-treated treatment regimen. If ≥ 5% of treated subjects have 
as-randomized regimen different than as-treated regimen, summaries are presented by both 
treatment regimens for select endpoints (see Section 7).
6.3
Populations for Analyses

Enrolled subjects are those who sign an informed consent form and are assigned a Patient 
Identification number (PID).  This cohort is used to assess subject disposition, deaths and 
serious adverse events during the pre-treatment period.

Randomized subjects are enrolled subjects who receive a treatment assignment from the 
central randomization center. This cohort is used to assess subject status and accrual.

Treated subjects are randomized subjects who receive at least 1 dose of study therapy. This 
cohort is used to assess all data domains.
o
Primary cohort is defined as at least the first 123 subjects randomized and treated. The 
Primary Cohort is used for the primary analyses.

Off-treatment follow-up subjects are treated subjects who discontinue study therapy and 
have at least 1 of the following assessments during the off-treatment follow-up period (see 
Section 6.1): death date if it exists; adverse event onset date; HBV related diagnosis date;
vital signs date; physical measurement date; physical exam date; neurologic exam date; 
laboratory test date (safety, pregnancy, serology and virology); liver biopsy date; Tanner 
staging date. This cohort is used to assess safety during the off-treatment follow-up period.

Long-term follow-up subjects are treated subjects who discontinue study therapy and have 
at least 1 of the following assessments during the long-term follow-up period (see Section 
6.1): death date if it exists; adverse event onset date; HBV related diagnosis date; vital signs 
date; physical measurement date; physical exam date; neurologic exam date; laboratory test 
date (safety, pregnancy, serology and virology); liver biopsy date; Tanner staging date. This 
cohort is used to assess safety during the long-term follow-up period.

Alternative ETV follow-up subjects are treated subjects who discontinue study therapy, 
receive at least 1 dose of alternative ETV therapy, and have at least 1 of the following 
assessments during the alternative ETV follow-up period (see Section 6.1): death date if it 
exists; adverse event onset date; HBV related diagnosis date; vital signs date; physical 
measurement date; physical exam date; neurologic exam date; laboratory test date (safety, 
pregnancy, serology and virology); liver biopsy date; Tanner staging date. This cohort is used 
to assess safety during the alternative ETV follow-up period.
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
Year 2 Efficacy Cohort is treated subjects grouped as-randomized and according to 
observed Week 48 seroconversion status: ETV, PBO, ETV S48, PBO S48, ETV NS48 and 
PBO NS48 (S = seroconverter; NS = non-seroconverter). All treated subjects are included in 
ETV and PBO.
o
Year 2 Primary Efficacy Cohort is treated subjects in both Primary and Year 2 Efficacy 
Cohorts.

Year 3 Efficacy Cohort is observed Week 48 non-seroconverters grouped as-randomized 
according to observed Week 96 seroconversion status: ETV S96, ETV NS96, PBO S96 and 
PBO NS96.

Year 4 Efficacy Cohort is PBO-randomized observed non-seroconverters at both Weeks 48 
and 96 who seroconverted at Week 144.

All ETV Efficacy Cohort is treated as-randomized ETV subjects and PBO-randomized 
subjects who received open-label ETV.

Post-Year 1 Efficacy Cohort is treated subjects grouped as-randomized: ETV, PBO, PBO 
subjects who only received blinded PBO (PBO BL), PBO subjects who received open-label 
ETV (PBO OL), and All ETV (ETV and PBO OL combined; see previous bullet). 

Year 2 Safety Cohort is treated subjects grouped as-treated: ETV, PBO subjects who only 
received blinded PBO (PBO BL), and PBO subjects who received open-label ETV (PBO 
OL). In addition, subjects must have received open-label ETV or > 54 weeks of study 
therapy (the upper bound of the Week 48 visit window; see Sections 7.4.1 and 8.4).

All ETV Safety Cohort is as-treated ETV subjects and as-treated PBO subjects who 
received open-label ETV.  

Post-Year 1 Safety Cohort is treated subjects grouped as-treated: ETV, PBO, PBO subjects 
who only received blinded PBO (PBO BL), PBO subjects who received open-label ETV 
(PBO OL), and All ETV (ETV and PBO OL combined; see previous bullet). 
7
STATISTICAL ANALYSES
7.1
General Methods
All analyses (efficacy, safety and PK) are presented by treatment regimen, ie, ETV vs PBO,
based on the appropriate cohort and dataset defined in the earlier section. For Week 48 analysis, 
all the endpoints are to be cut off through Week 48, unless specified otherwise.
The PK analyses are described in Section 7.7. The methods described below are used to analyze 
safety and efficacy data.
Categorical variables are summarized either with counts and percents or with proportions 
(number with event divided by number evaluable) and percents, depending on the endpoint.
Continuous variables are summarized with univariate statistics (eg, n, mean, median, standard 
deviation, standard error, quartiles, minimum, and maximum).
Longitudinal analyses of efficacy and safety parameters use pre-defined visit week windows (see 
Section 8.4). Windows around planned measurement times are constructed based on the 
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midpoint between planned measurement visits unless specified otherwise. Data are summarized 
at each scheduled visit through the analysis week. 
Analyses of HBV DNA use values only from the central laboratory from the Roche COBAS
TaqMan HBV Test with limit of quantitation (LOQ) of 29 IU/mL and limit of detection (LLD) 
of 10 IU/mL.
Analyses of laboratory tests and serology use values from the central or local laboratory.
Laboratory parameters are summarized using US standard values and units. Refer to Section 8.11
for conversion of select laboratory test values from the Abbott Architect system to the Roche 
Diagnostics Hitachi Modular system.
Formats of tables, listings and graphs are described in the Data Presentation Plan (DPP).
7.2
Study Conduct
Relevant protocol deviations are summarized by treatment regimen for treated subjects. Relevant 
protocol deviations are those that could potentially affect the interpretability of the study results. 
A list of programmable relevant protocol deviations is provided in Appendix 1, including:

Eligibility deviations (based on deviations of subject inclusion and exclusion criteria from 
Protocol Sections 4.2.1 and 4.2.2 which can be programmed from the database) during the 
pre-treatment period. If multiple measurements are available, a subject is considered to have 
a deviation only if all measurements fail the inclusion or exclusion criterion, except for 
pregnancy. 

Deviations during the on-treatment period (eg, incorrect dosing received).

