A Phase IIIb, Randomized, Open-Label Study of Pegylated Interferon Alfa-2A in Combination With Lamivudine or Entecavir Compared With Untreated Control Patients in Children With HBeAg Positive Chronic Hepatitis B in the Immune-Tolerant Phase
Phase: PHASE3
Conditions: Pediatric Immuno-Tolerant Chronic Hepatitis B
Sponsor: Hoffmann-La Roche

Official Title: Phase IIIb, Randomized, Open-Label Study of Pegylated Interferon 
Alfa-2A in Combination With Lamivudine or Entecavir Compared With 
Untreated Control Patients in Children With HBeAg Positive Chronic 
Hepatitis B in the Immune-Tolerant Phase 
NCT Number: 
NCT02263079  
Document Date: 
Protocol Version 13: 26-October-2018 

PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the 
property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to 
you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is 
understood that this information will not be disclosed to others without written 
authorization from Roche except to the extent necessary to obtain informed consent from 
persons to whom the drug may be administered.
Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
PROTOCOL
TITLE:
PHASE IIIB, RANDOMIZED, OPEN-LABEL STUDY OF 
PEGYLATED INTERFERON ALFA-2A IN 
COMBINATION WITH LAMIVUDINE OR ENTECAVIR
COMPARED WITH UNTREATED CONTROL PATIENTS
IN CHILDREN WITH HBEAG-POSITIVE CHRONIC 
HEPATITIS B IN THE IMMUNE-TOLERANT PHASE
PROTOCOL NUMBER:
NV25361
VERSION NUMBER:
13
EUDRACT NUMBER:
2006-000977-31
IND NUMBER:
10,144
TEST PRODUCT:
Pegasys® (RO 25 8310)
MEDICAL MONITOR:
, Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  22 February 2006
DATES AMENDED:
Version 2:  Unavailable
Version 3:  2 June 2008
Version 4:  26 October 2009
Version 5:  29 April 2010
Version 1 (6):  2 January 2013
Version 2 (7):  8 May 2013
Version 8:  22 August 2013
Version 9:  3 February 2014
Version 10:  26 June 2014
Version 11: 31 July 2015
Version 12: 15 February 2016
Version 13:  See electronic date stamp below.
 
26-Oct-2018 15:36:53
Title
Approver's Name
Company Signatory
Date and Time (UTC)

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
2
PROTOCOL AMENDMENT, VERSION 13:
RATIONALE
The results from two multicenter clinical trials (sponsored by the National Institutes of 
Health [NIH]) evaluating the entecavir plus Pegasys® treatment regimen in patients with
immune-tolerant chronic hepatitis B (CHB) were made available in October 2017 at the 
American Association for the Study of Liver Diseases Congress in Washington, USA 
(Rosenthal et al. 2017 [pediatric patients]; Feld et al. 2017 [adult patients]). These two
NIH studies demonstrated minimal to no efficacy of the intervention in both adult and 
pediatric patient populations with immune-tolerant CHB. Moreover, both studies had a 
similar design to Study NV25361. The conclusion was that the combination of entecavir 
with Pegasys®, administered for up to 48 weeks, rarely led to loss of hepatitis B 
envelope antigen with sustained suppression of hepatitis B virus (HBV) DNA levels and 
was associated with frequent but not serious adverse events. The authors also 
concluded that more potent and more broadly targeted regimens against HBV are 
needed to treat children in the immune-tolerant phase of chronic HBV infection.  
Because of the similar study design, treatment regimen and efficacy assessments
compared with these two NIH-sponsored studies, Study NV25361 is not expected to 
demonstrate efficacy in the target patient population. 
Based on the results of the NIH pediatric study and following a Pediatric Investigational 
Plan (PIP) modification procedure, the PDCO agreed in March 2018 to modify the PIP
for Pegasys® and remove Study NV25361 from the PIP commitments. After this 
decision, the Sponsor terminated recruitment in the study on 28 March 2018 after 
enrollment of 62 patients (26 patients had been randomized to the active combination 
treatment, and 3 patients had been randomized to Pegasys® monotherapy before Roche 
became the study sponsor). This decision to terminate recruitment was also in 
accordance with the recommendation from the Data Safety Monitoring Board on 
22 March 2018 based on the NIH results demonstrating minimal efficacy and a changed 
benefitrisk assessment.  No specific safety concerns were identified in their scheduled 
review of the study. 
The protocol for Study NV25361 has been amended because of the expected lack of 
efficacy of the treatment regimen and the premature termination of recruitment, as 
follows:

The background section on Pegasys® has been updated to summarize the recently 
disclosed data from the two NIH studies in patients with immune-tolerant CHB, 
which demonstrated minimal efficacy with a similar treatment intervention
(see Section 1.2).

The background section on Pegasys® has been updated with the results of the 
primary analysis of Study YV25718 in pediatric patients with immune-active CHB
(see Section 1.2).

The benefitrisk assessment has been updated (see Section 1.5).

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
3

The protocol has been updated to reflect that recruitment into the study was 
prematurely terminated (see Section 1.5).

The duration of patient follow-up has been modified from up to 5 years to 1 year 
after the end of treatment (see revised Figure 1).  This modification is due to the low 
number of patients enrolled and that the small amount of data that would now be 
collected during the long-term follow up would limit the interpretation of any 
long-term effects of Pegasys®. Consequently, study objectives associated with the 
long-term follow-up period have been removed (see Section 2).

Clarification has been made to highlight that the final analysis from the study will be 
reported when the last patient completes the last study visit at 1-year of follow up
(see Sections 3.2 and 6).

Language regarding post-study access to study drug has been removed as no 
clinical benefit is expected (see Section 4.3.4).

The total volume of blood that will be collected during the study has been updated to 
reflect the shorter duration of the follow-up period (see Sections 4.5.1 and 4.5.1.7).

Pharmacokinetic and anti-drug antibody sample collection has been removed 
(see Appendix 1B) and the planned pharmacokinetic analysis has been updated.

The Medical Monitor of the study has changed (see Section 5.4.1).
Additional minor changes have been made to improve clarity and consistency and to 
align the protocol with the Sponsor’s current internal guidelines and standard operating 
procedures. The Protocol Amendment Acceptance Form page has also been added to 
the document.  Substantive new information appears in italics.  

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM...................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 20
1.1
Background on Chronic Hepatitis B....................................... 20
1.2
Background on Pegasys........................................................ 21
1.3
Background on Lamivudine ................................................... 23
1.4
Background on Entecavir....................................................... 24
1.5
Study Rationale and BenefitRisk Assessment..................... 25
2.
OBJECTIVES.............................................................................................. 30
2.1
Efficacy Objectives ................................................................ 30
2.2
Safety Objective .................................................................... 30
2.3
Pharmacokinetic Objective .................................................... 30
2.4
Exploratory Objectives........................................................... 30
3.
STUDY DESIGN......................................................................................... 31
3.1
Description of Study .............................................................. 31
3.1.1
Overview of Study Design ..................................................... 31
3.1.2
Length of Study ..................................................................... 32
3.1.3
Data Safety Monitoring Board................................................ 32
3.1.4
Internal Monitoring Committee............................................... 32
3.1.5
Patients Previously Randomized to Investigator-
Sponsored Trials including Pegasys 
Monotherapy Group............................................................... 33
3.2
End of Study.......................................................................... 33
3.3
Rationale for Study Design.................................................... 34
3.3.1
Rationale for Test Product Dosage........................................ 34
3.3.1.1
Pediatric Dosing .................................................................... 34
3.3.2
Rationale for Patient Population ............................................ 37
3.3.3
Rationale for Untreated Control Group .................................. 38
3.4
Outcome Measures ............................................................... 39
3.4.1
Efficacy Outcome Measures.................................................. 39

