Clinical trial NCT02058108
Conditions: Chronic Hepatitis B
Keywords: Chronic hepatitis B, pediatrics, antiviral treatment, telbivudine
Sponsor: Novartis Pharmaceuticals
Start date: 2014-10-31; Completion date: 2019-01-09
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study was to assess the efficacy and safety of telbivudine at a dose of 20 mg/kg up to a maximum of 600 mg q.d. in compensated pediatric HBeAg-positive and negative CHB patients aged 2 to \<18 years with the indication of antiviral CHB treatment. This study was part of the commitments of the pediatric development plan for telbivudine in Europe and US.

Detailed description:

Arms: arm 1: Patients of any age and weight\< 30kg: telbivudine oral solution (20 mg/mL): 20 mg/kg up to 600 mg q.d corresponding to weight (kg) x1mL, p.o. once daily Patients \< 12 years old and weight≥ 30kg: telbivudine oral solution (20mg/mL), 600 mg/day corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: telbivudine film-coated tablet, 600 mg/day, corresponding to 1 tablet p.o. once daily arm 2: Patients of any age and weight \< 30kg: placebo oral solution corresponding to weight (kg) x1mL, p.o. once daily Patients \< 12 years old and weight ≥ 30kg: placebo oral solution corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: placebo tablet, corresponding to 1 tablet p.o. once daily
Interventions: intervention 1: Telbivudine intervention 2: Placebo
Intervention descriptions: intervention 1: Patients of any age and weight\< 30kg: telbivudine oral solution (20 mg/mL): 20 mg/kg up to 600 mg q.d corresponding to weight (kg) x1mL, p.o. once daily Patients \< 12 years old and weight≥ 30kg: telbivudine oral solution (20mg/mL), 600 mg/day corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: telbivudine film-coated tablet, 600 mg/day, corresponding to 1 tablet p.o. once daily intervention 2: Patients of any age and weight \< 30kg: placebo oral solution corresponding to weight (kg) x1mL, p.o. once daily Patients \< 12 years old and weight ≥ 30kg: placebo oral solution corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: placebo tablet, corresponding to 1 tablet p.o. once daily

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine
LDT600A/Telbivudine
Clinical Trial Protocol CLDT600A2306 / NCT02058108
A randomized, double-blind, 104-weeks treatment study to 
evaluate the efficacy, safety, tolerability and 
pharmacokinetics of telbivudine oral solution and tablets in 
children and adolescents with compensated HBeAg-
positive and negative chronic hepatitis B virus infection
Authors:
Document type:
Amended Clinical Trial Protocol Clean
EUDRACT number:
2012-004942-14 
Version number:
v02 
Development phase:
III
Document status
Final
Release date:
22-Nov-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0, November, 2013
 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Amendment 2 ....................................................................................................................11
Protocol synopsis...............................................................................................................13
1
Introduction .......................................................................................................................19
1.1
Background............................................................................................................19
1.2
Purpose ..................................................................................................................23
2
Study objectives.................................................................................................................23
2.1
Primary and key secondary objectives ..................................................................23
2.2
Secondary objectives .............................................................................................23
24
3
Investigational plan ...........................................................................................................24
3.1
Study design...........................................................................................................24
3.2
Rationale of study design.......................................................................................25
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....27
3.4
Rationale for choice of comparator .......................................................................29
3.5
Purpose and timing of interim analyses/design adaptations..................................29
3.6
Risks and benefits..................................................................................................30
4
Population..........................................................................................................................31
4.1
Inclusion criteria ....................................................................................................31
4.2
Exclusion criteria...................................................................................................32
5
Treatment...........................................................................................................................34
5.1
Protocol requested treatment .................................................................................34
5.1.1
Investigational treatment.......................................................................34
5.1.2
Additional study treatment....................................................................34
5.2
Treatment arms ......................................................................................................34
5.3
Treatment assignment............................................................................................35
5.4
Treatment blinding.................................................................................................36
5.5
Treating the patient................................................................................................36
5.5.1
Patient numbering .................................................................................36
5.5.2
Dispensing the study treatment .............................................................37
5.5.3
Handling of study treatment..................................................................37
5.5.4
Instructions for prescribing and taking study treatment........................38
 


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5.5.5
Permitted dose adjustments and interruptions of study treatment ........39
5.5.6
Rescue medication ................................................................................39
5.5.7
Concomitant treatment..........................................................................39
5.5.8
Prohibited treatment..............................................................................39
5.5.9
Discontinuation of study treatment and premature patient 
withdrawal.............................................................................................41
5.5.10
Withdrawal of consent ..........................................................................43
5.5.11
Loss to follow-up ..................................................................................43
5.5.12
Emergency unblinding of treatment assignment...................................43
5.5.13
Study completion and post-study treatment..........................................44
5.5.14
Early study termination.........................................................................44
6
Visit schedule and assessments .........................................................................................44
6.1
Information to be collected on screening failures..................................................50
6.2
Patient demographics/other baseline characteristics .............................................50
6.3
Treatment exposure and compliance .....................................................................51
6.4
Efficacy..................................................................................................................51
6.4.1
Serum HBV DNA .................................................................................52
6.4.2
HBV serological markers......................................................................52
6.4.3
Serum ALT............................................................................................52
6.4.4
Genotypic Resistance surveillance........................................................53
6.4.5
Appropriateness of efficacy assessments..............................................53
6.5
Safety.....................................................................................................................53
6.5.1
Physical examination ............................................................................54
6.5.2
Vital signs..............................................................................................54
6.5.3
Height and weight .................................................................................54
6.5.4
Laboratory evaluations..........................................................................54
6.5.5
Liver ultrasound ....................................................................................55
6.5.6
Electrocardiogram (ECG) .....................................................................55
6.5.7
Pregnancy and assessments of fertility .................................................55
6.5.8
Appropriateness of safety measurements..............................................56
56
56
56
56
57
57
7
Safety monitoring ..............................................................................................................57
 


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7.1
Adverse events.......................................................................................................57
7.2
Serious adverse events...........................................................................................59
7.2.1
Definition of SAE .................................................................................59
7.2.2
Serious adverse event reporting ............................................................60
7.3
Liver safety monitoring .........................................................................................60
7.4
Renal safety monitoring.........................................................................................61
7.5
Pregnancy reporting...............................................................................................61
7.6
Prospective suicidality assessment ........................................................................62
7.7
Adverse events of special interest (AESI) reporting .............................................62
8
Data review and database management.............................................................................64
8.1
Site monitoring ......................................................................................................64
8.2
Data collection.......................................................................................................64
8.3
Database management and quality control............................................................65
8.4
Data Monitoring Committee..................................................................................65
8.5
Adjudication Committee........................................................................................66
9
Data analysis......................................................................................................................66
9.1
Analysis sets ..........................................................................................................66
9.2
Patient demographics and other baseline characteristics.......................................66
9.3
Treatments .............................................................................................................67
9.4
Analysis of the primary variable............................................................................67
9.4.1
Variable(s).............................................................................................67
9.4.2
Statistical model, hypothesis, and method of analysis..........................67
9.4.3
Handling of missing values/censoring/discontinuations.......................68
9.4.4
Supportive analyses...............................................................................68
9.5
Analysis of secondary variables ............................................................................68
9.5.1
Efficacy variables..................................................................................68
9.5.2
Safety variables .....................................................................................68
69
69
70
70
70
9.6
Interim analyses .....................................................................................................70
9.7
Planned analyses....................................................................................................70
9.8
Sample size calculation..........................................................................................71
10 Ethical considerations........................................................................................................71
10.1
Regulatory and ethical compliance........................................................................71
 


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10.2
Informed consent procedures.................................................................................71
10.3
Responsibilities of the investigator and IRB/IEC..................................................72
10.4
Publication of study protocol and results...............................................................72
11 Protocol adherence ............................................................................................................72
11.1
Protocol Amendments ...........................................................................................72
12 References .........................................................................................................................73
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................76
14 Appendix 2: Assessment of sexual maturation in males and females under 18 years 
of age (Tanner staging)......................................................................................................79
15 Appendix 3: Muscle management algorithm ....................................................................80
16 Appendix 4: Muscle symptom Questionnaire (initial and follow-up visits) .....................81
17 Appendix 5: Muscle strength testing exam .......................................................................85
18 Appendix 6: Recommended pediatric dose of acetaminophen/paracetamol.....................86
List of tables
Table 3-1
Comparison of PK parameters of telbivudine in Adults and 
Children by Age Groups .......................................................................27
Table 3-2
Comparison of predicted LDT600 pharmacokinetics at the steady 
state in children age 2 to < 18 years to a historical study of healthy 
adults .....................................................................................................28
Table 5-1
Study medication assignment and dosage.............................................38
Table 5-2
Prohibited treatment..............................................................................40
Table 6-1
Assessment schedule.............................................................................46
57
Table 13-1
Clinically notable laboratory values and vital signs .............................76
Table 16-1
Muscle Symptom Questionnaire (Initial and follow-up visits).............81
Table 17-1
Muscle Strength Testing Exam.............................................................85
List of figures
Figure 3-1
Study design*........................................................................................25
Figure 15-1
Muscle management algorithm.............................................................80
 


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List of abbreviations
AASLD
American Association of the Study of Liver Diseases
ADR
Adverse Drug Reaction
ADV
Adefovir
AE
adverse event
AESI
adverse event of special interest
Alb
albumin
ALT
alanine aminotransferase
AFP
alpha-fetoprotein
AST
aspartate aminotransferase
ALP
alkaline phosphatase
b.i.d.
twice a day
B-US
B-Ultra Sound
CFR
US Code of Federal Regulations
CHB
Chronic Hepatitis B
CK
Creatine Kinase
CMV
Cytomegalovirus
CRF
Case Report/Record Form (paper or electronic)
CPO
Country Pharma Organization
CRO
Contract Research Organization
CTP
Child-Turcotte-Pugh
DNA
Deoxyribonucleic acid
DS&E
Drug Safety & Epidemiology
EASL
European Association for the Study of the liver
EBV
Epstein-Barr virus
ECG
Electrocardiogram
EDC
Electronic Data Capture
ETV
Entecavir
eGFR
estimated Glomerular Filtration Rate
EMG
Electromyography
FAS
full analysis set
GCP
Good Clinical Practice
 


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HAV
Hepatitis A virus
HBeAb
Hepatitis Be antibody
HBeAg
Hepatitis Be antigen
HBsAb
Hepatitis B surface antibody
HBsAg 
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCG (β-HCG)
β-human Chorionic Gonadotropin
HCV
Hepatitis C virus
HDV 
Hepatitis D virus
HEV 
Hepatitis E virus
HIV
Human immunodeficiency virus type 1 and type 2
HSV
Herpes Simplex virus
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IFN
Interferon
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Randomization Technology
i.v.
intravenous
IVRS
Interactive Voice Response System
IWRS 
Interactive Web Response System
LAM
Lamivudine
LDT (LdT)
Telbivudine
LOQ
Lower Limit of Quantification
MedDRA
Medical Dictionary for Regulatory Activities
NLA
National Lipid Association
NSAID
Non-steroidal Anti-Inflammatory Drug
o.d.
once a day
PCR
Polymerase Chain Reaction
PNR
Primary Non-Response
 


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PK 
Pharmacokinetic
p.o.
oral
PPS
per protocol set
PPW
Premature patient withdrawal
PT
Prothrombin time
PTY
Patient treatment years
q.d.
quaque die (daily)
SAE
serious adverse event
SDD
Study drug discontinuation
SUSAR
Suspected Unexpected Serious Adverse Reactions
SPC
Summary of Product Characteristic
TB / TBil
total bilirubin
TDF
Tenofovir Disiproxil Fumarate
ULN
Upper Limit of Normal
VB
Virological breakthrough
WBC
White Blood cells
WHO 
World Health Organization
 


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Glossary of terms
AESI
For the purpose of this study, adverse events of special interest 
(AESI) include defined muscle-related events and renal function 
related events (Section 7.7)
ALT normalization
Elevated baseline ALT level return to below ULN during treatment
ALT flare
ALT elevation >10×ULN and >2×Baseline (AASLD definition)
Assessment
A procedure used to generate data required by the study
Baseline visit
Day 1 of treatment for patient schedule of events from which all 
subsequent visits are determined
Compliance (adherence) of the 
patient at each visit
The degree to which a patient correctly follows the intake of study 
drug according to the given schedule in the protocol. Using the pill 
or liquid volume count and the compliance questionnaire used by 
the investigator, the investigator will record whether compliance is 
good (≥90%), fair (70 – 89%) or poor (< 70%). 
Control drug
Drugs(s) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study 
validity, and/or evaluate comparative effects of the investigational 
drug
Copies/mL & IU/mL
1 IU/mL = 5.9 copies/mL
51 IU/mL = 300 copies/mL
29 IU/mL = 169 copies/mL
Early Discontinuation visit
Day of final clinical and laboratory evaluation during the Treatment 
phase if a patient has prematurely withdrawn from the study and 
includes all evaluations performed at Week 104 visit
eGFR
Estimated Glomerular Filtration Rate, evaluated with the 
abbreviated Schwartz formula (Schwartz 2009): 
Abbreviated Schwartz formula: eGFR = 0.413×(height/serum 
creatinine) (height in cm; serum creatinine in mg/dL)
Enrollment
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol)
Genotypic Resistance
On treatment drug related resistance mutation while not present at 
baseline in a compliant patient with confirmed virological 
breakthrough (VB), or with HBV DNA ≥300 copies/mL (51 IU/mL) at 
Week 24 and discontinued from the study treatment (or at 
discontinuation if prior to Week 24 for subjects with at least 16 
weeks of LDT treatment), and confirmed by genotypic sequencing.
HBV DNA reduction
Change of HBV DNA from Baseline
Investigational drug
The drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug” or “investigational 
medicinal product.”
Investigational treatment
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage 
or tested in a fixed combination. 
Investigational treatment generally does not include other 
 


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treatments administered as concomitant background therapy 
required or allowed by the protocol when used within approved 
indication/dosage
International normalized ratio
The INR is used to standardize the results of Prothrombin Time.
Medication number
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system
Subject Number 
A number assigned to each patient who enrolls into the study 
Part 
A subdivision of a single protocol into major design components. 
These parts often are independent of each other and have different 
populations or objectives. For example, a single dose design, a 
multiple dose design that are combined into one protocol, or the 
same design with different patient populations in each part.
PCR
An acronym for Polymerase Chain Reaction. PCR is a technique 
which is used to amplify the number of copies of a specific region 
of DNA, in order to produce enough DNA to be adequately tested.
Period
A subdivision of a cross-over study
Premature patient withdrawal
Point/time when the patient exits from the study prior to the 
planned completion of all investigational/study treatment 
administration and all assessments (including follow-up)
Primary Non-Response (PNR)
Treatment compliant patient with 12 weeks of treatment who fails to 
achieve a HBV DNA decline ≥ 1log10 copies/mL (1log10 IU/mL) from 
baseline for two consecutive visits is defined as Primary Non-
Response. 
Prothrombin Time (PT)
The Prothrombin time is used to evaluate the extrinsic pathway of 
coagulation. 
Randomization number
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stop study participation
Point/time at which the patient came in for a final evaluation visit or 
when study/investigational treatment was discontinued whichever 
is later
Study drug/ treatment
Any single drug or combination of drugs administered to the patient 
as part of the required study procedures; includes investigational 
drug (s), active drug run-ins or background therapy 
Study/investigational treatment 
discontinuation
Point/time when patient permanently stops taking 
study/investigational treatment  for any reason; may or may not 
also be the point/time of premature patient withdrawal
Variable
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified time 
points
Virological Breakthrough (VB)
An increase of HBV DNA ≥1 log10 copies/mL (1log10 IU/mL) above 
nadir (nadir=lowest on treatment HBV DNA value prior to the VB 
evaluation time point)
or
HBV DNA ≥300 copies/mL (51 IU/mL) after initial response with 
HBV DNA < 300 copies/mL (51 IU/mL)
Virological breakthrough should be confirmed on two consecutive 
visits within 4 weeks interval or at last on-treatment visit in non-
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Amendment 2
Amendment rationale
The purpose of amendment 2 is to add clarifications on the role of Data Monitoring 
Committee (DMC) and add clarifying wording for the timing of interim analyses.
Changes to the protocol
Protocol Section 3.5, Section 8.4, Section 9.6 and Section 9.7 are updated.
A copy of this amended protocol will be sent to the Institutional Review Boards (IRBs)/ 
Independent Ethics Committees (IECs) and Health Authorities. 
Summary of previous amendments 
Amendment 1
The main purpose of this amendment is to reflect a 
 request regarding one of the
inclusion criteria of the protocol. The request was made because of availability of an approved
medication for the treatment of compensated, chronic Hepatitis B infection in South Korea,
which eliminates children 12 years of age or older from study participation in South Korea. In
addition, a number of changes are introduced to clarify ambiguities in inclusion and exclusion
criteria and support improved enrollment in the study. Finally, a small number of editorial
changes are implemented in support of these protocol amendment changes and to clarify other
ambiguities in current language.
Although recruitment has been limited to date, it has become apparent from the experience of
the small number of sites that have begun to recruit patients that certain clarifications and
minor modifications to the protocol can greatly improve recruitment efforts.
The purpose of this amendment is to:
1. Update inclusion criteria for children enrolled in the Republic of South Korea by specified 
age groups to align with the availability of alternative treatments for CHBV infection for 
the specified age groups. It is also clarified that age limits apply to the study subject’s age 
at time of randomization.
2. Clarify serum ALT criteria for study inclusion – the current language of the protocol is
ambiguous, as it could be misinterpreted to allow for serum ALT samples to be repeated 
during the screening period. Eliminate the inclusion criterion for patients with normal 
ALT levels to substantiate moderate to severe hepatic inflammation by histology report or 
FibroScan.
3. Eliminate acute infection with HSV as exclusion criteria. Clarification was also made in 
the language concerning condom use by sexually active adolescents, as previous wording 
was not stated in a negative “exclusionary” manner.
4. Eliminate duplication of list of viral causes of infectious hepatitis (Exclusion Criteria 7
and 12).
5. Permit the inclusion of results of abdominal B-US performed within the month prior to
screening in lieu of the ultrasound to be performed at the screening visit.
 


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6. Clarify the timing of planned statistical analyses for the protocol and absence of a planned 
interim analysis in Sections 9.6 and 9.7 to align with Section 3.5.
7. Support provision of post-study medication to benefit patients where continued treatment 
is medically indicated and feasible from regulatory perspective.
8. Clarify the management of patient discontinuation and premature patient withdrawal.
9. Remove the Serum ALT requirements for eligibility criteria for placebo treated patients to 
start telbivudine treatment at week 28 (Section 5.2).
10. Reduce the number of required storage samples for assessment 
 in
patients with Virological Breakthrough and genetic sequencing.
11. Reduce the number of assays to rule out other viral infections with a potential to cause
hepatitis in order to align the protocol with current diagnostic practices and to reduce
required blood volume for diagnostic tests.
12. Extend screening period up to 10 weeks in cases of operational or administrative issues 
(e.g. blood samples not reaching central laboratory in good condition or lost specimens, 
that require replacement of samples, delay in obtaining results) in order to complete 
assessment of eligibility criteria.
13. Implement other minor editorial changes and updating the assessments and Table of
Events in Section 6 to reflect these changes.
 


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Protocol synopsis
Protocol number
CLDT600A2306
Title
A randomized, double-blind, 104-weeks treatment study to evaluate the 
efficacy, safety, tolerability and pharmacokinetics of telbivudine oral 
solution and tablets in children and adolescents with compensated 
HBeAg-positive and negative chronic hepatitis B virus infection
Brief title
Study of efficacy and safety, tolerability and pharmacokinetics of 
telbivudine in children and adolescents with compensated chronic hepatitis 
B virus infection 
Sponsor and Clinical 
Phase
Novartis 
Phase 3
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of the study is to assess the efficacy and safety of telbivudine 
at a dose of 20 mg/kg up to a maximum of 600 mg q.d. in compensated 
pediatric HBeAg-positive and negative CHB patients aged 2 to <18 years 
with the indication of antiviral CHB treatment. This study is part of the 
commitments of the pediatric development plan for telbivudine in Europe 
and US.
Primary Objective
The primary objective of this study is to demonstrate the antiviral efficacy 
of telbivudine compared to placebo in pediatric patients (2- < 18 years) by 
determining the percentage of patients achieving serum HBV DNA level of 
<300 copies/mL (51 IU/mL) at Week 24.
Secondary Objectives
The main secondary objectives are to assess 

the antiviral efficacy as evaluated by the proportion of patients 
achieving HBV DNA< 300 copies/mL (51 IU/mL) at Week 52 and 
Week 104

the biochemical response at Week 24, 52 and 104 as evaluated by 
proportion of patients whose baseline ALTs were abnormal and 
subsequently normalized

the serological response at Week 24, 52 and 104 (Proportion of 
HBeAg positive patients at baseline who subsequently have HBeAg 
loss and HBeAg seroconversion and proportion of HBsAg positive 
patients at baseline who subsequently have HBsAg loss and HBsAg 
seroconversion)

the percentage of patients achieving composite endpoints at Week 52 
and 104 (evaluated by HBV DNA < 300 copies/mL (51 IU/mL), ALT 
normalization and HBeAg seroconversion)

the cumulative rate of virological breakthrough (VB) at Week 52 and 
104

the presence of treatment emergent genotypic resistance associated 
with VB, or in patients with HBV DNA≥300 copies/mL (51 IU/mL) at 
Week
24 and discontinued from the study treatment (or at 
discontinuation if prior to Week 24 for subjects with at least 16 weeks 
of LDT treatment)
 


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
the safety and tolerability of telbivudine at Week 52 and 104 defined 
by AEs, SAEs, adverse events of special interest (AESI) (including 
muscle related events) and death; laboratory evaluations specifically 
on-treatment and post-treatment ALT flares, incidence and clinical 
significance of CK elevations; growth and development; development 
of liver decompensation and/or HCC
Study design
This protocol will enroll HBeAg positive and HBeAg negative patients into 
a randomized, double-blind and placebo-controlled study. A screening 
period of 6 weeks (which may be extended up to 10 weeks in case of 
operational or administrative issues) will be used to assess patient 
eligibility; patients will be treated for a total of 104 weeks and will have a 
12-weeks safety follow-up period.
Patients will be stratified by 1) age group and 2) HBV DNA level. 
Approximately 80% of patients with lower HBV DNA at screening (i.e. for 
HBeAg positive patients HBV DNA <9 log10 and HBeAg negative patients 
with HBV DNA <7 log10 copies/mL) are expected to be recruited.
Subsets of patients by age are defined as: Age group 1: from 2 to less 
than 6 years old; Age group 2: from 6 to less than 12 years old; Age group 
3: from 12 to less than 18 years old.
At the baseline visit, eligible patients will be randomized in a double blind 
method to telbivudine or placebo in a ratio 5:1. The total double-blind 
placebo-controlled period will be 24 weeks.
At Week 24 (visit 6), all patients will be unblinded and HBV DNA level will 
be assessed:

For telbivudine treated patients: Patients with HBV DNA <300 
copies/mL (51 IU/mL) at Week 24 will remain on telbivudine treatment 
until Week 104; Patients with confirmed HBV DNA ≥300 copies/mL (51 
IU/mL) at Week 24 will be discontinued from study drug at the next 
visit (Week 28).

For patients on placebo, eligibility to start telbivudine treatment will be 
checked at Week 24 (positive serum HBsAg at baseline and Week 24, 
for HBeAg positive patients: serum HBV DNA level ≥ 5 log10 copies/mL 
(or 20 000 IU/mL); for HBeAg negative patients: serum HBV DNA level 
≥ 4log10 copies/mL (or 2000 IU/mL) at Week 24 and patients will 
initiate treatment with telbivudine at Week 28. After 24 weeks on 
telbivudine treatment (at Week 52), HBV DNA level will be assessed. 
Patients with HBV DNA <300 copies/mL (51 IU/mL) will remain on 
treatment until last on-treatment study visit (Week 104); patients taking 
telbivudine with confirmed HBV DNA ≥300 copies/mL (51 IU/mL) will 
be discontinued from study after Week 52. Placebo patients not 
eligible to start treatment at Week 28 may continue to be followed in 
the study until Week 52 and start telbivudine treatment at a later visit 
until Week 52.
Population
The study population will be comprised of male or female patients between 
2 and <18 years of age (at time of randomization), with HBeAg-positive 
and HBeAg-negative CHB and compensated liver disease. In the Republic 
of South Korea, children aged 2 years to < 12 years only (at the time of 
randomization) will be enrolled. It is planned to randomize at least 150 
patients from multiple centers worldwide.
Inclusion criteria
Key inclusion criteria: 
 


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
Male or female outpatients between 2 and < 18 years of age (at the 
time of randomization), except in the Republic of South Korea, where 
children aged 2 years to < 12 years (at the time of randomization) only 
will be enrolled.

Clinical history compatible with compensated chronic hepatitis B 

Documented compensated
chronic hepatitis B defined by the 
following:
o
Positive serum HBsAg at screening and at least one other 
documentation of HBsAg positive at least 6 months prior to 
screening
o
For HBeAg positive patients at screening, significant biologic 
and/or histologic signs of disease activity following EASL 
guidelines recommendations for CHB pediatric patients (Sokal 
et al 2013)

serum HBV DNA level ≥ 5 log10 copies/mL (or 20 000 
IU/mL) (COBAS Taqman®) at screening as assessed 
by central laboratory and

serum ALT ≥ 1.5×ULN and < 10×ULN (pediatric ULN) 
either once during the screening period or twice (2 
times) within the 6 months prior to screening
o
For HBeAg negative patients at screening, significant biologic 
and/or histologic signs of disease activity following EASL 
guidelines recommendations for CHB pediatric patients (Sokal 
et al 2013) 

serum HBV DNA level ≥ 4 log10 copies/mL (or 2 000 
IU/mL) (COBAS Taqman®) at screening as assessed 
by central laboratory and

serum ALT ≥ 1.0 ×ULN and < 10×ULN (pediatric ULN) 
either once during the screening period or twice (2 
times) within the 12 months prior to screening
Exclusion criteria
Key exclusion criteria: 

Patients with acute or chronic infection of HCV, HDV, HIV, or with 
acute infection of HAV, HEV, CMV or EBV.

Patient 
has
received 
treatment 
of 
interferon 
or 
any 
other 
immunomodulatory agents within the last 12 months prior to screening

Patient has received treatment of any nucleoside or nucleotide drugs 
or other anti-CHB treatment (approved or investigational) at any time 
before screening 

Patient has a medical condition that requires frequent use of systemic 
acyclovir or famciclovir, systemic corticosteroids (topical and inhaled 
corticosteroids are allowed). 

Patient has a decompensated liver disease defined as a Child-
Turcotte-Pugh (CTP) Score ≥7 (Class B or C).

Patient has one or more additional known primary or secondary 
causes of liver disease, other than infectious agents, including 
alcoholic or non-alcoholic liver disease, fatty liver, hepatobiliary 
disease, Wilson disease and alpha-1 antitrypsin deficiency, Gilbert’s 
syndrome, Dubin-Johnson syndrome etc. 

Liver transplant recipients. Organ or bone marrow transplant 
recipients.
 


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
Patient is currently abusing illicit drugs, or has a history of illicit
substance abuse.

All patients are required to be abstinent from alcohol during the course
of the study otherwise excluded.

Patient has a medical condition requiring the chronic or prolonged use
of potentially hepatotoxic drugs or nephrotoxic drugs or chemotherapy

History of any other acute or chronic medical condition (including
congenital 
diseases, 
metabolic 
diseases, 
malignant 
diseases,
neurological disorders, nephrotic diseases, pancreatitis, autoimmune
disorders, diabetes, etc.) that in the opinion of the investigator would
make the patient unsuitable for inclusion into the study.

Patient has a history of myopathy, myositis, persistent muscle
weakness or persistent high serum CK levels (≥7×ULN), any muscular
disease including but not limited to congenital / metabolic etiology, or
with abnormal neuromuscular signs at screening or any screening CK
values suggestive of muscular disease, or age at which independent
walking time first achieved after 16 months of age (based on birthday).