Deviations related to PK data.
7.3
Study Population
7.3.1
Pre-Randomization Subject Status and Accrual Pattern
Pre-randomization subject status is summarized for enrolled subjects. This presents the number 
of subjects enrolled, randomized and not randomized. Reasons for not randomized are also 
included (eg, AE, death, lost to follow-up).
The numbers of subjects enrolled and randomized are summarized by site for each country.
Enrollment by age group is summarized analogously. Age groups are: in utero; preterm newborn 
(gestational age < 37 weeks); newborns (0 to 27 days); infants and toddlers (28 days to 23 
months); children (2 to 11 years); adolescents (12 to 17 years); adults (18 to 64 years); adults (65 
to 84 years); adults (≥ 85 years).
7.3.2
Accounting for Patient Identification Number (PID) Assignments
PIDs assigned by the RIVRS randomization system at enrollment are listed in an Appendix to 
the study report.  
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7.3.3
Subject Disposition
Summaries are presented by as-treated treatment regimen unless specified otherwise.
Subject disposition from the start to end of treatment is based on the end of treatment subject 
status CRF, and varies according to the analysis (see Section 9): the number of subjects treated, 
discontinued before Week 48, discontinued at Week 48 or before Week 96, discontinued at or 
after Week 96, continuing treatment and completed treatment. Reasons for discontinuation are 
also included (eg, AE, lost to follow-up). The lower bounds of the on-treatment Week 48 and 96
visit windows are used to define the cuts on discontinuation (see Section 8.4).
Subject disposition from start to end of treatment is also summarized analogously by age 
randomization strata for each treatment regimen.
If ≥ 5% of treated subjects have as-randomized regimen different than as-treated regimen, then 
subject disposition from the start to end of treatment is summarized analogously by as-
randomized treatment regimen for treated subjects.
Subject disposition from the start to end of long-term follow-up is based on the end of study 
subject status CRF, and is summarized for the Post-Year 1 Safety Cohort. The summary presents 
the number of subjects who entered long-term follow-up, did not complete long-term follow-up, 
completed long-term follow-up, continuing in long-term follow-up, and did not enter long-term 
follow-up. Reasons for not completing are also included. For subjects who entered long-term 
follow-up but indicated they were not continuing in the study on the end of treatment subject 
status CRF, the reason for not completing is set to the reason for not continuing.
7.3.4
Demographic and Other Baseline Characteristics
Summaries are presented by as-treated treatment regimen for treated subjects unless specified 
otherwise. Summaries identify the number and percent of subjects with not reported (i.e., 
missing) measurements, unless specified otherwise. 
If ≥ 5% of treated subjects have as-randomized regimen different than as-treated regimen, then 
demographics and baseline disease HBV characteristics are summarized analogously by as-
randomized treatment regimen for treated subjects.
Demographic and other baseline characteristics are summarized by treatment regimen and 
overall for treated subjects:

Demographics: age (years), age randomization strata (≥ 2 to ≤ 6, > 6 to ≤ 12, > 12 to < 18 
years), gender, race, ethnicity, geographic region (Asia, Europe, North America, South 
America), country

HBV disease characteristics: HBV DNA (log10 IU/mL), Hepatitis B Surface Antigen
(positive, negative, indeterminate), Hepatitis B E Antigen (positive, negative, indeterminate), 
Hepatitis B E Antibody (positive, negative, indeterminate), HBV genotype (e.g., A, B, C, D, 
E, indeterminate), INR, albumin (g/dL), ALT (U/L), ALT categories (2 x ULN, > 2 x 
ULN), total bilirubin (mg/dL), creatinine (mg/dL), glomerular filtration rate (< 50, 50 - 75, > 
75 mL/min/1.73 m2) estimated with Schwartz’s formula, route of transmission (mother-to-
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child transmission; household/close contact exposure; transfusion; sexual contact; IV drug 
use; other)

Physical measurements: height (cm), height for age Z score (HAZ), height for age percentile 
(HAP), weight (kg), weight for age Z score (WAZ), weight for age percentile (WAP), body 
mass index (BMI; kg/m2), BMI for age Z score (BMIAZ), BMI for age percentile (BMIAP)
(see Section 7.6.7)

Laboratory tests (see Section 7.6.6.1)
o
Hematology by toxicity grade (ie, normal, Grade 1, 2, 3, 4)
o
Liver function tests by toxicity grade 
o
Pancreatic enzymes by toxicity grade 
o
Renal function tests by toxicity grade   
o
Electrolytes (low and high) by toxicity grade
o
Glucose categories regardless of fasting status

Medical history by body system

Prior medications, defined as non-study medications taken before the first dose of study 
therapy.  
Demographics and baseline disease HBV characteristics are also summarized analogously for the 
following: Primary Cohort; All ETV Safety Cohort; by age randomization strata for each 
treatment regimen.
For the All ETV Safety Cohort, age and HBV disease characteristics are summarized at ETV 
baseline. Age at ETV baseline is defined as (first dose date of active ETV - birth date + 
1)/365.25.
See Sections 8.5 and 8.9 for additional conventions.
7.4
Extent of Exposure
Extent of exposure is presented by as-treated treatment regimen for treated subjects to support 
safety.
7.4.1
Study Therapy
Extent of exposure to study therapy is summarized for blinded therapy (ETV active or PBO), 
open-label ETV, active ETV (blinded active ETV or open-label ETV), and all therapy (blinded 
therapy or open-label ETV) by treatment regimen as follows:

Time on therapy (weeks): (last dose date of drug - first dose date of drug + 1)/7. 

Cumulative dose: total amount (mg) of drug summed across dosing records. 

Average daily dose: cumulative dose divided by time on therapy.
Extent of exposure to study therapy is also summarized analogously for the following: Primary 
Cohort; All ETV Safety Cohort; by age randomization strata for each treatment regimen.
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Time on study therapy is also described by a Kaplan-Meier plot and life table. Discontinuations 
from study therapy are considered events in this analysis, and are identified by subjects with non-
missing last dose date of study therapy. For subjects who have not discontinued, time on study 
therapy is censored at the maximum of the last dose date of study drug (ETV blinded active or 
PBO, ETV open-label).
Time in long-term follow up is summarized by treatment regimen for long-term follow-up 
subjects in the Post-Year 1 Safety Cohort. Time in long-term follow-up (weeks) is defined as 
(last contact date - last dose date of study therapy)/7.
Time in off-treatment follow up is summarized by treatment regimen for off-treatment follow-up 
subjects in the Post-Year 1 Safety Cohort. Time in off-treatment follow-up (weeks) is defined as 
(minimum(last contact date, start date of alternative anti-HBV therapy - 1) - last dose date of 
study therapy)/7.
Dose interruptions of study therapy more than 3 days are summarized by treatment regimen.
Reasons for interruption are also identified.
See Section 8.9 for additional conventions.
7.4.2
Concomitant Medications
Concomitant medications are summarized by treatment regimen for the on-treatment and long-
term follow-up periods. Medications are presented alphabetically by anatomic class, therapeutic 
class and generic name using the WHO dictionary.
Concomitant medications on treatment are those taken any time on or after the first dose of study 
therapy through the day preceding the earlier of the last dose of study therapy or open-label 
therapy. These also include prior medications with ‘continuing’ stop dates.  
Concomitant medications during long-term follow-up are those taken on or after the day of last 
dose of study therapy. These also include on-treatment concomitant medications with 
‘continuing’ stop dates.  
Alternative anti-HBV medications are summarized separately for the long-term follow-up
period.
7.5
Efficacy
Efficacy endpoints are presented by as-randomized treatment regimen for treated subjects.
Binary efficacy endpoints are analyzed using 2 algorithms:

Non-Completer = Failure (NC = F): The numerator is based on subjects meeting the response 
criteria. The denominator is based on treated subjects. Subjects who have missing data at the 
analysis week are considered as failures.