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
5
3.4.2
Safety Outcome Measures .................................................... 39
3.4.3
Pharmacokinetic Outcome Measures.................................... 40
3.4.4
Exploratory Outcome Measures ............................................ 40
4.
MATERIALS AND METHODS .................................................................... 40
4.1
Patients.................................................................................. 40
4.1.1
Inclusion Criteria.................................................................... 40
4.1.2
Exclusion Criteria................................................................... 41
4.2
Method of Treatment Assignment.......................................... 43
4.3
Study Treatment.................................................................... 43
4.3.1
Formulation, Packaging, and Handling.................................. 43
4.3.1.1
Pegasys................................................................................. 43
4.3.1.2
Lamivudine ............................................................................ 43
4.3.1.3
Entecavir................................................................................ 44
4.3.2
Dosage, Administration, and Compliance.............................. 44
4.3.3
Study Treatment Accountability............................................. 45
4.3.4
Continued Access to Pegasys............................................... 46
4.3.4.1
Patients who Become Immune Active ................................... 46
4.4
Concomitant Therapy ............................................................ 46
4.4.1
Permitted Therapy................................................................. 46
4.4.2
Prohibited Therapy ................................................................ 46
4.5
Study Assessments ............................................................... 47
4.5.1
Description of Study Assessments ........................................ 47
4.5.1.1
Safety Assessments .............................................................. 48
4.5.1.2
Neuropsychiatric Questionnaire............................................. 50
4.5.1.3
Electrocardiograms................................................................ 51
4.5.1.4
Laboratory Assessments ....................................................... 51
4.5.1.5
Pharmacokinetic Analysis...................................................... 53
4.5.1.6
Lamivudine and Entecavir Resistance................................... 53
4.5.1.7
Samples for Roche Clinical Repository.................................. 54
4.5.2
Timing of Study Assessments ............................................... 57
4.5.2.1
Screening and Pretreatment Assessments............................ 57
4.5.2.2
Re-Testing Laboratory Inclusion/Exclusion............................ 57
4.5.2.3
Re-Screening......................................................................... 58

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
6
4.5.2.4
Assessments during Treatment and Untreated 
Observation ........................................................................... 58
4.5.2.5
Pharmacokinetic Assessments.............................................. 58
4.5.2.6
Lamivudine or Entecavir Viral Resistance 
Assessments ......................................................................... 59
4.5.2.7
Assessments at Study Drug Discontinuation......................... 59
4.5.2.8
Assessments at Study Completion or Early 
Termination............................................................................ 59
4.5.2.9
Follow-Up Assessments ........................................................ 59
4.5.2.10
Assessments at Unplanned Visits ......................................... 60
4.5.3
Assessment of Sexual Maturity ............................................. 60
4.6
Patient, Study, and Site Discontinuation................................ 60
4.6.1
Patient Discontinuation.......................................................... 60
4.6.1.1
Untreated Control Patients who become 
Immune-Active....................................................................... 60
4.6.1.2
Discontinuation from Study Drug........................................... 60
4.6.1.3
Withdrawal from Study........................................................... 61
4.6.2
Study and Site Discontinuation.............................................. 62
5.
ASSESSMENT OF SAFETY....................................................................... 62
5.1
Safety Plan ............................................................................ 62
5.1.1
Risks Associated with Pegasys ............................................. 63
5.1.1.1
Neutropenia, Lymphopenia, and 
Thrombocytopenia................................................................. 63
5.1.1.2
Elevated ALT......................................................................... 63
5.1.1.3
Thyroid................................................................................... 63
5.1.1.4
Growth................................................................................... 64
5.1.1.5
Neuropsychiatric.................................................................... 64
5.1.1.6
Ophthalmic ............................................................................ 64
5.1.1.7
Fertility................................................................................... 64
5.1.2
Risks Associated with Lamivudine......................................... 65
5.1.3
Risks Associated with Entecavir............................................ 65
5.2
Safety Parameters and Definitions ........................................ 66
5.2.1
Adverse Events ..................................................................... 66

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
7
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 67
5.2.3
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 67
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 68
5.3.1
Adverse Event Reporting Period ........................................... 68
5.3.2
Eliciting Adverse Event Information....................................... 68
5.3.3
Assessment of Severity of Adverse Events ........................... 68
5.3.4
Assessment of Causality of Adverse Events ......................... 69
5.3.5
Procedures for Recording Adverse Events............................ 69
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 69
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 70
5.3.5.3
Persistent or Recurrent Adverse Events................................ 70
5.3.5.4
Abnormal Laboratory Values ................................................. 70
5.3.5.5
Abnormal Vital Sign Values ................................................... 71
5.3.5.6
Abnormal Liver Function Tests.............................................. 72
5.3.5.7
Deaths ................................................................................... 72
5.3.5.8
Preexisting Medical Conditions.............................................. 72
5.3.5.9
Lack of Efficacy or Worsening of CHB................................... 73
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 73
5.3.5.11
Overdoses ............................................................................. 73
5.3.5.12
Patient-Reported Outcome Data ........................................... 73
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 74
5.4.1
Emergency Medical Contacts................................................ 74
5.4.2
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 75
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 75
5.4.2.2
Events That Occur after Study Drug 
Administration........................................................................ 75
5.4.3
Reporting Requirements for Pregnancies.............................. 75
5.4.3.1
Pregnancies in Female Patients............................................ 75

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
8
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 76
5.4.3.3
Abortions ............................................................................... 76
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 76
5.5
Follow-Up of Patients after Adverse Events .......................... 76
5.5.1
Investigator Follow-Up........................................................... 76
5.5.2
Sponsor Follow-Up ................................................................ 77
5.6
Post-Study Adverse Events................................................... 77
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 77
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 78
6.1
Determination of Sample Size ............................................... 78
6.2
Summaries of Conduct of Study............................................ 79
6.3
Summaries of Treatment Group Comparability ..................... 79
6.4
Efficacy Analyses .................................................................. 79
6.4.1
Primary Efficacy Endpoint...................................................... 79
6.4.2
Secondary Efficacy Endpoints............................................... 79
6.5
Safety Analyses..................................................................... 80
6.6
Pharmacokinetic Analyses..................................................... 81
6.7
Exploratory Analyses............................................................. 81
6.8
Interim Analyses .................................................................... 81
7.
DATA COLLECTION AND MANAGEMENT ............................................... 82
7.1
Data Quality Assurance......................................................... 82
7.2
Electronic Case Report Forms............................................... 82
7.3
Source Data Documentation.................................................. 82
7.4
Use of Computerized Systems .............................................. 83
7.5
Retention of Records............................................................. 83
8.
ETHICAL CONSIDERATIONS.................................................................... 84
8.1
Compliance with Laws and Regulations ................................ 84
8.2
Informed Consent.................................................................. 84
8.3
Institutional Review Board or Ethics Committee.................... 85
8.4
Confidentiality........................................................................ 86
8.5
Financial Disclosure .............................................................. 86

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
9
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 87
9.1
Study Documentation ............................................................ 87
9.2
Protocol Deviations ............................................................... 87
9.3
Site Inspections ..................................................................... 87
9.4
Administrative Structure......................................................... 87
9.5
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 88
9.6
Protocol Amendments ........................................................... 89
10. REFERENCES ........................................................................................... 90

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
10
LIST OF TABLES
Table 1
Pegasys Pediatric Dosing Regimen............................................ 36
Table 2
Entecavir Dosing for Nucleoside Naïve Pediatric Patients 
Aged 2 to < 18 Years .................................................................. 37
Table 3
Safety Assessments ................................................................... 49
Table 4
Laboratory Assessments ............................................................ 52
Table 5
Adverse Event Severity Grading Scale ....................................... 69
LIST OF FIGURES
Figure 1
Schematic of Study Design......................................................... 32
LIST OF APPENDICES
Appendix 1A
Schedule of Assessments: Pegasys Monotherapy for 
Previous IST Patients Only ......................................................... 94
Appendix 1B
Schedule of Assessments: Pegasys + Lamivudine or 
Entecavir..................................................................................... 97
Appendix 1C
Schedule of Assessments: Untreated Control........................... 102
Appendix 2
Child Pugh Classification of Severity of Liver Disease.............. 105
Appendix 3
Liver Biopsy Scores .................................................................. 106
Appendix 4
Pegasys Dose Modification Guidance ...................................... 108
Appendix 5
Estimated Creatinine Clearance Schwartz Formula 2009......... 113
Appendix 6
Tanner Stages .......................................................................... 114