Patient receiving any drugs potentially associated with myopathy (e.g.,
chloroquine, hydroxychloroquine, HMGCoA reductase inhibitors, fibric
acid derivatives, penicilamine, zidovudine, cyclosporine, erythromycin,
niacin, azole antifungals, etc) within 3 months prior to screening

Any other clinical significant disease, condition or abnormality,
unrelated to their HBV infection at screening, as assessed by the
investigator, including:

Hemoglobin < 11 g/dL (110g/L) for males or < 10 g/dL (100g/L) for
females

Total WBC < 3,500/mm3  (3.5×109/L)

Absolute neutrophil count (ANC) < 1,500/mm3 (1.5×109/L)

Platelet count < 120,000/mm3 (120×109/L)

Prothrombin time prolonged by more than 3 seconds (based on
ULN; of the reference value); or INR > 1.5

Serum amylases or lipase  ≥ 1.5×ULN

Serum albumin (<3.5g/dL); (<35g/L)

Total bilirubin (≥ 2.0 × ULN )

estimated GFR < 50 mL/min using Schwartz formula

Serum phosphate < 1.5 mg/dL
Investigational and 
reference therapy
Patients will be assigned to one of the two treatment arms in a ratio 5:1
Arm 1: Telbivudine: 

patients of any age and weight < 30kg: telbivudine oral solution (20
mg/mL): 20 mg/kg up to 600 mg q.d. corresponding to weight (kg)
x1mL, p.o. once daily

patients < 12 years old and weight ≥ 30kg: telbivudine oral solution
(20mg/mL), 600 mg/day corresponding to 30 mL p.o. once daily

patients ≥ 12 years old and weight ≥ 30kg: telbivudine film-coated
tablet, 600 mg/day, corresponding to 1 tablet p.o. once daily
Arm 2: Placebo: 

patients of any age and weight < 30kg: placebo oral solution
 


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corresponding to weight (kg) x1mL, p.o. once daily

patients < 12 years old and weight ≥ 30kg: placebo oral solution
corresponding to 30 mL p.o. once daily

patients 
≥ 12 years old and weight ≥ 30kg: placebo tablet,
corresponding to 1 tablet p.o. once daily
Efficacy 
assessments
Key efficacy assessments include:

Serum HBV DNA level

HBV Serologic markers; HBsAg/Ab and HBeAg/Ab

ALT

VB and Resistance surveillance
Safety assessments
Key safety endpoints include:

Proportion of patients that discontinue study drug or require dose
interruption due to treatment-emergent AEs

Proportion of patients who develop SAEs

Proportion of patients who develop Grade 3-4 AEs and AEs
related to study drug  (and if study drug temporarily interrupted)

Proportion of patients who develop AESI (muscle related events)

Other classical adverse events related to anti-HBV nucleos(t)ides
analogues (including peripheral neuropathy, ALT flare, lactic
acidosis, acute pancreatitis and hypersensitivity reactions)

Proportion of patients with hepatic decompensation  or HCC

Proportion of patients who develop Grade 3-4 chemistry
abnormality (including CK, ALT, AST, ALP, TB, PT, serum
creatinine, serum cystatin C, serum phosphate, blood glucose),
urinalysis abnormality and  Grade 3-4 hematology abnormalities
Other safety assessments include physical exams (including growth 
(including Body weight, Body height and BMI) and development (Tanner 
Score),vital signs and pregnancy monitoring
Data analysis
The primary analysis will be performed when all patients complete Week 
24. An additional analysis will be performed when all patients complete
Week 52 and a report generated. Final analysis will be performed at the
end of study including the 12 -week follow-up period after Week 104
treatment completion.
The primary objective of the study is to demonstrate the antiviral efficacy 
of telbivudine compared to placebo in pediatric patients (2 - < 18 years) by 
determining the percentage of patients achieving serum HBV DNA level of 
<300 copies/mL (51 IU/mL) at Week 24. The Fisher Exact test method will 
be used to evaluate the null hypothesis (proportion of patients in the 
overall population achieving HBV DNA <300 copies/mL (51 IU/mL) in the 
telbivudine arm is not different from in the placebo arm) and the alternative 
hypothesis (the proportion of patients in the overall population achieving 
HBV DNA <300 copies/mL (51 IU/mL) between the two groups is not the 
same). Two sets of supportive analyses will be performed: (1) analysis on 
 


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Per Protocol set and (2) Age by baseline HBV DNA strata (low vs. high) 
adjusted estimate, using Mantel-Haenszel weighted estimated method. 
The primary analysis will be done when all patients complete Week 24 of 
study and the final analysis will be done when all patients complete Week 
104 of study.
Secondary efficacy variables will be summarized by treatment groups; for 
Week 24 treatment comparison, dichotomous variables will be analyzed 
with Fisher’s Exact Test, similar to primary efficacy analysis, and 
continuous variables will be analyzed with Analysis of Covariance 
(ANCOVA) 
model, 
including 
treatment, 
stratification 
factors,  
country/region and baseline values as co-factors. Time to event variables 
will be analyzed using survival analysis (Kaplan-Meier estimates).
The safety analyses will be based on AEs, laboratory values, physical 
exams and vital signs. All safety data will be summarized by treatment 
group.  
Key words
Chronic hepatitis B, pediatrics, antiviral treatment, telbivudine
 


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1
Introduction
1.1
Background
Epidemiology and natural history of pediatric HBV infection
More than 240 million people worldwide have chronic hepatitis B (CHB) infection (WHO 
2013). The World Health Organization (WHO) and the World Gastroenterology Organization 
(WGO) recommend joint immune-prophylaxis with the hepatitis B vaccine (HBVac) and 
HBIG to prevent mother-to-child transmission (MTCT) of HBV. Despite the introduction of 
universal infant vaccination since 1990, hepatitis B infection in children has not been 
eradicated (Haber et al 2009). Approximately 10% to 15% of neonates born to HBV infected 
mothers suffer from HBV infection through intrauterine transmission (Farmer et al 1987; 
Grosheide et al 1993).
Children at risk for hepatitis B virus (HBV) infection include 1) those born to a mother who 
has CHB or 2) who are not vaccinated or not given immune globulin, or 3) had an inadequate 
response to perinatal treatment or vaccination, or 4) were exposed prior to being vaccinated 
(Jonas et al 2010). 
The likelihood of chronic HBV infection in children is mainly determined by effectiveness of 
vaccination, the child’s age at acquisition and by the transmission route. The likelihood of 
chronicity of HBV infection is almost 90% in patients infected by mother-to-child 
transmission; 25-50% in children between the ages of 1 to 5 years of age, and about 6 to 10% 
in older children (Jonas et al 2010). A Japanese survey has categorized the route of 
transmission of HBV to pediatric patients into five types of transmission: maternal, intra-
familial horizontal, iatrogenic horizontal, other horizontal, and unknown (Litsuka et al 2010). 
Recently, a large, multi-center, cross-sectional study (LDT600A2414) designed to collect 
epidemiological data in 1640 patients with CHB aged 2 to <18 years showed that the majority 
of patients were Hepatitis B e-Antigen (HBeAg) positive, and older than 7 years (Zhang et al 
2012).
Among adults who acquired CHB as an infant or child, ~ 15% to 25% overall die of 
premature liver-disease-related death (Haber et al 2009). Patients infected by HBV during 
childhood who have evidence of ongoing viral replication are at the highest risk for 
development of progressive liver disease (Hsieh et al 1992).
Antiviral treatment goals and indication in pediatric CHB
HBV infection in children presents a therapeutic challenge for the practitioner. Decisions 
regarding selection of patients who may benefit from treatment, appropriate timing of 
treatment, and the choice of antiviral therapy are complex and are confounded by the limited 
number of therapies that have been studied in children (Jonas et al 2010). 
The current goals of antiviral therapy in children with CHB are to suppress viral replication, 
reduce liver inflammation, and reverse liver fibrosis, and thereby protect the liver. Treatment 
is geared toward reducing viral load until serum HBV DNA levels become undetectable by a 
sensitive polymerase chain reaction (PCR) assay and, for patients who are HBeAg-positive, 
 


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achieving durable HBeAg seroconversion. Another desirable endpoint is normalization of 
alanine aminotransferase (ALT) level, indicative of improvement in liver histology. Hepatitis 
B surface antigen (HBsAg) seroconversion occurs in a minority of persons receiving 
treatment, but it is the ultimate therapeutic goal because the risk of hepatocellular carcinoma 
(HCC) is reduced (Jonas et al 2010).
For children in the immune active or reactivation phases (mostly characterized by high HBV 
DNA and elevated ALT), liver histology can help guide treatment decisions, and family 
history of liver disease, especially hepatocellular carcinoma, may argue for early treatment in 
some cases. There are a few situations when treatment is indicated regardless of HBV DNA or 
alanine aminotransferase levels such as glomerulonephritis due to HBV infection, liver 
transplantation, immunosuppression or chemotherapy, etc. There is still much to be elucidated 
about the appropriate use of HBV therapy in children. Until more clinical data and therapeutic 
options are available, a conservative approach is warranted (Jonas et al 2010).
At this time, there is no established benefit of treatment for children in the immune tolerant 
phase which is characterized by high HBV DNA but persistent normal ALT levels (Jonas et al 
2010). In addition, there is no indication for antiviral treatment of children in the “inactive 
HBsAg carrier” state which is characterized by undetectable or low HBV DNA and normal 
ALT levels (Jonas et al 2010).
Current treatment options
There are now seven drugs worldwide approved for treatment of adult patients with CHB: two 
forms of interferon (i.e., common IFN alfa and peg interferon alfa (peg-IFN)), as well as five 
nucleos(t)ide analogues: lamivudine (LAM), adefovir dipivoxil (ADV), entecavir (ETV), 
telbivudine (LDT), and tenofovir disoproxil fumarate (TDF).  None of these seven drugs is 
currently approved in Europe for the treatment of children suffering from CHB. LAM, ADV, 
TDF and common IFN-alfa are approved in the US for use in pediatric patients with CHB.  In 
the US, lamivudine may be used from 2 to 17 years of age, adefovir and tenofovir for those 
aged 12 years and older, and common IFN-alfa for patients as young as 12 months of age. 
Treatment is not usually required for children under the age of 1 year.
In the randomized, open-label, placebo-controlled study of LAM, after 52 weeks of treatment 
23% of children in the LAM group (n=191) vs. 13% in the placebo group (n=95) (p=0.04) 
achieved virologic response (i.e., undetectable HBV DNA and HBeAg loss). At Week 52, 
61% patients in the LAM group vs. 16% in placebo group (p < 0.001) achieved undetectable 
HBV DNA rates (based on branched-chain DNA assay with a lower limit of detection of 0.7 
meq / mL, approximately 7 ×105 copies/mL) (Jonas et al 2002). 
In the multicenter, randomized, double-blind, placebo-controlled ADV pivotal trial in 
pediatric CHB patients, at the end of 48 weeks 19.1% of the patients in the ADV group 
(n=115) vs. 1.7% in the placebo group (n=58) (p< 0.001) reached the primary endpoint of 
serum HBV DNA <1,000 copies/mL and normal ALT. At Week 48, 11% in the ADV group 
vs. 2% in placebo group (no p value in the reference) achieved HBV DNA undetectable rates 
(based on COBAS Taqman® assay with a lower limit of quantitation of 29 IU/mL, equivalent 
to 169 copies/mL) (Jonas et al 2008). 
 


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In the multicenter, randomized, double-blind, placebo-controlled phase III pivotal trial in 
adolescent CHB patients aged 12 to < 18 years; at Week 72, 89% of TDF treated patients 
(n=52) vs. 0% in placebo treated patients (n=54) achieved HBV DNA < 400 copies/mL 
(Murray et al 2012).
A phase 2b ETV pharmacokinetics and efficacy clinical trial in patients as young as 2 years 
old, as well as a phase 3 study are currently underway (Jonas et al 2010).
In the multinational, randomized, open-label, placebo-controlled trial of IFN-alfa therapy in 
pediatric CHB patients, 26% of IFN treated children (n=72) vs. 11% of untreated controls 
(n=77) (p=0.029) became HBeAg and HBV DNA negative at the end of 24 weeks of 
treatment. At Week 24, 22.9% in IFN vs. 6.5% in placebo group (no p value in the reference) 
achieved undetectable HBV DNA rates (based on liquid hybridization technique that detects 
viral genome at levels at or above 1.6pg/mL, approximately 4×105 copies/mL) (Sokal et al 
1998).
Epidemiological survey: CLDT600A2414
The study CLDT600A2414 was a cross-sectional, epidemiological multi-center retrospective 
data collection survey in Western and Asian countries in pediatric patients with chronic HBV 
infection aged from 2 to <18 years. This survey was conducted to support the feasibility of 
conducting the phase III pediatric clinical development program for telbivudine, and to 
adequately design future studies part of Novartis telbivudine clinical pediatric program. The 
survey was initiated in June 2009 involving 80 centers and was closed in September 2011, 
after 1640 patients enrolled from 17 countries.
The main results were summarized as below:
Demographic
The mean age was 11.8 years. Most patients were aged 13 to < 18 years (52.6%), children 
aged 2-6 years represented 17.3% and children aged 7-12 year represented 30.1%.
Disease Status
The majority of patients were HBeAg-positive (54.4%) vs HBeAg negative (32.4%). For the 
892 HBeAg positive, the HBV DNA level of the three measurements was < 9 log10 copies/mL
in 84-88% of patients and for the 532 HBeAg negative patients, HBV DNA level was <7 log10
copies/mL in 87-93% of patients . 
The disease was stable for the majority of patients (disease progression over the last 12 
months was reported in 4.2% of the overall population). The ALT level was low for the 
majority of patients (ALT < 63-66 IU/L in 75% of HBeAg positive patients and ALT< 40-50 
IU/L in 75% of HBeAg negative patients).
Treatment status
About 37.3% of patients previously received treatment or currently receiving treatment during 
the survey with a higher proportion in 13-<18 year age group (42.8%) as compared to 2-6 
year age group (31.4%) and 7-12 year age group (31.2%) . 
New diagnosed or clinically managed CHB patients
 


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On 78 centers the mean number of patients aged from 2 to < 18 years newly diagnosed with 
HBV per year was 43 in 2008, 40 in 2007 and 38 in 2006. The mean number of clinically 
treated patients for HBV was 43 in 2008, 41 in 2007 and 40 in 2006.
Summary
The results of the epidemiological study provide a comprehensive understanding of chronic 
HBV infection in the pediatric population worldwide and provide basic information on the 
feasibility for clinical trials in pediatric CHB patients. 
Based on 1640 enrolled pediatric CHB patients from 80 clinical sites, this epidemiological 
survey reported the key patient’s characteristics:

The disease prevalence was higher for patient from age group 13 - <18 years (52.6%)

The majority of patients were HBeAg positive with a majority of them having an HBV 
DNA <9 log10 copies/mL (84-88%)

The disease progression over last 12 months was stable for the majority (>80%) of 
patients in all countries assessed 
Telbivudine introduction
Telbivudine (Sebivo®/Tyzeka®) is approved for the treatment of CHB in adult patients with 
compensated liver disease and evidence of viral replication, persistently elevated serum ALT 
levels and histological evidence of active inflammation and/or fibrosis (Telbivudine CDS). 
Telbivudine (β-L-2'-deoxythymidine; LdT), is a deoxynucleoside with the L-configuration of 
thymidine and a highly specific and potent inhibitor of HBV replication in vitro (Bryant et al 
2001). Robust data from preclinical and clinical studies in adults indicate that telbivudine 
provides effective antiviral activity with a favorable safety profile. 
In the pivotal GLOBE trial, a phase III randomized, double-blind, active-controlled study to 
compare telbivudine versus LAM, telbivudine demonstrated statistically significant 
superiority over LAM in HBeAg-positive and HBeAg negative adults patients on most key 
study endpoints after 52 and 104 weeks, respectively (Lai et al 2007; Liaw et al 2009).
There are 2 formulations of telbivudine, 600 mg film-coated tablets and 20 mg/mL oral 
solution. The recommended telbivudine dose in adult patients with chronic hepatitis B is 600 
mg administered once daily.
A phase I pharmacokinetics study (CLDT600A2104) of Sebivo® 20mg/mL oral solution has 
explored the pharmacokinetics and safety of a single dose of telbivudine in pediatric CHB 
patients.  Based on the data from this study in subjects aged 2 to <18 years a dose of 20mg/kg 
up to a maximum of 600 mg/day would give exposure to telbivudine in children similar to that 
which has been demonstrated to be safe and effective for the treatment of CHB in adults 
(Section 3.3).
Telbivudine is readily bioavailable following oral administration, is rapidly absorbed, and 
widely distributed throughout the body, and exhibits dose-proportional pharmacokinetics and 
dose/exposure-related anti-HBV activity. The oral solution and the tablet formulations are 
bioequivalent and approved for marketing in multiple countries.
More details about telbivudine are provided in the IB (Sebivo IB).
 


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1.2
Purpose 
The purpose of the study is to assess the efficacy and safety of telbivudine at a dose of 20 
mg/kg up to a maximum of 600 mg q.d. in compensated pediatric HBeAg-positive and 
negative CHB patients aged from 2 to <18 years with the indication to antiviral CHB 
treatment. This study is part of the commitments of the pediatric development plan for 
telbivudine in Europe and US.
2
Study objectives
2.1
Primary and key secondary objectives
The primary objective of this study is to demonstrate the antiviral efficacy of telbivudine 
compared to placebo in pediatric patients by determining the percentage of patients achieving 
serum HBV DNA level of <300 copies/mL (51 IU/mL) at Week 24.
2.2
Secondary objectives
The secondary objectives of this study are:
1. To assess the antiviral efficacy as evaluated by:
a.
Proportion of patients achieving HBV DNA <300 copies/mL (51 IU/mL) at Week 
52 and Week 104
b. Proportion of patients achieving HBV DNA < Lower Limit of Quantification 
(LLOQ) (< LLOQ defined as undetectable HBV DNA, ≥ LLOQ defined as 
detectable HBV DNA), <1000 copies/ml (or 200 IU/mL), <10,000 copies/ml (or 2 
000 IU/mL) and ≥10,000 copies/mL (or 2 000 IU/mL) at Week 24, 52 and 104
c.
Serum HBV DNA reduction from baseline 
d. Time to achieve HBV DNA <300 copies/mL (51 IU/mL)
e.
Proportion of patients with Primary non-response
2. To assess the biochemical response at Week 24, 52 and 104 as evaluated by proportion of 
patients whose baseline ALTs were abnormal (defined as ALT >1 x Upper Limit of 
Normal [ULN]) and subsequently normalized 
3. To assess the serological responses at Week 24,  52 and 104 as evaluated by:
a.
Proportion of HBeAg positive patients at baseline who subsequently have HBeAg 
loss and HBeAg seroconversion (defined as loss of HBeAg with detectable 
HBeAb) 
b. Proportion of HBsAg positive patients at baseline who subsequently have HBsAg 
loss and HBsAg seroconversion (defined as loss of HBsAg with detectable 
HBsAb) 
4. To assess the percentage of patients achieving composite endpoints at Week 52 and 104:
a.
HBV DNA <300 copies/mL (51 IU/mL), ALT normalization and HBeAg 
seroconversion for HBeAg positive patients only 
b. HBV DNA <300 copies/mL (51 IU/mL) and ALT normalization for HBeAg 
negative patients
 


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5. To assess virological breakthrough (VB) as evaluated by:
a.
Cumulative rate of patients with confirmed VB at Week 52 and 104  
b. Time to VB 
6. To assess the presence of treatment emergent genotypic resistance associated with 
virological breakthrough over the study period, or in patients with HBV DNA≥300 
copies/mL (51 IU/mL) at Week 24 and discontinued from the study treatment (or at 
discontinuation if prior to Week 24 for subjects with at least 16 weeks of LDT treatment)
7. To evaluate the safety and tolerability of telbivudine at Week 52 and 104 defined by AEs, 
SAEs, adverse events of special interest (AESI) (including muscle related events) and 
death; laboratory evaluations specifically on-treatment and post-treatment ALT flares, 
incidence and clinical significance of CK elevations; growth and development (linear 
growth and sexual maturation); development of liver decompensation and/or HCC
3
Investigational plan
3.1
Study design
This protocol will enroll HBeAg positive and HBeAg negative patients into the randomized, 
double-blind and placebo-controlled, 104-weeks treatment study. A screening period of 6-10
weeks will be used to assess patient eligibility. Patients will be treated for a total of 104 weeks 
and will have a 12-weeks safety follow-up period.
Patients will be stratified by 1) age group and 2) HBV DNA level. Approximately 80% of 
patients with lower HBV DNA at screening (i.e. for HBeAg positive patients HBV DNA <9 
log10 and HBeAg negative patients with HBV DNA <7 log10 copies/mL) are expected to be
recruited.
Subsets of patients by age (calculated based on birthday at randomization visit [baseline: 
day1]) are defined as:

Age group 1: from 2 to less than 6 years old

Age group 2: from 6 to less than 12 years old

Age group 3: from 12 to less than 18 years old
 


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At Baseline (visit 2), eligible patients will be randomized in a double blind method to 
telbivudine or placebo in a ratio 5:1. The total double-blind period will be 24 weeks. 
At Week 24 (visit 6), all patients will be unblinded (see Section 5.4):

patients receiving telbivudine with HBV DNA <300 copies/mL (51 IU/mL) at Week 
24 (visit 6) will remain on telbivudine treatment until Week 104 (visit 13); 

patients receiving telbivudine treatment with confirmed HBV DNA ≥300 copies/mL
(51 IU/mL) at Week 24 ( visit 6) will be discontinued from study drug at the next visit 
(Week 28) as described in Section 5.5.9.

for patients on placebo, eligibility will be checked at Week 24 (visit 6):
o
Patients with confirmed eligibility will initiate treatment with telbivudine at 
Week 28 (visit 7). After 24 weeks on telbivudine treatment (Week 52 (visit 9), 
HBV DNA level will be assessed. Patients with HBV DNA <300 copies/mL 
(51 IU/mL) will remain on treatment until last on-treatment study visit (Week 
104 (visit 13)); patients with HBV DNA ≥300 copies/mL (51 IU/mL) will be 
discontinued from the study at Week 52 (visit 9) as described in Section 5.5.9. 
o
Placebo patients not eligible for telbivudine treatment at Week 28 (visit 7) may 
continue in the study until Week 52 (visit 9) and may start telbivudine 
treatment at a later visit until Week 52 (visit 9) based on investigator’s decision 
and patient agreement
Figure 3-1
Study design*
*Note: Screening period may be extended up to 10 weeks in case of operational or administrative issues.
3.2
Rationale of study design
This protocol will evaluate HBeAg positive and HBeAg negative patients with randomized, 
double-blind, and placebo-controlled design. A randomized double-blinded study design is 
well-established for the class of drug investigated. Patients and investigator will be blinded to 
treatment for 24 weeks and the primary efficacy endpoint will be assessed at Week 24.
Immunotolerant patients defined as HBeAg-positive, with high serum levels of HBV DNA 
and normal serum ALT are generally considered as not eligible for treatment. Abnormal ALT 
 


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for at least 6 months (12 months if HBeAg-negative) is the recommended criterion for study 
inclusion (Sokal et al 2013).
EASL guidelines and current clinical practice in adults recommend HBV DNA monitoring at 
least every 6 months during treatment with telbivudine. These guidelines also point out that 
virologic response (undetectable HBV DNA <300 copies/mL) at 24 weeks is associated with 
a lower incidence of resistance. Zoulim et al., reported that telbivudine treated adult patients 
with specific baseline characteristics (HBV DNA <9log10 copies/mL and ALT ≥2×ULN in 
HBeAg positive patients; HBV DNA <7log10 copies/mL for HBeAg negative patients) and 
undetectable HBV DNA (<300 copies/mL) after 24 weeks of treatment had no resistance at 
Week 52 and very low resistance (2%) at Week 104 (Zoulim et al 2012). The stratification 
procedure will be used to achieve a distribution of approximately 80% of recruited patients 
with lower HBV DNA at screening (HBV DNA <9 log10 for HBeAg positive patients and 
with HBV DNA <7 log10 copies/mL for HBeAg negative patients).
EASL guidelines also recommend that in case of detectable HBV DNA at Week 24, 
telbivudine treated adults patients should be intensified with nucleotides (TDF or ADV). 
Currently none of the marketed nucleotides (tenofovir or adefovir) have an approved 
indication for pediatrics in the EU (EASL 2012). Therefore intensification is not an option in 
this trial and patients with HBV DNA ≥300 copies/mL (51 IU/mL) after 24 weeks of 
telbivudine treatment will be discontinued from study and handled at the discretion of treating 
physicians (see Section 5.5.9).
Based on treatment monitoring recommendation with telbivudine, treatment stopping rule has 
to be applied at Week 24. In addition, since patients on the placebo arm will be given the 
option of telbivudine treatment at Week 24, it is required to unblind patient’s treatment after 
24 weeks of treatment.
There is no indication for treatment of children in the “inactive HBsAg carrier” state which is 
characterized by undetectable or low HBV DNA and normal ALT levels (Jonas et al 2010). 
Following consultation with experienced CHB pediatricians, there is a clear consensus that 
HBeAg negative children are hardly eligible for antiviral treatment since most of them have 
low HBV DNA levels and normal ALT levels (Jonas et al 2010). Few patients are expected 
from this population and therefore the primary endpoint will be analyzed on the entire 
population including both HBeAg positive and negative patients.
Following Health authorities requirements, the study design has been agreed with the 
followings:

HBeAg positive patients with HBV DNA > 5 log10 copies/mL (or 20 000 IU/mL) and 
HBeAg negative with HBV DNA > 4 log10 copies/mL (or 2 000 IU/mL), can be eligible
(based on epidemiological survey (CLDT600A2414), 80% of patients with lower HBV 
DNA at screening are expected to be recruited). 

All patients with confirmed HBV DNA ≥300 copies/mL (51 IU/mL) after 24 weeks of 
telbivudine treatment will be discontinued from the study. 
 


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3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
Single- and multiple-dose pharmacokinetics of telbivudine has been evaluated in healthy 
adults and in adults with chronic HBV infection. Telbivudine pharmacokinetics is similar in 
both populations. Telbivudine pharmacokinetics are dose proportional over the range of 25 
mg to 1800 mg. Steady state is achieved after 5 to 7 days of once daily administration with an 
approximate 1.5-fold accumulation in systemic exposure. Inter-subject variability (CV %) for 
measures of systemic exposure (Cmax, AUC) was typically ≤30%. A pivotal bioequivalence 
study (NV-02B-025) showed that the FMI (final market image, 600-mg tablets) formulation is 
bioequivalent to the oral solution (30 mL x strength 20 mg/mL).
CLDT600A2104 was a single dose safety and pharmacokinetics study of telbivudine given as 
oral solution at either 15 or 25 mg/kg up to a maximum dose of 600 mg/day in HBsAg 
positive children aged 2 to < 18 years.  Extensive plasma PK samples (a total of 10 time 
points) were collected from each patient up to 120 hours post dosing. Twenty three children 
were enrolled and evaluated for safety, tolerability, and pharmacokinetic parameters. There 
were no significant safety issues identified in the study. Pharmacokinetic parameters in 
pediatric patients derived from study CLDT600A2104 along with the PK parameters obtained 
from a previous PK study (NV-02B-025) in healthy adults are summarized in Table 3-1.
Table 3-1
Comparison of PK parameters of telbivudine in Adults and Children 
by Age Groups
PK 
parameters
n
Tmax
(h)
Cmax
(ng/mL)
AUC0-24h
(ng.h/mL)
AUClast
(ng.h/mL)
AUCinf
(ng.h/mL)
T1/2
(h)
CLDT600A2104   >12-< 18 years dosed with 600 mg oral solution
Mean
8
2.59
3510
22300
26800
27700
38.7
SD*
(1.97-4.00)
1190
5720
6590
6830
7.42
CV%
33.9
25.7
24.6
24.6
19.1
CLDT600A2104   6-12 years dosed with 15 mg/kg oral solution
Mean
4
2.53
3290
17600
20700
21500
36.2
SD
(1.83-3.00)
748
3400
4550
4610
6.8
CV%
22.7
19.3
22.0
21.5
18.8
CLDT600A2104   6-12 years dosed with 25 mg/kg oral solution
Mean
4
2.48
5430
33100
39700
40500
28.0
SD
(1.92-3.00)
1530
9530
9760
9680
7.03
CV%
28.2
28.8
24.6
23.9
25.1
CLDT600A2104   2-<6 years dosed with 15 mg/kg oral solution
Mean
6
2.00
2910
17900
21200
22100
29.9
SD
(1.28-3.03)
453
3550
4520
4760
10.5
CV%
15.6
19.8
21.3
21.6
35.2
CLDT600A2104   2-<6 years dosed with 25 mg/kg oral solution
Mean
1
4.00
2440
15300
19900
20400
28.3
NV-02B-025 in adults dosed with 600 mg oral solution
Mean
23
3.00
3456
25437
30752
32440
43.8
SD
(2.00-6.00)
1170
7457
8032
8444
11.1
 