Non-Completer = Missing (NC = M): The numerator is based on subjects meeting the 
response criteria. The denominator is based on subjects with data at the analysis week. 
Subjects who have missing data at the analysis week are excluded.
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Treatment regimens are compared using a difference in proportions (ETV - PBO), 95% 
confidence interval (CI) and p-value based on NC = F for the primary endpoint and key 
secondary endpoints. Analyses are stratified by age randomization strata (see Section 7.3.4). The 
proportions are computed within each stratum, and combined using a weighted average with 
weights proportional to stratum size (Cochran-Mantel-Haenszel [CMH] weighting). ETV will be 
considered superior to PBO if the p-value is < 0.05. CIs for differences in proportions are based 
on the stratified normal approximation to the binomial distribution with unpooled proportions 
used in the computation of the standard error of the difference. 
A two-stage testing procedure will be employed for testing the primary and key secondary 
endpoints using NC = F. In the first stage, the test for primary endpoint will be performed. 
Provided the test result of the primary endpoint is significant (p-value < 0.05), the second stage 
tests of the key secondary endpoints will be conducted. Because the tests for the key secondary 
endpoints will be conducted sequentially only if the test for the primary endpoint is successful, 
significance levels will not be adjusted for the first stage testing. All tests for treatment 
comparison will be two-sided at a significance level of 0.05.
For binary composite endpoints involving several components (eg, primary efficacy endpoint), 
only subjects who meet the response criteria for all components are considered to be responders 
for the composite endpoint. In addition, subjects who meet the response criteria for some 
components but are missing other components are considered to be missing the composite 
endpoint.
See also Sections 8.4 to 8.8 for additional conventions.
7.5.1
Primary Efficacy Endpoint
The primary efficacy endpoint is a composite endpoint defined as the proportion of treated 
subjects with HBV DNA < 50 IU/mL (approximately 300 copies/mL) and HBeAg 
seroconversion (HBeAg negative and HBeAb positive) at Week 48 on treatment. Response rates 
are presented by treatment regimen with a difference in proportions (ETV - PBO), 95% CI and 
p-value using NC = F. The difference in proportions and p-value are presented only at Week 48 
for the Primary Cohort at the primary analysis (see Sections 6.3 and 9).
A sensitivity analysis using NC = M presents response rates. 
Another sensitivity analysis using NC = F presents response rates by imputing successes for 
subjects randomized to PBO who are missing the primary efficacy endpoint and started rescue
open-label ETV before or at Week 48, i.e., (start date of rescue open-label ETV - first dose date 
of study therapy + 1)/7 ≤ 54 (see Sections 8.4 and 8.9).
The proportions of subjects with HBV DNA < 50 IU/mL and HBeAg seroconversion are also 
summarized at baseline and each scheduled on-treatment visit through Week 48 by treatment 
regimen. Response rates are presented using NC = F and NC = M.
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The primary efficacy endpoint is also summarized using NC = F and NC = M by treatment 
regimen and subgroups to examine consistency of effect. Subgroups may include, but are not 
limited to, the following:

Age randomization strata (see Section 7.3.4)

Gender (male, female)

Baseline HBV DNA (< 8 log10 IU/mL, ≥ 8 log10 IU/mL)

Baseline ALT (2 x ULN, > 2 x ULN) 

Geographic region (Asia, Europe, North America, South America)

HBV genotype (e.g., A, B, C, D, E, etc.)

Route of transmission (mother-to-child transmission; household/close contact exposure; 
transfusion; sexual contact; IV drug use; other)
Subgroup categories may be combined based on the availability of data.
7.5.2
Key Secondary Endpoints
The tests of the key secondary endpoints are conducted sequentially in the order specified below, 
provided the test result of the primary endpoint is significant. The nth key secondary endpoint is 
tested provided the test result of the (n-1)st key secondary endpoint is significant (n = 1, 2, ..., 5). 
Treatment regimens are compared (ETV - PBO) with a difference in proportions and p-value at 
Week 48 on treatment for the Primary Cohort at the primary analysis (see Sections 6.3 and 9)
using NC = F, unless specified otherwise.
7.5.2.1
HBV DNA Below 50 IU/mL
Analyses described in Section 7.5.1 are performed for the proportions of subjects with HBV 
DNA < 50 IU/mL on treatment.
7.5.2.2
ALT Normalization
Analyses described in Section 7.5.1 are performed for the proportions of subjects with ALT 
normalization (ALT ≤ 1 x ULN) on treatment.
7.5.2.3
HBV DNA Below LOQ
Analyses described in Section 7.5.1 are performed for the proportions of subjects with HBV 
DNA < LOQ on treatment.
7.5.2.4
HBeAg Seroconversion
Analyses described in Section 7.5.1 are performed for the proportions of subjects with HBe 
seroconversion on treatment.
7.5.2.5
Sustained HBeAg Seroconversion During Off-Treatment Follow-up 
Response rates of HBeAg seroconversion are presented by treatment regimen at EOD (end of 
dosing) and each scheduled visit during off-treatment follow-up through Week 192 using NC = F 
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and NC = M for the Year 2 Efficacy Cohort with HBeAg seroconversion at EOD. Rates using
NC = F are shown only through off-treatment follow-up Week 48.
Treatment regimens are compared between treated subjects with HBeAg seroconversion at both 
on-treatment Week 48 and EOD (ETV S48 - PBO S48; NC = F) with a difference in proportions 
and p-value at off-treatment follow-up Week 24 at the final analysis, provided the test result of 
HBeAg seroconversion was significant at the primary analysis (see Section 9).
Sustained HBeAg seroconversion is summarized analogously with response rates using NC = M 
for the Post-Year 1 Efficacy Cohort with HBeAg seroconversion at EOD.
Sustained HBeAg seroconversion at off-treatment follow-up Week 24 is also summarized by 
subgroups for treated subjects with HBeAg seroconversion at EOD (see Section 7.5.1).
7.5.3
Other Year 1 Efficacy
7.5.3.1
Response Rates
The following binary endpoints are summarized by treatment regimen with response rates using 
NC = F and NC = M at baseline and each scheduled visit on treatment through Week 48:

HBV DNA < 50 IU/mL and ALT normalization

HBV DNA < LLD

HBV DNA < LOQ, LOQ - < 50, 50 - < 172, 172 - < 1,720, 1,720 - < 17,200 and ≥ 17,200 
IU/mL

HBeAg loss (HBeAg negative)

HBsAg loss (HBsAg negative)

HBsAg seroconversion (HBsAg negative and HBsAb positive).
7.5.3.2
HBV DNA Reduction from Baseline
HBV DNA values and changes from baseline (log10 IU/mL) are summarized by treatment 
regimen at baseline and each scheduled visit on treatment through Week 48. 
The difference (ETV - PBO) and 95% CI at Week 48 are also presented. The difference and CI 
are estimated from a linear regression model of Week 48 HBV DNA change from baseline on 
covariates baseline HBV DNA, treatment regimen and age randomization strata.
7.5.4
Year 2 Efficacy
The following binary endpoints are summarized by treatment regimen with response rates using 
NC = F and NC = M at baseline and each scheduled visit on treatment through Week 96 for the 
Year 2 Efficacy Cohort (see Section 6.3):

HBV DNA < 50 IU/mL

HBV DNA < 50 IU/mL and HBeAg seroconversion

HBV DNA < 50 IU/mL and ALT normalization
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
HBV DNA < LOQ

HBV DNA < LLD 

HBV DNA < LOQ, LOQ - < 50, 50 - < 172, 172 - < 1,720, 1,720 - < 17,200 and ≥ 17,200 
IU/mL

ALT normalization

HBeAg loss

HBeAg seroconversion

HBsAg loss

HBsAg seroconversion
The Year 2 Efficacy Cohort is defined by as-randomized treatment regimen for all treated 
subjects and observed (NC = M) Week 48 HBeAg seroconversion status. Therefore, the analysis 
of HBeAg seroconversion addresses maintenance of HBeAg seroconversion at Week 96 for 
those who seroconverted at Week 48. Endpoints are summarized for PBO only through Week 48.
Key binary endpoints (e.g., HBV DNA < 50 IU/mL, ALT normalization, HBeAg 
seroconversion) at Week 96 are summarized by subgroups defined in Section 7.5.1 using NC = F 
and NC = M for ETV subjects.
HBV DNA values and changes from baseline (log10 IU/mL) are summarized by treatment 
regimen at baseline and each scheduled visit on treatment through Week 96 for the Year 2 
Efficacy Cohort. 
7.5.5
Year 3 Efficacy
The following binary endpoints are summarized by treatment regimen with response rates using 
NC = M at baseline and each scheduled visit on treatment through Week 144 for the Year 3 
Efficacy Cohort (see Section 6.3):