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
11
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
PHASE IIIB, RANDOMIZED, OPEN-LABEL 
STUDY OF PEGYLATED INTERFERON ALFA-2A 
IN COMBINATION WITH LAMIVUDINE OR 
ENTECAVIR COMPARED WITH UNTREATED 
CONTROL PATIENTS IN CHILDREN WITH 
HBEAG-POSITIVE CHRONIC HEPATITIS B IN 
THE IMMUNE-TOLERANT PHASE
PROTOCOL 
NUMBER:
NV25361
VERSION NUMBER:
13
EUDRACT NUMBER:
2006-000977-31
IND NUMBER:
10,444
TEST PRODUCT:
Pegasys® (RO 25 8310)
MEDICAL MONITOR:
, Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please return the signed original of this form as instructed by your local study monitor.  
Please retain a signed copy for your study files.  

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
12
PROTOCOL SYNOPSIS
TITLE:
PHASE IIIB, RANDOMIZED, OPEN-LABEL STUDY OF 
PEGYLATED INTERFERON ALFA-2A IN COMBINATION 
WITH LAMIVUDINE OR ENTECAVIR COMPARED WITH 
UNTREATED CONTROL PATIENTS IN CHILDREN WITH 
HBEAG-POSITIVE CHRONIC HEPATITIS B IN THE 
IMMUNE-TOLERANT PHASE
PROTOCOL NUMBER:
NV25361
VERSION NUMBER:
13
EUDRACT NUMBER:
2006-000977-31
IND NUMBER:
10,144
TEST PRODUCT:
Pegasys® (RO 25 8310)
PHASE:
IIIb
INDICATION:
Chronic Hepatitis B
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Recruitment into the study was terminated prematurely; therefore, the data collected will be
descriptively summarized.  No formal statistical hypothesis testing or formal treatment group 
comparisons will be performed.
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of Pegasys® lamivudine or entecavir for 48 weeks compared with 
an untreated control in children with CHB, as measured by loss of HBsAg 24 weeks post-
treatment/end of untreated observation
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of Pegasys® lamivudine or entecavir compared with an untreated 
control in children with CHB, as measured by seroconversion to anti-HBs, seroconversion 
to anti-HBe, loss of HBeAg, and HBV DNA levels, at 24 weeks post- treatment/end of 
untreated observation 

To evaluate the efficacy of Pegasys® lamivudine or entecavir in children with CHB, as 
measured by seroconversion to anti-HBs, seroconversion to anti-HBe, loss of HBsAg, loss 
of HBeAg, HBV DNA levels, at 1 year post-treatment
Safety Objective
The safety objective for this study is as follows:

To evaluate the safety of the Pegasys® lamivudine or entecavir group compared with the 
untreated control group in children with CHB, by assessment of adverse events (including 
neuropsychiatric assessment), laboratory test results (including thyroid function), vital signs 
and growth, up to 24 weeks post-treatment/end of untreated observation and up to 1 year 
post-treatment

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
13
Pharmacokinetic Objective
The pharmacokinetic objective for this study is as follows:

To evaluate the pharmacokinetics of Pegasys® in children with CHB treated with 
Pegasys®lamivudine or entecavir following administration of a body surface area 
(BSA)based dosing regimen
Exploratory Objectives
The exploratory objectives for this study are as follows:

To explore the relationship between quantitative HBsAg/quantitative HBeAg and treatment 
response in children with CHB

To explore lamivudine or entecavir viral resistance in children with CHB

To explore the incidence of anti-drug antibodies (ADAs) in children with CHB treated with 
Pegasys®lamivudine or entecavir
Study Design
Description of Study
Study NV25361 was planned as a randomized, controlled, parallel group, open-label, 
multicenter superiority study in approximately 114 children, aged 3 to less than 18 years with 
immune-tolerant CHB.  
To allow for the varying response rates associated with different genotypes, patients will be 
stratified by HBV genotype A vs. B/C vs. D/other) and randomized 1:1 to one of two groups:

Lamivudine or entecavir alone for 8 weeks followed by Pegasys® lamivudine or entecavir
for 48 weeks

Untreated control
The screening period will be up to 6 weeks.  All treated patients will be followed for up to 1 year
after the end of treatment.  Primary analysis will be performed at 24 weeks post-treatment 
(follow-up Week 24)/end of untreated observation (Week 80).
Pegasys® will be given subcutaneously once weekly with dosing based on BSA categories.  
Lamivudine or entecavir will be given as a film-coated tablet or oral solution once daily with 
dosing based on weight.  Once the nucleoside analog is chosen, the patient must continue on 
that nucleoside analog throughout the study.
The study will comprise evaluation of efficacy (seroconversion to anti-HBe/anti-HBs, loss of 
HBeAg/HBsAg, and HBV DNA levels), safety (adverse events, laboratory abnormalities, dose 
modifications/discontinuations, vital signs, and growth), and pharmacokinetics (measurement of 
Pegasys® blood levels), as well as exploratory measures (quantitative HBsAg/HBeAg, 
lamivudine or entecavir viral resistance, and ADAs).
Patients will be enrolled from approximately 55 sites worldwide. 
Number of Patients
n ~ 114 
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Male and female patients age 3 to less than 18 years of age at baseline (12 to 18 years 
of age at baseline in Russia and India)

Positive for HBsAg and HBeAg for more than 6 months prior to baseline 

Detectable HBV-DNA (20,000 IU/mL, as measured by PCR or hybridization) on at least 2 
occasions at least one month apart with the latest determination obtained 42 days prior to 
baseline.

Compensated liver disease (Child-Pugh Class A clinical classification)

Either 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
14
Liver biopsy performed within 2 years prior to baseline showing no or minimal fibrosis 
(Liver Biopsy Scores) and stable normal ALT levels (upper limit of normal [ULN])
during the 6 months leading up to baseline (including two separate occasions at least 1 
month apart over the 6 months prior to baseline).  Screening ALT levels must be normal 
(ULN). 
OR
Stable normal ALT levels (ULN), during the 1-year leading up to baseline (including 
three separate occasions at least 1 month apart over the 1 year prior to baseline) and no
signs of HCC, advanced fibrosis/cirrhosis, or splenomegaly on liver abdominal 
ultrasound at screening. Screening ALT levels must be normal (ULN).

Signed informed consent from parent/legal guardian and willingness of parent/legal 
guardian to abide by the requirements of the study, and signed informed consent or assent 
from child where appropriate.  Patients 18 years of age at baseline who are legally 
considered to be adults according to their national legislation must consent in their own 
right if required.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Patients who have received investigational drugs or licensed treatments with anti-HBV 
activity (e.g., IFNs, lamivudine, tenofovir, emtricitabine, adefovir, entecavir, telbivudine, 
systemic acyclovir, systemic famciclovir) (Exception: Patients who have had a limited [7-
day] course of acyclovir for herpetic lesions more than 1 month before the study baseline 
visit are not excluded)  

Patients who have participated in any other clinical trial or who have received any 
investigational drug within 6 months prior to baseline

Known hypersensitivity to IFN, Pegasys®, lamivudine, or entecavir

BSA 0.51 m2 (based on Mosteller formula)

Positive test results at screening for HAV immunoglobulin M (IgM) antibody (Ab), anti-HCV 
Ab, anti-HDV Ab, or anti-HIV Ab

History or other evidence of bleeding from esophageal varices

Decompensated liver disease (e.g., Child-Pugh Class B or C clinical classification or clinical 
evidence such as ascites or varices)

Advanced fibrosis or cirrhosis (assessed by liver biopsy or ultrasound)

Suspicion of HCC on liver abdominal ultrasound (all patients to have liver abdominal 
ultrasound within 6 months prior to baseline)

History or other evidence of a medical condition associated with chronic liver disease other 
than CHB, including metabolic liver diseases such as hemochromatosis, Wilson’s disease, 
or -1 anti-trypsin deficiency

Screening alfa-fetoprotein (AFP) ULN

Screening neutrophil count 1.5 109 cells/L, platelet count 90 109 cells/L, or 
hemoglobin lower limit of normal (LLN)

Screening albumin of LLN or direct and indirect bilirubin of ULN (Exception: patients 
with non-hepatitis related factors which may elevate bilirubin such as Gilbert’s disease 
where screening indirect bilirubin must be 3.0 mg/dL.)