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PK 
parameters
n
Tmax
(h)
Cmax
(ng/mL)
AUC0-24h
(ng.h/mL)
AUClast
(ng.h/mL)
AUCinf
(ng.h/mL)
T1/2
(h)
CV%
33.9
29.3
26.1
26.0
25.3
*Median and range are reported for Tmax
Compartmental analysis of the single dose data from the enrolled children was performed to 
predict the steady state exposure of telbivudine in pediatric patients based on the above PK 
data. Plasma telbivudine concentration versus time profiles for children aged 2 to 12 years 
administered a single 15 mg/kg dose of telbivudine and for children aged >12 to < 18 years 
administered a single 600 mg of telbivudine were fitted to a two-compartment 1st order, 
micro-constant, lag time, 1st order elimination PK model (WinNolin version 5.2). Following 
20 mg/kg/day and 600 mg/day oral administration for children age 2 to 12 years and children 
age >12 to < 18 years, respectively, the model predicted systemic, steady state telbivudine 
exposures that closely matched those observed in healthy adults receiving 600 mg of 
telbivudine once daily. The summary predicted steady state pharmacokinetic parameters for 
all the children as compared to the target exposure in adults receiving the approved dose of 
600mg/day, is presented in Table 3-2.
Table 3-2
Comparison of predicted LDT600 pharmacokinetics at the steady state 
in children age 2 to < 18 years to a historical study of healthy adults
PK parameters
Dose
Tmax
(h)
Cmax
(ng/mL)
AUC0-24h
(ng.h/mL)
Ctrough
(ng/mL)
Adultsa
600 mg/day
2 (1-4)b
3690±1250
26100±7200
200-300
Children (2 to 12 
years)
20 mg/kg/day
2.10
3750±1120c
28300±8490c
268-280
Children (>12 to < 
18 years)
600 mg/day
2.16
3340±1000c
25070±7520c
227-244
a All values from US label. b Mean (range). 
c Estimation of SD based on typical inter-patient variability (CV 30%) for LDT600
The study result of a daily dose of 20 mg/kg for children was in the middle of the range 
predicted by comparing the telbivudine CL/F in children and adults based on previous 
experience with extrapolation of renally excreted nucleosides, such as lamivudine, from adults 
to children. In adults, a 600 mg dose (average 7.5 mg/kg) of telbivudine produces an AUC 0-∞
of approximately 23,000 ng/mL*h (AUC0-24h, ~20,000 ng/mL*h). To achieve similar 
exposures in children 2-6 years old, a weight-based dose of 21–27 mg/kg was predicted; for 
the 7–12 year age group a dose of 13–20 mg/kg was proposed. The full analysis with the final 
data on all 23 subjects agrees with the preliminary analysis that a dose of 20 mg/kg up to a 
total of 600 mg of telbivudine will result in similar exposure in children from age 2- < 18 
years as observed in previous clinical studies conducted in adults receiving the marketed dose 
of 600 mg/day. This assessment is based on the plasma exposure results from all the children, 
the linear pharmacokinetics of telbivudine, and extrapolation of the data by standard 
pharmacokinetic modeling methods. 
The prior relationship established in adults of telbivudine exposure and the antiviral activity  
at Week 4 (Zhou et al 2006) indicated a significant sigmoid-Emax exposure response 
relationship with 50% of maximal antiviral activity  (EC50) at a steady state AUC0-t of 410+/-
 


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140 ng*h/mL. This is below the steady AUC0-t of a 25mg daily dose. The maximal antiviral 
effect plateaued rapidly with 99.9% reduction in viral load (3 log10) from baseline predicted at 
an AUC0–t of 3360 ng*h/mL which below the exposures achieved by a dose of 100 mg/day.
The comparable exposure of telbivudine in children to adults based on the pharmacokinetic 
data detailed above and the modeling is predicted at the recommended dosing of 20mg/kg up 
to a maximum of 600mg/day (Table 3-2). The exposure from the recommended dosing is 
expected to lead to the antiviral activity and safety established from the adult exposures. As 
noted in Table 3-2 the variability in PK parameters is similar. 
The current study has 2 year treatment duration, which has been agreed with Health 
Authorities in line with treatment guidelines as being the treatment period required for safety 
and efficacy evaluation in pediatrics.
3.4
Rationale for choice of comparator
Out of the seven drugs approved worldwide for the treatment of CHB in adults (two forms of 
interferon (IFN alfa and peg-interferon alfa), and five nucleos(t)ide analogues (LAM, ADV, 
ETV, LDT and TDF)), none are currently approved in Europe for the treatment of children 
suffering from CHB. In the US, lamivudine is indicated for patients from 2-17 years of age, 
adefovir and tenofovir are labeled for children aged 12 years and older and common IFN-alfa 
is approved for use in children as young as 12 months of age. 
No antiviral drug is approved worldwide to be used as control drug in an international 
multicenter phase III trial in pediatrics CHB patients. Therefore placebo will be used as 
comparator as agreed with European and US Health Authorities. 
Placebo was used as a comparator in the pivotal phase III studies of IFN, LAM, ADV and 
TDF, as well as in most recent phase III study for other antiviral (ETV) treatments (Sokal et al 
1998; Jonas et al 2002; Jonas et al 2008; Murray et al 2012).
In the current study, the placebo arm is 6 months delayed treatment arm. All patients initially 
randomized to placebo will be provided with telbivudine treatment at Week 28 if they are still 
eligible for antiviral treatment at Week 24; patients not eligible for telbivudine treatment at 
Week 24 may start telbivudine treatment at a later visit until Week 52 based on investigator’s 
decision and patient agreement. 
3.5
Purpose and timing of interim analyses/design adaptations
Interim analyses are planned for weeks 24 (primary analysis) and 52. 
A DMC is planned to conduct regular safety data review for patient monitoring and where 
appropriate, to request and review additional safety and/or efficacy analyses (See Section 8.4).  
The DMC may request information on the current status of the study at any time according to 
their mission.
 


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3.6
Risks and benefits
Benefits
The short-term benefits of antiviral therapy in children with CHB are to suppress viral 
replication, reduce liver inflammation, and reverse liver fibrosis, thereby protecting the liver. 
The long-term benefit is to reduce the risk of end stage liver disease including decompensated 
liver cirrhosis or hepatocellular carcinoma (HCC) (Jonas et al 2010). HBeAg negative patients 
would further benefit of antiviral treatment since they are generally associated with a more 
severe liver disease with a very low rate of spontaneous disease remission (Marcellin et al 
2005). These are the anticipated short- and long-term benefits of telbivudine treatment for the 
patients in this study.
Risks Management
Currently telbivudine film-coated tablets have been approved for treatment of CHB in
approximately 91 countries worldwide. Since the US launch in 2006 until 29-Feb-2012, the 
total worldwide exposure of telbivudine reached 329,556 PTY (patient treatment years) in 
adult CHB patients showing proven benefits without major safety concerns.
According to the 2012 EASL Guidelines (EASL 2012), resistance rates with telbivudine 
treatment are relatively low in patients with low baseline viremia (<9 log 10 copies/mL for 
HBeAg-positive and <7 log10 copies/mL for HBeAg-negative patients), and who achieve 
undetectable HBV DNA (<300 copies/mL) at 6 months of therapy.
In order to manage the risk of drug related resistance for the patients in this study, the 
following provisions have been made:

After 24 weeks of telbivudine treatment, patients with confirmed HBV DNA ≥300 
copies/mL (51 IU/mL) will be discontinued from the study and treated at the discretion of 
their investigators.

Patients with primary non-response or virological breakthrough will be discontinued from 
the study and treated at the discretion of their investigators.

Patients will be closely monitored to ensure good treatment compliance.
Among telbivudine treated patients in the GLOBE study, there were rare reports of myopathy 
(0.3%), all of which resolved after discontinuation of telbivudine (Lai et al 2007). This risk of 
muscle related events will be managed in this study through close monitoring and the use of a 
muscle symptom management algorithm for children and adolescents. The algorithm will 
provide guidance for patient management including drug discontinuation criteria.
A common laboratory abnormality observed in previous clinical studies was an increase in 
serum creatine kinase (CK) levels with 7.5% of patients having Grade 3 or 4 CK elevations 
within 1 year of treatment. Most CK elevations were asymptomatic and CK values typically 
decreased by the next visit on continued treatment. Baseline or on-treatment CK elevation 
does not predict myopathy (Dong et al 2011). Treatment was rarely interrupted or 
discontinued as a result of elevated CK. CK levels in this study will be closely monitored (Lai 
et al 2007; Liaw et al 2009). More details can be found in the Investigator Brochure.
 


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The risk to subjects in this trial will be minimized by ongoing DMC data review, compliance 
with the inclusion/exclusion criteria, close clinical monitoring and treatment stopping rules, 
close safety monitoring including CK and muscle symptoms and the 24 weeks placebo 
treatment period with a planned full analysis once all patients have completed their Week 24 
visit. Using all the above considerations and measurements, potential risks to patients will be 
minimized to ensure patient’s benefits and risks maintained at a favorable level.
All other known classical adverse events related to anti-HBV nucleos(t)ide analogues
(including peripheral neuropathy, ALT flare, lactic acidosis, acute pancreatitis and 
hypersensitivity reactions) will be monitored and reported in this study following the normal 
AE / SAE process.
4
Population
The study population will be comprised of male or female patients between 2 and <18 years 
of age (at the time of randomization), with HBeAg-positive and HBeAg-negative CHB and 
compensated liver disease. In the Republic of South Korea, children aged 2 years to < 12 
years (at the time of randomization) only will be enrolled. It is planned to randomize at least 
150 patients from multiple centers worldwide. Age inclusion criteria limits apply to the study 
subject’s age at time of randomization.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. A signed informed consent / assent must have been obtained from both parents or legal 
guardian(s) before any assessment is performed.
2. Male or female out-patients between 2 and < 18 years of age (at time of randomization), 
except in the Republic of South Korea, where children aged 2 years to < 12 years only (at 
time of randomization) will be enrolled.
3. Clinical history compatible with compensated chronic hepatitis B.
4. Documented compensated chronic hepatitis B defined by the following:
a
Positive serum HBsAg at screening and at least one other documentation of HBsAg 
positive at least 6 months prior to screening
b
For HBeAg positive patients at screening, significant biologic signs of disease activity 
following EASL guidelines recommendations for CHB pediatric patients (Sokal et al 
2013)
i)
serum HBV DNA level ≥ 5 log10 copies/mL (COBAS Taqman®) (or 20 000 
IU/mL) at screening as assessed by central laboratory and
ii) serum ALT ≥ 1.5×ULN and < 10×ULN (pediatric ULN) either once during the 
screening period or twice (2 times) within 6 months prior to screening
c
For HBeAg negative patients at screening, significant biologic signs of disease activity 
following EASL guidelines recommendations for CHB pediatric patients (Sokal et al 
2013) 
i)
serum HBV DNA level ≥ 4 log10 copies/mL (COBAS Taqman®) (or 2 000 IU/mL)
at screening as assessed by central laboratory and
 


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ii) serum ALT  ≥ 1.0 ×ULN and < 10×ULN (pediatric ULN) either once during the 
screening period or twice (2 times) within 12 months prior to screening
5. Patients and parent (or legal guardian) are willing to comply with the study drug regimen
and all other study requirements.
6. Patient meeting criteria for treatment according to local guidelines.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1.
Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days, 
whichever is longer.
2.
History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes.
3.
History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases. Patients, who have ultrasonographic findings 
of hepatic mass and/or elevated AFP suggestive of possible HCC prior to enrollment, 
should have the disease ruled-out prior to entrance into the study.
4.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
HCG laboratory test.
5.
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant unless they are using effective methods of contraception during 
dosing of study treatment and up to 12 days after stopping study treatment.  
Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository 

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception

Placement of an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception female subjects should have been stable on the same 
pill for a minimum of 3 months before taking study treatment. 
6.
Sexually active adolescent males who do not agree to use a condom during intercourse 
while taking drug and for 12 days after stopping medication to fathering a child in this 
period; by vasectomized adolescent male patients who do not agree to condom use in 
order to prevent delivery of the drug via seminal fluid.
 


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7.
Patients with acute or chronic infection of HCV, HDV, HIV, or with acute infection of 
HAV, HEV, CMV or EBV.
8.
Patient has received treatment of interferon or any other immunomodulatory agents 
within the last 12 months prior to screening.
9.
Patient has received treatment of any nucleoside or nucleotide drugs or other anti-CHB 
treatment (approved or investigational) at any time before screening.
10. Patient has a medical condition that requires frequent use of systemic acyclovir or 
famciclovir, systemic corticosteroids (topical and inhaled corticosteroids are allowed).
11. Patient has decompensated liver disease defined as a Child-Turcotte-Pugh (CTP) Score 
≥7 (Class B or C).
12. Patient has one or more additional known primary or secondary causes of liver disease, 
other than infectious agents, including alcoholic or non-alcoholic liver disease, fatty liver, 
hepatobiliary disease, Wilson disease and alpha-1 antitrypsin deficiency, Gilbert’s 
syndrome, Dubin-Johnson syndrome etc.
13. Liver transplant recipients. Organ or bone marrow transplant recipients.
14. Patient is currently abusing illicit drugs, or has a history of illicit substance abuse. 
15. All patients are required to be abstinent from alcohol during the course of the study 
otherwise excluded.
16. Patient has a medical condition requiring the chronic or prolonged use of potentially 
hepatotoxic drugs or nephrotoxic drugs or chemotherapy.
17. History of any other acute or chronic medical condition (including congenital diseases, 
metabolic diseases, malignant diseases, neurological disorders, nephrotic diseases, 
pancreatitis, autoimmune disorders, diabetes, etc.) that in the opinion of the investigator 
would make the patient unsuitable for inclusion into the study.
18. Patient has a history of myopathy, myositis, persistent muscle weakness or persistent 
high serum CK levels (≥7×ULN), any muscular disease including but not limited to 
congenital / metabolic etiology, or with abnormal neuromuscular signs at screening or 
any screening CK values suggestive of muscular disease, or age at which independent 
walking first achieved after 16 months of age (based on birthday).
19. Patients receiving any drugs potentially associated with myopathy (e.g chloroquine, 
hydroxychloroquine, HMGCoA redutase inhibitors, fibric acid derivatives, penicilamine, 
zidovudine, cyclosporine, erythromycin, niacin, azole antifungals, etc.) within 3 months 
prior to screening.
20. Any other clinical significant disease, condition or abnormality, unrelated to their HBV 
infection at screening, as assessed by the investigator, including:

Hemoglobin < 11 g/dL (110g/L) for males or < 10 g/dL (100g/L) for females

Total WBC < 3,500/mm3  (3.5×109/L)

Absolute neutrophil count (ANC) < 1,500/mm3 (1.5×109/L)

Platelet count < 120,000/mm3 (120×109/L)

Prothrombin time prolonged by more than 3 seconds (based on ULN; of the 
reference value); or INR > 1.5
 


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
Serum amylases or lipase  ≥ 1.5×ULN

Serum albumin (<3.5g/dL); (<35g/L)

Total bilirubin (≥ 2 ×ULN)

estimated GFR < 50 mL/min using Schwartz formula

Serum phosphate < 1.5 mg/dL
All the above laboratory parameters need to consider age adjusted ULN changes. 
If selected patients meet all other eligibility criteria, patients with a single laboratory value 
outside of the allowable range, may be considered eligible for enrolment, as long as that 
abnormal lab value is within 10% of the allowable value.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
The following study medication will be supplied to the sites: 

LDT600 (telbivudine, manufactured by Novartis) oral solution (20mg/mL) will be 
used as a dosage of 20 mg/kg

LDT600 (telbivudine, manufactured by Novartis) 600 mg film-coated tablets 

Placebo to LDT600 oral solution

Placebo to LDT600 film-coated tablets
Formulation, dose and frequency of administration by patient age are detailed in Table 5-1
5.1.2
Additional study treatment
No additional treatment beyond investigational treatment is requested for this trial.
5.2
Treatment arms
Patients will be assigned to one of the two treatment arms in a ratio 5:1
Arm 1: Telbivudine:

Any age and weight < 30kg: telbivudine oral solution (20mg/mL): 20 mg/kg up to 600 
mg q.d, corresponding to weight (kg) x1ml, p.o. once daily

< 12 years old and weight ≥ 30kg: telbivudine oral solution (20mg/mL): 600 mg/day 
corresponding to 30 mL p.o. once daily 

≥ 12 years old and weight ≥ 30kg: telbivudine film-coated tablet 600 mg/day, 
corresponding to 1 tablet p.o. once daily
Arm 2: Placebo:
 


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
Any age and weight < 30kg: placebo oral solution corresponding to weight (kg) x1mL, 
p.o. once daily

< 12 years old and weight ≥ 30kg: placebo oral solution corresponding to 30 mL p.o. 
once daily, 

≥ 12 years old and weight ≥ 30kg: placebo tablet, corresponding to 1 tablet p.o. once 
daily.
Eligibility criteria for placebo treated patients to start telbivudine treatment at 
week 28
1. Positive serum HBsAg at baseline and at Week 24
2. For HBeAg positive patients:
a.
Serum HBV DNA level ≥ 5 log10 copies/mL (COBAS Taqman®) (or 20 000 
IU/mL) at Week 24 (visit 6) as assessed by central lab
3. For HBeAg negative patients:
a.
Serum HBV DNA level ≥ 4 log10 copies/mL (COBAS Taqman®) (or 2 000 
IU/mL) at Week 24 (visit 6) as assessed by central lab
Placebo patients who are not eligible for telbivudine treatment at week 28 may start 
telbivudine at a later visit until Week 52. The similar eligibility criteria will be used.
5.3
Treatment assignment
At Visit 2, all eligible patients will be randomized via Interactive Voice Response System 
IVRS/IWRS) to one of the treatment arms. The investigator or his/her delegate will contact 
the IVRS/IWRS after confirming that the patient fulfills all the inclusion/exclusion criteria.  
The IVRS/IWRS will assign a randomization number to the patient, which will be used to link 
the patient to a treatment arm and will specify a unique medication number for the first 
package of study drug to be dispensed to the patient.  The randomization number will not b e 
communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IVRS/IWRS provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing each of the study drugs.
Randomization will be stratified by age group (age at baseline (visit 2)) and by HBV DNA 
level (screening value, available at the time of baseline visit (visit 2)). Patients will be 
randomized to treatment arm 1 (telbivudine) or treatment arm 2 (placebo) in a ratio 5:1.
Stratification at baseline is done to balance the number of patients randomized to telbivudine 
or placebo within the levels of stratification factors. Patients will be stratified into 6 strata: 
three age groups and the HBV DNA status (low and high) where HBV DNA low is <9 log10 
copies/mL for HBeAg positive patients and <7 log10 copies/mL for HBeAg negative patients. 
 


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Approximately 80% of patients with lower HBV DNA at screening (i.e. for HBeAg positive 
patients HBV DNA <9 log10 and HBeAg negative patients with HBV DNA <7 log10
copies/mL) are expected to be recruited.
Subsets of patients by age (based on birthday at randomization visit (baseline: day1)) are 
defined as: 

Age group 1: from 2 to less than 6 years old 

Age group 2: from 6 to less than 12 years old 

Age group 3: from 12 to less than 18 years old
The randomization scheme for patients will be reviewed and approved by Novartis
Randomization Office.
5.4
Treatment blinding
The total double-blind treatment period will be 24 weeks. 
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until Week 24 (visit 6), 
using the following methods: (1) Randomization data are kept strictly confidential until the 
time of unblinding, and will not be accessible by anyone else involved in the study with the 
following exceptions: expert pharmacokineticists will be unblinded and will have access to 
the randomization list in order to analyze the PK samples in a timely manner ; (2) the identity 
of the treatments will be concealed by the use of study drugs that are all identical in packaging, 
labeling, schedule of administration, appearance, taste and odor. Specific laboratory 
assessments (HBV DNA and ALT) will be blinded for patients, investigator staff, persons 
performing the assessments, and data analysts in order to remain blinded to the identity of the 
treatment from the time of randomization until Week 24. Alert messages will be received by 
investigator staff to ensure safety monitoring of the patients during this period.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.12) or on 
request by the Data Monitoring Committee.
At Week 24 (visit 6), all patients will be unblinded and HBV DNA level will be assessed.  
The therapeutic decision will be taken for all patients at Week 28, based on Week 24 
assessments.
5.5
Treating the patient
5.5.1
Patient numbering
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. Upon 
signing the informed consent form, the patient is assigned a patient number by the investigator. 
At each site, the first patient is assigned patient number 1, and subsequent patients are 
assigned consecutive numbers (e.g. the second patient is assigned patient number 2, the third 
patient is assigned patient number 3). The investigator or his/her staff will contact the 
IVRS/IWRS and provide the requested identifying information for the patient to register them 
into the IVRS/IWRS. Only the assigned patient number should be entered in the field labeled 
 


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“Patient ID” on the EDC data entry screen (e.g. enter ‘1’, ‘2’, etc.)  Once assigned to a patient, 
the patient number will not be reused.  If the patient fails to be randomized for any reason, the 
IVRS/IWRS must be notified within 2 days that the patient was not randomized. The reason 
for not being randomized will be entered on the Screening Log, and the Demography CRF 
pages should also be completed.
5.5.2
Dispensing the study treatment
Each study site will be supplied by Novartis with study drug in packaging of identical 
appearance. LDT600 (telbivudine, manufactured by Novartis) oral solution (20mg/mL) will 
be identical in appearance to the Placebo to LDT600 oral solution, and the LDT600 
(telbivudine, manufactured by Novartis) 600mg film-coated tablets will be identical in 
appearance to the Placebo to LDT600 film-coated tablets.
The investigational treatment packaging has a 2-part label. A unique medication number is 
printed on each part of this label which corresponds to one of the 2 treatment arms and ac tive 
or placebo treatment. Investigator staff will contact IVRS/IWRS to obtain the medication 
number (s) to be dispensed to the patient, either active or placebo. Immediately before 
dispensing the package to the patient, investigator staff will complete the label indicating the 
patient randomization number,  will detach the outer part of the label from the packaging and 
affix it to the source document (Drug Label Form) for that patient’s unique patient number.
5.5.3
Handling of study treatment
5.5.3.1
Handling of investigational treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Upon receipt, all study drugs should be stored according to 
the instructions specified on the drug labels. Clinical supplies are to be dispensed only in 
accordance with the protocol. Technical complaints are to be reported to the respective 
Novartis CPO Quality Assurance.

Medication labels will be in the local language and comply with the legal requirements 
of each country. They will include storage conditions for the drug, but no information 
about the patient except for the medication number.

The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug 
accountability will be performed by the field monitor during site visits and at the 
completion of the trial. Patients will be asked to return all unused investigational 
treatment and packaging at the end of the study or at the time of discontinuation of 
investigational treatment. 

At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused investigational treatment, packaging, drug labels, 
and a copy of the completed drug accountability log to the Novartis monitor or to the 
Novartis address provided in the investigator folder at each site.
 


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5.5.3.2
Handling of other study treatment
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
Investigator staff will instruct the patients to take the medication orally every morning either 
with or without food. The investigator should instruct the patient to take the study drug 
exactly as prescribed. 
The tablets should be taken as whole and must not be divided for dose adjustment purposes. 
The oral solution intake should follow the instructions as described in the oral dispensing 
instructions.
The first dose of study medication will be taken on Baseline (Day 1) under the supervision of 
the study nurse. Dosing will be continued for 104 weeks until the Week 104 study visit unless 
treatment discontinuation is required or patient withdraws from the study (Section 5.5.9).
For two visits on Week 4 and 24, each patient will be required to come to the clinic before 
taking LDT600 on that day for a blood sample to measure a trough (pre-dose) level. After 
collecting the trough sample, LDT600 will be taken by mouth in the clinic (Section 6.6.3).
Table 5-1
Study medication assignment and dosage
Patient age
Patient 
weight
Formulation
Dosage
Amount/day
Any age
Weight < 30kg
oral solution telbivudine 
20mg/mL or placebo solution 
20 mg/kg up 
to 600 mg q.d.
Weight (kg) x 1 
mL
< 12 years old
Weight ≥30kg
oral solution telbivudine 
20mg/mL or placebo solution 
600 mg/day
30 mL
≥12 years old
Weight ≥30kg
film-coated tablet telbivudine 
600 mg or placebo tablet
600 mg/day 
1 tablet
Patients who will have their 12th birthday during the 24-week double-blind treatment period 
will continue receiving the oral solution until the end of the 24-week period. Afterwards these 
patients will be provided with the opportunity to change treatment formulation from oral 
solution to tablet only every half year after Week 24 double-blind treatment period (i.e. at 
Week 52, 76 and 104) if body weight increase ≥30kg.
The patient should be instructed to contact the investigator if he/she is unable for any reason 
to take the study drug as prescribed. Patients’ ≥12 years old and weight ≥30kg that are unable 
to swallow the tablets can be switched to oral solution (IRT call required).
All kits of investigational treatment assigned by the IRT will be recorded/databased in the IRT.
The investigator should promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient should be instructed to contact the investigator 
if he/she is unable for any reason to take the study treatment as prescribed.
Week 24 unblinding and instructions for taking study treatment 
At Week 24 (visit 6), all patients will be unblinded: 
 


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Patients randomized to treatment arm 1 (telbivudine):

Patients with HBV DNA <300 copies/mL (51 IU/mL) at Week 24 will remain on 
telbivudine treatment until Week 104.

Patients with confirmed HBV DNA ≥300 copies/mL (51 IU/mL) at Week 24 will be 
discontinued from study at the next visit (Week 28) as described in Section 5.5.9. 
Patients randomized to treatment arm 2 (placebo):

Treatment eligibility will be confirmed using Week 24 (visit 6) assessments (see 
Section 5.2) and eligible patients will initiate antiviral treatment with telbivudine at 
Week 28 (visit 7). At Week 52 (visit 9, which represents 24 weeks of telbivudine 
treatment for this group of patients), HBV DNA level will be assessed:
o
Patients with HBV DNA <300 copies/mL (51 IU/mL) at Week 52 will remain 
on telbivudine treatment until last on-treatment study visit (Week 104); 
o
Patients with confirmed HBV DNA ≥300 copies/mL (51 IU/mL) at Week 52 
will be discontinued from study as described in Section 5.5.9.

Placebo randomized patients who are non-eligible for telbivudine treatment at Week 
24, may continue in the study until Week 52 and may start telbivudine treatment at a 
later visit until Week 52 based on investigator’s decision and patient agreement.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Study drug interruptions are not permitted.
5.5.6
Rescue medication
No rescue antiviral therapy will be provided. In the event of discontinuation of investigational 
treatment for insufficient therapeutic effect or viral breakthrough, or for ALT flare upon study 
completion at Week 104, the patient may be treated by the investigator according to local 
practice. The reason for discontinuation of investigational treatment and any intervention will 
be clearly described in the CRF (e.g., for insufficient therapeutic effect, safety). 
5.5.7
Concomitant treatment
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study drug. All medications and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the patient 
was enrolled into the study must be listed on the Concomitant medications/Significant non-
drug therapies into the CRF. 
5.5.8
Prohibited treatment
Use of the treatments displayed in Table 5-2 is NOT allowed after the start of study treatment. 
These drugs will either confound the efficacy or safety of the study, or they have potential 
drug-drug interaction with the study drug. In addition any drugs which has any known or 
potential risks for pediatrics population in terms of growth, bone, liver, neurological system 
etc. are strictly prohibited in this study.
 


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Investigators need to guide the patients not to take any prohibited medication. In case they are 
used and they cause hepatotoxicity or nephrotoxicity, investigators also need to monitor the 
relevant organic function (Table 5-2).
For the patient’s safety, it is within the Investigator’s responsibility to carefully educate the 
patient about prohibited medication and compliance to study medication.
Table 5-2
Prohibited treatment
Medication
Action to be taken
Any drug which has any known or potential risks 
for pediatrics population in terms of growth, bone, 
liver, neurological system etc are strictly 
prohibited in this study
Stop the prohibited drug immediately otherwise 
patients will be discontinued from the study
Any other investigational drug
Stop prohibited treatment; monitor relevant ADR
LAM, ADV, ETV, TDF, FTC, etc.
Stop prohibited treatment; monitor ALT, HBV 
DNA, etc.
Systemic use of Acyclovir, famciclovir
Stop prohibited treatment if taken > 10d over 3 
months
IFNs, Thymosin, interleukins, any immune 
modulator
Stop prohibited treatment; monitor ALT, AST, 
relevant ADR
Systemic corticosteroids
Stop prohibited treatment; monitor CK, ALT, AST, 
relevant ADR
Hepatotoxic drugs (dapsone, erythromycin, 
systemic azole antifungals, anti-tuberculosis 
drugs, toxic dose of acetaminophen/paracetamol, 
herbal medications)
Stop prohibited treatment; monitor ALT, AST, TB, 
Alb, PT, etc.
Nephrotoxic drugs (aminoglycosides, 
amphotericin B, foscarnet, vancomycin, 
cyclosporine, tacrolimus, frequent use of NSAIDs 
or aspirin)
Stop prohibited treatment; monitor GFR, 
creatinine, cystatin C, urinalysis
Chemotherapy drugs for malignant diseases or 
immune-suppressive therapy for transplantation
Stop prohibited treatment or discontinue from 
study treatment; monitor GFR, WBC, RBC, ALT, 
AST, TB. 
Alcohol abuse
Stop alcohol consumption for all pediatrics 
patients during the study period
Illicit drug abuse 
Stop illicit drug abuse; monitor relevant ADR
Drugs associated with myopathy (Chloroquine, 
hydroxychloroquine, HMGCoA reductase 
inhibitors, fibric acid derivatives, penicilamine, 
zidovudine, cyclosporine, erythromycin, niacin, 
azole antifungals, etc)
Stop prohibited treatment immediately otherwise 
discontinued from the study treatment; monitor 
CK, muscle symptoms, muscle strength, etc.
If prohibited treatment is taken and the actions as given in the table above (Table 5-2) are not 
followed, patients have to be discontinued from the study (Section 5.5.9). The following list 
of medications can only be administered under certain circumstances or is restricted by a 
maximum dose or duration. However, new medications for study patients should be initiated 
with caution, since they may increase the onset of adverse events. All concomitant 
medications will be captured on the concomitant medication CRF with the indication for use 
documented.
 


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
Short term use of systemic acyclovir or famciclovir defined as periods of less than 10 days 
over 3 months is allowed.

Topical and inhaled corticosteroids are permitted.