HBeAg loss

HBeAg seroconversion

HBsAg loss

HBsAg seroconversion
The Year 3 Efficacy Cohort is defined for observed (NC = M) Week 48 HBeAg non-
seroconverters by observed (NC = M) Week 96 HBeAg seroconversion status. Endpoints are 
summarized for ETV Week 96 non-seroconverters only through Week 96.
7.5.6
Year 4 Efficacy
The binary endpoints described in Section 7.5.5 are summarized with response rates using NC = 
M at baseline and each scheduled visit on treatment through Week 192 for the Year 4 Efficacy 
Cohort (see Section 6.3), defined as PBO-randomized observed HBeAg non-seroconverters at 
both Weeks 48 and 96 who HBeAg seroconverted at Week 144 (NC = M).
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7.5.7
All ETV On-Treatment Efficacy
The following binary endpoints are summarized with response rates using NC = M at baseline 
and each scheduled visit on ETV treatment through Week 144 for the All ETV Efficacy Cohort 
(see Sections 6.3 and 8.4):

HBV DNA < 50 IU/mL

HBV DNA < 50 IU/mL and HBeAg seroconversion

HBV DNA < 50 IU/mL and ALT normalization

HBV DNA < LOQ

HBV DNA < LLD 

HBV DNA < LOQ, LOQ - < 50, 50 - < 172, 172 - < 1,720, 1,720 - < 17,200 and ≥ 17,200 
IU/mL

ALT normalization

HBeAg loss

HBeAg seroconversion

HBsAg loss

HBsAg seroconversion
7.5.8
Efficacy During Off-Treatment Follow-up
The following binary endpoints are summarized by treatment regimen with response rates using 
NC = M at EOD (see Section 8.5) and each scheduled visit during off-treatment follow-up 
through Week 192 for off-treatment follow-up subjects in the Post-Year 1 Efficacy Cohort (see 
Section 6.3): 

HBV DNA < LOQ, LOQ - < 50, 50 - < 172, 172 - < 1,720, 1,720 - < 17,200 and ≥ 17,200 
IU/mL

HBeAg loss

HBeAg seroconversion

HBsAg loss

HBsAg seroconversion

ALT ≤1 x ULN, > 1 - 2 x ULN, > 2 - 5 x ULN, and > 5 x ULN
In addition, the efficacy response shifts from EOD using an HBV DNA cut-off of 50 IU/mL are 
summarized at Weeks 24, 48, 72, 96 and 120 during off-treatment follow-up for off-treatment 
follow-up subjects in the Post-Year 1 Efficacy Cohort (limited to ETV, PBO OL, and All ETV). 
Efficacy response shift categories are defined as follows:

Complete response: HBV DNA < 50 IU/mL, ALT normalization, and HBeAg 
seroconversion.
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
Partial response: HBV DNA < 50 IU/mL and ALT normalization without HBeAg 
seroconversion (including missing HBeAg).

Virologic response: HBV DNA < 50 IU/mL without ALT normalization and HBeAg 
seroconversion (including missing ALT or HBeAg).

Non-response: HBV DNA ≥50 IU/mL.
Results are presented by total ETV duration: overall, < 2 years, and ≥ 2 years, using 102 weeks 
as 2 years.
Efficacy response shifts from EOD using an HBV DNA cut-off of 2000 IU/mL are also 
summarized analogously.
7.5.9
Histology  
Histological parameters are listed, including most recent liver biopsy date, scoring system 
(Knodell, Ishak, Metavir, other), hepatitis activity index, fibrosis score and findings.
7.5.10
Genotypic Resistance
Analyses of genotypic resistance will be addressed in a separate integrated resistance SAP for 
studies AI463-028 and AI463-189.
7.6
Safety
The investigators determine the intensity of AEs and the relationship of AEs to study therapy. 
The investigators’ terms are coded and grouped by system organ class using the latest version of 
the Medical Dictionary for Regulatory Activities (MedDRA) in production at BMS.
In order to account for AEs with multiple occurrences in the same subject, AE records are 
collapsed for each subject and preferred term when records have the same onset date, or when 
records are contiguous or overlapping (see Section 8.10). All AE presentations are based on 
collapsed records.
AEs are presented by system organ class and preferred term, both in descending order of 
incidence on ETV, unless specified otherwise.
AE presentations include both non-serious and SAEs as defined in the protocol, unless specified 
otherwise. If a subject had an AE with different intensities during the study period, then only the 
greatest intensity is reported.
On-treatment safety is assessed for the following 3 cohorts (see Sections 6.1 and 6.3):

Through Week 48 on blinded therapy for treated subjects

ETV and PBO are assessed on treatment up to the Week 48 cut, ie, the earlier of (a) 54
weeks, the upper bound of the Week 48 visit window (see Section 8.4), and (b) the first 
dose of open-label ETV.

After Week 48 on blinded therapy or on open-label ETV through Week 96 for the Year 2 
Safety Cohort
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
ETV, PBO BL and PBO OL are assessed on treatment after the Week 48 cut and up to 
102 weeks, the upper bound of the Week 96 visit window (see Section 8.4).

On ETV treatment for All ETV Safety Cohort
Note that AEs with onset on the first day of study therapy are considered on treatment, AEs with 
onset on the first day of ETV are considered on ETV treatment and AEs with onset on the first 
day of open-label ETV are considered on open-label ETV.
Follow-up safety is assessed for the following 3 cohorts (see Sections 6.1 and 6.3):

During off-treatment follow-up for off-treatment follow-up subjects in the Post-Year 1 Safety 
Cohort

During long-term follow-up for long-term follow-up subjects in the Post-Year 1 Safety 
Cohort.

During alternative ETV follow-up for alternative ETV follow-up subjects in the Post-Year 1 
Safety Cohort (select endpoints only).
7.6.1
Deaths
Deaths are listed for enrolled subjects without regard to study period.  The listing includes 
treatment regimen, death date, start and end date of dosing, source of information, and cause of
death.  Deaths from multiple sources of information are identified:

Subject status: study discontinuation reason of death;

AE/SAE: MedDRA higher level, lower level or preferred term contains ‘death’; SAE 
outcome of death; SAE category of death; death date.
Deaths are also summarized without regard to study period for treated subjects for the following 
categories: total; due to AE.
7.6.2
Other Serious Adverse Events
Pre-treatment SAEs are summarized by treatment regimen for enrolled subjects (ETV, PBO, not 
treated).  Pre-treatment SAEs are those that occurred prior to the first dose of study therapy.  
SAEs are also summarized by treatment regimen for the following cohorts and study periods:

Through Week 48 on blinded therapy for treated subjects 

After Week 48 on blinded therapy or on open-label ETV through Week 96 for the Year 2 
Safety Cohort

On ETV treatment for the All ETV Safety Cohort

Off-treatment follow-up for off-treatment follow-up subjects in the Post-Year 1 Safety 
Cohort

Long-term follow-up for long-term follow-up subjects in the Post-Year 1 Safety Cohort

Alternative ETV follow-up for alternative ETV follow-up subjects in the Post-Year 1 Safety 
Cohort.
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SAEs leading to death and SAEs related to study therapy and leading to death are also 
summarized analogously during the on-treatment period for the 3 cohorts.
Multiple on-treatment SAEs (all; related to study therapy) are also summarized for the 3 cohorts, 
presenting the numbers of events and exposure-adjusted incidence rates (see Section 8.10).
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
AEs leading to discontinuation of study therapy are summarized by treatment regimen for the 
following cohorts and study periods:

Through Week 48 on blinded therapy for treated subjects 

After Week 48 on blinded therapy or on open-label ETV through Week 96 for the Year 2 
Safety Cohort