Evidence of renal impairment

History of immunologically mediated disease to include, but not limited to autoimmune 
hepatitis, inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus 
erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis, or clinical 
evidence of rheumatoid arthritis

Major depression or history of psychiatric disorder, such as major psychoses, suicidal 
ideation, and/or suicide attempt, for which clinical trial participation would be inappropriate

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
15

Evidence or history of chronic pulmonary or cardiac disease associated with clinically 
significant functional limitation

History of thyroid disease that was poorly controlled on prescribed medications, or clinically 
relevant abnormal thyroid function tests (thyroid-stimulating hormone [TSH], free 
triiodothyronine [FT3], free thyroxin [FT4], thyroid peroxidase [TPO] antibodies, and TBG) 
at screening 

Poorly controlled diabetes

History of solid organ or bone marrow transplantation

Evidence of an active or suspected cancer or a history of malignancy in which the risk of 
recurrence was/is 20% within 2 years

History of having received any systemic anti-neoplastic (including radiation) or 
immunomodulatory treatment (including systemic corticosteroids) 6 months prior to the 
study baseline visit or the expectation that such treatment will be needed at any time during 
the study (Exception: topical corticosteroids, corticosteroids prescribed as physiological 
replacement therapies, or short courses [7 days] of systemic corticosteroids)

Coagulopathy (screening international normalized ratio 1.5), hemoglobinopathy, 
hemophilia, or history of severe illness or other blood disorders that would make patient 
unsuitable for the study

History of seizure disorder requiring treatment with anticonvulsant medication (excluding 
febrile seizures)

History or other evidence of severe retinopathy

History or other evidence of severe illness or any other conditions that would make the 
patient, in the opinion of the investigator, unsuitable for the study

Active substance abuse within 6 months prior to screening

Sexually active females of childbearing potential and sexually active males who are not 
willing to utilize effective contraceptive measures (with abstinence being considered a 
satisfactory method), during treatment and for 90 days following the end of treatment   

Females who are pregnant or breastfeeding.  (Females of childbearing potential who have 
a positive urine or serum pregnancy test result at screening or at the baseline visit are 
excluded).
Length of Study
The study originally commenced as a single-site investigatorled study 
(i.e., investigator-sponsored trial [IST]) in November 2006.  The length of the Roche-sponsored 
global multicenter study from screening of first patient to end of study will be approximately 10
years.  
For treated patients, the approximate study length is 2 years and 2 months (with up to 6 weeks 
screening, 8 weeks of lamivudine or entecavir treatment, 48 weeks of Pegasys® lamivudine or 
entecavir treatment [i.e., 56 weeks of treatment], 24 weeks of initial follow-up, 28 weeks of 
additional follow-up [i.e., 52 weeks total or 1 year of follow-up]). 
For untreated patients, the approximate study length is 1.5 years (with up to 6 weeks screening 
and 80 weeks untreated observation).
End of Study
The end of the study is defined as the date when the last patient, last visit (LPLV) for the final 
analysis occurs.  
LPLV for primary analysis was planned at 24 weeks after end of treatment/end of untreated 
observation is expected to occur approximately 1 year and 8 months after last patient is enrolled.
LPLV for final analysis at 1 year after the end of treatment is expected to occur approximately 
2 years and 2 months after the last patient is enrolled.
Efficacy Outcome Measures
The primary efficacy outcome measure for this study at 24 weeks post- treatment/end of 
untreated observation is as follows:

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
16

Loss of HBsAg 
The secondary efficacy outcome measures for this study at 24 weeks posttreatment/end of 
untreated observation are as follows:

Loss of HBeAg

Seroconversion to anti-HBs (loss of HBsAg and presence of anti-HBs) 

Seroconversion to anti-HBe (loss of HBeAg and presence of anti-HBe)

HBV DNA 20,000 IU/mL, < 2000 IU/mL, undetectable and change from baseline (by 
polymerase chain reaction [PCR] or hybridization)

Combined endpoints:  HBeAg seroconversion and HBV DNA 20,000 IU/mL

Combined endpoints:  HBeAg seroconversion and HBV DNA 2000 IU/mL
The secondary efficacy outcome measures for this study at 1 year post-treatment are as follows:

Loss of HBeAg

Loss of HBsAg

Seroconversion to anti-HBs (loss of HBsAg and presence of anti-HBs)

Seroconversion to anti-HBe (loss of HBeAg and presence of anti-HBe)

HBV DNA 20,000 IU/mL< 2000 IU/mL, undetectable and change from baseline (by PCR 
or hybridization)

Combined endpoints:  HBeAg seroconversion and HBV DNA 20,000 IU/mL

Combined endpoints:  HBeAg seroconversion and HBV DNA 2000 IU/mL
Safety Outcome Measures
The safety outcome measures for this study at 24 weeks posttreatment/end of untreated 
observation are as follows:

Incidence, nature, and severity of serious and non-serious adverse events (including 
neuropsychiatric assessment)

Reasons for the discontinuation of any study medication

Dose modifications for laboratory abnormalities and clinical adverse events

Changes in vital signs and laboratory tests from screening/baseline, including thyroid 
function

Effect on growth (height, weight and sexual maturity status)
The safety outcome measures for this study at 1 year posttreatment are as follows:

Incidence, nature, and severity of persisting adverse events, new-onset related serious 
adverse events/non-serious adverse events of special interest

Changes in thyroid function from screening/baseline

Effect on growth (height, weight and sexual maturity status)
Pharmacokinetic Outcome Measures
Pharmacokinetic samples will be collected from all patients treated with Pegasys® lamivudine 
or entecavir for measurement of Pegasys®.
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Quantitative HBsAg and quantitative HBeAg 

Presence of lamivudine or entecavir viral resistance

Incidence of ADAs from all patients treated with Pegasys®lamivudine or 
Pegasys®+entecavir