Less than one week use of NSAID (e.g. aspirin, paracetamol / acetaminophen, and 
ibuprofen) at the recommended dose intended for anti-inflammatory therapy is permitted 
(see Appendix 6 for the recommended dosage of paracetamol / acetaminophen).

If medically necessary, treatment with non-hepatotoxic medications is allowed.
Predefined vaccination plan (except for HBV) for the subjects is recommended to be 
continued during the study. All the history vaccinations taken by the pediatrics are needed to 
be collected in the screening; and each new vaccination subjects taken during the study need 
be recorded in the study with the vaccine name, dosage, date, and adverse reactions.
Herbal medications will be allowed except for those that cause known hepatotoxicity or 
muscle toxicity. All herbal medications will be captured on the concomitant medication CRF 
as “herbal supplement” with the indication for use documented.
5.5.9
Discontinuation of study treatment and premature patient withdrawal 
Patients and parents (or legal guardian) may voluntarily discontinue treatment for any reason 
at any time. 
The investigator should discontinue study treatment for a given patient and/or withdraw the 
patient from study if, on balance, he/she believes that continuation would be detrimental to the 
patient’s well-being.
Study treatment must be discontinued under the following circumstances: 

Emergence of the following adverse events:
a.
Patient has clinical signs/symptoms of hepatic decompensation (Child-Pugh B or C)
b. Severe ALT flare on treatment (Glossary of terms)
c.
ALT > 3 × ULN and > 2 × baseline AND (TBiL > 2 × ULN or INR > 1.5)
d. Patient is diagnosed with cancer (other than basal cell or squamous cell carcinoma) 
including but not limited to HCC
e.
Patients experiencing muscle related symptoms as indicated in Section 7.7
f.
Patient co-infected with HCV, HDV or HIV. If patient is co-infected with HAV, HEV, 
CMV, or EBV during the study, patient disposition will be at the investigator’s 
discretion based on the severity of the other virus infection.
g. Any adverse event that could affect physical growth

Any laboratory abnormalities that, according to the investigator opinion, might affect 
study treatment (e.g eGFR < 50 mL/min)

Pregnancy

Withdrawal of informed consent

The following deviations from the prescribed dose regimen for study treatment: 
a. Patients receiving telbivudine treatment and with HBV DNA ≥300 copies/mL (51 
IU/mL) at Week 24 (see Section 3.1)
 


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b. unplanned treatment unblinding in the case of patient emergencies as judged by the 
treating physician

Use of prohibited treatment as per Table 5-2.

Any other protocol deviation that results in a significant risk to the patient’s safety  
The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any patient whose treatment code has been broken inadvertently 
for any reason. The investigator must contact the IRT to register the patient’s discontinuation 
from study treatment.
Patient discontinued from study treatment should complete the End of Treatment visit and the 
12-weeks safety follow-up visit. Post-treatment observation ceases either at 12-weeks post 
treatment follow-up visit or at the time of an alternative anti-HBV therapy is initiated before 
the 12-weeks safety follow-up visit.
These changes must be recorded on the Dosage Administration Record CRF.
Management of primary non-responder at Week 24
Primary response is defined as HBV DNA reduction of ≥ l log10 copies/mL (1 log10 IU/mL) at 
Week 12 on treatment compared with baseline and confirmed at the next visit (Week 16). 
Good compliant patients with a HBV DNA reduction at Week 12 of < l log 10 copies/mL 
compared with baseline and confirmed at the next visit (Week 16), meet the diagnosis criteria 
of Primary Non-Response (PNR). When the study treatment code is unblinded for all patients 
at Week 24, those patients identified as PNR but who have achieved a satisfactory viral 
response (HBV DNA < 300 log10 copies/mL) at week 24 (confirmed at week 28) will be
allowed to continue study treatment; those patients identified as PNR and who have a HBV 
DNA levels ≥ 300 log10 copies/mL will be discontinued from the study treatment at Week 28 
and managed at the discretion of the investigators.
Management of telbivudine patients with HBV DNA ≥300 copies/mL (51 IU/mL)
at Week 24 
Patients with confirmed HBV DNA ≥300 copies /mL (51 IU/mL) after 24 weeks of 
telbivudine treatment will be discontinued from the study treatment and managed at the 
discretion of the investigators.
For patients with HBV DNA ≥300 copies /mL (51 IU/mL) at Week 24 for the first occurrence 
after achieving initial response (< 300 copies/mL (51 IU/mL)) prior to Week 24, a 
confirmatory value (HBV DNA ≥300 copies/mL (51 IU/mL)) should be obtained at Week 26 
(unscheduled visit) before discontinuation.
Management of patients with virological breakthrough and/or genotypic 
resistance after Week 24
Virological breakthrough will be assessed in real time during the study. In case of confirmed 
VB, genotypic resistance testing should be performed. Patients who develop VB (confirmed) 
or genotypic resistance after 24 weeks of telbivudine treatment will be discontinued from the 
study treatment and will be managed at the discretion of the investigators.
 


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Management of patients with “complete response”
Complete response is defined as HBV DNA <300 copies/mL (51 IU/mL), HBeAg 
seroconversion and ALT normalization. Patients with confirmed complete response will 
continue telbivudine treatment for another 52 weeks from the day of confirmation. At the end 
of this “consolidation period”, if the complete response is maintained, patients could be 
considered for discontinuation of telbivudine at the discretion of the investigators and remain 
in the study to monitor off-treatment efficacy and safety.
Patients initially randomized to placebo at baseline and treated with telbivudine at Week 28 or 
at later visits will be managed similarly.
5.5.10
Withdrawal of consent
Patients and parents (or legal guardian) may voluntarily withdraw consent to participate in the 
study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contacts and does not allow analysis of already obtained biologic material.
If a patient withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Study treatment must be 
discontinued and no further assessments conducted. All biological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the patient 
are not allowed unless safety findings require communicating or follow-up.
5.5.11
Loss to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the 
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until his/her 
scheduled end of study visit would have occurred.
5.5.12
Emergency unblinding of treatment assignment
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, study treatment discontinuation and knowledge 
of the possible treatment assignments are sufficient to treat a study patient who presents with 
an emergency condition. Emergency treatment code breaks are performed using the IRT. 
When the investigator contacts the system to break a treatment code for a patient, he/she must 
provide the requested patient identifying information and confirm the necessity to break the 
treatment code for the patient. The investigator will then receive details of the investigational 
drug treatment for the specified patient and a fax or email confirming this information. The 
system will automatically inform the Novartis monitor for the site and the Global Trial Leader 
(GTL) that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact 
 


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his/her backup in cases of emergency when he/she is unavailable. The investigator will 
provide protocol number, study treatment name if available, patient number, and instructions 
for contacting the local Novartis CPO (or any entity to which it has delegated responsibility 
for emergency code breaks) to the patient in case an emergency treatment code break is 
required at a time when the investigator and backup are unavailable.
An assessment will be done by the appropriate site personnel, the Global Trial Leader and the 
Novartis Medical Specialist after an emergency treatment code break to assess whether or not 
study/investigational treatment should be discontinued for a given patient (Section 5.5.9).
5.5.13
Study completion and post-study treatment 
Study completion is defined for an individual patient who meets the screening requirements, 
attends the Baseline Day 1 visit, and completes the 104 weeks treatment phase of the study 
and 12 weeks post-treatment safety follow-up phase of the study. 
The study recruitment is completed when at least 150 patients have been randomized to the 
treatment arms. Patients already in screening at the time of enrollment completion (i.e. when 
150 patients have been randomized) should be allowed to enter the study if they meet all of 
the inclusion/exclusion criteria.
Patients who complete the study treatment period enter into the 12 weeks post-treatment 
follow-up phase (also called Safety Follow-up). It is up to the investigator’s discretion to 
decide on the requirement of additional HBV treatment based on local practice guidelines 
after study completion. The Sponsor will make all effort to supply post-study provision of 
telbivudine until marketing authorization is received, as permitted by local law and regulation 
and if patients who have responded to treatment with telbivudine may benefit from ongoing 
treatment after the end of treatment visit (Week 104) as determined by the investigator. Any 
HBV treatment prescribed for the post-treatment follow-up phase must be recorded as 
concomitant medication.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
5.5.14
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing IRBs and/or ECs of the early termination of the 
trial.
6
Visit schedule and assessments
Table 6-1 lists all the assessments from the Screening period until the Safety follow-up visit
and it is indicated with an “X” when each assessment has to be performed. Informed consent / 
assent will be collected from all patients prior to entering into the Screening period (Section 
10.2). Patients can be randomized as soon as all screening evaluations and results are 
available and eligibility confirmed. Patients, who have disqualified parameters for HBV 
 


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related markers, biochemistry or hematology at screening visit, can be considered for re-test 
every 3 months within a period of 6 months of initial screening.
Patients should be seen for all visits on the designated day, a ± 7 day window is recommended.
Patients who discontinue study treatment before completing the study, and those who 
prematurely withdraw from the study for any reason, should be scheduled for a visit as soon 
as possible, at which time all of the assessments listed for the visit 13 (Week 104) will be 
performed. A 12-weeks safety follow-up visit should be completed. Post-treatment 
observation ceases either at 12-weeks post-treatment follow-up visit or when alternative anti-
HBV therapy is started.
 


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Table 6-1
Assessment schedule
Study Phase
Screen 
Period
Baseline
Treatment Weeks Post-baseline
Safety 
follow-up3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
132
14
Week
-10
weeks 
prior to 
BL1
Day 1
4
12
16
24
284
40
52
64
76
88
104
End of 
Treatment 
or SDD/ 
PPW
116
End of 
Study or -
12 weeks
post 
treatment 
Informed consent 
S
S5
Inclusion/Exclusion 
x
X5
x5
Randomization (IRT 
contact)
X
Treatment unblinding (IRT 
contact)
x
Demography
x
X
Medical history 
x
X
HBV infection route, HBV 
history
x
X
Complete Physical 
Examination
S
S
S
S
Tanner Staging 
Assessment6
X
x
x
x
Vital signs 
x
X
x
x
x
x
x
x
x
x
x
x
x
x
Body height
x
X
x
x
x
x
x
x
x
x
x
x
x
x
Body weight
x
X
x
x
x
x
x
x
x
x
x
x
x
x
 


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Study Phase
Screen 
Period
Baseline
Treatment Weeks Post-baseline
Safety 
follow-up3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
132
14
Week
-10
weeks 
prior to 
BL1
Day 1
4
12
16
24
284
40
52
64
76
88
104
End of 
Treatment 
or SDD/ 
PPW
116
End of 
Study or -
12 weeks
post 
treatment 
HBV Sequencing7
As applicable in case of VB
Virology screening19
x
As applicable in case of liver event
PT, amylase, lipase
x
X
x
x
x
x
x
AFP
x
X
HBeAg/HBeAb, Anti-HBc 
x
X
x
x
x
x
x
HBV DNA
x
X
x
x
x
X 9, 
10
x
x
x
x
x
x
x
x
Pregnancy test 11
x
X
x
x
x
x
x
x
x
x
x
x
x
Hematology 12
x
X
x
x
x
x
x
x
Biochemistry 1 (ALT, AST, 
ALP, creatinine, CK, cystatin 
C, blood glucose, phosphate)
x
X
x
x
x
x 9
x
x
x
x
x
x
x
x
Biochemistry 2 (Total Bilirubin, 
Albumin)
x
X
x
x
x
x 9
x
x
x
x
x
x
x
Urinalysis 13
x
X
x
x
x 9
x
x
x
x
x
x
x
x
Serum for storage
x
X
x 9
x
x
Abdominal B-US 20
x
x
x
x
x
x
AEs, Con Meds
X
x
x
x
x
x
x
x
x
x
x
x
x
 


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Study Phase
Screen 
Period
Baseline
Treatment Weeks Post-baseline
Safety 
follow-up3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
132
14
Week
-10
weeks 
prior to 
BL1
Day 1
4
12
16
24
284
40
52
64
76
88
104
End of 
Treatment 
or SDD/ 
PPW
116
End of 
Study or -
12 weeks
post 
treatment 
Vaccination records
x
X
x
x
x
x
x
x
x
x
x
x
x
x
Compliance Questionnaire
x
x
x
x
x
x
x
x
x
x
x
Muscle management 
algorithm 15
As applicable in case of muscle event
Dispense telbivudine or 
placebo
X
x
x
x
x 17
x 4
x
x 18
x
x
x
SDD = Study drug discontinuation
PPW = Premature patient withdrawal
X = assessment to be recorded on clinical data base
S = assessment to be recorded on source documentation
1 Screening period may be extended up to 10 weeks in case of operational or administrative issues (see section 6.2)
2 End of Treatment visit or Early Discontinuation visit. IRT contact to record study treatment discontinuation date
3 Safety follow up visit to be performed for all patients discontinued from telbivudine prematurely 
4 Patients randomized to telbivudine treatment with HBV DNA ≥300 copies/mL(51 IU/mL) at Week 24 will be discontinued at Week 28
5 Confirm at Baseline Visit. For placebo patients, confirm eligibility with Week 24 assessments
6 Tanner Staging Assessment for age group 2 and 3 at Baseline, Week 24, Week 52, Week 104 visits
7 Genotypic sequencing will be tested for patients with confirmed VB or HBV DNA ≥300 copies/ml (51 IU/mL) at Week 24 and at any time after week 24 and
compared to baseline assessment
9 Eligibility assessment to start telbivudine treatment for placebo randomized patients
 


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Study Phase
Screen 
Period
Baseline
Treatment Weeks Post-baseline
Safety 
follow-up3
Visit
1
2
3
4
5
6
7
8
9
10
11
12
132
14
Week
-10
weeks 
prior to 
BL1
Day 1
4
12
16
24
284
40
52
64
76
88
104
End of 
Treatment 
or SDD/ 
PPW
116
End of 
Study or -
12 weeks
post 
treatment 
10 Patients on telbivudine with HBV DNA ≥300 copies/mL (51 IU/mL) will be discontinued at the next visit
11 Screening is a serum pregnancy test for patients with child bearing potential only, all following ones are urine tests
12 Including hemoglobin (Hgb), hematocrit (Hct), red blood cell count, white blood cell count (WBC) and differential and platelet count
13 Including specific gravity, pH, protein, glucose, blood, 
15 Only applicable to patients who follow the Muscle Symptom Algorithm. It includes Muscle strength test, muscle symptom questionnaire and muscle pain 
score assessment.
17 Patients treatment to be unblinded, eligible patients on placebo to start telbivudine treatment at Week 28
18 Patients randomized to placebo with HBV DNA ≥300 copies/mL (51 IU/mL) at Week 52 to discontinue treatment
19 Virology screening (Anti-HIV-1+2, Anti-HCV, Anti-HDV, Anti-HAV IgM, Anti-HEV IgM,, Anti-EBV IgM & IgG to Viral Capsid Ag, Anti-CMV IgM and IgG)
20 If an ultrasound was performed during the month prior to screening it is not necessary to obtain one during the screening period.
 


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6.1
Information to be collected on screening failures
All patients who have signed informed consent but not entered into the next study phase will 
have the study completion page for the screening period, demographics, inclusion/exclusion, 
and SAE data collected in the CRF pages. Adverse events that are not SAEs will be followed 
by the investigator and collected only in the source data.
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
6.2
Patient demographics/other baseline characteristics 
At the screening visit, patient demographic and baseline characteristic data to be collected on 
all patients include: date of birth, age, sex, race, ethnicity, child-bearing potential, origin of 
HBV infection and source of patient referral.
The screening period should not exceed 10 weeks. 
Relevant medical history/current medical condition data includes data until the start of study 
drug (at the baseline visit). Where possible, diagnoses will be recorded and not symptoms.
Furthermore, the following will be assessed at the screening and / or baseline visits:
•
Complete physical examination at baseline visit only
•
Vital signs 
•
Body height and weight 
•
Tanner staging assessment for age group 2 (from 6 to less than 12 years old) and age 
group 3 (from 12 to less than 18 years old) at baseline visit only
•
Virology screening (at screening visit only): Anti-HIV1+2, Anti-HCV, Anti-HDV, Anti-
HAV IgM, Anti-HEV IgM, Anti-EBV IgM & IgG to Viral Capsid Ag and Anti-CMV IgM 
and IgG
•
AFP, PT, amylase and lipase levels 
•
HBeAg/HBeAb and anti-HBc 
•
HBsAg/HBsAb 
•
HBV DNA level 
•
Pregnancy test (serum pregnancy test for patients with child bearing potential only at 
screening, urine pregnancy test at baseline)
•
Hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count and 
differential and platelet count) 
•
Biochemistry (ALT, AST, ALP, creatinine, CK, cystatin C, blood glucose, phosphate, 
total Bilirubin, Albumin) 
•
Urinalysis (specific gravity, pH, protein, glucose, blood, WBC, RBC sediments, 
proteinuria, urine creatinine and phosphates)
 


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•
Abdominal B-Ultra Sound at screening visit; if an abdominal B-US has been performed
during the month prior to screening, these results may be used in lieu of the screening 
abdominal B-US.
Laboratory tests may be repeated, if required, due to operational reasons (e.g., insufficient 
specimen, coagulated sample, lost specimen, etc.).
All data will be reported on the relevant CRF page.
Age and HBV DNA level will be used for patient stratification at baseline.
6.3
Treatment exposure and compliance
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient should be instructed to contact the investigator if he/she 
is unable for any reason to take the study drug as prescribed.
Compliance will be assessed by the investigator and/or study personnel at each visit using the 
pill counts or volume solution evaluation and some specific questions raised to the patient to 
assess the compliance. The pill count method is based on the number of pills returned by the 
patient at the succeeding visit minus the total number of pills received by the patient. The 
volume count method is based on the volume remaining in the bottle at the succeeding visit 
minus the volume total of telbivudine or placebo received by the patient.
The investigator will record the percentage of compliance between visits in the case record 
form (CRF), using the pill count, the volume solution evaluation, the answers provided by the 
patients on specific compliance questions and his/her experience with the patient.
There are three categories of compliance:

Good compliance equals  ≥ 90% -≤100%

Fair compliance equals  ≥70% – ≤ 89%

Poor compliance equals < 70%
If the compliance is < 90%, the investigator needs to educate the patient to improve 
compliance. If the patient compliance does not improve, the investigator could consider 
discontinuing the patient from the study on the basis of the length of time and the number of 
pills or volume solution missed. 
6.4
Efficacy
Efficacy assessments will be evaluated by central laboratory as described in Table 6-1. Key 
assessments are:

Serum HBV DNA

HBV Serologic Markers: HBsAg/Ab and HBeAg/Ab

ALT

Genotypic resistance
 


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6.4.1
Serum HBV DNA
Serum HBV DNA is the best viral marker for the management of HBV disease. Serum HBV 
DNA level generally stands for the replication level of HBV in the patients and it is an 
indicator of disease prognosis. Several studies have shown that increasing HBV DNA level, 
starting at 104copies/mL, is a predictor of risk for the development of cirrhosis and 
hepatocellular carcinoma, regardless of 
 baseline serum 
ALT level. Importantly, the suppression of HBV DNA level is correlated with higher rates of 
histologic response and lower rates of complications of liver disease.
HBV DNA analyses will be performed at a central reference laboratory through use of the 
COBAS TaqMan® HBV Test (Roche Molecular Systems, Branchburg, NJ, USA). Details of 
samples handling and methodology (including level of LLOQ and LOD) will be specified in 
the lab manual.
Serum samples for HBV DNA will be obtained at the defined visits in Table 6-1. 
 
6.4.2
HBV serological markers
HBV Serologic Markers include HBsAg/Ab, HBeAg/Ab and Anti-HBc. 
Hepatitis B surface antigen (HBsAg) clearance is the ultimate goal of therapy in patients with 
CHB. Emerging evidence has shown that on-treatment HBsAg levels may be a useful marker 
of antiviral efficacy and predictive of outcomes for pegylated interferon alfa-2a in patients 
with CHB. Current data on HBsAg kinetics during long-term treatment with oral antiviral 
treatment is limited. Emerging evidence suggests that rapid on-treatment HBsAg decline 
might be predictive of future HBsAg clearance in HBeAg negative patients treated with 
telbivudine (Wursthorn et al 2010).
Qualitative HBsAg/Ab, HBeAg/Ab will be assessed at the central laboratory using standard 
commercially available enzyme immunoassays. 
 
Serum for HBsAg/Ab, HBeAg/Ab and Anti-HBc will be obtained according to the schedule 
in Table 6-1.
HBsAb will only be measured for patients with undetectable HBsAg.
6.4.3
Serum ALT
Serum ALT normalization is an important clinically relevant efficacy endpoint. Elevated 
serum ALT levels are thought to reflect underlying hepatitis disease activity (i.e. active liver 
inflammation). Correspondingly, ALT normalization is an accepted therapeutic goal in 
hepatitis studies as it is thought to reflect a substantial reduction in hepatic disease activity.
ALT levels will be determined from serum samples obtained at all applicable study visits, via 
standard central laboratory testing.
 


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6.4.4
Genotypic Resistance surveillance
Genotypic resistance will be assessed in real time in patients with virological breakthrough, in 
a central laboratory using serum storage samples, if available for VB at Weeks 24, 52, and 
104. For VB confirmed at other times during the trial a specimen will be obtained from the 
patient to assess genotypic resistance. The genotypic sequencing results at the time of 
confirmed VB will be compared with the baseline results to assess treatment-emergent 
genotypic resistance and the cumulative rates of VB and/or genotypic resistance at Week 52 
and 104 will be reported. 
During the study, patients with confirmed VB and/or resistance will be discontinued from the 
clinical study.
Genotypic resistance will also be assessed in patients with HBV DNA ≥300 copies/mL (51 
IU/mL) at Week 24 and discontinued from the study treatment (or at discontinuation if prior 
to Week 24 for subjects with at least 16 weeks of LDT treatment). Genotypic sequencing will 
be performed on stored serum samples from study visit at Week 24 and sequencing results 
will be compared with baseline sample assessment. Cumulative treatment-emergent genotypic 
resistance rates will be reported.
6.4.5
Appropriateness of efficacy assessments 
The measurements of HBV DNA, HBV serological markers, ALT, and resistance surveillance 
are standard for CHB as evidenced by international CHB treatment guidelines (Jonas et al 
2010). 
 
In case of insufficient serum volume taken at a certain visit to perform the required 
assessments as indicated in Table 6-1, HBV DNA and biochemistry tests (including ALT and 
CK) should be measured as a priority.
6.5
Safety
Key safety endpoints:

Proportion of patients that discontinue study drug or require dose interruption due to 
treatment-emergent AEs

Proportion of patients who develop SAEs

Proportion of patients who develop Grade 3-4 AEs and AEs related to study drug  (and 
if study drug temporarily interrupted) 

Proportion of patients who develop AESI (muscle related events)

Other classical adverse events related to anti-HBV nucleos(t)ides analogues (including 
peripheral neuropathy, ALT flare, lactic acidosis, acute pancreatitis and 
hypersensitivity reactions)

Proportion of patients with hepatic decompensation or HCC
 


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
Proportion of patients who develop Grade 3-4 chemistry abnormality (including CK, 
ALT, AST, ALP, TB, PT, serum creatinine, serum cystatin C, serum phosphate, blood 
glucose), urinalysis abnormality and  Grade 3-4 hematology abnormalities
Other safety assessments include physical exams (including growth (including Body weight, 
Body height and BMI) and development (Tanner Score)), vital signs and pregnancy 
monitoring.
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
and extremities, vascular and neurological. Complete physical examination is required at 
Baseline, Week 24, Week 52 and Week 104 (see Table 6-1). 
Assessment of sexual maturation in males and females patients (for age group 2 and 3 at 
baseline visit) using Tanner staging (Appendix 2) should be performed at the following study 
visit: Baseline (visit 2), Week 24, Week 52 and Week 104. 
Information for all physical examinations must be included in the source documentation at the 
study site. Information on sexual maturation assessment should be recorded on the specific 
Assessment of sexual maturation using Tanner Staging CRF page. 
Significant findings that are present prior to the Inform consent signature must be included in 
the Relevant Medical History/Current Medical Conditions screen on the patient’s CRF. 
Significant findings made after signing the inform consent form which meet the definition of 
an Adverse Event must be recorded on the Adverse Event screen of the patient’s CRF.
6.5.2
Vital signs
The investigator will assess vital signs (heart rate, blood pressure, temperature and 
respirations) at each visit as indicated in Table 6-1 and at the Early Treatment Discontinuation 
visit, or as necessary in case of AEs or under patient request.
Vital signs include BP and pulse measurement. After the patient has been sitting for five 
minutes, with back supported and both feet placed on the floor, systolic and diastolic blood 
pressure will be measured three times using an automated validated device, e.g. OMRON with 
an appropriately sized cuff. The repeat sitting measurements will be made at 1-2min intervals 
and the mean of the three measurements will be used. In case the cuff sizes available are not 
large enough for the patient’s arm circumference, a sphygmomanometer with an appropriately 
sized cuff may be used.
6.5.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured at each visit as defined in Table 6-1.
6.5.4
Laboratory evaluations
All specimens collected will be sent to the central lab. Details on the collections, shipment of 
samples, normal ranges and standard units for laboratory values and reporting of results by the 
central laboratory, are provided to investigators in the laboratory manual. 
 


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Additional blood will be collected as defined in Table 6-1 for re-testing and storage purposes 
(i.e. genotypic sequencing). No genetic testing on patients’ DNA will be performed. 
The sample will be destroyed if no further testing is necessary. 
Clinically notable laboratory findings are defined in Appendix 1.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured. Blood samples for hematology will be collected at screening 
and selected visits as defined in the schedule of assessment Table 6-1.
6.5.4.2
Clinical chemistry
Serum will be collected for the following to be measured: ALT, AST, alkaline phosphatase 
(ALP), total bilirubin (TB), albumin, blood glucose, creatinine, cystatin C, serum phosphate, 
CK, serum amylase and lipase. The Serum samples will be collected as defined in Table 6-1.
The estimated glomerular filtration rate will be assessed by central lab using abbreviated 
Schwartz formula.
Plasma will be collected for Prothrombin time (PT and INR) at selected visits as shown in 
Table 6-1.
6.5.4.3
Urinalysis
Urine pregnancy test and dipstick measurements for specific gravity, pH, protein, glucose and 
blood will be performed. Any confirmed abnormalities of urine test will be managed 
according to guidelines and clinical practice. A positive urine pregnancy test requires serum 
B-HCG to be performed.
Samples for urinalysis will be collected as defined in Table 6-1.
6.5.5
Liver ultrasound
According to EASL 2013 guidelines (Sokal et al 2013), for HCC surveillance, liver 
ultrasound should be performed every 6 to 12 months depending on the stage of fibrosis. 
In the study, patients will be followed with liver ultrasound every 6 months as indicated in 
Table 6-1.
6.5.6
Electrocardiogram (ECG) 
Not applicable.
6.5.7
Pregnancy and assessments of fertility
Female adolescent patient must have a serum pregnancy test administered to rule out 
pregnancy at screening and a urine pregnancy test at scheduled time points throughout the 
study, at end of the study and at the discretion of the investigator.
A positive urine pregnancy test requires immediate interruption of study drug until serum B-
HCG is performed and found to be negative. If positive, the patient must be discontinued from 
 


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the trial and appropriate end of treatment procedure should be carried out. Such a pregnancy 
needs to be followed up by the investigator for safety analysis and reporting purposes.
Data collection: see Section 7.5 for details on reporting pregnancy.
All pregnancy cases need to be unblinded for safety management purposes. The unblinded 
information need to be communicated to the investigator on a case by case basis so that the 
patient can be informed.
6.5.8
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population.
 


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7
Safety monitoring
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. 
 


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Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1.
All adverse events must be recorded on the Adverse Events CRF page with the following 
information:
1. The severity grade (DMID AE grade)

Mild (Grade 1): usually transient in nature and generally not interfering with normal 
activities

Moderate (Grade 2): sufficiently discomforting to interfere with normal activities

Severe (Grade 3): prevents normal activities

Life-threatening (Grade 4)
2. Its relationship to the study drug(s) (suspected/not suspected)
3. Its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.
4. Whether it constitutes a serious adverse event (SAE)
5. Action taken regarding the study drug
All adverse events should be treated appropriately. Treatment may include one or more of the 
following:
no action taken (i.e. further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given; patient hospitalized/patient’s 
hospitalization prolonged; its outcome (not recovered/not resolved; recovered/resolved; 
recovering/resolving, recovered/resolved with sequelae; fatal; or unknown). 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed.
 