On ETV treatment for the All ETV Safety Cohort
7.6.4
Other Significant Adverse Events
7.6.4.1
Events of HBV Disease Progression
Events of HBV disease progression are summarized by treatment regimen for treated subjects
across the on-treatment and long-term follow-up periods combined (see Table 7.6.4.1-1).
Table 7.6.4.1-1:
Events of HBV Disease Progression
Serious and non-serious AEs: preferred terms in MedDRA dictionary
Ascites, Gastric varices, Gastric varices haemorrhage, Hepatic cirrhosis, Hepatic encephalopathy, Hepatic 
neoplasm malignant, Hepatorenal syndrome, Oesophageal varices haemorrhage, Peritonitis bacterial, 
Varices oesophageal
7.6.4.2
Neoplasms and Pre-Malignant Lesions
Malignant neoplasms are summarized by treatment regimen for treated subjects across the on-
treatment and long-term follow-up periods combined. 
A listing of neoplasms and pre-malignant lesions is also provided for enrolled subjects regardless 
of diagnosis date. The listing includes exposure to treatment regimens through the event onset. 
Exposure is measured from the first dose of study therapy to the earlier of the event onset or the 
end of study therapy.
Neoplasm terms of special interest are identified from 2 sources: (1) all MedDRA preferred 
terms in the “neoplasms benign, malignant or unspecified” system organ class (SOC) plus the 
preferred term “hepatic mass”; (2) a list of selected MedDRA preferred terms which represent 
pre-malignant lesions (see Table 7.6.4.2-1). The list is generated by searching MedDRA for all 
terms containing “plasia” or “blood disorder”, and adding these to all terms in the pre-neoplasm
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high level term group within the skin and subcutaneous disorders SOC. The resulting list is 
reviewed and edited by a BMS safety clinician for appropriateness. Note some of these terms
also derive from the neoplasms SOC.
All terms are further categorized as benign, malignant, pre-malignant or unclassifiable by a BMS 
medical monitor, with concurrence from another BMS medical monitor, who are both blinded to 
treatment regimen.
Table 7.6.4.2-1:
Selected Pre-Malignant Lesions
Serious and non-serious AEs: preferred terms in MedDRA dictionary
Actinic keratosis, Adrenal cortex dysplasia, Anogenital dysplasia, Blood disorder, Breast dysplasia, 
Bronchial dysplasia, Cervical dysplasia, Dysplasia, Endometrial dysplasia, Epidermodysplasia 
verruciformis, Erythroplasia of lipa, Erythroplasia of penisa, Erythroplasia of vulvaa, Focal nodular 
hyperplasiaa, Gastric dysplasia, Gastrointestinal dysplasia, Hepatic dysplasia, Laryngeal dysplasia, 
Leukoplakia, Myeloid metaplasiaa, Nodular regenerative hyperplasia, Oesophageal dysplasia, Olfacto 
genital dysplasia, Palatal dysplasia, Penile dysplasia, Placental dysplasia, Precancerous skin lesion, 
Prostatic intraepithelial neoplasia, Queyrat erythroplasiaa, Tongue dysplasia, Vaginal dysplasia, Vulvar 
dysplasia.
aTerms derived from the neoplasms SOC.
7.6.5
Overall Adverse Events
AEs are summarized by intensity (All Grades; All Grades related; Grade 2 - 4 related; Grade 3 -
4) and treatment regimen for the following 3 cohorts:

Through Week 48 on blinded therapy for treated subjects 

After Week 48 on blinded therapy or on open-label ETV through Week 96 for the Year 2 
Safety Cohort

On ETV treatment for the All ETV Safety Cohort
If relationship to study therapy is missing, the AE is included in summaries of AEs related to 
study therapy.
AEs are also summarized by intensity (All Grades) and treatment regimen during (1) off-
treatment follow-up for off-treatment follow-up subjects in the Post-Year 1 Safety Cohort, (2) 
alternative ETV follow-up for alternative ETV follow-up subjects in the Post-Year 1 Safety 
Cohort, and (3) long-term follow-up for long-term follow-up subjects in the Post-Year 1 Safety 
Cohort.
On-treatment non-serious AEs (All Grades) occurring with incidence 5% on any treatment 
regimen are also summarized analogously for the 3 cohorts. Multiple on-treatment non-SAEs 
(All Grades) occurring with incidence ≥ 5% on any treatment regimen are also summarized for 
the 3 cohorts, presenting the numbers of events and exposure-adjusted incidence rates (see 
Section 8.10).
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Multiple on-treatment AEs (All Grades) occurring with incidence ≥5% on any treatment 
regimen are also summarized for the 3 cohorts, presenting the numbers of events and exposure-
adjusted incidence rates (see Section 8.10).
7.6.6
Clinical Laboratory Evaluations
Summaries are based on subjects with at least 1 laboratory measurement during the study period.
7.6.6.1
Laboratory Abnormalities
For each laboratory test, laboratory abnormalities by toxicity grade (Grade 1 - 4; Grade 3 - 4) on 
treatment are summarized by treatment regimen and baseline status (all, normal, abnormal, not 
reported) for the following 3 cohorts:

Through Week 48 on blinded therapy for treated subjects 

After Week 48 on blinded therapy or on open-label ETV through Week 96 for the Year 2
Safety Cohort

On ETV treatment for All ETV Safety Cohort
Laboratory tests include:

Hematology: hemoglobin, platelets, international normalized ratio (INR), white blood cell 
count (WBC) and neutrophils + bands (absolute)

Liver function tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total 
bilirubin and albumin

Pancreatic enzymes: lipase (colorimetric or turbidimetric assay)

Renal function tests: creatinine and BUN/urea (BUN or urea)

Electrolytes (low and high): chloride, potassium and sodium.
Toxicity grades are based on DAIDS, unless specified otherwise (see Protocol Appendix 2). 
BUN/urea and chloride are graded with modified WHO criteria.
Treatment emergent laboratory abnormalities by toxicity grade (increased to Grades 1, 2, 3 and 
4) are also summarized analogously by treatment regimen and baseline status for the 3 cohorts. 
On-treatment emergent abnormalities are those with a higher toxicity grade than the baseline 
toxicity grade (including not reported baseline).
In addition, the following select laboratory elevations and abnormalities on treatment are
summarized by treatment regimen for the 3 cohorts:

Any Grade 3 - 4 laboratory abnormality (see previous list of tests)

Liver function elevations > 2 and > 3 x baseline (ALT, AST, total bilirubin)

Liver function elevations > 2 x baseline and Grade 4 (ALT, AST and total bilirubin; includes 
ALT flares, defined as ALT > 2 x baseline and > 10 x ULN)

Simultaneous ALT and total bilirubin elevations (ALT > 2 x baseline, total bilirubin > 2 x 
baseline and > 2 x ULN; ie, those occurring on the same collection day).
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
Albumin < 2.5 g/dL

Lipase elevations > 3 x baseline 

Confirmed creatinine elevations ≥ 0.3 and ≥ 0.5 mg/mL from baseline (2 sequential 
measurement or last measurement meeting the elevation criteria)