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
17
Investigational Medicinal Products
Test Product
Pegasysfor 48 weeks subcutaneously once weekly with dosing based on the following body 
surface area (BSA) categories: 
Dose (µg)
BSA Range (m2)
45
0.51–0.53
65
0.54–0.74
90
0.75–1.08
135
1.09–1.51
180
>1.51
Pegasyswill be used in combination with lamivudine or entecavir.  
Treated patients will receive lamivudine as a film-coated tablet or oral solution once daily at a 
dose of 3 mg/kg (maximum daily dose 100 mg), or entecavir as a film-coated tablet or oral 
solution at a dose of 0.015 mg/kg once daily (maximum dose of 0.5 mg), given alone for 
8 weeks then in combination with Pegasysfor 48 weeks.  The first dose of lamivudine or 
entecavir should be taken at the study site during the baseline visit.  Pegasys® will be given 
subcutaneously once weekly with dosing based on BSA categories.  Pegasys® injection 
instructions will be provided for the parent/legal guardian and patients, if applicable.  A container 
will also be provided for disposal of all used needles.  The first dose of Pegasys® should be 
taken at the study site during the Week 8 visit (after approximately 8 weeks of lamivudine or 
entecavir monotherapy).  
Statistical Methods
Primary Analysis
The primary efficacy endpoint is defined as loss of HBsAg at 24 weeks post-treatment (follow-
up Week 24)/end of untreated observation (Week 80).  The number of observations, percentage 
of responders (response rate) and 95% CI (using the Clopper-Pearson method) for the 
response rate will be presented for each group.  
The primary analysis was planned as the comparison of the response rate in the 
Pegasys®lamivudine or entecavir group with that in the untreated control group.  Testing of 
the primary endpoint was planned as a superiority test based on the ITT population, which 
would comprise all randomized patients who received at least one dose of study medication 
and patients randomized to no treatment. The test would be using Fisher’s exact test, stratified 
by HBV genotype (A vs. B/C vs. D/other), and the significance level taken at 5% two-sided.  
Patients with missing data will be treated as non-responders.  Sensitivity analyses would 
include a last observation carried forward approach for missing data.  The Cochran 
Mantel Haenszel test stratified by genotype would also be provided.
Determination of Sample Size
Taking into account the comparable entecavir and lamivudine early viral kinetics and the low 
resistance rates observed during Pegasys®-combination therapy with entecavir or lamivudine, 
the efficacy of Pegasys® lamivudine and Pegasys® entecavir regimens in this study are 
expected to be comparable. The assumptions for the expected loss of HBsAg rates after 24 
weeks after the end of treatment/end of untreated observation are 17% in the 
Pegasys®lamivudine arm and 0.6% in the untreated control group.  These assumptions are 
based on the observed rate on conventional Interferon in a pilot study (D’Antiga et al. 2006) and 
observed spontaneous rates (Hsu 1992), respectively.  
With a two-sided 5% significance level, Fisher’s Exact test would have 80% power to detect a 
difference between a treated group and untreated control with 50 evaluable patients per group.  
Approximately 114 patients were planned to be recruited (57 per group) to ensure at least 50 
evaluable patients in each group.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
18
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
Ab
antibody
ADA
anti-drug antibody
AE
adverse event
AFP
-fetoprotein
anti-HBe
hepatitis B envelope antibody
anti-HBs
hepatitis B surface antibody
AUC
area under curve
BSA
body surface area
CDI
Children’s Depression Inventory
CHB
chronic hepatitis B
CHC
chronic hepatitis C
CL/F
clearance
CRF
Case Report Form
CSR
clinical study report
DAIDS
Division of AIDS
DAP
data analysis plan
DSMB
Data Safety Monitoring Board
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assays
EU
European Union
FDA
U.S. Food and Drug Administration
FT3
free triiodothyronine
FT4
free thyroxin
G-CSF
granulocyte colony-stimulating factor
HAV
hepatitis A virus
HbeAg
hepatitis B envelope antigen
HbsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDV
hepatitis D virus
ICH
International Conference on Harmonization
IFN
interferon 
IgM
immunoglobulin M 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
19
Abbreviation
Definition
IMC
Internal Monitoring Committee
IND
Investigational New Drug
IRB
Institutional Review Board
IST
investigator sponsored trial
ITT
intent to treat
IxRS
interactive voice or Web response system
LLN
lower limit of normal
LPLV
last patient last visit
PCR
polymerase chain reaction
PK
pharmacokinetic
PRO
patient-reported outcome
RCR
Roche Clinical Repository
SAE
serious adverse event
SMT
Study Management Team
SVR
sustained virological response
TBG
thyroxine-binding globulin
TP
triphosphate
TPO
thyroid peroxidase
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
UTC
coordinated universal time
V/F
volume of distribution
YMDD
tyrosine-methionine-aspartate-aspartate