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The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
 


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All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to local Novartis Drug Safety and Epidemiology Department as per Section 7.2.2.
7.2.2
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after the 30 days period (after the last study visit) should only be 
reported to Novartis if the investigator suspects a causal relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs (either initial or follow-up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship of any SAE to study drug, complete the SAE Report Form in English, and send 
the completed, signed form by fax within 24 hours after awareness of the SAE to the local 
Novartis Drug Safety and Epidemiology Department. The telephone and fax number of the 
contact persons in the local department of Drug Safety and Epidemiology, specific to the site, 
are listed in the investigator folder provided to each site. The original copy of the SAE Report 
Form and the fax confirmation sheet must be kept with the case report form documentation at 
the study site.
Follow-up information should be provided using a new paper SAE Report Form stating that 
this is a follow-up to a previously reported SAE
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.
7.3
Liver safety monitoring
Telbivudine is an antiviral nucleoside analogue with inhibitory effects on HBV DNA and an 
indication in compensated CHB. No liver toxicity has been reported with telbivudine from 
 


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preclinical studies and based on 9,715 subjects/patients exposure in clinical trials and 329,556 
PTY (Patient Treatment Years) post-marketing database (as of 31-Aug-2012). No liver 
toxicity was confirmed in another internal post marketing surveillance with a total exposure of 
392,452 PTY (as of 28-Feb-2013). 
The main liver events (ALT flare/ flare) reported from Telbivudine treated patients are due to
effects of treatment failure (associated with suboptimal antiviral effect - HBV DNA increase 
and / or VB). Some of these situations could be prevented by monitoring HBV DNA at each 
visit (EASL 2012). 
Another potential reason of ALT increase / flare under CHB treatment could be associated 
with a positive antiviral treatment response, i.e., HBeAg seroconverion (EASL 2012). 
In the current protocol, the assessment schedule will adequately monitor liver events and has 
been used as current standards for CHB trials. 

Standard serum blood chemistry tests for monitoring hepatotoxicity (ALT, AST, ALP, 
total bilirubin) are performed at each scheduled visit every 4-12 wks.

Any patients with ALT flare (defined as ALT elevation > 10×ULN and > 2× baseline, per 
AASLD guideline); or ALT > 3 × ULN & > 2 × baseline AND (TBil > 2 × ULN or INR > 
1.5) or with hepatic decompensation will be discontinued from the study (see Section 
5.5.9). 

Exclusion criteria: ALT > 10×ULN or < 1.5×ULN. Patients with liver decompensation or 
other causes of liver diseases or total bilirubin ≥ 2 × ULN or INR > 1.5 excluded.  
7.4
Renal safety monitoring
Telbivudine is an antiviral nucleoside analogue with no known potential to cause Drug 
induced nephrotoxicity (no adverse preclinical in vitro or in vivo renal safety signal, mode of 
action well characterized with no known nephrotoxicity (no renal safety findings)).
Renal events in the pediatric population should be defined as 25% decrease in eGFR (Akcan-
Arikan et al 2007) using age-specific normal values for eGFR and serum/urinary normal 
values (Appendix 1).
Serum and urine samples are collected as defined in Table 6-1 for the measures of creatinine, 
cystatin C, serum phosphate, urine analysis for specific gravity, pH, protein, and blood. 
Any confirmed abnormalities of urine test should be managed according to guidelines and 
clinical practice. 
To estimate the glomerular filtration rate, the abbreviated Schwartz formula (Schwartz 2009) 
based on length (L= height (cm)) and serum creatinine (Scr) should be used in the 
pediatric population:
eGFR = 0.413×(height/serum creatinine) (height in cm; serum creatinine in mg/dl).
7.5
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
 


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details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. Pregnancies that are noted prior to administration 
of study medication but after the informed consent process may be considered to be reported 
at the discretion of the investigator especially where causality is suspected.
Pregnancy should be recorded on a Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Pregnancy Registry: to monitor fetal outcomes of pregnant women exposed to 
telbivudine, investigators are encouraged to register such patients in the 
Antiretroviral Pregnancy Registry.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on the SAE Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study during the perinatal or neonatal (first 28 days of life for a newborn 
child) periods. Consent to report information regarding these pregnancy outcomes should be 
obtained from the female partner.
7.6
Prospective suicidality assessment
Not applicable.
7.7
Adverse events of special interest (AESI) reporting
For the purpose of this study, the diagnosis and reporting of adverse events of special interest 
(AESI) defined as muscle related events (including myopathy and other types of muscle 
events) will follow specific guidance as described in this section. All AESIs’ should be 
reported on AE CRF page and SAE (if applicable). All other known classic adverse events 
under telbivudine treatment will be monitored and reported in this study following the normal 
AE process.
Patients with complaints or observation by parents of new or worsening muscle weakness, OR 
with new or worsening muscle pain (myalgia), OR patients with complaints or observation by 
parents of change in the urine color (e.g., dark urine) should be managed according to the 
algorithm provided in Appendix 3. 
All patients being followed with this algorithm should have muscle strength tested (Appendix 
5), Muscle Symptom Questionnaire (Appendix 4) administered, and serum CK checked at 
initial and follow up visits following the muscle management algorithm. More detailed 
neurological evaluation, EMG or muscle biopsy will not be routinely recommended for the 
diagnosis of myopathy in this pediatric study; and the need of conducting these procedures 
will be decided at the discretion of the investigators.
Muscle Strength Testing
Each of the muscle groups tested in the arms and legs will be graded on the Medical Research 
Council (MRC) grading system (0 to 5) (Appendix 5). The muscle strength testing exam 
 


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should be performed for all patients (≥ 6 years) with muscle related events as described in the 
muscle management algorithm. If the muscle strength testing exam can’t be performed 
(patients too young or physical examination not feasible), a subjective evaluation will be 
assessed using Muscle Symptom Questionnaire (Appendix 4). 
Muscle Symptom Questionnaire
The Muscle Symptom Questionnaire includes subjective assessments of muscle strength of 
legs (Question A), arms (Question B), and muscle pains (myalgia) (Question C) (Appendix 4). 
This questionnaire must be administered to all patients with complaints or observation by 
parents of new or worsening muscle weakness, OR new or worsening muscle pain (myalgia), 
OR patients’ complaints or observation by parents of change of urine color (e.g dark urine). 
The data collected from the questionnaire will be recorded in the study CRF.
Discontinuation criteria defined in the algorithm
There are 3 situations defined in the algorithm

Situation A: MRC score < 58 or ≥ 1 drop in MRC in 2 or more muscle groups OR 2 or 
more situations with ≥ Grade 2 in arms or legs as defined in muscle questionnaire (if < 6 
years or if strength tests not measurable) 

Situation B: Muscle pain score  > 5 OR myalgia affect functions (2 or more situations with 
≥ Grade 2 in arms or legs as defined in muscle questionnaire)

Situation C: CK elevation ≥ 7 × ULN
The study drug should be discontinued if meeting either one of below discontinuation criteria: 

If all 3 situations (A, B, C) occur at the same visit independently of degree / score / value, 
study drug should be discontinued at the current visit. 

If 2 out of the 3 situations (A, B, C) occur at one visit, study drug should be discontinued 
at the current visit.

If 1 of 3 situations (A, B, C) occurs at one visit, patients should be followed after 2 visits, 
if there is no improvement / is worsening in 2 weeks, study drug should be discontinued. 

In addition, if the patient is diagnosed with rhadbomyolysis (defined as CK > 50 × ULN 
(or 10,000 IU/L (Joy et al 2009)) with organ damage, usually renal compromise), the drug 
should be discontinued.
Definition of myopathy
The definition of myopathy is based on the definition recommended by NLA (National Lipid 
Association) for statins (McKenney et al 2006). In this protocol, patients with symptoms of 
myalgia (muscle pain, soreness, or cramps), weakness, AND creatine kinase ≥ 10×ULN will 
be assessed for the diagnosis as myopathy.  
Reporting of AESIs
All AESI’s should be recorded on the AE CRF pages. For muscle related AESIs, specific 
CRF pages should be filled and the muscle related AESI Report Form must be sent via FAX 
 


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to the Novartis Global Medical Specialist. The telephone and fax number of the contact 
persons will be listed on the AESI document. The original copy of the muscle related AESI 
Report Form (initial and follow up) and the fax confirmation sheet must be kept with the 
source documentation at the study site. 
Follow-up information should be sent to the same person to whom the original AESI Report 
Form was sent, using a new AESI Report form stating that it is a follow-up to the previously 
reported AESI and giving the date of the original report. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, and whether 
the patient continued or withdrew from study participation.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
CRO representative will review the protocol and CRFs with the investigators and their staff. 
During the study, Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The field monitor will visit the site 
regularly to check the completeness of patient records, the accuracy of entries on the CRFs, 
the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and to 
ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits.
If needed, continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis CRA organization. Additionally, a central analytics organization may 
analyze data & identify risks & trends for site operational parameters, and provide reports to 
Novartis Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
 


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requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive a CD-ROM or paper copies of the patient data for 
archiving at the investigational site.  
8.3
Database management and quality control 
CRO staff working on behalf of Novartis review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked. Any changes to the database after that time can only be made after written agreement 
by Novartis Development management.
8.4
Data Monitoring Committee
An independent Data Monitoring Committee composed of clinicians experienced in clinical 
care and/or clinical research in CHB pediatric population and a statistician, will perform
regular safety data review and where appropriate, to request and review additional safety 
and/or efficacy analyses during the course of the trial. A separate charter will be prepared to 
define the scope of the DMC (e.g. data to be reviewed, access to reports, actions on the study 
conduct, frequency and method of data transfers, format/timing of reports).
 


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8.5
Adjudication Committee
Not required.
9
Data analysis
The primary analysis will be done at Week 24. Additional analyses will be done at Week 52 
(intended for submissions to Health Authorities) and Week 104 (final analysis).
9.1
Analysis sets
The following analysis sets will be used in this trial:
Randomized set: The randomized set will be defined as all subjects who were randomized. 
Unless otherwise specified, mis-randomized subjects (mis-randomized in IRT) will be 
excluded from the randomized set. (Mis-randomized subjects are defined as cases where IRT 
contacts were made by the site either prematurely or inappropriately prior to confirmation of 
the subject’s final randomization eligibility and double-blind medication was not administered 
to the subject).
Full analysis set (FAS): The FAS will be comprised of all subjects from the randomized set 
to whom study treatment has been assigned. Following the intent-to-treat principle, subjects 
will be analyzed according to the treatment assigned to at randomization. If the actual stratum 
is different to the assigned stratum in IRT, the actual stratum will be used in analyses. The 
FAS is the primary efficacy analysis set.
Safety set: The Safety set will consist of all subjects who received at least one dose of study 
drug during the treatment period. Subjects will be analyzed according to treatment received. 
All safety analysis will be done on the safety set. 
Per-protocol set (PPS): The PPS will be defined as a subset of FAS who do not have major 
protocol deviations, such as patient has poor compliance or patient takes prohibited 
medications during treatment period. Other criteria for major protocol deviations will be 
established and documented based upon the review of data before clinical database lock for 
the Week 24 primary data analysis.
Modified Full analysis set (mFAS): The mFAS (a subset of FAS) will be used for selected 
efficacy and safety analyses beyond Week 24. The set will be defined only for telbivudine 
randomized group. Criteria for inclusion in this set will be detailed in the statistical analysis 
plan (RAP), to be finalized before clinical database lock for the Week 24 primary data 
analysis.
 
Patients will be kept in the same age group from baseline for data analysis during the whole 
study period.
9.2
Patient demographics and other baseline characteristics 
Descriptive statistics of demographics and baseline characteristics will be provided for overall 
 populations.    
 


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9.3
Treatments
The numbers of patients who receive each treatment and the duration of exposure will be 
summarized for the Safety set. In calculation of duration, periods of temporary interruption of 
study medication for safety reasons will be included. Further, frequency of dose change 
(including temporary dose interruption) by reasons will be presented.
Prior and concomitant therapies will be listed. The frequency and percentage of patients who 
used prior or concomitant medication will be summarized by preferred term (WHO Drug) and 
treatment arm. Concomitant medications will also be checked for protocol deviations. Patients 
who took prohibited concomitant medications will be noted in the summary of protocol 
deviations.
The Investigator will assess the patient’s compliance for each visit during treatment. Patients’ 
compliance will be summarized by visit.
9.4
Analysis of the primary variable
The primary objective of this study is to evaluate the antiviral efficacy of telbivudine using 
the percentage of pediatric patients achieving HBV DNA <300 copies/mL (51 IU/mL) at 
Week 24. The analysis of primary efficacy variable, as well as all other analyses, will be done 
for overall 
 patient population. 
 
 
 
 
The primary variable will be summarized by treatment groups (arms). Comparisons will be 
made between the telbivudine arm and the placebo arm for the overall population. The same 
analysis will be done by age groups, except in the younger group (from 2 to less than 6 years 
old) where the number of patients enrolled is anticipated to be small. 
 
 
Descriptive statistics will be provided for all endpoints.
9.4.1
Variable(s)
The primary efficacy variable is the proportion of patients achieving HBV DNA <300 
copies/mL (51 IU/mL) at Week 24.
9.4.2
Statistical model, hypothesis, and method of analysis
For the primary analysis, the null hypothesis (H0) is that the proportion of patients in the 
overall population achieving HBV DNA <300 copies/mL (51 IU/mL) in the telbivudine arm 
is not different from that of placebo arm. The alternative hypothesis (H1) is the proportion of 
patients in the overall population achieving HBV DNA <300 copies/mL (51 IU/mL) between 
the two groups is not the same.  That is:
H0:  π1 = π2   vs.
H1: π1 ≠π2
 


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Where, π1 and π2 are the proportion of HBV DNA <300 copies/mL (51 IU/mL) patients in the 
telbivudine and placebo arms, respectively. 
The hypothesis will be tested using Fisher Exact test method. The two sided test will be done 
at a significance level of 5% (Type I error, α = 0.05).
Two sided 95% exact confidence interval will be provided for the difference of proportions of 
the two groups.            
9.4.3
Handling of missing values/censoring/discontinuations
Missing HBV DNA value at Week 24 will be imputed with the closest HBV DNA value to 
Week 24 (either before or after Week 24) for primary endpoint (HBV DNA < 300 copies/mL
(51 IU/mL)). In case of equal distances from Week24, the measurement before week 24 will 
be used.
Patients who discontinue the treatment due to satisfied efficacy as described in Section 5.5.9
(complete response defined by HBV DNA < 300 copies/mL (51 IU/mL), ALT normalization 
and HBeAg seroconversion) will be treated as responders.
9.4.4
Supportive analyses
To check the robustness of the primary analysis as described in Section 9.4.2, two sets of 
supportive analyses will be performed: (1) analysis on Per Protocol set and (2) Age by 
baseline HBV DNA strata (low vs. high) adjusted estimate, using Mantel-Haenszel weighted 
estimated method, as described in Agresti and Hartzel (Agresti and Hartzel 2000). The 
younger age group will be pooled in to the middle age group, as there will be only a few 
patients in the younger age group.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
The secondary efficacy variables (corresponding to the secondary objectives in Section 2.2) 
will be summarized by treatment groups (arms). 
For Week 24 treatment comparison, where applicable:
(1) Dichotomous variables will be analyzed with Fisher’s Exact Test, similar to 
primary efficacy analysis, 
(2) Continuous variables will be analyzed with Analysis of Covariance (ANCOVA) 
model, including treatment, stratification factors, country/region and baseline 
values as co-factors.
Time to event variables will be analyzed using survival analysis (Kaplan-Meier estimates).
9.5.2
Safety variables
The safety analyses will include SAEs, AEs (all grades, AEs related to study drug, leading to 
study drug discontinuation or dose interruption), AESI (including muscle related events, 
Grade 3-4 CK elevations, as well as other compound class-related AESI (Section 3.6)), 
laboratory values (hematology and chemistry), development of liver decompensation and/or 
 


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HCC, physical exams (including growth (including Body weight, Body height and BMI) and 
development (Tanner Score), as well as abdominal B-US) and vital signs. All safety data will 
be summarized by treatment group; the placebo randomized patients will be included in the 
safety analysis set.
To estimate the glomerular filtration rate, the abbreviated Schwartz formula (Schwartz 2009) 
based on length (L= height (cm)) and serum creatinine (Scr), will be used:
eGFR = 0.413×(height/serum creatinine) (height in cm; serum creatinine in mg/dl).
 


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9.6
Interim analyses
Interim analyses are planned for weeks 24 (primary analysis) and 52. 
9.7
Planned analyses
Data will be analyzed at three time points: 
1.
The primary analysis will be at Week 24; a comparison between treatment groups will 
be carried out only at the Week 24 analysis.
2.
An additional analysis will be performed when all patients complete Week 52, and a 
52 week report will be prepared for that analysis. 
3. 
The final analysis will be performed at the end of study, which includes a 12-weeks 
follow-up period following Week 104 treatment completion. The end of study analysis is the 
final analysis.
A DMC is planned to conduct regular safety analyses for patient monitoring and where 
appropriate, to request and review additional safety and/or efficacy analyses (See Section 8.4
for details).
 


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9.8
Sample size calculation
The primary objective of this study is to demonstrate the antiviral efficacy with percentage of 
patients with attainment of HBV DNA < 300 copies/mL (51 IU/mL) in telbivudine treatment 
compared to placebo at Week 24 in patients with chronic hepatitis B.
Based on the results from CLDT600A2414 epidemiological study, 84-88% of pediatric 
patients presented HBV DNA < 9 log10 for HBeAg positive patients. In this study, 80% of 
patients with baseline HBV DNA < 9 log10 are expected to be recruited. Based on these 
baseline patients characteristics, the efficacy rate in the overall population is estimated to be 
60%. 
Considering a 5% dropout rate (and imputed values as failure (worst case)), with the 
assumptions of 60% and 5% patients with HBV DNA <300 copies/mL (51 IU/mL) at Week 
24 for telbivudine and placebo arms, respectively a total of 150 patients with a randomization 
ratio of 5:1 for telbivudine: placebo (125 vs. 25) will provide > 99% power to test the primary 
hypothesis (Section 9.4.2), at 5% significance level (Type I error, α), for overall patients
population.
10
Ethical considerations 
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
10.2
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
 


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Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients.
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must 
inform Novartis immediately that this request has been made.
10.4
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
11
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC it cannot be implemented. All significant protocol deviations 
will be recorded and reported in the CSR.
11.1
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
 


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Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 (Safety Monitoring) should be followed. 
12
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[Wursthorn K, Jung M, Riva A, et al (2010)] Kinetics of hepatitis B surface antigen decline 
during 3 years of telbivudine treatment in hepatitis B e Antigen-positive patients. Hepatology; 
52:1611-20.
[Zhang HF, Chang MH, Mao Q et al (2012)]Worldwide Pediatric Epidemiological study 
(CHB). Hepatol Int; 6:67–309.
[Zhou XJ, Lim SG, Lloyd D, et al (2006)] Pharmacokinetics of Telbivudine following Oral 
Administration of Escalating Single and Multiple Doses in Patients with Chronic Hepatitis B 
Virus Infection: Pharmacodynamic Implications. Antimicrob. Agents Chemother; 50:874-879.
[Zoulim F, Zeuzem S, Piratvisuth T, et al (2012)] Genotypic resistance reduced to very low 
levels in Chronic Hepatitis B patients treated over 2-years with Telbivudine when considering 
baseline characteristics and roadmap. J Hepatol; 56: S195.
Internal references
Investigator Brochure v 15
Core data Sheet, version 1.0 (dated: 7-May-2014)
 


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Appendix 1: Clinically notable laboratory values and vital 
signs
Table 13-1
Clinically notable laboratory values and vital signs
GRADE 1
(Mild)
GRADE 2
(Moderate)
GRADE 3
(Severe)
GRADE 4
(Potential Life-
threatening)
Hematology
Hemoglobin for 
children greater than 
2 years of age
10-10.9 mg/dL
7.0-9.9 mg/dL
<7.0 mg/dL
Cardiac Failure 
secondary to anemia
Absolute Neutrophil 
Count
750-1200/mm3
400-749/mm3
250-399/mm3
<250/mm3
Platelets
-------
50,000-75,000/mm3
25,000-49,999/mm3
<25,000/mm3
Prothrombin Time 
(PT)
1.1-1.2 x ULN
1.3 -1.5 x ULN
1.6 -3.0 x ULN
>3.0 x ULN
Partial 
Thromboplastin 
Time (PTT)
1.1-1.6 x ULN
1.7-2.3 x ULN
2.4 -3.0 x ULN
>3.0 x ULN
Gastrointestinal
Bilirubin (when 
accompanied by any 
increase in other 
liver function test)
1.1 - <1.25 x ULN
1.25 - <1.5 x ULN
1.5 – 1.75 x ULN
> 1.75 x ULN
Bilirubin (when 
other liver function 
are in the normal 
range)
1.1 - <1.5 x ULN
1.5 - <2.0 x ULN
2.0 – 3.0 x ULN
> 3.0 x ULN
AST (SGOT)
1.1 - <2.0 x ULN
2.0 – <3.0 x ULN
3.0 – 8.0 x ULN
> 8 x ULN
ALT (SGPT)
1.1 - <2.0 x ULN
2.0 – <3.0 x ULN
3.0 – 8.0 x ULN
> 8 x ULN
 


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GGT
1.1 - <2.0 x ULN
2.0 – <3.0 x ULN
3.0 – 8.0 x ULN
> 8 x ULN
Pancreatic Amylase
1.1-1.4 x ULN
1.5-1.9 x ULN
2.0-3.0 x ULN
>3.0 x ULN
Uric Acid
7.5-9.9mg/dL
10-12.4 mg/dL
12.5-15.0 mg/dL
>15.0 mg/dL
Creatine 
Phosphokinase
>1.0 – 3.0 x ULN
>3.0 – 7.0 x ULN
>7.0 – 10.0 x ULN
>10 x ULN
Electrolytes
Creatinine
2 Years- 12 Years of 
age
0.7-1.0 x ULN
1.1-1.6 x ULN
1.7-2.0 x ULN
>2.0 x ULN
Greater than 12 
Years of age
1.0-1.7 x ULN
1.8-2.4 x ULN
2.5-3.5 x ULN
>3.5 x ULN
Hypernatremia
<145-149 mEq/L
150-155 mEq/L
>155 mEq/L or 
abnormal sodium 
AND mental status 
changes
Hyponatremia
130-135 mEq/L
129-124 mEq/L
<124 mEq/L or 
abnormal sodium 
AND mental status 
changes
Hyperkalemia
5.0-5.9 mEq/L
6.0-6.4 mEq/L
6.5-7.0 mEq/L
>7.0 mEq/L or 
abnormal potassium 
AND cardiac 
arrhythamia
Hypokalemia
3.0-3-5 mEq/L
2.5-2.9 mEq/L
2.0-2.4 mEq/L
<2.0 mEq/L or 
abnormal potassium 
AND cardiac 
arrhythmia
Hypercalcemia
10.5-11.2mg/dL
11.3-11.9 mg/dL
12.0-12.9 mg/dL
>13.0 mg/dL
Hypocalcemia
7.8-8.4 mg/dL
7.0-7.7 mg/dL
6.0-6.9 mg/dL
<6.0 mg/dL
 


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Hypomagnesemia
1.2-1.4 mEq/L
0.9-1.1 mEq/L
0.6-0.8 mEq/L
<0.6 mEq/L or 
abnormal 
magnesium AND 
cardiac arrhythmia
Hypoglycemia
55-65 mg/dL
40-54 mg/dL
30-39 mg/dL
<30 mg/dL or 
abnormal glucose 
AND mental status 
changes
Hyperglycemia
116-159 mg/dL
160-249 mg/dL
250-400 mg/dL
>400 mg/dL or 
ketoacidosis
Proteinuria
Tr-1+ or <150 
mg/day
2+ or 150-499 
mg/day
3+ or 500-1000 
mg/day
4+ or Nephrotic 
syndrome >1000 
mg/day
Hematuria
Microscopic <25
cells/hpf
Microscopic >25
cells/hpf
Gross hematuria
Glomerular filtration rate *
eGFR values
60–89 
ml/min/1.73m2
30–59 
ml/min/1.73m2
15–29 
ml/min/1.73m2
<15 ml/min/1.73m2
Description 
Kidney damage 
with mild 
reduction of GFR
Moderate reduction 
of GFR
Severe reduction 
of GFR
Kidney failure
* Adapted from National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical 
practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, 
and stratification (Hogg et al 2003)
 


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Appendix 2: Assessment of sexual maturation in males and 
females under 18 years of age (Tanner staging)
Male patients - Development of external genitalia
• Stage 1: Pre-adolescent. Testes, scrotum, and penis are of about the same size and proportion 
as in early childhood.
• Stage 2: The scrotum and testes have enlarged and there is a change in the texture of the 
scrotal skin.
• Stage 3: Growth of the penis has occurred, at first mainly in length; these has been further 
growth of testes and scrotum
• Stage 4: Penis further enlarged in length and breadth with development of glans. Testes and 
scrotum further enlarged. There is also further darkening of the scrotal skin
• Stage 5: Genitalia adult in size and shape
Female patients - Breast development
• Stage 1: Pre-adolescent; elevation of papilla only.
• Stage 2: Breast bud stage; elevation of breast and papilla as a small mound, enlargement of 
areola diameter.
• Stage 3: Further enlargement of breast and areola, with no separation of their contours.
• Stage 4: Projection of areola and papilla to form a secondary mound above the level of the 
breast.
• Stage 5: Mature stage; projection of papilla only, due to recession of the areola to the general 
contour of the breast.
The girls will be asked at each visit if they had begun to menstruate.
Male and female patients - Pubic hair
• Stage 1: Pre-adolescent (can see velus hair similar to abdominal wall).
• Stage 2: Sparse growth of long, slightly pigmented, downy hair, straight or only slightly 
curled, appearing chiefly along the labia or the base of the penis.
• Stage 3: Considerably darker, coarser and more curled hair. The hair spreads sparsely over 
the junction of the pubes.
• Stage 4: Hair is now adult in type, but the area covered by is still considerably smaller than 
in most adults. There is no spread to the medial surface of thighs.
• Stage 5: Adult in quantity and type, distributed as an inverse triangle of the classically 
feminine pattern.
Marshall and Tanner (1970); Marshall and Tanner (1969)
 


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Appendix 3: Muscle management algorithm
Figure 15-1
Muscle management algorithm
 


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Appendix 4: Muscle symptom Questionnaire (initial and 
follow-up visits)
Questions to be raised by the investigators answered by patient or parents and transcribed by 
site staff in the eCRF.
Table 16-1
Muscle Symptom Questionnaire (Initial and follow-up visits)
Question A: Assessment on Muscle Strength of Legs *
Have you experienced or as parents you noticed for your child, new or worsening
# difficulty 
in either one of the following 4 situations? If yes, please provide a grade per the grading 
system below the table, and provide a time (dd-mmm-yy) when did you first notice this?
1. Walking 
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Comments: 
2. Running
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Comments: 
3. Climbing Steps
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Comments:
4. Rising from sitting positions 
Have you experienced (or the parents noticed) any difficulty in standing from the sitting 
position? or if arising from the floor 
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Comments: 
 


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*Grading systems for the answer of the above questions A (1-4) for Legs 
0 = Normal 
1 = Minor symptoms in one or both legs but not affecting the functions listed 
2 = Moderate symptoms in one or both legs affecting but not preventing the function listed 
3 = Severe symptoms in one or both legs preventing the functions listed 
4 = Severe symptoms in both legs preventing the functions listed but some purposeful movement still possible 
5 = Severe symptoms in both legs preventing purposeful movements
Note: If a child had an injury in one side of body and can’t perform the muscle strength test
on this particular side, the muscle strength score of the other body side needs to be evaluated 
and need be doubled as the scores of both sides.
Comments: 
How long have you noticed muscle weakness in your legs?
< 3 days  
    3 - <6 days  
   6 - < 9 days  
  9 - < 14 days  
   ≥14 days  
  NA  
Adapted from Merkies et al 2002.
Question B: Assessment on Muscle Strength of Arms **
Have you experienced or as parents you noticed for your child new or worsening
# difficulty 
in either one of the following 4 situations? If yes, please provide a grade per the grading 
system below the table, and provide a time (dd-mmm-yy) when did you first notice this?
1. Reaching overhead e.g  brushing or combing hair
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Comments: 
2. Reaching for things above the shoulders
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Comments: 
3. Pulling or pushing objects, e.g lifting a liter of milk
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Comments: 
 


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4. Throwing a ball
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Comments: 
** Grading systems for the answer of the above questions A (1-4) for Arms
0 = Normal 
1 = Minor symptoms in one or both arms but not affecting the functions listed 
2 = Moderate symptoms in one or both arms affecting but not preventing the functions listed 
3 = Severe symptoms in one or both arms preventing the functions listed 
4 = Severe symptoms in both arms preventing the functions listed but some purposeful movements still possible 
5 = Severe symptoms in both arms preventing the purposeful movements
Note: If a child had an injury in one side of body and can’t perform the muscle strength test 
on this particular side, the muscle strength score of the other body side needs to be evaluated 
and need be doubled as the scores of both sides.
Comments: 
How long have you noticed muscle weakness in your arms?
< 3 days  
    3-<6 days  
   6-< 9 days  
    9-< 14 days  
   ≥14 days  
     NA  
Adapted from Merkies et al 2002.
Question C: Assessment on Muscle Pains (Myalgia)
Have you experienced or as parents you noticed for your child any new or worsening muscle 
pain since starting study drug treatment for CHB in CLDT600A2306 study in one or more limbs at 
rest or after exercise? If yes, please provide a grade per the grading system in the lower part 
of the table, and provide a date (dd-mm-yy) when did you first notice this?
Reference: Muscle pain scaling system – Wong-Baker FACES Pain Rating Scale 
 


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Please select a score for the muscle pain (myalgia): 
Comments: 
Where is the muscle pain on your body?    Legs    
               Arms  
      
                                                                  Other locations  
    if ticked, please specify
_________                
Does it occur during rest or exercises?   Rest    
               Exercises  
      
How long have you noticed muscle pain (myalgia)?
< 3 days    
    3 - <6 days  
   6 - < 9 days  
    9  - < 14 days  
   ≥14 days  
NA  
Also please use the symptom questionnaire above to note if the pain is affecting any of the 
functions listed in the muscle symptom questionnaire above.
Hockenberry and Wilson 2009, Used with permission. Copyright Mosby.
0
2
4
6
8
10
 


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Appendix 5: Muscle strength testing exam
Table 17-1
Muscle Strength Testing Exam
Neuromuscular Exam with Strength Testing - Medical Research Council (MRC) Score
Was a neuromuscular exam with strength testing performed?   No       Yes* 
*If YES, please provide results. 
Location
Specify Muscle Group
(Enter only one major muscle 
group per line)
Muscle 
strength 
score 
for 
left 
muscles (L)
Muscle 
strength score 
for 
right 
muscles (R)
Subtotal 
Arm
Abduction of Arm
Flexion of the forearm
Extension of the wrist
Leg
Flexion of the Hip
Extension of the Knee
Dorsal flexion of the foot
Total**
Body 
Location
A = Arm
L = Leg
Strength Score
0 = no contraction
1 = muscle flicker, but no movement
2 = movement possible, but not against gravity (test the joint in its horizontal plane)
3 = movement possible against gravity, but not against resistance by the examiner
4 = movement possible against some resistance by the examiner
5 = normal strength
** Note: if total MRC score is < 58, refer to muscle algorithm for patients management. 
Adapted from  Kleyweg et al 1991.
 