Glucose categories (< 50, 200 mg/dL) regardless of fasting status.
For PBO-treated subjects who receive open-label ETV, baseline is used during blinded dosing, 
while ETV baseline is used during open-label ETV dosing.
Laboratory abnormalities by toxicity grade (Grade 1 - 4; Grade 3 - 4) are also summarized by 
treatment regimen and EOD status (all, normal, abnormal) for the first 2 follow-up cohorts: (1) 
off-treatment follow-up for off-treatment follow-up subjects in the Post-Year 1 Safety Cohort; 
(2) long-term follow-up for long-term follow-up subjects in the Post-Year 1 Safety Cohort.
Laboratory abnormalities by toxicity grade (Grade 1 - 4; Grade 3 - 4) are also summarized by 
treatment regimen during alternative ETV follow-up for alternative ETV follow-up subjects in 
the Post-Year 1 Safety Cohort.
Emergent laboratory abnormalities by toxicity grade (increased to Grades 1, 2, 3 and 4) are also 
summarized analogously by treatment regimen and EOD status for the first 2 follow-up cohorts. 
Emergent abnormalities are those with a higher toxicity grade than the EOD toxicity grade.
Select laboratory elevations and abnormalities are summarized relative to the EOD value for the 
3 follow-up cohorts.  In addition, elevations of liver function tests (including ALT flares, defined 
as ALT > 2 x reference and > 10 x ULN) during the follow-up periods are summarized using the 
reference value (REF) (ie, minimum of the baseline and EOD values) for the 3 follow-up 
cohorts. Note that for PBO-treated subjects who receive open-label ETV, reference is the 
minimum of the ETV baseline and EOD values.
ALT multiples of ULN and HBV DNA values are plotted over time for each subject who had an 
ALT flare on study. The duration of an ALT flare is measured from the first ALT measurement 
meeting the ALT flare criteria to resolution, defined as (1) the first ALT baseline or 5 x ULN 
on treatment, or (2) the first ALT reference or 5 x ULN during follow-up.  If (1) and (2) are 
not met, an ALT flare is considered unresolved, and the last ALT measurement is used to 
estimate duration.
The time to and duration of ALT flares (weeks) during off-treatment follow-up are summarized 
for off-treatment follow-up subjects in the Post-Year 1 Safety Cohort (limited to ETV, PBO OL, 
and All ETV). Analyses are based on the first ALT flare during off-treatment follow-up.
The laboratory value during the study period with the highest toxicity grade is reported for each 
test. Grade 1 abnormalities are reset to normal if the original (unconverted) values are between 
the lower and upper limits of normal.
7.6.6.2
Laboratory Tests over Time
Laboratory test values are summarized by treatment regimen at baseline and each scheduled visit 
(see Section 8.4) for the following cohorts:
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
On treatment through Week 48 for treated subjects

On treatment through Week 96 for the Year 2 Safety Cohort 

On ETV treatment for the All ETV Safety Cohort
Values are also summarized by treatment regimen at EOD and each scheduled visit during (1) 
off-treatment follow-up for off-treatment follow-up subjects in the Post-Year 1 Safety Cohort,
and (2) long-term follow-up for long-term follow-up subjects in the Post-Year 1 Safety Cohort.
Laboratory tests include:

Hemoglobin

Platelets

INR

WBC

ALT

Total bilirubin

Albumin

Lipase (colorimetric assay only)

Creatinine
7.6.7
Growth/Development Assessment
Growth assessment values and changes from baseline are summarized by treatment regimen at 
baseline and each scheduled visit (see Section 8.4) for the following cohorts:

For treated subjects across the on-treatment and long-term follow-up periods combined

For the Year 2 Safety Cohort across the on-treatment and long-term follow-up periods 
combined

For the All ETV Safety Cohort across the ETV treatment and long-term follow-up periods 
combined
Growth assessment parameters include HAZ, HAP, WAZ, WAP, BMIAZ, and BMIAP. These 
parameters are derived using 2000 CDC growth charts.7
Longitudinal plots display mean growth changes from baseline in growth assessment (HAZ, 
HAP, WAZ, WAP, BMIAZ, BMIAP) versus visit week by treatment regimen with error bars 
representing ± 1 SE of the reported statistic for treated subjects across the on-treatment and long 
term follow-up periods combined.
Tanner stage is a development assessment parameter that is summarized analogously by age 
randomization strata for each staging category (pubic hair, breast/genitals) and treatment regimen
(see Section 7.6.8). Stages I - V are assessed as integers 1 - 5, respectively.
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7.6.8
Results by Subgroups
The following key safety endpoints are summarized by subgroups of age randomization strata, 
geographic region, HBV genotype and route of transmission (see Section 7.5.1) on blinded 
therapy through Week 48 for treated subjects, unless specified otherwise:

SAEs

AEs leading to discontinuation of study therapy

Events of HBV disease progression  (on-treatment and long-term follow-up periods 
combined)

AEs by intensity (All Grades; Grade 2 - 4 related; Grade 3 - 4)

Laboratory abnormalities by toxicity grade (Grade 1 - 4; Grade 3 - 4)