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
20
1.
BACKGROUND
1.1
BACKGROUND ON CHRONIC HEPATITIS B
Hepatitis B virus (HBV) infection is a major public health problem with an estimated 
300 million hepatitis B surface antigen (HBsAg) carriers worldwide.  In endemic areas 
like China and Africa, where the HBsAg carrier rate is as high as 15%20%, hepatitis B 
is primarily a disease of childhood, acquired either perinatally from HBsAg-positive 
mothers or horizontally from infected mates or family members (Beasley et al. 1982; 
Kiire 1990).  In areas of intermediate endemicity (Italy, Japan, Spain, Greece, and 
Portugal), where 2%10% of the population are HBsAg carriers, infection occurs in both 
adults and children.  In low endemicity areas, including the United Kingdom, infection 
during infancy and childhood is uncommon and 1% of the population has chronic HBV
infection (Maynard et al. 1988), which usually, though not exclusively, affects ethnic 
minorities originating from endemic countries or travelers to endemic areas.  These 
epidemiological data are, however, changing with the introduction of effective 
vaccination in some countries whereas in others, prevalence is maintained by either 
incomplete vaccination coverage or an increase in travel and international adoption from 
countries with less successful prevention strategies. 
The virus is highly infectious, much more than hepatitis C virus (HCV) or HIV, and 
chronically infected individuals readily infect unvaccinated family members, mates, and 
sexual partners.  The probability of becoming a chronic HBV carrier is correlated to age 
at infection and the efficiency of the immune system, being highest in children infected 
within the first year of life who tend to become “tolerant” to the virus.  Thus, more than 90% 
of infected infants, including the 5% who do not respond to HBV vaccination, become 
chronic carriers, as compared with 6%10% if the infection occurs after the 6th year of 
life (Chu et al. 1985; Chang et al. 1989).  Chronically infected children are usually 
asymptomatic with normal or minimally abnormal liver function tests, but their liver 
histology can show progressive inflammatory changes (Bortolotti et al. 1986). 
Chronic HBV infection in children is typically characterized by three phases: 1) the 
immune-tolerant phase, 2) the immune-active phase, and 3) the inactive carrier state.  
Most children with perinatally acquired HBV infection and hepatitis B envelope antigen 
(HBeAg)positive disease are considered to be in the immune-tolerant phase.  This 
phase of disease is associated with minimal or no evidence of clinical symptoms, normal 
ALT levels, high serum HBV DNA, and minimal activity or injury (e.g., minimal or mild 
inflammation and fibrosis) on liver biopsy (see Appendix 3).  This phase can persist 
throughout childhood, with disease becoming active with consequent liver damage in a 
proportion of patients only later in life.  Importantly, this immune-tolerant phase of the 
disease in childhood is when most person-to-person transmission of HBV occurs in 
sub-Saharan African and Mediterranean countries (Lok and McMahon 2009).  The 
immune-active phase normally follows the immune-tolerant phase.  Early in this phase, 
there may be high HBV DNA levels, but these may decrease to 10,000 copies/mL.  It is 
characterized by varying degrees of liver inflammation and fibrosis and increased levels 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
21
of AST and ALT.  Seroconversion with loss of HBeAg and production of hepatitis B 
envelope antibody (anti-HBeAb) may occur, leading to the next phase: the inactive 
carrier state.  In the inactive carrier state, patients are HBeAg negative, AST and ALT 
levels return to normal, and HBV DNA levels remain very low.
Besides posing a serious infection risk to the community, chronically HBV infected 
children, particularly if male, have a high risk of progressing to cirrhosis and 
hepatocellular carcinoma (HCC) (Bortolotti et al. 1986; Hsu et al. 1987, 1988; 
de Potter et al. 1987; Leuschner et al. 1988), the likelihood of developing these 
complications being correlated to the length of time to achieve anti-HBe seroconversion.  
Spontaneous HBeAg loss in chronically infected children occurs at an annual rate of 
10% -16% (Bortolotti et al. 1986; Moyes et al. 1993), whereas spontaneous loss of 
HBsAg is as low as 0.6% per year (Hsu et al. 1992), the children achieving earlier 
seroconversion being those with biochemical and/or histological evidence of active 
disease.  Moreover, the annual HBsAg clearance rate is significantly higher in those 
children who are already anti-HBe positive (i.e., low viral load) than in those with HBeAg 
(i.e., high viral load) (1.7% vs. 0.4%).
1.2
BACKGROUND ON PEGASYS®
Roche has chemically modified the interferon alfa-2a molecule by covalently attaching a 
branched methoxy polyethylene glycol moiety.  Pegasys® has a decreased systemic 
clearance rate and an approximately 10-fold increase in serum half-life compared with 
interferon alfa-2a; as a result, Pegasys® circulates in the blood much longer than the 
parent compound.  
A development program exploring the use of Pegasys® in the treatment of chronic 
hepatitis B (CHB) was initiated with a Phase II study using 90-, 180-, and 270-g doses 
of Pegasys®, which were compared against the licensed dose of conventional 
-interferon (IFN) for 24 weeks of therapy (Study NV16037).  This pilot trial showed a 
two-fold improvement in efficacy of Pegasys® over non-pegylated IFN and the 270-g 
dose did not show any indication of additional benefit over the 180-g dose.  Two large 
Phase III studies were performed and showed that 180 g of Pegasys® was superior to 
lamivudine in both HBeAg-positive and HBeAg-negative disease when assessed 
24 weeks after stopping 48 weeks of therapy.  Furthermore, both studies contained a 
third arm containing the combination of Pegasys® with lamivudine.  Although this 
combination showed significantly greater HBV DNA suppression on treatment than 
lamivudine monotherapy, it did not show any improvement over Pegasys® monotherapy 
at 24 weeks after the end of therapy (Study WV16240, Study WV16241).  These HBV 
studies included more than 1500 patients and led to regulatory approval of Pegasys® 
use in CHB in the European Union, United States, and many other countries with high 
incidence of HBV disease.  The safety profile of 180-g of Pegasys® in patients with 
CHB was no worse and possibly slightly better tolerated than in HCV patients treated 
with Pegasys®, particularly with regards to the incidence of depression. 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
22
The NEPTUNE study (Clinical Study Report WV19432) was a Phase IV trial that 
examined two doses of Pegasys® (90 and 180 g/week), and two durations (24 and 
48 weeks) in adults with HBeAg-positive chronic HBV infection.  This trial incorporated a 
non-inferiority study design and showed that the highest response rate was achieved in 
the 180-g/week, 48-week treatment group, confirming the registered dose and duration 
of the 180-g/week, 48-week treatment as the most efficacious regimen.  For the 
secondary endpoints tested, the overall trends were consistent with the primary endpoint, 
with the highest response rates being achieved in the 180-g/week, 48-week treatment 
group.  The results confirmed that the overall safety profile of Pegasys® in patients with 
HBeAg-positive CHB was consistent with the currently approved label, with no new 
signals identified. 
Study YV25718 is a prospective, open-label, randomized pediatric study evaluating the 
efficacy and safety of Pegasys® monotherapy compared with untreated control in 
children with immune-active, HBeAg-positive CHB disease.  The study met the primary 
efficacy endpoint of HBeAg seroconversion at 24 weeks after the end of the treatment
(principal) observation period.  At this timepoint, 26 patients treated with Pegasys® 
achieved HBeAg seroconversion (25.7%; 95% CI: 17.6%, 35.4%) compared with
3 patients in the untreated control group (6%; 95% CI: 1.3%, 16.6%), which was 
statistically significant (p 0.0043). Safety data were consistent with the known safety 
profile of Pegasys® and the patient population (Wirth et al. 2018).  After completion of 
the 24-week follow-up period, patients entered into a long-term follow-up (LTFU) 
period for up to 4.5 years after the study visit for the primary analysis.  The study is 
currently ongoing.  
The present study (NV25361) aims to assess the safety and efficacy of Pegasys® in 
combination with lamivudine or entecavir versus untreated control, in a randomized trial 
evaluating treatment of the immune-tolerant pediatric HBV population.  
Following pivotal Phase III Study NV17424 conducted in 114 children with HCV aged 5 
to 17 years, Pegasys® is indicated in the European Union and the United States for 
treatment of chronic hepatitis C in treatment-naive children and adolescents 5 years of 
age and older with compensated liver disease.  The most common adverse reactions in 
pediatric patients were similar to those seen in adults, with the exception of growth 
inhibition during the course of treatment with Pegasys® and Ribavirin (see 
Section 5.1.1.4).  Safety and efficacy in pediatric patients younger than 5 years of age 
have not been established.
During the recruitment period of the present study, results from a large National 
Institutes of Health (NIH) study evaluating Pegasys® in combination with entecavir in 
60 pediatric patients with CHB in the immune-tolerant phase were presented at the 
2017 American Association for the Study of Liver Diseases (AASLD) Congress in 
Washington, DC (Rosenthal et al. 2017). In this study, entecavir was given for 8 
weeks followed by combination therapy with entecavir and Pegasys® for an additional 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
23
40 weeks. Two of 60 patients (3%) met the primary endpoint of lack of HBeAg and 
HBV DNA levels less than 1000 IU/mL and also achieved HBsAg loss. HBsAg loss 
was achieved by 3 of 60 patients (5%) by the end of the treatment period at Week 48. 
The conclusion from this study was that the combination of entecavir and Pegasys®,
administered for up to 48 weeks, rarely led to loss of HBeAg with sustained suppression 
of HBV DNA levels and was associated with frequent though not serious adverse events. 
The results of a second NIH study in adults with immune-tolerant CHB, with the same 
design and treatment regimen as the above pediatric study, were also presented at the 
2017 AASLD Congress (Feld et al. 2017). In this 28-patient adult study, no patients 
achieved the primary endpoint of HBeAg loss and HBV DNA levels below 1000 IU/mL.  
In addition, no patients achieved HBsAg loss.
See the Pegasys® Investigator's Brochure for details on nonclinical and clinical studies.
1.3
BACKGROUND ON LAMIVUDINE
Lamivudine is a potent synthetic nucleoside analog reverse transcriptase inhibitor with 
activity against HBV and HIV.  It can inhibit both types (1 and 2) of HIV reverse 
transcriptase and also the reverse transcriptase of hepatitis B.  It is phosphorylated to 
active metabolites that compete for incorporation into viral DNA.  The active metabolites 
inhibit the HIV/HBV reverse transcriptase enzyme competitively and act as a chain 
terminator of DNA synthesis (Epivir-HBV U.S. Package Insert).  Viral resistance to 
lamivudine has been observed after prolonged therapy in patients infected with 
hepatitis B and was mapped to amino acid changes in the HBV polymerase region 
(tyrosine-methionine-aspartate-aspartate [YMDD or YMDD motif]) (Lai et al. 2003).
Lamivudine is currently approved for the treatment of chronic hepatitis B associated with 
evidence of hepatitis B viral replication and active liver inflammation in adults, and some 
health authorities have approved the use of lamivudine in children and/or adolescents 
infected with hepatitis B (e.g., in the United States for children 2 years old); it improves 
the seroconversion of eantigen-positive hepatitis B and also improves histology staging 
of the liver. The safety and efficacy of lamivudine in pediatric patients with HBV were 
evaluated in a double-blind clinical trial in 286 patients aged 217 years of age with 
elevated ALT levels (immune active phase).  The combination of loss of HBeAg and 
reduction of HBV DNA to below the assay limit of the research assay, evaluated at 
Week 52, was observed in 23% of lamivudine patients and in 13% of placebo patients.  
Normalization of serum ALT was achieved and maintained to Week 52 more frequently 
in patients treated with lamivudine compared with placebo (55% vs. 13%, respectively) 
(Epivir-HBV U.S. Package Insert). A previous study in adult HBV population 
(Study WV16241) has shown no effect of lamivudine on the pharmacokinetics of 
Pegasys®.
For more information on lamivudine, see local prescribing information.  