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Appendix 6: Recommended pediatric dose of 
acetaminophen/paracetamol
Usual Pediatric Dose for Fever
Infants and Children:
IV: 2 to 12 years: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours
Maximum single dose 15 mg/kg
Maximum total daily dose: 75 mg/kg/day not to exceed 3750 mg/day
Oral: 10 to 15 mg/kg/dose every 4 to 6 hours as needed; do not exceed 5 doses in 24 hours
Alternatively, the manufacturer lists the following recommended doses:
10.9 to 16.3 kg or 24 to 35 pounds: 2 to 3 years: 160 mg
16.4 to 21.7 kg or 36 to 47 pounds: 4 to 5 years: 240 mg
21.8 to 27.2 kg or 48 to 59 pounds: 6 to 8 years: 320 mg
27.3 to 32.6 kg or 60 to 71 pounds: 9 to 10 years: 400 mg
32.7 to 43.2 kg or 72 to 95 pounds: 11 years: 480 mg
The manufacturer recommends the use of weight to select the dose as the preferred method. If 
weight is not available, then age may be used.
Rectal: 10 to 20 mg/kg/dose every 4 to 6 hours as needed (Although the perioperative use of 
high dose rectal acetaminophen (e.g., 25 to 45 mg/kg/dose) has been investigated in several 
studies, its routine use remains controversial; optimal doses and dosing frequency to ensure 
efficacy and safety have not yet been established; further studies are needed).
Children greater than or equal to 12 years:
IV: Less than 50 kg: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours
Maximum single dose: 750 mg/dose
Maximum total daily dose: 75 mg/kg/day (less than or equal to 3750 mg/day)
IV: Greater than or equal to 50 kg: 650 mg every 4 hours or 1000 mg every 6 hours
Maximum single dose: 1000 mg/dose
Maximum total daily dose: 4000 mg/day
Oral or Rectal: 325 to 650 mg every 4 to 6 hours or 1,000 mg 3 to 4 times daily
Maximum daily dose: 4000 mg/day
Usual Pediatric Dose for Pain
Infants and Children:
IV: Less than 2 years: 7.5 to 15 mg/kg/dose every 6 hours
Maximum daily dose: 60 mg/kg/day
IV: 2 to 12 years: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours
Maximum single dose 15 mg/kg
Maximum total daily dose: 75 mg/kg/day not to exceed 3750 mg/day
Oral: 10 to 15 mg/kg/dose every 4 to 6 hours as needed; do not exceed 5 doses in 24 hours
Alternatively, the manufacturer lists the following recommended doses:
10.9 to 16.3 kg or 24 to 35 pounds: 2 to 3 years: 160 mg
16.4 to 21.7 kg or 36 to 47 pounds: 4 to 5 years: 240 mg
21.8 to 27.2 kg or 48 to 59 pounds: 6 to 8 years: 320 mg
27.3 to 32.6 kg or 60 to 71 pounds: 9 to 10 years: 400 mg
 


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32.7 to 43.2 kg or 72 to 95 pounds: 11 years: 480 mg
The manufacturer recommends the use of weight to select the dose as the preferred method. If 
weight is not available, then age may be used.
Rectal: 10 to 20 mg/kg/dose every 4 to 6 hours as needed (Although the perioperative use of 
high dose rectal acetaminophen (e.g., 25 to 45 mg/kg/dose) has been investigated in several 
studies, its routine use remains controversial; optimal doses and dosing frequency to ensure 
efficacy and safety have not yet been established; further studies are needed).
Children greater than or equal to 12 years:
IV: Less than 50 kg: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours
Maximum single dose: 750 mg/dose
Maximum total daily dose: 75 mg/kg/day (less than or equal to 3750 mg/day)
IV: Greater than or equal to 50 kg: 650 mg every 4 hours or 1000 mg every 6 hours
Maximum single dose: 1000 mg/dose
Maximum total daily dose: 4000 mg/day
Oral or Rectal: 325 to 650 mg every 4 to 6 hours or 1,000 mg 3 to 4 times daily
Maximum daily dose: 4000 mg/day
(Accessed in Sep 2013:
http://www.drugs.com/dosage/acetaminophen.html#ruMACzji6CtEOkhZ.99)
 

SAP_001.pdf: 
Clinical Research and Development
LDT600 (Telbivudine, Sebivo®/Tyzeka®)
Clinical Trial Protocol CLDT600A2306 / NCT02058108
A randomized, double-blind, 104-weeks treatment study to 
evaluate the efficacy, safety, tolerability and 
pharmacokinetics of telbivudine oral solution and tablets in 
children and adolescents with compensated HBeAg-
positive and negative chronic hepatitis B virus infection
Phase III
RAP Module 3 – Detailed Statistical Methodology
Author(s):
, Novartis Trial Statistician
, CRO Trial Statistician
Document type:
RAP Documentation
Document status:
Amendment 2, Final version 1.0
Release date:
25Sep2017
Number of pages:
55
Property of Novartis 
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis 


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Document History:
Version
Date
Changes
Amendment 1
14Feb2017
Analyses abridged due to early termination of the study
 
Amendment 2 
v1 draft
05Jul2017
Updates transpiring after the review of the dry 1 TLFs.
Amendment 2 
v2 draft
22Sep2017
Further feedback from the clinical team


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Table of Contents
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Objectives ................................................................................................................9
2
Statistical methods.............................................................................................................11
2.1
General...................................................................................................................11
2.1.1
Statistical considerations.......................................................................11
2.1.2
Baseline definition ................................................................................11
2.1.3
Efficacy censoring date.........................................................................11
2.1.4
On-treatment definition.........................................................................11
2.1.5
Handling of missing data ......................................................................11
2.2
Visit windows........................................................................................................12
2.3
Analysis set............................................................................................................12
2.3.1
Randomized set.....................................................................................12
2.3.2
Safety set ...............................................................................................13
2.3.3
Full Analysis Set (FAS) ........................................................................13
2.3.4
Per-protocol set (PPS)...........................................................................13
2.3.5
Protocol deviations leading to exclusion from populations..................13
2.4
Disposition, demographics, background characteristics and analysis 
populations.............................................................................................................13
2.5
Study medication ...................................................................................................15
2.5.1
Exposure................................................................................................15
2.5.2
Compliance ...........................................................................................16
2.6
Prohibited medications ..........................................................................................16
2.7
Efficacy evaluation................................................................................................17
2.7.1
Efficacy endpoints and analysis populations ........................................17
2.7.2
Efficacy endpoints definitions...............................................................18
20
2.7.4
Analysis methods ..................................................................................21
2.8
Safety evaluation ...................................................................................................22
2.8.1
Adverse events ......................................................................................22
2.8.2
Laboratory assessments.........................................................................24
2.8.3
Graded laboratory abnormalities...........................................................24
2.8.4
ALT flares .............................................................................................24
2.8.5
Vital signs..............................................................................................24
2.8.6
Muscle symptoms..................................................................................24


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2.8.7
Glomerular filtration rate ......................................................................24
2.8.8
Relationship of muscle events and CK elevations................................25
2.8.9
Abdominal Ultrasound..........................................................................27
2.8.10
Tanner staging assessment....................................................................27
28
2.9
Interim analyses.....................................................................................................28
2.10
Other topics............................................................................................................28
3
Sample size and power considerations..............................................................................28
4
Appendix 1. Mantel-Haenszel weighted estimated method..............................................29
5
Appendix 2. Preferred terms for the Adverse Events of Special Interest..........................30
6
Appendix 3: Protocol Deviations ......................................................................................47
7
References .........................................................................................................................55


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List of abbreviations
AASLD
American Association of the Study of Liver Diseases
ADR
Adverse Drug Reaction
ADV
Adefovir
AE
adverse event
AESI
adverse event of special interest
Alb
albumin
ALT
alanine aminotransferase
AFP
alpha-fetoprotein
AST
aspartate aminotransferase
ALP
alkaline phosphatase
b.i.d.
twice a day
CFR
US Code of Federal Regulations
CHB
Chronic Hepatitis B
CK
Creatine Kinase
CMV
Cytomegalovirus
CRF
Case Report/Record Form (paper or electronic)
CPO
Country Pharma Organization
CRO
Contract Research Organization
CTP
Child-Turcotte-Pugh
DNA
Deoxyribonucleic acid
DS&E
Drug Safety & Epidemiology
EASL
European Association for the Study of the liver
EBV
Epstein-Barr virus
ECG
Electrocardiogram
EDC
Electronic Data Capture
ETV
Entecavir
eGFR
estimated Glomerular Filtration Rate
EMG
Electromyography
FAS
full analysis set
GCP
Good Clinical Practice
HAV
Hepatitis A virus


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HBeAb
Hepatitis Be antibody
HBeAg
Hepatitis Be antigen
HBsAb
Hepatitis B surface antibody
HBsAg 
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCG (β-HCG)
β-human Chorionic Gonadotropin
HCV
Hepatitis C virus
HDV 
Hepatitis D virus
HEV 
Hepatitis E virus
HIV
Human immunodeficiency virus type 1 and type 2
HSV
Herpes Simplex virus
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IFN
Interferon
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Randomization Technology
i.v.
intravenous
IVRS
Interactive Voice Response System
IWRS 
Interactive Web Response System
LAM
Lamivudine
LDT (LdT)
Telbivudine
LOQ
Lower Limit of Quantification
MedDRA
Medical Dictionary for Regulatory Activities
NLA
National Lipid Association
NSAID
Non-steroidal Anti-Inflammatory Drug
o.d.
once a day
PCR
Polymerase Chain Reaction
PNR
Primary Non-Response
PK 
Pharmacokinetic


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p.o.
oral
PPS
per protocol set
PT
Prothrombin time
PTY
Patient treatment years
q.d.
quaque die (daily)
SAE
serious adverse event
SUSAR
Suspected Unexpected Serious Adverse Reactions
SPC
Summary of Product Characteristic
TB / TBil
total bilirubin
TDF
Tenofovir Disiproxil Fumarate
ULN
Upper Limit of Normal
VB
Virological breakthrough
WBC
White Blood cells
WHO 
World Health Organization


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1
Introduction
1.1
Study design
This protocol will enroll HBeAg positive and HBeAg negative patients into the randomized, 
double-blind and placebo-controlled, 104-weeks treatment study. A screening period of 6 
weeks will be used to assess patient eligibility. Patients will be treated for a total of 104 weeks 
and will have a 12-weeks safety follow-up period.
Patients will be stratified by 1) age group and 2) HBV DNA level. Approximately 80% of 
patients with lower HBV DNA at screening (i.e. for HBeAg positive patients HBV DNA <9 
log10 and HBeAg negative patients with HBV DNA <7 log10 copies/mL) are expected to be 
recruited.
Subsets of patients by age (calculated based on birthday at randomization visit (baseline: 
day1)) are defined as: 

Age group 1: from 2 to less than 6 years old 

Age group 2: from 6 to less than 12 years old 

Age group 3: from 12 to less than 18 years old
At Baseline (visit 2), eligible patients will be randomized in a double blind method to 
telbivudine or placebo in a ratio 5:1. The total double-blind period will be 24 weeks. 
At Week 24 (visit 6), treatment will be unblinded: 

patients receiving telbivudine with HBV DNA <300 copies/mL (51 IU/mL) at Week 
24 (visit 6) will remain on telbivudine treatment until Week 104 (visit 13); 

patients on telbivudine treatment with confirmed HBV DNA ≥300 copies/mL (51 
IU/mL) at Week 24 (visit 6) will be discontinued from study drug at the next visit 
(Week 28). 

for patients on placebo, eligibility will be checked at Week 24 (visit 6):
o
Patients with confirmed eligibility will initiate treatment with telbivudine at 
Week 28 (visit 7). After 24 weeks on telbivudine treatment (Week 52 (visit 9), 
HBV DNA level will be assessed. Patients with HBV DNA <300 copies/mL 
(51 IU/mL) will remain on treatment until last on-treatment study visit (Week 
104 (visit 13)); patients with HBV DNA ≥300 copies/mL (51 IU/mL) will be 
discontinued from the study at Week 52 (visit 9). 
o
Placebo patients not eligible for telbivudine treatment at Week 28 (visit 7) may 
continue in the study until Week 52 (visit 9) and may start telbivudine 
treatment at a later visit until Week 52 (visit 9) based on investigator’s decision 
and patient agreement
Patients with confirmed complete response (defined as HBV DNA <300 copies/mL (51 
IU/mL), HBeAg seroconversion and ALT normalization) will continue telbivudine treatment 
for another 52 weeks from the day of confirmation. At the end of this “consolidation period”, 
if the complete response is maintained, patients could be considered for discontinuation of 
telbivudine at the discretion of the investigators and remain in the study to monitor off-
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On Jan 6, 2017, patient recruitment and randomization was placed on temporary hold and an 
interim analysis for futility was requested by the Data Monitoring Committee.  Following 
DMC review of the interim analysis and a recommendation by the DMC to stop the study, 
Novartis made a decision to terminate the study.  At that time, 53 patients had been 
randomized into the study.
1.2
Objectives
Primary objective:
The primary objective of this study is to demonstrate the antiviral efficacy of telbivudine 
compared to placebo in pediatric patients by determining the percentage of patients achieving 
serum HBV DNA level of <300 copies/mL (51 IU/mL) at Week 24.
Secondary objectives:
The secondary objectives of this study are:
1. To assess the antiviral efficacy as evaluated by:
a.
Proportion of patients achieving HBV DNA <300 copies/mL (51 IU/mL) at Week 
52 and Week 104
b. Proportion of patients achieving HBV DNA < Lower Limit of Quantification 
(LLOQ) (< LLOQ defined as undetectable HBV DNA, ≥ LLOQ defined as 
detectable HBV DNA), <1000 copies/ml (or 200 IU/mL), <10,000 copies/ml (or 2 
000 IU/mL) and ≥10,000 copies/mL (or 2 000 IU/mL) at Week 24, 52 and 104
c.
Serum HBV DNA reduction from baseline 
d. Time to achieve HBV DNA <300 copies/mL (51 IU/mL)
e.
Proportion of patients with Primary non-response
2. To assess the biochemical response at Week 24, 52 and 104 as evaluated by proportion of 
patients whose baseline ALTs were abnormal (defined as ALT >1 x Upper Limit of 
Normal [ULN]) and subsequently normalized 
3. To assess the serological responses at Week 24,  52 and 104 as evaluated by:


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a.
Proportion of HBeAg positive patients at baseline who subsequently have HBeAg 
loss and HBeAg seroconversion (defined as loss of HBeAg with detectable 
HBeAb) 
b. Proportion of HBsAg positive patients at baseline who subsequently have HBsAg 
loss and HBsAg seroconversion (defined as loss of HBsAg with detectable 
HBsAb) 
4. To assess the percentage of patients achieving composite endpoints at Week 52 and 104:
a.
HBV DNA <300 copies/mL (51 IU/mL), ALT normalization and HBeAg 
seroconversion for HBeAg positive patients only 
b. HBV DNA <300 copies/mL (51 IU/mL) and ALT normalization for HBeAg 
negative patients.
5. To assess virological breakthrough (VB) as evaluated by:
a.
Cumulative rate of patients with confirmed VB at Week 52 and 104  
b. Time to VB 
6. To assess the presence of treatment emergent genotypic resistance associated with 
virological breakthrough over the study period, or in patients with HBV DNA≥300 
copies/mL (51 IU/mL) at Week 24 and discontinued from the study treatment (or at 
discontinuation if prior to Week 24 for subjects with at least 16 weeks of LDT treatment)
7. To evaluate the safety and tolerability of telbivudine at Week 52 and 104 defined by AEs, 
SAEs, adverse events of special interest (AESI) (including muscle related events) and 
death; laboratory evaluations specifically on-treatment and post-treatment ALT flares, 
incidence and clinical significance of CK elevations; growth and development (linear 
growth and sexual maturation); development of liver decompensation and/or HCC.
Due to early termination of the trial, objectives related to Week 52 and Week 104 will not be 
addressed.


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2
Statistical methods
2.1
General
2.1.1
Statistical considerations
SAS version 9.3 or later will be used in all analyses.
All confidence intervals will be based on 2-sided 95% confidence intervals, unless otherwise 
specified.
The total patient accrual in this study is expected to be 150 patients.
Summary statistics will include the mean, standard deviation, median, minimum, and 
maximum values for continuous variables, and frequencies and percentages in each category 
(including a category labeled as ‘missing’ when appropriate) for categorical variables.  
The primary analysis will be done at Week 24. As the study is being terminated, and only 2-3
patients are anticipated to reach 52 weeks of treatment with telbivudine, no formal analysis 
will be performed beyond week 24.  
The following treatment grouping will be used for all efficacy and safety analyses:

Initial LdT: patients initially treated with Telbivudine.

Initial Placebo: patients initially treated with Placebo.

Overall: patients from both groups.
2.1.2
Baseline definition
Baseline will be defined as the last available assessment, from scheduled or unscheduled visit, 
prior to the first dose of study drug.
2.1.3
Efficacy censoring date  
A patient’s censoring date is the date of the first occurrence of: two days after the last dose of 
the study drug, the start date of first prohibited Hep-B related medication, pregnancy date (if 
any) and any protocol deviation with codes C01, C02, all codes starting with D, M01, M02, 
S05, as defined in Appendix 3: Protocol Deviations.
2.1.4
On-treatment definition
On-treatment for all summaries except adverse events will be defined as any assessment after 
the first dose of the study drug up to and including one day after the last dose of the study 
drug. 
For adverse events summaries 30 days will be added to the end of the on-treatment period 
definition.
2.1.5
Handling of missing data
All efficacy observations on or after censoring date will be treated as missing.


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To assess the robustness of the results due to missing data, the analysis of primary and all 
secondary efficacy endpoints will be performed based on two analysis populations. 

Full Analysis Set (FAS) population with imputation.  In this analysis, the missing data will 
be imputed as described below in section 2.7.1;

Per Protocol Set analysis with observed data only.  Missing data will not be imputed for 
this analysis, except in the following case: patients with confirmed complete response who 
discontinue due to satisfied efficacy will have their response prior to discontinuation
carried forward to all subsequent scheduled visits.
Statistical comparisons of GFR between the treatment groups or between baseline and post-
baseline visits will be performed in two ways:

Missing GFR assessments imputed using the LOCF method, i.e. carrying forward the 
last available post-baseline observation up to Week 24.

Missing GFR assessments not imputed.
In other GFR summaries missing assessments will not be imputed.
HBV DNA assay results below the lower limit of detection (LLD, 1.30 log IU/mL) of the 
assay of laboratory performing the test will be assigned a value equal to one half of the LLD 
for the statistical analyses and tabulations.
2.2
Visit windows
Assessments will be generally assigned to study weeks based on the nominal visit week 
number. However, assessments from early termination visits will be assigned to the next
scheduled visit after the last scheduled visit that the subject has attended prior to early 
termination.
Unscheduled visits generally will not be used in by-visit summaries. However, unscheduled 
visits will be used in the following situations:

If a patient does not have a scheduled assessment at a particular visit, but has an 
unscheduled assessment within +/- 7 days of the scheduled visit date, this unscheduled 
assessment will be used for this visit in by-visit summaries. In case multiple 
unscheduled assessment exist within the window, the one closest to the scheduled visit 
date will be used. In case two equidistant unscheduled visit exist, one before and one 
after the scheduled visit date, the earlier one will be used.

As mentioned in the baseline definition, unscheduled visits will be considered for the 
selection of baseline assessment.
2.3
Analysis set 
2.3.1
Randomized set
The randomized set will be defined as all subjects who were randomized. Unless otherwise 
specified, mis-randomized subjects (mis-randomized in IRT) will be excluded from the 
randomized set. (Mis-randomized subjects are defined as cases where IRT contacts were made 
by the site either prematurely or inappropriately prior to confirmation of the subject’s final 
randomization eligibility and double-blind medication was not administered to the subject). 


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2.3.2
Safety set
The Safety set will consist of all subjects who received at least one dose of study drug during 
the treatment period. Subjects will be analyzed according to treatment received. All safety 
analysis will be done on the safety set. 
2.3.3
Full Analysis Set (FAS)
The FAS will be comprised of all subjects from the randomized set to whom study treatment 
has been assigned. Following the intent-to-treat principle, subjects will be analyzed according 
to the treatment assigned to at randomization. If the actual stratum is different to the assigned 
stratum in IRT, the actual stratum will be used in analyses. The FAS is the primary efficacy 
analysis set. 
2.3.4
Per-protocol set (PPS)
The PPS will be defined as a subset of FAS who do not have major protocol deviations, as 
shown in the table below
2.3.5
Protocol deviations leading to exclusion from populations
Protocol deviations defined in the Appendix 3: Protocol Deviations that lead to patient 
classification into the analysis set as follows:
Analysis Set
PD criteria which leads patient to be 
excluded (PD group codes)
Non-PD criteria which leads 
patient to be excluded 
Randomized
None
Patient is not randomized
Safety
None
Patient did not take study 
drug
FAS
None
Patient is not randomized
PPS
All 
inclusion/exclusion 
criteria 
(codes 
starting with I and E), S02
Patient is not randomized
All exceptional cases and problems and the final decisions on the allocation of patients to 
populations will be fully defined and documented before database lock (in particular before 
breaking the blind where applicable) and will be fully identified and summarized in the 
clinical study report according to ICH E9.
2.4
Disposition, demographics, background characteristics and 
analysis populations
Disposition
The number and percentage of patients in the following subsets will be summarized by 
treatment group:


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
randomized

completing Week 24 visit

completing the treatment period per CRF

completing the study (with follow-up period) per CRF 

discontinuing the treatment period or the study with reasons of discontinuation.  
For patients in the Initial Placebo treatment group the number and percentage of patients 
switching and not switching to LdT after Week 24 will be presented along with the reasons 
for not switching.
All disposition information will be listed.
The number and percentage of patients with protocol deviations will be summarized by 
treatment arm and also presented in a data listing.
Analysis populations
The number and percentage of patients included in each population will be summarized by 
treatment group. Data listing will also be presented.
Demographics and baseline characteristics
The following demographic variables and baseline disease characteristics will be summarized 
by treatment group.
Demographic variables 
Continuous variables:

Age (years) 
Age will be calculated as the number of whole years from the patient's date of birth to the date 
of baseline visit.
Categorical variables:

Age group (2 - <6, 6 - <12, 12-<18 years)

Sex (male, female)

Predominant race (Caucasian, Black, Asian, Native American, Pacific Islander, Other)

Ethnicity (Hispanic/Latino, Chinese, Indian (Indian subcontinent), Japanese, Mixed
Ethnicity, Other)

Source of subject referral.

Geographic region (Asia, Europe)

Country
Baseline characteristics
Continuous variables:

Weight (kg)

Height (cm)

BMI


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
HBV DNA (log10 copies/mL)

ALT (IU/L)

AST (IU/L)

CK (IU/L)

Glomerular filtration rate by Schwarz formula

Liver stiffness measurement by FibroScan (if available).
Categorical variables:

ALT – multiples of ULN (<1x, 1x-<2x, 2x-<5x, 5x or more, Missing)

AST - multiples of ULN (<1x, 1x-<2x, 2x-<5x, 5x or more, Missing)

CK - multiples of ULN (Grade 0: ≤1x; Grade 1: >1x - ≤3x, Grade 2: >3x - ≤7x, Grade 
3: >7x - ≤10x, Grade 4: 10x or more, Missing)

HBV DNA (log10 copies/mL) (low, defined as < 9 log for HBeAg-positive patients and < 
7 log for HBeAg negative vs. high, defined as >= 9 log for HbeAg-positive patients 
and >= 7 log for HBeAg negative).
Mean, median, standard deviation, minimum and maximum values will be presented for 
continuous variables by treatment group. The number and percentage of patients in each 
category for categorical variables will be presented by treatment group.
This summary will be performed for all patients in the safety set and also separately for 
HBeAg positive and HBeAg negative.
Hepatitis B related medical history
The following characteristics will be summarized in a frequency table by treatment group:

If the patient was treated before for Hepatitis B

If treated, which prior treatments were taken (Common IFN, Peg-IFN, Lamivudine, 
Entecavir, Adefovir, Tenofovir or other); patients will count in all applicable 
categories.

Probable route of HBV acquisition (Mother known to be HBV carrier, Other family 
member(s) known to be HBV carrier(s), History of other parenteral exposure(s), Other 
risk factor(s) or Unknown); patients will count in all applicable categories.
Medical history
General medical history will be coded to MedDRA (version 19.1) and summarized by 
treatment group, system organ class and preferred term.
2.5
Study medication
2.5.1
Exposure
Study drug administration information will be included in data listings.  


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Duration of exposure to each of the study drugs (Telbivudine or Placebo) will be summarized
separately. For patients who switched from Placebo to Telbivudine both durations will be 
summarized separately.
Duration of exposure to Telbivudine or Placebo will be defined as the number of weeks from 
the day of the first dose of the drug to the day of the last dose of the drug.
For the exposure summary descriptive statistics for the duration of exposure will be presented.
For each patient, time-weighted average dose will be calculated. It will be defined as follows:
[Sum of (Total Daily Dose (mg) / Patients' weight (kg) * (End date of Dose – Start date of 
Dose + 1) taken over all patient's doses] / [Total duration of exposure (days)]
Time-weighted average dose will be summarized descriptively by treatment groups for LdT 
treatment only.
The analysis will be performed for the safety set. Data listing will also be provided.
Expected daily dose (mg) will be calculated for each patient as follows:

If subject weight is < 30 kg: as 20mg * weight (kg)

If subject weight is >= 30 kg: 600 mg
This calculated daily dose will be compared with actual daily dose. A listing of subjects with 
actual daily dose that differs from the expected daily dose by more than 10% of the expected 
daily dose will be provided.
2.5.2
Compliance
Compliance will be assessed by the investigator and/or study personnel at each visit using the 
pill counts or volume solution evaluation and some specific questions raised to the patient to 
assess the compliance.
The investigator will record the percentage of compliance between visits in the case record 
form (CRF), using the pill count, the volume solution evaluation, the answers provided by the 
patients on specific compliance questions and his/her experience with the patient.
There are three categories of compliance:

Good compliance equals ≥ 90%

Fair compliance equals between 70% – 89%

Poor compliance equals < 70%
Compliance will be summarized based on investigator’s rating (poor, fair or good) by all 
nominal visits in the study using FAS.
2.6
Prohibited medications
Prohibited medications will be coded using the WHO Drug Reference List that employs the 
Anatomical Therapeutic Chemical classification system.  


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Efficacy data will be censored after the start date of first use Hepatitis B related medications 
other than protocol-assigned Telbivudine. 
Summary tables will be provided presenting the number and percentage of patients receiving 
the prohibited medications after the start of study drug administration, by ATC class and 
preferred term. 
2.7
Efficacy evaluation
2.7.1
Efficacy endpoints and analysis populations
The following endpoints are defined by the protocol and will be used for efficacy evaluation.

Primary efficacy endpoint: rate of HBV DNA < 300 copies/mL (51 IU/mL) at week 
24.