Select laboratory elevations and abnormalities

Growth/development assessment values and changes from baseline over time (on-treatment 
and long-term follow-up periods combined). Tanner stage is assessed only by age 
randomization strata for each staging category (see Section 7.6.7).
AEs are presented by system organ class and preferred term alphabetically.
7.7
Pharmacokinetic (PK) Analysis
Individual subject ETV plasma concentrations are listed and plotted versus time. Mean plasma 
concentration vs. time profiles in original scale as well as in log scale are provided to compare 
pediatric subjects by age randomization strata.
Individual subject pharmacokinetic parameter values are derived by noncompartmental methods 
by a validated pharmacokinetic program.  Concentration data are only considered valid if 
complete information is available on sampling time and dosing time. Additionally, pre-dose 
samples for semi-intensive PK are only be considered valid if they are collected prior to the dose 
on the day of semi-intensive PK sampling and if sampling time and dosing time information are 
complete. To assess the exposure of ETV in pediatric patients, summary statistics are provided 
for all of the pharmacokinetic parameters of ETV by age randomization strata and treatment 
regimen.  Geometric means and coefficients of variation as well as medians, minima, and 
maxima are reported for Cmax, Cmin. Medians, minima, and maxima are reported for Tmax. 
8
CONVENTIONS
8.1
Missing, Unknown or Partial Dates
Rho will provide conventions for imputing values for missing or partial dates for non-study 
medication start and stop dates and for AE onset dates. 
8.2
Unknown Study Medication End Dates
End dates of dosing that are left as ‘UNKNOWN’ or partial because a subject is lost to follow-up 
or the subject couldn’t remember the exact dosing end date are assumed to be equal to the last 
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recorded dose start date, thus crediting the subject with 1 day of dosing.  All missing dates are 
queried.
8.3
Partial or Missing Safety Information
A missing AE intensity is not imputed.  AEs with missing intensity are included in the AE tables 
for All Grades.  AEs with missing relationship are included in tables of “related” AEs.
8.4
Visit Week Windows
For longitudinal presentations, values are first selected within their respective study periods (see 
Section 6.1). Next, windows around scheduled measurement times are constructed based on the 
midpoint between scheduled measurement visits and the value closest to the scheduled visit for 
each measurement is selected from those that fall within the window.  
Visit windows are defined in Table 8.4-1:
Table 8.4-1:
Visit Week Windows
Week
On Treatment or ETV 
Treatment (Combined with 
or without Long-Term 
Follow-up)
Off-Treatment or Long-Term 
Follow-up
On Treatment/ETV 
treatment and Long-Term 
Follow-up Combined (Tanner 
Stage only)
  0*
Day ≤ 1
Day ≤ Last dose + 5
Day ≤ 1
4
>  2 -  6 wks#
--
--
6
--
≤ 9 wks
--
8
> 6 - 10 wks#
--
--
12
> 10 - 18 wks
>  9 - 18 wks
--
24
> 18 - 30 wks
> 18 - 30 wks
> 12 - 36 wks
36
> 30 - 42 wks
> 30 - 42 wks
--
48
> 42 - 54 wks
> 42 - 54 wks
> 36 - 60 wks
60
> 54 - 66 wks
> 54 - 66 wks
--
72
> 66 - 78 wks
> 66 - 78 wks
> 60 - 84 wks
84
> 78 - 90 wks
> 78 - 90 wks
--
96
> 90 - 102 wks
> 90 - 102 wks
> 84 - 108 wks
108
> 102 - 114 wks
> 102 - 114 wks
--
120
> 114- 126 wks
> 114- 126 wks
> 108 - 132 wks
132      
> 126 - 138 wks
> 126 - 138 wks
--
  144
> 138 - 150 wks
> 138 - 150 wks
> 132 - 156 wks
156
> 150 - 162 wks
> 150 - 162 wks
--
168
> 162 - 174 wks
> 162 - 174 wks
> 156 - 180 wks
180
> 174 - 186 wks
> 174 - 186 wks
--
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Table 8.4-1:
Visit Week Windows
Week
On Treatment or ETV 
Treatment (Combined with 
or without Long-Term 
Follow-up)
Off-Treatment or Long-Term 
Follow-up
On Treatment/ETV 
treatment and Long-Term 
Follow-up Combined (Tanner 
Stage only)
192
> 186 - 198 wks
> 186 - 198 wks
> 180 - 204 wks
204
> 198 - 210 wks
> 198 - 210 wks
--
216
> 210 - 222 wks
> 210 - 222 wks
> 204 - 228 wks
228
> 222 - 234 wks
> 222 - 234 wks
240
> 234 wks
> 234 wks
> 228 wks
*  “Week 0” is formatted according to treatment period: “Baseline” for the on-treatment period; 
“ETV Baseline” for the ETV treatment period; “EOD” for the off-treatment and long-term 
follow-up periods.
# On treatment (combined with or without long-term follow-up) only.
Additional visit windows after Week 240 are defined analogously as needed.
For the on-treatment period, weeks are calculated as (measurement date - first dose date of study 
therapy + 1)/7.  This also applies to the on-treatment and long-term follow-up periods combined.
For the ETV treatment period, weeks are calculated as (measurement date - first dose date of 
active ETV + 1)/7. This also applies to the ETV treatment and long-term follow-up periods 
combined.
For the off-treatment and long-term follow-up periods, weeks are calculated as (measurement 
date - last dose date of study therapy)/7.
8.5
Baseline and EOD Measurements
Baseline values are the last non-missing assessments taken prior and up to the first dose of study 
therapy, or the enrollment date for subject never receiving study therapy, unless specified 
otherwise. 
HBV genotype is derived as the first non-missing assessment regardless of study period. Missing 
values include those that are labeled “ND” or “UAS”. Indeterminate values are not considered 
missing.
End of dosing (EOD) values are the last non-missing assessments taken after the first dose of 
study therapy and up to the last dose of study therapy plus 5 days.
For analyses of ETV treatment for the All ETV Efficacy and Safety Cohorts, the baseline values 
are the last non-missing assessments taken prior and up to the first dose of active ETV (i.e., 
“ETV baseline”). For these cohorts, the following parameters are derived only at baseline and 
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not re-derived at ETV baseline: gender, race, ethnicity, geographic region, country, HBV 
genotype.
Subjects are excluded from any changes from baseline (or EOD) analysis for which they have a 
missing baseline (or EOD) value.
8.6
HBV DNA Below LOQ or LLD
HBV DNA < LOQ is identified by the specify field “DETECTED BUT BELOW LOQ” or NOT 
DETECTED”.
HBV DNA < LLD is identified by the specify field “NOT DETECTED”.
In analyses of HBV DNA as a continuous variable, HBV DNA < LOQ or LLD is assigned a 
value 1 IU less than the LOQ i.e., 28 IU/mL.
8.7
Multiple Measurements
If more than one specific test result is reported in a given visit window, the result closest to the 
scheduled visit week is used in the analysis (as determined by the absolute difference in days 
between the planned visit and the measurement date).  In addition:

For HBV DNA by PCR from multiple HBV DNA samples collected on the same date, the 
one assayed at an earlier date is reported in the analysis.  

For multiple ALT, HBeAg and HBeAb values obtained from the same collection date, the 
‘worst case’ is selected in the efficacy analyses (i.e., “POSITIVE” for HBeAg and 
“NEGATIVE” for HBeAb for subjects who were HBeAg-positive at baseline, and the 
highest ALT value after start of dosing).

For growth parameters based on height and weight, the ‘worst case’ is selected in the safety 
analyses: if values are of equal distance or there are multiple values on same date, then select 
the pair (height, weight) with smallest percentile across all measurements.
8.8
Indeterminate Serology Results
Serum HBeAg, HBeAb, HBsAg and HBsAb values of “INDETERMINAT”, “BORDERLINE” 
and “EQUIVOCAL” are considered indeterminate. 
For efficacy analyses in Section 7.5, indeterminate values are imputed to be “worst case”, i.e., 
“POSITIVE” for HBeAg and “NEGATIVE” for HBeAb. 
8.9
Derived Dates
Derived dates that are used commonly in analyses are defined as follows. Derivations of dose 
dates exclude rescue open-label ETV.

First dose date of study therapy is the earliest start date of drug (ie, blinded therapy [ETV
active or PBO] or open-label ETV) identified from valid dosing records, ie, non-missing start 
date and number of units per day > 0, from blinded therapy study medication CRFs. This 
date is used to identify treated subjects and to distinguish measurements across study periods.
Note that this is also first dose date of blinded study therapy.
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
Dose end date of study therapy is the latest start or end dates of drug (ie, blinded therapy 
[ETV active or PBO] or open-label ETV) identified from valid dosing records, ie, non-
missing start or end date and number of units per day > 0 or total dose > 0. This date is is 
used to asses time on study therapy.

Last dose date of study therapy is the dose end date of study therapy derived only for subjects 
with an end of treatment subject status CRF indicating whether the subject completed the 
treatment period. This date is used to exclude data in antiviral activity and safety analyses, 
and to distinguish measurements across study periods.

Dose end date of blinded therapy is the latest start or end date of blinded therapy (ETV active 
or PBO) identified from valid dosing records, ie, non-missing start or end date and number of 
units per day > 0, from blinded therapy study medication CRFs. This date is used to assess 
time on blinded study therapy.

First dose date of open-label ETV is the earliest start date of open-label ETV identified from 
valid dosing records, ie, non-missing start date and total dose > 0, from open-label study 
medication CRFs. This date is used to distinguish measurements across blinded vs open-label 
treatment, and to assess time on open-label therapy.

Dose end date of open-label ETV is the latest start or end date of open-label ETV identified 
from valid dosing records, ie, non-missing start or end date and total dose > 0, from open-
label study medication CRFs. This date is used to assess time on open-label therapy.

First dose date of active ETV is the first dose date of study therapy for ETV-randomized 
subjects, and the first dose date of open-label ETV for PBO-randomized subjects. This date is 
used to identify all ETV-treated subjects and to distinguish measurements across study 
periods.

Dose end date of active ETV is the dose end date of study therapy for ETV-randomized 
subjects and the dose end date of open-label ETV for PBO-randomized subjects. This date is 
used to assess time on active ETV.

Last dose date of active ETV is the dose end date of active ETV derived only when the last 
dose date of study therapy is not missing.

Start date of rescue open-label ETV is the earliest start date of rescue open-label ETV 
identified from valid dosing records, ie, non-missing start date and total dose > 0, from 
rescue open-label ETV study medication CRFs.

Start date of alternative ETV therapy is the earliest start date of (1) rescue open-label ETV, 
or (2) concomitant ETV taken on treatment or during long-term follow-up.