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
24
1.4
BACKGROUND ON ENTECAVIR
Baraclude® is the tradename for entecavir, a guanosine nucleoside analogue with 
activity against HBV polymerase. It is efficiently phosphorylated to the active 
triphosphate (TP) form, which has an intracellular half-life of 15 hours. By competing 
with the natural substrate deoxyguanosine TP, entecavir-TP functionally inhibits the 
three activities of the viral polymerase: 1) priming of the HBV polymerase, 2) reverse 
transcription of the negative strand DNA from the pregenomic messenger RNA, and 
3) synthesis of the positive strand HBV DNA. Entecavir inhibited HBV DNA synthesis 
(50% reduction, EC50) at a concentration of 0.004 μM in human HepG2 cells transfected 
with wild-type HBV. The median EC50 value for entecavir against LVDr HBV (rtL180M 
and rtM204V) was 0.026 μM (range: 0.0100.059 μM). An analysis of the inhibitory 
activity of entecavir against a panel of laboratory and clinical HIV-1 isolates using a 
variety of cells and assay conditions yielded EC50 values ranging from 0.026 to 10 μM; 
the lower EC50 values were observed when decreased levels of virus were used in the 
assay. In cell culture, entecavir selected for an M184I substitution at micromolar 
concentrations, confirming inhibitory pressure at high entecavir concentrations. HIV 
variants containing the M184V substitution showed loss of susceptibility to entecavir fully 
susceptible to entecavir. (BARACLUDE® SmPC).
Entecavir is approved for the treatment of hepatitis B in adults, and, since 2014, in 
children of 2 years of age and older in both Europe and U.S.
Entecavir was evaluated in two clinical trials of pediatric subjects 2 years of age and 
older with HBeAg-positive chronic HBV infection and compensated liver disease. The 
exposure of entecavir in nucleoside-inhibitor, treatment-naïve, and 
lamivudine-experienced pediatric subjects 2 years of age and older with HBeAg-positive 
chronic HBV infection and compensated liver disease receiving 0.015 mg/kg (up to 
0.5 mg once daily) or 0.03 mg/kg (up to 1 mg once daily), respectively, was evaluated in 
Study AI463028. Safety and efficacy of the selected dose in treatment-naïve pediatric 
subjects were confirmed in Study AI463189, a randomized, placebo-controlled treatment 
trial. The pharmacokinetics, safety, and antiviral activity of entecavir in pediatric subjects 
were initially assessed in Study AI463028. Twenty-four treatment-naïve and 19 
lamivudine-experienced HBeAg-positive pediatric subjects aged 2 to less than 18 years 
with compensated CHB and elevated ALT were treated with entecavir 0.015 mg/kg (up 
to 0.5 mg) or 0.03 mg/kg (up to 1 mg) once daily. Fifty-eight percent (14/24) of 
treatment-naïve subjects and 47% (9/19) of lamivudine-experienced subjects achieved 
HBV DNA 50 IU/mL at Week 48 and ALT normalized in 83% (20/24) of treatment-naïve
subjects and 95% (18/19) of lamivudine-experienced subjects. 
Safety and antiviral efficacy were confirmed in Study AI463189, an ongoing study of 
entecavir among 180 nucleoside-inhibitor, treatment-naïve pediatric subjects 2 to less 
than 18 years of age with HBeAg-positive chronic hepatitis B infection, compensated 
liver disease, and elevated ALT. Subjects were randomized 2:1 to receive blinded 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
25
treatment with entecavir 0.015 mg/kg up to 0.5 mg/day (N120) or placebo (N60). 
The randomization was stratified by age group (2 to 6 years; 6 to 12 years; and 12 to 
18 years). Baseline demographics and HBV disease characteristics were comparable 
between the 2 treatment arms and across age cohorts. At study entry, the mean HBV 
DNA was 8.1 log10 IU/mL and mean ALT was 103 U/L. The primary efficacy endpoint 
was a composite of HBeAg seroconversion and serum HBV DNA 50 IU/mL at Week 48 
assessed in the first 123 subjects reaching 48 weeks of blinded treatment. Twenty-four 
percent (20/82) of subjects in the entecavir-treated group and 2% (1/41) of subjects in 
the placebo-treated group met the primary endpoint. Forty-six percent (38/82) of 
entecavir-treated subjects and 2% (1/41) of placebo-treated subjects achieved HBV 
DNA 50 IU/mL at Week 48. ALT normalization occurred in 67% (55/82) of 
entecavir-treated subjects and 22% (9/41) of placebo-treated subjects; 24% (20/82) of 
entecavir-treated subjects and 12% (5/41) of placebo-treated subjects had HBeAg 
seroconversion.
Entecavir has a high barrier to resistance as it requires at least three codon substitutions, 
including rtL180M, rtM204I/V, plus a substitution at one of the following amino acids: 
rtT184S/G, rtS202I/G and/or rtM250V (Zoulim F, Locarnini S., 2013). Among 
treatment-naïve adult patients, entecavir resistance is very rare; in the long-term follow
up of the international trial on HBeAg-positive and HBeAg-negative patients and in a 
long-term follow-up study in Hong Kong, the cumulative probability of entecavir 
resistance was 1.2% after 5 years of entecavir treatment (Seto et al., 2015).
No pharmacokinetic (PK) interactions between Pegasys® and entecavir have been 
reported.  
For more information on entecavir, see local prescribing information.
1.5
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
Given the low spontaneous HBeAg/HBsAg loss and seroconversion rates observed in 
children infected with chronic HBV (spontaneous HBeAg loss of 10%16% per year 
[Bortolotti 1986; Moyes et al.1993], spontaneous loss of HBsAg ~0.6% per year 
[Hsu 1992]) and the fact that spontaneous HBsAg seroconversion rates are significantly 
higher in those who have HBeAg seroconverted (anti HBeAg positive and lower HBV 
DNA viral load) than in those who have not (1.7% vs. 0.4%), any treatment that can 
speed up the HBeAg/HBsAg loss and seroconversion rate would avoid the long-term 
complications of chronic infection such as cirrhosis and cancer and have a major impact 
on reducing the spread of infection of Hepatitis B in the population.  This would bring 
added benefits of reducing the stigma of carrying an infectious disease, avoiding the 
other potential social sequelae of impaired career choices, and reducing the impact on
personal relationships/marriages.  An additional consideration is that because most 
pediatric patients are in the immune-tolerant phase of disease, they have lower HBeAg 
seroconversion rates than those in the immune-active phase and therefore a lower 
chance of HBsAg seroconversion.  Annual rates of spontaneous HBeAg seroconversion 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
26
in immune-tolerant children with CHB of 0.8% in children 6 years of age, 1.4% in 
children 611 years of age, and 5.6% in children 1217 years of age have been reported 
(Park et al. 2012).  
Hepatitis B virus 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 compounded 
by the limited number of drugs that have been studied in children. 
Current consensus statements and reviews in the treatment of HBV-infected children 
and adult HBV treatment guidelines (Murray et al. 2008; Kurbergov and Sokol 2009; 
Lok and McMahon 2009; Giacchino and Cappelli. 2010; Jonas et al. 2010; 
Papatheodoridis et al. 2012) favored treatment of children in the immune-active phase of 
pediatric HBV disease, with non-pegylated IFN-as the first-line agent of choice 
(outside of clinical trials) because of the higher HBeAg seroconversion response rates 
achieved and higher HBsAg seroconversion rates seen in comparison with lamivudine.  
These recommendations have been based upon current indications for therapy in adults 
with chronic HBV infection since there are limited therapeutic options that have been 
studied and licensed for use in children.  Because of the lack of robust data regarding 
treatment of children with CHB, this has resulted in a lack of consensus among 
international experts regarding the need for HBV therapy during childhood and the 
subsequent lack of pediatric HBV guidelines.  However, these review articles agree that 
further studies are necessary to generate robust pediatric data. Study YV25718
evaluated Pegasys® as a treatment for pediatric patients with immune-active HBV
infection.  This study established Pegasys® for the treatment of CHB in children and has 
provided an additional therapeutic option for this population.
Although the consensus statements and reviews in the treatment of HBV-infected 
children and adult HBV treatment guidelines (Murray et al. 2008; 