Secondary efficacy endpoints:
o
rate of HBV DNA < low limit of detection at Week 24;
o
rate of HBV DNA < 1000 copies/mL and < 10000 copies/mL at Week 24
o
Serum HBV DNA reduction from baseline 
o
Time to achieve HBV DNA <300 copies/mL (51 IU/mL)
o
Proportion of patients with Primary non-response
o
Proportion of patients with ALT normalization at Week 24among those with 
abnormal ALT at baseline.
o
Serum ALT and its change from baseline.
o
Proportion of HBeAg positive patients at baseline who subsequently have 
HBeAg loss and HBeAg seroconversion at Week 24.
o
Proportion of HBsAg positive patients at baseline who subsequently have 
HBsAg loss and HBsAg seroconversion at Week 24.
o
Composite endpoint: HBV DNA <300 copies/mL (51 IU/mL), ALT 
normalization and HBeAg seroconversion for HBeAg positive patients only at 
Week 24Composite endpoint: HBV DNA <300 copies/mL (51 IU/mL) and 
ALT normalization for HBeAg negative patients at Week 24
o
Cumulative rate of patients with confirmed Virologic Breakthrough  (VB) at 
Weeks 24.
o
Time to initial Virologic Breakthrough.
o
Proportion of patients with cumulative treatment emergent genotypic resistance 
at Weeks 24.
All efficacy endpoints will be analyzed for FAS and PPS populations. In the FAS analysis the 
following method will be used to impute missing values. If no assessment, scheduled or 
unscheduled, is available within a particular visit window, then the value from the available 
visit closest in time to the scheduled date of the missing visit will be used to impute the value 


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for this visit. In case of equal distances from the scheduled visit date, the earlier measurement 
will be used.
The analysis for Per Protocol Set will be performed on observed values without any 
imputation, except in the following case: patients with confirmed complete response who 
discontinue due to satisfied efficacy will have their response prior to discontinuation carried 
forward to all subsequent scheduled visits.
The main analysis will be for the FAS population with the above imputation rules. PPS 
analysis will be supportive.
2.7.2
Efficacy endpoints definitions
When deriving all following efficacy endpoints, all efficacy observations on or after the 
censoring date (section 2.1) will be treated as missing. 
HBV DNA < 300 copies/mL:  
Serum HBV DNA < 300 copies/mL. 
HBV DNA < LLOQ (PCR Negativity):  
Serum HBV DNA < 169 copies/mL, the low limit of quantification (LLOQ) of the COBAS 
TaqMan HBV Test that is used in this study.
HBV DNA < 1000 copies/mL, HBV DNA < 10000 copies/mL:  
Serum HBV DNA < 1000 copies/mL (3log) or < 10000 copies.mL (4 log). 
ALT normalization:
ALT normalization is defined as ALT within normal limits on two successive visits for a 
patient with an elevated ALT (> 1.0 × ULN) at the baseline. Relative to the two successive 
visits, a visit can be scheduled or unscheduled and missing values are not considered in 
determining if a patient has ALT normalization.
Hence, for a particular visit, a patient is considered to have ALT normalization if the patient’s 
ALT value at that visit and either the previous or subsequent ALT value are ≤ 1.0 ULN and 
the patient’s baseline ALT is elevated (> 1.0 × ULN).    If a patient’s last ALT value is ≤ 1.0 × 
ULN the patient will be defined as having ALT normalization at that time-point.   The “last 
visit” is defined as the last visit occurring prior to the patient’s censoring date.
In patients with baseline ALT <= 1.0 X ULN, this endpoint is not defined.
1 log above Nadir virologic breakthrough
1 log above nadir virologic breakthrough is defined as a confirmed (i.e. on two consecutive 
visits or on the last on-treatment visit) HBV DNA increase of >=1 log10 copies/mL above 
nadir HBV DNA (the lowest post baseline HBV DNA level achieved) or HBV DNA ≥ 300 
copies/mL (51 IU/mL) after initial response with HBV DNA < 300 copies/mL (51 IU/mL). 
Note: the protocol specifies that the two consecutive visits when the patient’s HBV DNA is 1 
log above nadir have to occur within 4 weeks interval, as this reflects clinical practice. 
However, no time restriction on these two visits will be placed in the analysis.


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Cumulative virologic breakthrough
A patient is defined to have a cumulative virologic breakthrough at a visit if the patient had 1 
log above nadir virologic breakthrough at any time prior to this visit.
Cumulative treatment-emergent resistance:
Treatment-emergent resistance is defined as 1 log above nadir virologic breakthrough or HBV 
DNA >300 copies/mL confirmed by genotypic mutation. Cumulative treatment-emergent 
resistance at timepoint is defined as resistance at any time before or at the timepoint.
HBeAg loss/E-Loss:  
HBeAg loss is defined as loss of detectable serum HBeAg in a patient who was HBeAg-
positive at baseline. This endpoint is not defined for patients who were HBeAg-negative at 
baseline.
HBeAg seroconversion/E-seroconversion: 
HBeAg seroconversion is defined as HBeAg loss and a gain of detectable HBeAb.  
HBsAg loss/S-Loss:  
HBsAg loss is defined as loss of detectable serum HBsAg in a patient who was HBsAg-
positive at baseline. Since positive HBsAg is one of the study’s inclusion criteria, this 
endpoint is defined for all randomized patients.
HBsAg seroconversion/S-seroconversion: 
HBsAg seroconversion is defined as HBsAg loss and a gain of detectable HBsAb.  
HBV DNA Change from baseline
HBV DNA change from baseline will be defined as the difference between the Week 24 HBV 
DNA value (log10 copies/mL) and baseline HBV DNA value (log10 copies/mL).
Time to achieve HBV DNA < 300 copies/mL
This endpoint will be defined in two ways: in the initial double-blind period and for the 
overall LdT treatment.
In the initial double-blind period time to achieve HBV DNA < 300 copies/mL is defined as 
the number of days from the baseline to the first on-treatment visit when the patient has 
achieved HBV DNA < 300 copies/mL. If the patient never achieves HBV DNA < 300 
copies/mL while on the initial treatment (Placebo or LdT) and before his/her efficacy 
censoring date, the time is censored at the date of the last dose of the initial treatment or the 
efficacy censoring date, whichever comes first.
For the overall LdT treatment time to achieve HBV DNA < 300 copies/mL is defined for all 
subjects who were treated with LdT, including those initially randomized to LdT and those 
initially randomized to placebo, but switching to LdT after Week 24. Subjects who were never 
treated with LdT will be excluded, as well as subjects, if any, who achieved HBV DNA < 300 
copies/mL during initial placebo treatment. Time to event will be calculated as the number of 
days from the first LdT dose to the first on-treatment visit when the patient has achieved HBV 


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DNA < 300 copies/mL. If the patient never achieves HBV DNA < 300 copies/mL before 
his/her efficacy censoring date, the time is censored at the efficacy censoring date.
Time to Initial Virologic Breakthrough
This endpoint will also be defined in two ways: in the initial double-blind period and for the 
overall LdT treatment.
In the initial double-blind period, for patients that experience Virologic Breakthrough while 
on initial treatment, time to Initial Virologic Breakthrough is defined as the number of days 
from the baseline to the first of the two visits when patient’s HBV DNA is 1 log above nadir, 
as required by the Virologic Breakthrough definition. For patients that do not experience 
Virologic Breakthrough while on the initial treatment (Placebo or LdT) and before their 
efficacy censoring date, the time is censored at the date of the last dose of the initial treatment 
or the efficacy censoring date, whichever comes first.
For the overall LdT treatment time to Virologic Breakthrough is defined for all subjects who 
were treated with LdT, including those initially randomized to LdT and those initially 
randomized to placebo, but switching to LdT after Week 24. Subjects who were never treated 
with LdT will be excluded, as well as subjects who experienced Virologic Breakthrough 
during the initial placebo treatment. Time to event will be calculated as the number of days 
from the first LdT dose to the first of the two visits when patient’s HBV DNA is 1 log above 
nadir, as required by the Virologic Breakthrough definition. If the patient never experiences 
Virologic Breaktrhough before his/her efficacy censoring date, the time is censored at the 
efficacy censoring date.
Primary non-response
A patient is defined to have primary non-response if after 12 weeks of treatment he/she has
HBV DNA decline < 1log10 copies/mL from baseline for two consecutive visits.
Composite response
Composite response is defined as HBV DNA <300 copies/mL, ALT normalization (if patient 
had abnormal ALT at baseline) or normal ALT (if patient had normal ALT at baseline) and 
HBeAg seroconversion (if patient was HBeAg-positive at baseline) at the same visit. For 
patients who were HBeAg-negative at baseline the requirement of HBeAg seroconversion 
does not apply.


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2.7.4
Analysis methods
2.7.4.1
Primary efficacy endpoint
The primary objective of this study is to evaluate the antiviral efficacy of telbivudine using 
the percentage of pediatric patients achieving HBV DNA <300 copies/mL (51 IU/mL) at 
Week 24. To this end, the proportion of patients achieving the primary efficacy endpoint will 
be presented for each treatment group for the FAS population. The proportions will be 
compared using Fisher’s exact test with significance level of 5%. Two sided 95% exact 
confidence interval will be provided for the difference of proportions of the two groups.
 
 
 
 
To check the robustness of the primary analysis, two sets of supportive analyses will be 
performed: 
1. Analysis on Per Protocol set.
2. Age group by baseline HBV DNA strata (low vs. high) adjusted estimate, using 
Mantel-Haenszel weighted estimated method, as described in Agresti and Hartzel 
(Agresti and Hartzel 2000). The younger age group will be pooled in to the middle age 
group, as there will be only a few patients in the younger age group. The details of the 
Mantel-Haenszel weighted estimated method are given in Appendix 1.
Secondary 
 efficacy endpoints
Secondary 
 efficacy endpoints can be grouped into three categories and all 
endpoints belong to a same category will be analyzed using the same approach. All endpoints 
will be analyzed for FAS and PPS.
2.7.4.2
Continuous endpoints
Continuous endpoints include serum HBV DNA in log10 copies/mL, serum ALT, 
 
. Summary statistics of absolute value and of change from baseline, 
including means, standard deviations, medians, minimum and maximum will be presented by 
visit and treatment group.
These endpoints will be analyzed and compared between the treatment group using Analysis 
of Covariance (ANCOVA) model, including treatment, age group (<12 years vs. >= 12 years), 
baseline HBV DNA group (low or high), geographic region as classification effects and 
baseline value as covariate. Least Square means (LSMeans) for each treatment group will be 


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presented with their standard errors, as well as difference between LS means with its 95% 
confidence interval and p-value for the test of no treatment effect.
2.7.4.3
Dichotomous endpoints
Dichotomous endpoints include HBV DNA < 300 copies/mL, 1000 copies/mL and 
10000copies/mL, HBV DNA < LLOQ, ALT normalization, HBeAg loss, HBeAg 
seroconversion, HBsAg loss, composite response, cumulative virologic breakthrough, 
cumulative treatment emergent genotypic resistance and primary non-response.
For dichotomous endpoints, statistical summaries will include counts and percentages of 
patients with a positive response (response rate), 95% confidence intervals for the difference 
in percentage between the treatment groups and p-value from the Fisher’s exact test 
comparing the two treatment groups. 
2.7.4.4
Time to event endpoints
Time to event endpoints include time to HBV DNA < 300 copies/mL, time to initial virologic 
breakthrough.
Estimates of median time to event with 95% confidence intervals will be provided by 
treatment group. The two groups will be compared using log-rank test.
2.8
Safety evaluation
All safety analyses will be performed on the safety set. 
Safety information will be summarized for the on-treatment period, as defined in Section 2.1.4. 
2.8.1
Adverse events 
Adverse events will be coded by primary system organ class and preferred term according to 
the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1.  
Adverse events occurring in patients in the Initial Placebo group will be assigned to either 
Placebo or LdT treatment based on their onset date:

Placebo: AEs with onset before the first date of LdT treatment after switching; for 
patients who did not switch to LdT, all AEs will be assigned to Placebo

LdT: AEs with onset date on or after the first date of LdT treatment after switching.
The following treatment groups will be used for AE summaries:

Initial LdT;

Initial Placebo on Placebo treatment;


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
Initial Placebo on LdT treatment after switching. The denominator for percentages in 
this group will be the total number of patients who switched from Placebo to LdT;

All LdT (Initial LdT and Initial Placebo on LdT treatment after switching combined);

Overall (all events combined).
The frequency and percentage of patients with adverse events will be summarized by 
treatment group.  Levels of classification will include primary system organ class and 
preferred term and also by preferred term only. At each level of classification, a patient will
be counted only once for each AE experienced within that level.
Adverse events will be deemed on-treatment if the onset date is on or after the date of first 
study drug administration and up to 30 days after the patient has stopped study treatment.
The following subgroups of adverse events will be summarized:

Adverse events regardless of study drug relationship

Adverse events suspected to be related to study drug

Serious adverse events regardless of study drug relationship

Serious adverse events suspected to be related to study drug

Adverse events for patients who discontinued study due to an adverse event.

Adverse events of special interest identified by the investigator

Adverse events of special interest defined for LdT project.
In addition, patient listing will be provided for adverse events, serious adverse events and 
adverse events of special interest.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on 
treatment-emergent adverse events that are not serious adverse events with an incidence 
greater than 5%  and on treatment-emergent serious adverse events and SAE suspected to be 
related to study treatment will be provided by system organ class and preferred term on the 
safety set.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE’s in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
Adverse events of special interest
The preferred terms to be used to identify adverse events of special interest for LdT project 
are provided in Appendix 2.


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Death
Patient deaths, if any, will be listed.
2.8.2
Laboratory assessments
Descriptive statistics of the mean, median, standard deviation, minimum, maximum, and 
number of patients will be presented for the key laboratory parameters: ALT, AST, CK,
serum creatinine, Cystatin C, Phosphate, Blood Glucose, Total Bilirubin, Albumin at all 
scheduled visits. This data will also be presented in listings.
2.8.3
Graded laboratory abnormalities
The frequency and percent of patients experiencing new on-set on-treatment grades 1/2 and 
3/4 lab abnormality will be summarized by periods: baseline to Week 24, Week 24 to Week 
52 , Week 52 to Week 104 and baseline to Week 104. For each parameter each patient will be 
assigned to the worst grade during the period.
2.8.4
ALT flares
ALT flares as defined by 2007 AASLD guideline (ALT elevation > 2× Baseline and ALT 
elevation > 10× ULN) will be summarized.
Proportion of patients experiencing on-treatment ALT flares will be summarized by periods: 
baseline to Week 24, Week 24 to Week 52, and baseline to week 52
In addition, data listings for patients who had on-treatment ALT flare will be presented.
2.8.5
Vital signs
Vital signs will include height, weight, systolic/diastolic pressure, heart rate, body 
temperature and respiration rate. Vital signs and their change from baseline will be 
summarized descriptively by scheduled visit.
2.8.6
Muscle symptoms
Patients with complaints of muscle weakness, muscle pain or achiness, or effort-related 
fatigue (summarized as muscle related events) will be administered Muscle Symptom 
Questionnaire and perform neuromuscular exam with strength testing. Results of the Muscle 
Symptom Questionnaire and neuromuscular exam with strength testing will be listed.
2.8.7
Glomerular filtration rate
Analysis of estimated Glomerular filtration rate (eGFR) will be performed by visit. GFR will 
be calculated by the Schwartz formula:
eGFR = 0.413×(height/serum creatinine) (height in cm; serum creatinine in mg/dL)
The height will be used as assessed at the closest visit.
Only on-treatment GFR values will be analyzed. Generally, analysis will be performed in two 
ways:

"as observed", with no imputation of missing values


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
with LOCF imputations of missing on-treatment values up to Week 24.
Simple summaries without statistical comparisons will be performed "as observed" only.
Mean, median, standard deviation, minimum and maximum values will be presented by visit.
Actual GFR values as well as absolute and percent changes from baseline will be summarized.
For each post-baseline visit, GFR values will be compared to baseline values within treatment 
groups with paired t-test. This summary will be created for the overall safety set as well as for 
two sub-populations of patients with renal function impairment at baseline:
1. eGFR < 60 mL/min/1.73m2
2.
60-90 mL/min/1.73m2
3. 60-80 mL/min/1.73m2
4. > 90 mL/min/1.73m2.
This summary will be performed both "as observed" with no imputations and with LOCF 
imputations.
Number and percentage of patients with abnormal baseline eGFR (60-90 mL/min/1.73m2 or 
60-80 mL/min/1.73m2) shifting to normal eGFR (>90 mL/min/1.73m2) at Week 24, 52 and
104 will be presented by treatment group. The shifting rate will be compared between the two 
treatment groups using Fisher's exact test. This summary will be performed both "as 
observed" with no imputations and with LOCF imputations.
Also, GFR will be categorized into the following categories: < 60, 60 – 90, >90. Shift table 
comparing GFR categories at each post-baseline visit to baseline will be created.
Percent change from baseline in GFR by MDRD formula over time will be presented 
graphically.
2.8.8
Relationship of muscle events and CK elevations
Muscle events (ME) are defined as adverse events with the preferred terms identified in 
“Appendix 2. Preferred terms for the Adverse Events of Special Interest” for the 
“Rhabdomyolysis/myopathy” category.
Only on-treatment MEs will be considered.
Abnormal CK value is defined as CK measurement higher than the upper limit of norm (ULN). 
New-onset abnormal CK value is defined as abnormal CK value with the grade higher than 
baseline CK grade.


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A grade 3/4 abnormal CK episode is defined as a sequence of consecutive on-treatment visits 
with abnormal CK assessments of grade 3 or 4. The start of the episode is the first visit within 
the sequence with grade 3 or 4 CK, and the end of the episode is the last visit within the 
sequence with grade 3 or 4 CK.
A new onset grade 3/4 abnormal CK episode is defined as a grade 3/4 abnormal CK episode 
with the grade at the first visit higher than baseline CK grade. Only new onset grade 3/4 
abnormal CK episodes will be considered.
The resolution of grade 3/4 abnormal CK episode is defined as follows:
-
The episode is said to resolve to normal if there exists a normal CK assessment after 
the end of the episode and before the start of next episode or the patient’s last on-
treatment visit (whichever comes first).
-
The episode is said to resolve to grade 1/2 if it does not resolve to normal, however, 
there exists a CK assessment of grade 1 or 2 after the end of the episode and before the 
start of next episode or the patient’s last on-treatment visit (whichever comes first).
-
The episode is said to be not resolved if none of the above happened, i.e. grade 3 or 4 
abnormal CK continued to the last on-treatment visit.
An episode is said to return to baseline grade if there exists a CK assessment with grade less 
than or equal to the baseline CK grade after the end of the episode and before the start of next 
episode or the patient’s last on-treatment visit (whichever comes first).
An episode is said to resolve at last visit if at the patient’s last on-treatment visit the CK value 
is normal or grade 1 or 2.
The following summaries describing muscle events, CK elevations and their relationship will 
be presented:
1. Proportion of patients with MEs, and among them:
a.
Experiencing any, grade 1/2, grade 3/4 new-onset abnormal CK during the 
study
b. Experiencing any, grade 1/2, grade 3/4 new-onset abnormal CK within 30 days 
of the ME (i.e. in the period from ME start day minus 30 days to ME end day 
plus 30 days)
c.
Experiencing any, grade 1/2, grade 3/4 new-onset abnormal CK at the 
assessment closest to ME start.
Only on-treatment CK assessments will be considered for this analysis.
2. Proportion of patients experiencing new-onset grade 3 or 4 abnormal CK episodes, 
and among them, experiencing and not experiencing ME in the study. Among those 
that do experience an ME within the study, proportion of patients with the ME within 
30 days of the episode (i.e. in the period from start of episode minus 30 days to end of 
episode plus 30 days) and outside of 30 days of the episode. Only on-treatment CK 
assessments will be considered for this analysis. 
3. Descriptive summary of CK levels and change from baseline at the study’s scheduled 
visits and proportion of normal, abnormal, and grade 3/4 CK values at each visit. Only 
baseline and on-treatment CK values will be considered. Only patients with both 


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baseline and post baseline timepoint value (i.e. having a non-missing change from 
baseline) will be summarized at each timepoint.
4. Proportion of new onset grade 3/4 CK episodes by resolution.
5. To represent the relationship among baseline CK, on-treatment CK and MEs, the 
following proportions:
a.
Patients with abnormal baseline CK, and among them experiencing and not 
experiencing at least one on-treatment ME.
b. Patients experiencing at least one on-treatment ME and among them with 
normal or abnormal (elevated) baseline CK.
c.
Patients with on-treatment new-onset abnormal CK of grade 3 or 4, and among 
them with having and not having abnormal CK at both baseline and screening 
visits.
6. For patients that experience at least one ME, descriptive summary of CK, ALT and 
AST levels at the visit closest to the first ME start and at the two visits preceding and 
two visits following the ME start.
7. For patients that experience at least one ME, breakdown of patients by ME preferred 
term (Myopathy, (Poly) myositis, Myalgia or Other MEs) and by the following CK 
assessments:
a.
Baseline CK (normal, grade 1 or 2, grade 3 or 4)
b. CK level at closest assessment to ME start (normal, grade 1 or 2, grade 3 or 4)
c.
Highest on-treatment CK level during the study (normal, grade 1 or 2, grade 3 
or 4)
In addition a listing of patients experiencing grade 3/4 abnormal CK within 30 days of ME 
will be provided, this will include all MEs and all CK assessments of these patients.
A graphical summary of median CK levels will be presented by visit. To maintain consistency 
with the table mentioned in item 3 above, only patients with both baseline and post baseline 
timepoint value (i.e. having a non-missing change from baseline) will be summarized at each 
timepoint.
All the above analyses will be performed on safety set.
2.8.9 Abdominal Ultrasound
Abdominal B-ultrasound will be performed at screening, Weeks 24, 52, 76, 104/End of 
treatment and 116/End of study. The investigator will record in the CRF if signs compatible 
with the context of chronic hepatitis B were observed and if signs of liver decompensation or 
HCC were observed. The frequency of responses will be summarized by treatment group and 
visit up to Week 24.
2.8.10 Tanner staging assessment
Assessment of sexual maturation in male and female patients (for age group >6 years at 
baseline visit) using Tanner staging will be performed at the following study visit: Baseline 
(visit 2), Week 24, Week 52 and Week 104. A frequency table of responses will be presented 
by treatment group and visit up to Week 24. All results will be listed.


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2.9
Interim analyses
There is no interim analysis planned for this study. The primary analysis was planned at week 
24 -when all patients complete 24 weeks of treatment. Additional analysis was planned to be
conducted when all patients complete 52 weeks of treatment. Final analysis as planned to be 
conducted after all patients completed week 104 of the study. However, due to early 
termination of the study only one analysis will be performed summarizing all available data 
with focus on data up to Week 24.
2.10
Other topics
No other topics were studied.
3
Sample size and power considerations
The primary objective of this study is to demonstrate the antiviral efficacy with percentage of 
patients with attainment of HBV DNA < 300 copies/mL (51 IU/mL) in telbivudine treatment 
compared to placebo at Week 24 in patients with chronic hepatitis B.
Based on the results from CLDT600A2414 epidemiological study, 84-88% of pediatric 
patients presented HBV DNA < 9 log10 for HBeAg positive patients. In this study, 80% of 
patients with baseline HBV DNA < 9 log10 are expected to be recruited. Based on these 
baseline patients characteristics, the efficacy rate in the overall population is estimated to be 
60%. 
Considering a 5% dropout rate (and imputed values as failure (worst case)), with the 
assumptions of 60% and 5% patients with HBV DNA <300 copies/mL (51 IU/mL) at Week 
24 for telbivudine and placebo arms, respectively a total of 150 patients with a randomization 
ratio of 5:1 for telbivudine: placebo (125 vs. 25) was expected to provide > 99% power to test 
the primary hypothesis, at 5% significance level, for overall patients population. However, 
due to early termination of the study the planned sample size was not achieved. Analysis will 
be performed on data available at the time of study termination.


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4
Appendix 1. Mantel-Haenszel weighted estimated method
The method, as described in Agresti and Hartzel (2000), is as follows. The patients will be 
stratified by HBV DNA level (low, defined as < 9 log for HBeAg-positive patients and < 7 
log for HBeAg negative vs. high, defined as >= 9 log for HbeAg-positive patients and >= 7 
log for HBeAg negative) and age group (<12 years vs. >= 12 years) at baseline into 4 strata. 
Let’s introduce the following notation:
n11k
is the number of patients in Strata K, Treatment group LdT, with a positive response.
n12k
is the number of patients in Strata K, Treatment group LdT, with a negative response.
n1+k
is the number of patients in Strata K, Treatment group LdT.
n21k
is the number of patients in Strata K, Treatment group Placebo with a positive 
response.
n22k
is the number of patients in Strata K, Treatment group Placebo, with a negative 
response.
n2+k
is the number of patients in Strata K, Treatment group Placebo.
n+1k
is the number of patients in Strata K with a positive response.
n+2k
is the number of patients in Strata K with a negative response.
n++k
is the number of patients in Strata K.
The Mantel-Haenszel proportion estimate controlling for strata is given by:
Telbivudine: 
Placebo: 
Where
are the weights
The difference in proportion is given by ∆ = PLdT – PPlacebo.
The variance estimate for the difference in proportions, Δ, is given by:
where
and


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Two-sided confidence intervals for the difference in proportions will be of the form:
Where Zα/2 is the 1–α/2 percentile from a standard normal distribution.
Two-sided p-value for the treatment group difference in proportions (versus 0) will be based 
on the estimated difference in proportions divided by the estimated standard error. Standard 
normal distribution theory for this statistic will be applied to estimate the p-value, such that it 
is consistent with the corresponding confidence interval, i.e.
Where Φ(x) is the probability that an observation from the standard normal distribution is less 
than or equal to x.
5
Appendix 2. Preferred terms for the Adverse Events of 
Special Interest
Category
Preferred Terms
Blood creatine phosphokinase increased
Blood creatine phosphokinase abnormal
Blood creatine phosphokinase increased
Blood creatine phosphokinase MB abnormal
Blood creatine phosphokinase MB increased
Blood creatine phosphokinase MM increased
Rhabdomyolysis/myopathy
Muscle necrosis
Myoglobin blood increased
Myoglobin blood present
Myoglobin urine present
Myoglobinaemia
Myoglobinuria
Myopathy
Myopathy toxic
Necrotising myositis
Rhabdomyolysis
Acute kidney injury
Anuria
Biopsy muscle abnormal
Blood calcium decreased
Blood creatine phosphokinase abnormal
Blood creatine phosphokinase increased
Blood creatine phosphokinase MM increased
Blood creatinine abnormal
Blood creatinine increased
Chromaturia


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Chronic kidney disease
Compartment syndrome
Creatinine renal clearance abnormal
Creatinine renal clearance decreased
Diaphragm muscle weakness
Electromyogram abnormal
End stage renal disease
Glomerular filtration rate abnormal
Glomerular filtration rate decreased
Hypercreatininaemia
Hypocalcaemia
Muscle disorder
Muscle enzyme increased
Muscle fatigue
Muscle haemorrhage
Muscle rupture
Muscular weakness
Musculoskeletal discomfort
Musculoskeletal disorder
Musculoskeletal pain
Myalgia
Myalgia intercostal
Myositis
Oliguria
Renal failure
Renal impairment
Renal tubular necrosis
Tendon discomfort
Peripheral neuropathy
Acute painful neuropathy of rapid glycaemic 
control
Acute polyneuropathy
Amyotrophy
Anti-myelin-associated glycoprotein 
associated polyneuropathy
Autoimmune neuropathy
Axonal neuropathy
Biopsy peripheral nerve abnormal
Decreased vibratory sense
Demyelinating polyneuropathy
Guillain-Barre syndrome


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Ischaemic neuropathy
Loss of proprioception
Miller Fisher syndrome
Multifocal motor neuropathy
Myelopathy
Nerve conduction studies abnormal
Neuralgia
Neuritis
Neuronal neuropathy
Neuropathic muscular atrophy
Neuropathy peripheral
Notalgia paraesthetica
Peripheral motor neuropathy
Peripheral nervous system function test
abnormal
Peripheral sensorimotor neuropathy
Peripheral sensory neuropathy
Polyneuropathy
Polyneuropathy chronic
Polyneuropathy idiopathic progressive
Radiation neuropathy
Sensorimotor disorder
Sensory disturbance
Sensory loss
Small fibre neuropathy
Tick paralysis
Toxic neuropathy
Anti-ganglioside antibody positive
Anti-myelin-associated glycoprotein 
antibodies positive
Areflexia
Autonomic failure syndrome
Autonomic neuropathy
Burning feet syndrome
Burning sensation
Decreased nasolabial fold
Dysaesthesia
Electromyogram abnormal
Formication
Gait disturbance


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Genital hypoaesthesia
Hereditary motor and sensory neuropathy
Hypoaesthesia
Hyporeflexia
Hypotonia
Mononeuritis
Mononeuropathy
Mononeuropathy multiplex
Motor dysfunction
Muscle atrophy
Muscular weakness
Nerve degeneration
Neuromuscular pain
Neuromuscular toxicity
Neuromyopathy
Neuropathy vitamin B6 deficiency
Neurotoxicity
Paraesthesia
Paraesthesia ear
Peripheral nerve lesion
Peripheral nerve palsy
Peripheral nerve paresis
Peroneal nerve palsy
Phrenic nerve paralysis
Skin burning sensation
Temperature perception test decreased
Tinel's sign
Ulnar neuritis
Vulvovaginal hypoaesthesia
ALT Flare in pt with chronic HBV treatment
Alanine aminotransferase abnormal 
Alanine aminotransferase increased
Lactic acidosis
Blood lactic acid increased
Hyperlactacidaemia
Lactic acidosis
Acid base balance abnormal
Acidosis
Anion gap abnormal
Anion gap increased
Blood bicarbonate abnormal
Blood bicarbonate decreased