Start date of alternative anti-HBV therapy is the earliest start date of (1) rescue open-label 
ETV, or (2) concomitant anti-HBV medication taken on treatment or during long-term 
follow-up. 

Last contact date is the death date, if it exists, or the latest of the following dates: 
randomization; first or last dose of study therapy; adverse event onset or resolution; hepatitis 
B related diagnosis; laboratory test (safety, pregnancy, serology and virology); liver biopsy; 
physical measurement; physical exam; neurologic exam; vital sign; non-study medication 
start or stop; last contact from end of treatment or end of study subject status; Tanner staging.
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8.10
Collapsed AEs and Exposure-Adjusted Incidence Rates
In order to account for AEs with multiple occurrences in the same subject, AE records are 
collapsed for each subject and preferred term when:

Records have the same onset date.

The onset date of an event record is either the same day or 1 day later than the resolution date 
of a preceding event record (contiguous events).

The onset date of an event record is after the onset date and prior to or on the resolution date 
of a preceding event record (overlapping events).
The collapsed record contains the earliest onset date (and time, if collected); latest resolution 
date (and time, if collected); highest intensity in the following order (highest to lowest: very 
severe, severe, moderate, or mild); AE type of SAE, if ever reported as a SAE, AE otherwise; 
latest causality, as determined by the last modification time stamp (highest causality in the 
following order [highest to lowest: related, not related], if records contain the same last 
modification time stamp with different causalities); treatment required of yes, if ever required;
highest action taken in the following order (highest to lowest: drug discontinued, drug 
interrupted, dose reduced, dose increased, none); latest reported term, as determined by the last 
modification timestamp.
Incidence rates per 100 person-years of exposure (IR/100 P-Y) are defined as event count * 100 /
person-years of exposure (see Section 7.6.5). Exposure is defined as time on study therapy (see 
Section 7.4.1), plus 5 days for subjects who discontinued study therapy to account for on-
treatment safety reporting.
8.11
Laboratory Test Conversion
ICON changed its chemistry testing platform from the Roche Diagnostics Hitachi Modular 
system to the Abbott Architect system. Thus, values from the Abbott system are converted to the 
Roche system for comparability.
Based on regression analyses, laboratory tests which fail to show statistical equivalence between 
the Roche and the Abbott systems are converted as follows:  x = (y - c)/m, where x is the Roche 
value, y is Abbott value, and m and c are respectively the slope and intercept of the regression 
line (see table below). 
Records from the Abbott system are identified with laboratory names containing “ARCHITEC”.
Values are converted before applying toxicity grades.
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9
CONTENT OF REPORTS
The primary analysis is conducted when the Primary Cohort has been treated for 48 weeks (see 
Section 6.3). Longitudinal analyses present data on treatment through Week 48. Efficacy is 
focused on the Primary Cohort. Safety is focused on blinded therapy through Week 48 for treated 
subjects, as well as on all ETV therapy for the All ETV Safety Cohort. Follow-up safety is 
presented only if ≥ 10% of treated subjects have post-dosing follow-up data.
An additional analysis is performed when all subjects have reached Week 48. Longitudinal 
analyses present efficacy data on treatment through Week 48 for treated subjects, efficacy data 
on treatment through Week 96 for the Year 2 Primary Efficacy Cohort, safety data on treatment 
through Week 96 for the Year 2 Safety Cohort, and all available safety data on ETV treatment 
for the All ETV Safety Cohort. All safety analyses described in this plan are performed.
An additional unplanned analysis is performed when all subjects have reached Week 96. All 
analyses described in this plan are performed, except for pre-treatment analyses of study 
population and efficacy/safety analyses on blinded therapy through Week 48.
An additional analysis is performed when all subjects have completed study therapy. All 
analyses described in this plan are performed, except for pre-treatment analyses of study 
population, efficacy/safety analyses on blinded therapy through Week 48, and efficacy/safety 
analyses on treatment through Week 96.
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The final analysis is performed when the last subject has completed long-term follow-up.  At a 
minimum, safety analyses are reported for the off-treatment and long-term follow-up periods.
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APPENDIX 1
RELEVANT PROTOCOL DEVIATIONS
The relevant protocol deviations that can be programmed from the database are identified below. 
The list may be updated as appropriate if, in the course of monitoring the study, additional 
protocol deviations are found and considered relevant. Non-study medications marked below 
with # are identified by a BMS physician prior to database lock from blinded listings.
Eligibility Deviations
Eligibility deviations (ie, protocol deviations of entry criteria) are listed below. 

Inclusion 2b: HBeAg negative or missing, or HBeAb positive or missing at screening

Inclusion 2c: ALT < 1.5 x ULN or ≥ 10 × ULN or missing at screening

Inclusion 2d: HBV DNA < 105 c/mL or missing at screening

Inclusion 3a: Age < 2 or ≥ 18 years

Exclusion 1d: Women with positive pregnancy test at screening

Exclusion 2a: Positive test for HIV, HCV or HDV at screening. 

HCV positive is defined as both HCV antibody positive and detectable HCV RNA.

HIV positive is defined as having a positive result for HIV-1 and HIV-2 screen and either 
HIV-1 confirmation or the HIV-2 confirmation immunoblot.

Exclusion 4a: Hemoglobin < 10.0 g/dL or missing at screening

Exclusion 4b: Platelets count < 70,000/mm3 or missing at screening

Exclusion 4c: Glomerular filtration rate < 50 mL/min/1.73 m2 or missing at screening. This is 
estimated using Schwartz formula.

Exclusion 4d: Total bilirubin > 2.5 mg/dL (> 42.75 mol/L) or missing at screening

Exclusion 4e: INR > 1.5 or missing at screening

Exclusion 4f: Albumin < 3 g/dL (< 30 g/L) or missing at screening

Exclusion 4 g: Alpha fetoprotein ≥ 50 ng/mL or missing at screening

Exclusion 6a: Prior therapy ≥ 12 weeks with any anti-HBV nucleoside or nucleotide. This 
includes, but is not limited to adefovir, tenofovir, famciclovir, clevudine, lamivudine, 
telbivudine or emtricitabine (#)

Exclusion 6b: Prior therapy with interferon alpha, thymosin alpha or any anti-HBV 
nucleos[t]ide antiviral agent within 24 weeks of screening (#)

Exclusion 6c: Prior ETV
On-Treatment Protocol Deviations
Protocol deviations during the on-treatment period are as follows:

Incorrect study therapy received: subjects randomized to active ETV who received PBO or 
the incorrect active dose; subjects randomized to PBO who received blinded active ETV. 
Subjects who received the incorrect study therapy during the entire treatment period are 
further identified.
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
Blinded therapy received after not seroconverting at Week 48 (defined as receiving blinded 
therapy after 54 weeks and not seroconverting at Week 48 based on NC = M)

Open-label ETV received after seroconverting at Week 48 without seroreversion (defined as 
receiving open-label ETV after 54 weeks, seroconverting at Week 48 based on NC = M, and 
seroreverting after Week 48 based on NC = M)

Average daily dose < 80% of target dose

Treatment continued after positive pregnancy test (defined as not discontinuing study therapy 
or discontinuing study therapy > 2 weeks after positive pregnancy test)

Treatment continued after positive HIV test (defined as not discontinuing study therapy or 
discontinuing study therapy > 2 weeks after positive HIV test)

Prohibited concomitant medications (#)
Protocol deviations related to semi-intensive PK data:

At least one of the sampling time, dosing time or meal time is missing

Sampling time ≥ 10% different from scheduled time

Meal taken within 2 hours before or within 2 hours after the previous day’s dose (inclusive)
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