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Blood gases abnormal
Blood lactic acid abnormal
Blood pH abnormal
Blood pH decreased
Coma acidotic
Kussmaul respiration
Metabolic acidosis
PCO2 abnormal
PCO2 decreased
Urine lactic acid increased
Acute pancreatitis
Cullen's sign
Grey Turner's sign
Haemorrhagic necrotic pancreatitis
Hereditary pancreatitis
Ischaemic pancreatitis
Oedematous pancreatitis
Pancreatic abscess
Pancreatic haemorrhage
Pancreatic necrosis
Pancreatic phlegmon
Pancreatic pseudocyst
Pancreatic pseudocyst drainage
Pancreatitis
Pancreatitis acute
Pancreatitis haemorrhagic
Pancreatitis necrotising
Pancreatitis relapsing
Pancreatorenal syndrome
Pancreatic enzymes abnormal
Pancreatic enzymes increased
Lack of efficacy  (with/without antiviral 
resistance development)
Device defective
Device failure
Device ineffective
Diet failure
Drug effect decreased
Drug effect delayed
Drug effect incomplete
Drug effect variable
Drug half-life reduced
Drug ineffective


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Drug ineffective for unapproved indication
Drug level decreased
Drug resistance
Drug specific antibody present
Drug tolerance
Drug tolerance increased
Multiple-drug resistance
Paradoxical drug reaction
Remission not achieved
Tachyphylaxis
Therapeutic product ineffective
Therapeutic product ineffective for 
unapproved indication
Therapeutic reaction time decreased
Therapeutic response changed
Therapeutic response decreased
Therapeutic response delayed
Therapeutic response shortened
Therapy non-responder
Therapy partial responder
Treatment failure
Vaccination failure
Virologic failure
Multiple-drug resistance
Disease progression
Condition aggravated
Pathogen resistance
Hypersensitivity/allergy
Acute generalised exanthematous pustulosis
Administration site dermatitis
Administration site eczema
Administration site hypersensitivity
Administration site rash
Administration site recall reaction
Administration site urticaria
Administration site vasculitis
Allergic bronchitis
Allergic colitis
Allergic cough
Allergic cystitis
Allergic eosinophilia


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Allergic gastroenteritis
Allergic hepatitis
Allergic keratitis
Allergic myocarditis
Allergic oedema
Allergic otitis externa
Allergic otitis media
Allergic pharyngitis
Allergic respiratory disease
Allergic respiratory symptom
Allergic sinusitis
Allergic transfusion reaction
Allergy alert test positive
Allergy test positive
Allergy to immunoglobulin therapy
Allergy to surgical sutures
Allergy to vaccine
Alveolitis allergic
Anaphylactic reaction
Anaphylactic shock
Anaphylactic transfusion reaction
Anaphylactoid reaction
Anaphylactoid shock
Anaphylaxis treatment
Angioedema
Antiallergic therapy
Antiendomysial antibody positive
Anti-neutrophil cytoplasmic antibody 
positive vasculitis
Application site dermatitis
Application site eczema
Application site hypersensitivity
Application site rash
Application site recall reaction
Application site urticaria
Application site vasculitis
Arthritis allergic
Aspirin-exacerbated respiratory disease
Atopy
Blepharitis allergic


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Blood immunoglobulin E abnormal
Blood immunoglobulin E increased
Bromoderma
Bronchospasm
Catheter site dermatitis
Catheter site eczema
Catheter site hypersensitivity
Catheter site rash
Catheter site urticaria
Catheter site vasculitis
Chronic eosinophilic rhinosinusitis
Chronic hyperplastic eosinophilic sinusitis
Circulatory collapse
Circumoral oedema
Conjunctival oedema
Conjunctivitis allergic
Contact stomatitis
Contrast media allergy
Contrast media reaction
Corneal oedema
Cutaneous vasculitis
Dennie-Morgan fold
Dermatitis
Dermatitis acneiform
Dermatitis allergic
Dermatitis atopic
Dermatitis bullous
Dermatitis contact
Dermatitis exfoliative
Dermatitis exfoliative generalised
Dermatitis herpetiformis
Dermatitis infected
Dermatitis psoriasiform
Device allergy
Dialysis membrane reaction
Distributive shock
Documented hypersensitivity to administered 
product
Drug cross-reactivity
Drug eruption


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Drug hypersensitivity
Drug provocation test
Drug reaction with eosinophilia and systemic 
symptoms
Eczema
Eczema infantile
Eczema nummular
Eczema vaccinatum
Eczema vesicular
Eczema weeping
Encephalitis allergic
Encephalopathy allergic
Eosinophilic granulomatosis with polyangiitis
Epidermal necrosis
Epidermolysis
Epidermolysis bullosa
Epiglottic oedema
Erythema multiforme
Erythema nodosum
Exfoliative rash
Eye allergy
Eye oedema
Eye swelling
Eyelid oedema
Face oedema
Fixed drug eruption
Giant papillary conjunctivitis
Gingival oedema
Gingival swelling
Gleich's syndrome
Haemorrhagic urticaria
Hand dermatitis
Henoch-Schonlein purpura
Henoch-Schonlein purpura nephritis
Heparin-induced thrombocytopenia
Hereditary angioedema
Hypersensitivity
Hypersensitivity vasculitis
Idiopathic urticaria
Immediate post-injection reaction


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Immune thrombocytopenic purpura
Immune tolerance induction
Immune-mediated adverse reaction
Implant site dermatitis
Implant site hypersensitivity
Implant site rash
Implant site urticaria
Incision site dermatitis
Incision site rash
Infusion site dermatitis
Infusion site eczema
Infusion site hypersensitivity
Infusion site rash
Infusion site recall reaction
Infusion site urticaria
Infusion site vasculitis
Injection site dermatitis
Injection site eczema
Injection site hypersensitivity
Injection site rash
Injection site recall reaction
Injection site urticaria
Injection site vasculitis
Instillation site hypersensitivity
Instillation site rash
Instillation site urticaria
Interstitial granulomatous dermatitis
Intestinal angioedema
Iodine allergy
Kaposi's varicelliform eruption
Kounis syndrome
Laryngeal oedema
Laryngitis allergic
Laryngospasm
Laryngotracheal oedema
Limbal swelling
Lip oedema
Lip swelling
Mast cell degranulation present
Medical device site dermatitis


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Medical device site eczema
Medical device site hypersensitivity
Medical device site rash
Medical device site recall reaction
Medical device site urticaria
Mouth swelling
Mucocutaneous rash
Multiple allergies
Nephritis allergic
Nikolsky's sign
Nodular rash
Oculomucocutaneous syndrome
Oculorespiratory syndrome
Oedema mouth
Oral allergy syndrome
Oropharyngeal blistering
Oropharyngeal spasm
Oropharyngeal swelling
Palatal oedema
Palatal swelling
Palisaded neutrophilic granulomatous 
dermatitis
Palpable purpura
Pathergy reaction
Periorbital oedema
Pharyngeal oedema
Pruritus allergic
Radioallergosorbent test positive
Rash
Rash erythematous
Rash follicular
Rash generalised
Rash macular
Rash maculo-papular
Rash maculovesicular
Rash morbilliform
Rash neonatal
Rash papulosquamous
Rash pruritic
Rash pustular


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Rash rubelliform
Rash scarlatiniform
Rash vesicular
Reaction to azo-dyes
Reaction to colouring
Reaction to drug excipients
Reaction to preservatives
Red man syndrome
Rhinitis allergic
Scleral oedema
Scleritis allergic
Scrotal oedema
Serum sickness
Serum sickness-like reaction
Shock
Shock symptom
Skin necrosis
Skin reaction
Skin test positive
Solar urticaria
Solvent sensitivity
Stevens-Johnson syndrome
Stoma site hypersensitivity
Stoma site rash
Swelling face
Swollen tongue
Symmetrical drug-related intertriginous and 
flexural exanthema
Tongue oedema
Toxic epidermal necrolysis
Toxic skin eruption
Tracheal oedema
Type I hypersensitivity
Type II hypersensitivity
Type III immune complex mediated reaction
Type IV hypersensitivity reaction
Urticaria
Urticaria cholinergic
Urticaria chronic
Urticaria contact


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Urticaria papular
Urticaria physical
Urticaria pigmentosa
Urticaria vesiculosa
Urticarial vasculitis
Vaccination site dermatitis
Vaccination site eczema
Vaccination site exfoliation
Vaccination site hypersensitivity
Vaccination site rash
Vaccination site recall reaction
Vaccination site urticaria
Vaccination site vasculitis
Vaccination site vesicles
Vaginal exfoliation
Vaginal ulceration
Vasculitic rash
Vessel puncture site rash
Vessel puncture site vesicles
Vulval ulceration
Vulvovaginal rash
Vulvovaginal ulceration
Acute renal failure
Acute kidney injury
Acute phosphate nephropathy
Acute prerenal failure
Anuria
Azotaemia
Continuous haemodiafiltration
Dialysis
Haemodialysis
Haemofiltration
Hyponatriuria
Neonatal anuria
Nephropathy toxic
Oliguria
Peritoneal dialysis
Prerenal failure
Renal failure
Renal failure neonatal
Renal impairment


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Renal impairment neonatal
Albuminuria
Blood creatinine abnormal
Blood creatinine increased
Blood urea abnormal
Blood urea increased
Blood urea nitrogen/creatinine ratio increased
Creatinine renal clearance abnormal
Creatinine renal clearance decreased
Creatinine urine abnormal
Creatinine urine decreased
Crystal nephropathy
Fractional excretion of sodium
Glomerular filtration rate abnormal
Glomerular filtration rate decreased
Hypercreatininaemia
Intradialytic parenteral nutrition
Kidney injury molecule-1
Nephritis
Oedema due to renal disease
Protein urine present
Proteinuria
Renal function test abnormal
Renal transplant
Renal tubular disorder
Renal tubular dysfunction
Renal tubular necrosis
Tubulointerstitial nephritis
Urea renal clearance decreased
Urine output decreased
Fertility Disorders
Adrenal androgen deficiency
Adrenal androgen excess
Adrenogenital syndrome
Albright's disease
Aspermia
Asthenospermia
Azoospermia
Delayed puberty
Dyspareunia
Ejaculation delayed


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Ejaculation delayed
Ejaculation disorder
Ejaculation failure
Erectile dysfunction
Erection increased
Female orgasmic disorder
Female sexual arousal disorder
Female sexual dysfunction
Fertility increased
Follicle stimulating hormone deficiency
Genito-pelvic pain/penetration disorder
Haematospermia
HAIR-AN syndrome
Hyperandrogenism
Hypergonadism
Hyperprogesteronism
Hypogonadism
Hypoprogesteronism
Hypospermia
Incomplete precocious puberty
Infertility
Infertility female
Infertility male
Libido decreased
Libido disorder
Libido increased
Luteinising hormone deficiency
Male orgasmic disorder
Male sexual dysfunction
Mauriac syndrome
Necrospermia
Nocturnal emission
Oligospermia
Organic erectile dysfunction
Orgasm abnormal
Orgasmic sensation decreased
Painful ejaculation
Painful erection
Precocious puberty
Premature ejaculation


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Priapism
Primary ciliary dyskinesia
Primary hypogonadism
Pseudoprecocious puberty
Psychogenic erectile dysfunction
Pubertal failure
Pyospermia
Retrograde ejaculation
Semen discolouration
Sexual dysfunction
Spermatogenesis abnormal
Spermatorrhoea
Spontaneous ejaculation
Spontaneous penile erection
Teratospermia
Young's syndrome
Antral follicle count
Antral follicle count high
Antral follicle count low
Antral follicle count normal
Fructose semen decreased
Fructose semen increased
Infertility tests
Infertility tests abnormal
Infertility tests normal
pH semen
pH semen abnormal
pH semen decreased
pH semen increased
pH semen normal
Prostatic fluid leukocytes increased
Red blood cells semen
Red blood cells semen negative
Red blood cells semen positive
Semen analysis
Semen analysis abnormal
Semen analysis normal
Semen liquefaction
Semen liquefaction abnormal
Semen liquefaction normal


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Semen liquefaction prolonged
Semen liquefaction shortened
Semen viscosity
Semen viscosity abnormal
Semen viscosity decreased
Semen viscosity increased
Semen viscosity normal
Semen volume abnormal
Semen volume decreased
Semen volume increased
Semen volume normal
Sperm analysis
Sperm analysis abnormal
Sperm analysis normal
Sperm concentration
Sperm concentration abnormal
Sperm concentration decreased
Sperm concentration increased
Sperm concentration normal
Sperm concentration zero
Spermatozoa abnormal
Spermatozoa morphology
Spermatozoa morphology abnormal
Spermatozoa morphology normal
Spermatozoa progressive motility
Spermatozoa progressive motility abnormal
Spermatozoa progressive motility decreased
Spermatozoa progressive motility normal
Total sperm count
Total sperm count decreased
White blood cells semen
White blood cells semen negative
White blood cells semen positive


6
Appendix 3: Protocol Deviations
Deviation 
code
Text description
Identification 
Method 
Identification Clarification
C01
Compliance was fair (70-89%) on > 2 
consecutive visits
Direct Hit 
Programming
If compliance was fair on > 2 consecutive visits,  it would be a PD counted from the first time it 
occurred 
C02
Compliance  is poor  (<70%) >=1 visit 
at any time during the study.
Direct Hit 
Programming
If compliance is poor >=1 visit at any time during the study,  it would be a PD, counted from the first
time it occurred 
C03
Patient receives expired study drug 
Manual by FM
Information needs to be in patient files 
C04A
Patient receives incorrect dosing
Direct Hit 
Programming
For Any age and weight < 30kg; total daily dose administered ranges <20 mg or >600 mg 
C04B
Patient receives incorrect dosing
Direct Hit 
Programming
If weight ≥ 30kg; total daily dose administered ≠ 600 mg
D01
Withdrawal of informed consent and/ or 
Assent
Manual by FM
Study treatment has  not been discontinued and parents or legal guardian  has withdrawn consent
I01C
Patient does not sign adult informed 
consent, after turning 18 years old, while 
on trial  
Manual by FM
Patient does not sign adult informed consent, after turning 18 years old, while on trial  
I01D
Patient turning 13 and at next visit failed 
to sign ICF and Assent for 13-18 years 
of age.
Manual by FM
Patient turning 13 and at next visit failed to sign ICF and Assent for 13-18 years of age.
D02A
Patients ALT>10xULN and > 2× 
baseline but patient not discontinued 
from the study.
Manual by FM
Visit 3 visit date onwards
D02B
Patient has ALT>3xULN and> 2x 
baseline value AND (TBiL>2 x ULN or 
INR>1.5) and not discontinued from the 
study.
Manual by FM
Visit 3 visit date onwards


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D02C
Patient has hepatic decompensation 
(Child-Pugh B or C) but patient not 
discontinued from the study.
Manual by FM
Visit 3 visit date onwards
D03
Study treatment has not been  
discontinued: Patient is diagnosed with 
cancer 
Manual by FM
Patient is diagnosed with cancer (other than basal cell or squamous cell carcinoma) including but not
limited to HCC – Visit 2 date onwards
D04
Patient met muscle algorithm criteria for 
discontinuation (strength, symptoms, 
abnormal lab data) but was not 
discontinued
Manual by FM
Patients experiencing muscle related symptoms as indicated in Section 7.7. Visit 2 date onwards
D05
Study treatment has not been  
discontinued: Patient co-infected with 
HCV, HDV or HIV
Manual by FM
Patient co-infected with HCV, HDV or HIV. Visit 2 date onwards.
D06
Study treatment has not been  
discontinued: Patient having an adverse 
event that affecting physical growth 
Manual by FM
Study treatment has not been  discontinued: Patient having an adverse event that affecting physical 
growth 
D07
Study treatment has not been  
discontinued: while presenting 
laboratory abnormalities which could 
affect study treatment (e.g. eGFR < 50 
mL/min) 
Manual by FM
According to protocol, it should be based on investigator’s opinion 
D08
Study treatment has not been 
discontinued: Patient was pregnant 
while on study 
Direct Hit 
Programming
Pregnancy was confirmed and patient was not discontinued
D09
Study treatment has not been 
discontinued at Week 28, while patient 
was confirmed HBV DNA >= 300 
copies at Week 24, and was on LDT
Manual by FM
Study treatment has not been discontinued at Week 28, while patient was confirmed HBV DNA >= 
300 copies at Week 24, and was on LDT
D10A
Patient on placebo until Week24, started 
with telbivudine even when found not 
meeting the eligibility criteria to receive 
telbivudine at Week28 or at a later visit 
until week 52 
Direct Hit 
Programming
Patient on placebo until Week24, started with telbivudine even when found not meeting the 
eligibility criteria to receive telbivudine at Week28 or at a later visit until week 52 


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D10B
Patient on placebo until Week24, started 
with telbivudine even when found not 
meeting the eligibility criteria to receive 
telbivudine at Week28 or at a later visit 
until week 52 
Direct Hit 
Programming
Patient on placebo until Week24, started with telbivudine even when found not meeting the 
eligibility criteria to receive telbivudine at Week28 or at a later visit until week 52 
D11
Patients, while being treated with 
placebo until Week24, who started 
receiving telbivudine at Week 28, did 
not discontinued from the trial even after 
having HBV DNA >= 300 copies/ml at 
Week 52
Direct Hit 
Programming
Patients, while being treated with placebo until Week24, who started receiving telbivudine at Week 
28, did not discontinued from the trial even after having HBV DNA >= 300 copies/ml at Week 52
D12
Patients, while being treated with 
placebo until Week24, who started 
receiving telbivudine at Week 40, did 
not discontinued from the trial even after 
having HBV DNA >= 300 copies/ml at 
Week 64
Direct Hit 
Programming
Patients, while being treated with placebo until Week24, who started receiving telbivudine at Week 
40, did not discontinued from the trial even after having HBV DNA >= 300 copies/ml at Week 64
D13
Patients, while being treated with 
placebo until Week24, who started 
receiving telbivudine at Week 52, did 
not discontinued from the trial even after 
having HBV DNA>= 300 copies/ml at 
Week 76
Direct Hit 
Programming
Patients, while being treated with placebo until Week24, who started receiving telbivudine at Week 
52, did not discontinued from the trial even after having HBV DNA>= 300 copies/ml at Week 76
D14
Study treatment has not been 
discontinued while unplanned  
unblinding of the treatment occurred
Manual by FM
Treatment unblinding unplanned and without emergency need as judged by the treating physician
D15
Study treatment has not been  
discontinued while patient presented a 
virological breakthrough or genotypic 
resistance after 24 weeks of LDT 
treatment
Direct Hit 
Programming
Study treatment has not been  discontinued while patient presented a virological breakthrough or 
genotypic resistance after 24 weeks of LDT treatment


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E01
Use of other investigational drugs at the 
time of enrollment, or within 30 days or 
5 half lives of enrollment whichever is 
longer
Manual by FM
Use of other investigational drugs
Information needs to be in patient files
E02
History of hypersensitivity to  any of the 
study drugs or to drugs of similar 
chemical classes
Manual by FM
Patient has a history of hypersensitivity  to any of the study drugs or to drugs of similar chemical 
classes. Information needs to be in patient files 
E03A
Patient has history of malignancy of any
organ system (other than localized basal 
cell carcinoma of the skin) within the 
past 5 years
Manual by FM
Patient has history of malignancy of any organ system  Information needs to be in patient files
E03B
Patient has ultrasonographic findings of 
hepatic mass and/or elevated AFP 
suggestive of possible HCC and is 
enrolled in the study
Manual by FM
Patient with  ultrasonographic  findings of hepatic  mass and/or elevated  AFP suggestive of possible 
HCC, should have the disease ruled-out prior to entrance into the study
E04
Confirmed positive serum test or beta-
HCG laboratory test (5 IU/L or 
mIU/mL) and patient not withdrawn
Direct Hit 
Programming
Patient is pregnant. 
Confirmed  by a positive 
beta-HCG laboratory test (> 5 IU/L or mIU/mL)-
Information needs to be in patient files
E05
Women of child-bearing potential  not 
using effective contraception  methods 
Manual by FM
Effective contraception include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception 
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/ vaginal suppository 
• Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or
transdermal hormone contraception
• Placement of an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception female subjects should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.


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E06
Sexually active adolescent males  not 
using  a condom during intercourse 
while taking drug and for 12 days after 
stopping medication and father a child 
Manual by FM
Sexually active adolescent males not using  a condom during intercourse while taking drug and for 
12 days after stopping medication and father a child
E07
Patients with acute or chronic infection 
of HCV, HDV, HIV, or with acute 
infection of HAV, HEV, CMV or EBV
Manual by FM
Patient is co-infected with acute or chronic HCV, 
HDV or HIV infection  and with acute infection  of HAV, HEV, CMV or EBV at V1 or Baseline.
E08
Patient has received treatment of 
interferon or any other 
immunomodulatory agents
within the last 12 months prior to 
screening.
Manual by FM
Patient has received treatment of interferon or any other immunomodulatory agents
within the last 12 months prior to screening.
E09
Patient was treated with nucleoside or 
nucleotide drugs or other anti-CHB 
treatment (approved or investigational) 
at any time before screening.
Manual by FM
Patients need to be treatment naive with nucleos(t)ides. Information needs to be in patient files
E10A
Patient has medical condition that 
requires frequent use of systemic 
corticosteroids.
Manual by FM
Patient use of systemic corticosteroids, (topical and inhaled corticosteroids are allowed). Information
needs to be in patient files
E10B
Patient has medical condition that 
requires frequent use of systemic 
acyclovir or famcyclovir
Manual by FM
Patient use of systemic acyclovir or famcyclovir. Information needs to 
be in patient files
E11
Patient  has decompensated liver disease 
defined as a Child-Turcotte-Pugh score 
of > =7 (B or C)
Manual by FM
Patient had clinical signs/symptoms of hepatic decompensation with Child-Pugh score of B or C 
Information needs to be in patient files
E12
Patient has one or more additional 
known primary or secondary causes of 
liver disease
Manual by FM
Patient has one or more additional known primary or secondary causes of liver disease 
E13
Patient is liver or other organ transplant 
recipient, or bone marrow transplant 
recipient
Manual by FM
Patient is organ or bone marrow transplant recipient
Information needs to be in patient files
E14
Patient is currently abusing illicit drugs, 
or has a history of illicit substance 
abuse.
Manual by FM
Patient is currently abusing illicit drugs, or has a history of illicit substance abuse.


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E15
Patient is not abstinent from alcohol 
during the course of the study
Manual by FM
Patient is not abstinent from alcohol during the course of the study
E16
Patient has a medical condition requiring 
the chronic or prolonged use of 
potentially
hepatotoxic drugs or nephrotoxic drugs 
or chemotherapy
Manual by FM
Use of  chemotherapy
Information needs to be in patient files
E18A
Patient has history of myopathy, 
myositis, or persistent muscle weakness 
or persistent high serum CK levels (>=7 
ULN)
Manual by FM
Patient has history of myopathy, myositis, or persistent muscle weakness or persistent high CK 
levels ((≥7 ULN).
Information needs to be in patient files
E18B
Muscular disease or abnormal 
neuromuscular signs or CK values at 
screening suggestive of muscular 
disease, or age at which independent 
walking first achieved after 16 months 
of age
Manual by FM
Patient has any muscular disease including but not limited to congenital / metabolic etiology, or with 
abnormal neuromuscular signs at screening or any screening CK values suggestive of muscular 
disease, or age at which independent walking first achieved after 16 months of age (based on 
birthday).
Information needs to be in patient files
E19
Patient has received any drugs 
potentially associated with myopathy 
within 3 months prior to screening
Manual by FM
Patient has received any drugs potentially associated with myopathy (e.g. chloroquine, 
hydroxychloroquine, HMGCoA redutase inhibitors, fibric acid derivatives, penicilamine, 
zidovudine, cyclosporine, erythromycin, niacin, azole antifungals, etc) within 3 months prior to 
screening.
Information needs to be in patient files
E20
Patient has at baseline other laboratory 
abnormalities as listed  under exclusion 
criterion 20 in the protocol 
Manual by FM
Patient has at baseline other laboratory abnormalities as listed  under exclusion criterion 20 in the 
protocol 
I01B       Patient has not provided Assent prior to 
study start.
Manual by FM
Assent (if requested) was not provided before study start
I01A
Informed consent not provided prior to 
any study related procedures were done 
Manual by FM
Main ICF and Assent (if requested) was not provided before study start 
I02A
Subject is <2 years
Direct Hit 
Programming
Subject is <2 years


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I02B
Subject is >= 12 years and site=South 
Korea
Manual by FM
Derived Age is more than or equal to12 at Visit 1
Missing Age is a PD
I02C
Subject is >= 18 years at time of 
screening
Direct Hit 
Programming
Derived Age is more than or equal to18 at Visit 1
Missing Age is a PD
I04A
Non-detectable or not available  serum 
HBsAg at the screening and at least once 
in the last 6 months prior to V1
Manual by FM
1) HBsAg was not detected or not available at Visit 1 visit date and not detected in the last 6 months 
prior to V1
2) HBsAg was detected at Visit 1 visit date but not in the last 6 months prior to V1
3) HBsAg was not detected at Visit 1 but was detected in the last 6 months prior to V1
I4B1
Patient HBeAg positive and serum HBV 
DNA < 5 log10 copies/ml (20 000 IU/L) 
at screening 
Direct Hit 
Programming
Patient HBeAg positive and serum HBV DNA < 5 log10 copies/ml (20 000 IU/L) at screening 
I4B2
Patient HBeAg positive and serum HBV 
DNA < 5 log10 copies/ml (20 000 IU/L) 
at visit 2 (baseline)
Direct Hit 
Programming
Patient HBeAg positive and serum HBV DNA < 5 log10 copies/ml (20 000 IU/L) at visit 2 
(baseline)
I04C
Patient HBeAg positive and did NOT 
have serum ALT > or = 1.5×ULN and < 
10×ULN  (pediatric ULN) two times in 
the last 6 months beforeV1 or once 
during screening period
Manual by FM
Patient HBeAg positive and did NOT have serum ALT > or = 1.5×ULN and < 10×ULN  (pediatric 
ULN) two times in the last 6 months beforeV1 or once during screening period
I04D
Patient HBeAg negative and serum 
HBV DNA < 4 log10 copies/ml (2 000 
IU/L) at screening
Direct Hit 
Programming
Patient HBeAg negative and serum HBV DNA < 4 log10 copies/ml (2 000 IU/L) at screening CHK 
should fire only for randomized subject
I4D1
Patient HBeAg negative and serum 
HBV DNA < 4 log10 copies/ml (2 000 
IU/L) at baseline  
Direct Hit 
Programming
Patient HBeAg negative and serum HBV DNA < 4 log10 copies/ml (2 000 IU/L) at baseline  
I04E
Patient HBeAg negative and did not 
have ALT > or =1 xULN and <10×ULN 
(pediatric ULN) two times in the last 12 
months before V1 or once during 
screening period 
Manual by FM
Patient HBeAg negative and did not have ALT > or =1 xULN and <10×ULN (pediatric ULN) two 
times in the last 12 months before V1 or once during screening period 


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I4B3
ALT >= 10 ULN (pediatric) at screening 
or baseline pre-treatment visit
Manual by FM
ALT >= 10 ULN (pediatric) at screening or baseline pre-treatment visit
M01
Patient has taken prohibited treatment
Manual by FM
Patient took any drug which has any known or potential risks for pediatrics population in terms of 
growth, bone, liver, neurological system, etc.
M02
Patient has taken prohibited treatment 
and prohibited treatment not stopped 
Section 5.5.8, Table 5-2
Manual by FM
Patient took any of the following prohibited treatments: drugs with known potential risks for 
pediatric population in terms of growth bone, liver, neurological system, LAM, ADV, ETV, TDF, 
FTC, investigational drugs; systemic acyclovir or famciclovir, immune modulators such as IFN, 
thymosin, interleukins; systemic steroids; hepatoxic drugs such as dapsone, erythromycin, systemic 
azole anti-fungals, anti-tuberculosis drugs, toxic dose of acetaminophen/paracetamol, herbal 
medications; nephrotoxic drugs (aminoglycosides, amphotericin B, foscarnet, vancomycin, 
cyclosporine, tacrolimus, request use of NSAIDs or aspirin; alcohol or illicit drug abuse,             
Chemotherapy drugs for malignant diseases or immune-suppressive therapy for transplantation; 
drugs associated with myopathy (chloroquine, hydroxychloroquine, HMGCoA reductase inhibitors, 
fibric acid derivatives, penicilamine, zidovudine, cyclosporine, erythromycin, niacin, azole 
antifungals, etc.)
O02
Last drug intake (Week 104 - Treatment 
Period) >=2 days before last visit V13 
date>
Direct Hit 
Programming
PD only in case the patient is Completer.
S01
Patient enrolls in another clinical trial
Manual by FM
Patient enrolls in another 
clinical trial of an 
investigational agent while 
participating in this study.
S02
Study drug intake is not the same as 
randomized arm according to IVRS
Manual by FM
The given study drug via 
IVRS randomization does 
not match actual intake of 
study drug from Visit 2 visit 
date until Visit 7 visit date
S05
Randomized placebo patients who are 
qualified for LDT treatment did not start 
treatment at relevant qualifying visit
Manual by FM
Initiation of study treatment was delayed after the patient became eligible for telbivudine treatment. 


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7
References
[Agresti and Hartzel (2000)] Strategies for comparing treatments on a binary response with multi-centre data. Stat Med; 19:115-1139.