Kurbegov and Sokol 2009; Lok and McMahon 2009; Giacchino and Cappelli 2010; 
Jonas et al. 2010; Papatheodoridis et al. 2012; Terrault et al. 2015; Sarin et al. 2015) 
favored treatment of children in the immune-active phase of pediatric HBV disease, 
there is no established benefit of treatment of children in the immune-tolerant phase.  
Historical clinical trial data of immune-active patients suggest that patients with normal or 
minimally elevated ALT respond poorly to current therapies (Jonas et al. 2002), or 
showed lower efficacy response rates with lower ALT levels in pegylated-IFN studies 
(Liaw et al. 2011).  Therefore, the current recommendations are not to treat 
immune-tolerant adult and pediatric patients with CHB.
However, two literature references from small pilot studies treating pediatric patients with 
CHB in the immune-tolerant phase reported results for the treatment groups showing 
impressive HBeAg and HBsAg loss, seroconversion, and sustained virological 
responses, compared with controls (D’Antiga et al. 2006; Poddar et al. 2013), but also 
compared with historical spontaneous loss and seroconversion rates.  The rate of 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
27
HBsAg loss and hepatitis B surface antibody (anti-HBs) seroconversion reported by 
Poddar et al. (2013) is the highest observed in immune-tolerant children and similar if 
not better than that observed within treatment trials of HBV-infected children with active 
disease.  
In the pilot study (D’Antiga et al. 2006), 23 immune-tolerant children, all infected during 
the first year of life and HBsAg, HBeAg, and HBV DNA positive, 17 of Asian (China and 
South East Asia) ethnicity, 21 with normal transaminase levels, and 15 with high viral 
load (HBV DNA 1000 pg/mL [Digene test]) at baseline, were treated for 8 weeks with 
lamivudine (3 mg/kg, maximum 100 mg daily), and then for 10 months with lamivudine 
(same dose) and Viraferon (5 Mu/m2 subcutaneously three times per week).  At the end 
of treatment, 19 patients (82%) were HBV DNA negative and 3 months later, 5 (22%) 
continued to be HBV DNA negative.  All 5 (22%) seroconverted to anti-HBe during a 
6-month follow-up, and 4 (17%) cleared HBsAg and become persistently anti-HBs 
positive (latest follow-up, 3648 months).  No patients developed resistant HBV (YMDD) 
mutations at the end of treatment, and the authors suggested that IFN in this regimen 
may protect from lamivudine-induced YMDD mutations.  No serious adverse events 
were reported by the authors, but all patients reported influenza-like symptoms during 
the first few weeks of treatment.  Reported adverse events comprised decreased 
appetite in 7 of 23 (30%) patients, epistaxis or menorrhagia in 7 of 23 (30%) patients, 
tiredness 5 of 23 (22%) patients, headache 4 of 23 (17%) patients, hair loss 4 of 
23 (17%) patients, abdominal pain 2 of 23 (9%) patients, arthralgia 1 of 23 (4%) patients, 
rash 1 of 23 (4%) patients, and sleepiness 1 of 23 (4%) patients.  The authors reported 
raised transaminases in 3 of the 5 responders, but also in 9 of 18 non-responders.  
Persistent loss of height but not weight was reported at 1 year after treatment, consistent 
with reports in HCV interferon trials.  
The other pilot study examined the treatment of immune-tolerant pediatric patients with 
HBV using the same sequence of lamivudine followed by a combination of lamivudine 
and non-pegylated interferon (Poddar et al. 2013).  Twenty-eight children were treated in 
a prospective cohort of clinic patients, and these were compared against 34 untreated 
controls.  HBeAg seroconversion was reported in 11 of 28 (39.3%) patients in the 
treatment group versus 2 of 34 (5.9%) patients in the control group.  Six patients (21.4%) 
achieved HBsAg loss 6 months after the end of treatment and remain HBsAg 
seroconverted after a mean follow-up period of 21.111.9 months, compared with 
0 of 34 controls. Viral resistance to lamivudine was not assessed.  No serious adverse 
events were reported in this study, although 2 children (2 of 28 [7%]) developed 
leukopenia that required dose modification but not discontinuation.  Other adverse 
events reported were fever in all patients, anorexia in 15 of 28 (54%) patients, malaise in 
8 of 28 (29%) patients, and recurrent oral apthous ulcers in 1 of 28 (4%) patients.  No 
growth effects were reported in this study. 
Low response rates to treatment with IFN monotherapy have been seen in two 
randomized controlled trials (Lai et al. 1987, 1991) using IFN in children with CHB.  Of 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
28
the 110 immune-tolerant children enrolled across the two studies, 70 received IFN and 
40 received placebo.  Sustained off-treatment response (from 15 to 18 months after 
treatment) was observed in only 3 of 70 (4%) patients and 1 of 70 (1%) patients for 
HBeAg and HBsAg loss, respectively in IFN group compared with 0 of 40 (0%) for both 
HBeAg and HBsAg in the control group.  Similar findings were observed in adults with 
CHB (Lok et al. 1992), where 1 of 40 (2.5%) immune tolerant patients achieved HBeAg 
or HBsAg loss at 12 months post-end of 16-weeks of IFN treatment compared with 0 of 
20 (0%) untreated immune-tolerant patients for HBeAg or HBsAg loss.  Although these 
trials employed non-pegylated IFN (alfa-2a and alfa-2b) and shorter treatment duration 
(1216 weeks), the results showed no improvement in efficacy for IFN treatment 
compared with control groups. 
Prevalence of viral resistance to lamivudine at baseline in untreated patients has been 
reported from low (~1%) to high (~20%) in several studies, depending mainly on the 
population studied and the sequencing methodologies used to detect the resistance 
(Akarsu et al. 2006; Salpini et al. 2011; Lee et al. 2012; Zhao et al. 2012).  Early 
emergence of lamivudine resistance in treated patients has not been well studied thus 
far, and only a few reports have been published showing lamivudine resistance 
emergence in some patients at the first time point analyzed, which was still 56 months 
after the beginning of treatment (Chayama et al. 1998; Zöllner et al. 2004; Natsuizaka et 
al. 2005).  Efficacy of treating lamivudine-resistant patients with a combination of 
Pegasys® and lamivudine has not been widely reported: 3 patients who enrolled in 
Study WV16240 and for whom lamivudine resistance was detected at baseline (2 
receiving the Pegasys® and lamivudine combination, and 1 receiving lamivudine 
monotherapy) had no detectable HBV DNA at Week 48 (CSR WV16240).
Combining the antiviral effect of lamivudine or entecavir with the immune-boosting action 
of IFN in sequence may be a more appropriate therapeutic approach for children, 
particularly in those who are less likely to respond to IFN alone because of infection at a 
very young age, who have normal transaminase levels, high HBV DNA and who are 
“tolerant” to the virus.  The use of a lead-in phase consisting of 8 weeks of lamivudine or 
entecavir monotherapy to lower the viral load, followed by interferon-containing 
combination therapy that has both antiviral and immune-stimulatory effects, is 
hypothesized to produce better effects than previous treatment strategies on antigen 
loss, seroconversion rates, and sustained virological control in the immune-tolerant 
population.
However, during the recruitment period of the present study, the results from two NIH 
trials that were conducted with an 8-week, lead-in period of treatment with entecavir 
followed by 40 weeks of treatment with entecavir plus Pegasys® showed minimal 
efficacy for this intervention in both pediatric and adult patients with immune-tolerant 
CHB (see Section 1.2). The available data together suggest that this novel strategy of 
sequential use of a nucleoside analogue followed by the combination of this nucleoside 
analogue with an interferon is not a suitable strategy for the management of pediatric 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
29
immune-tolerant HBV disease.  The data from both studies showed a minimal chance 
for both HBeAg and HBsAg loss and seroconversion through lowering viral load in 
patients.
The adverse event profile of interferons is predictable, well established, and clinically 
manageable.  Adverse events reported in the literature with combination therapy 
(nucleoside analogues and IFN) in children are commonly associated with interferon 
treatment, and include fever, influenza-like symptoms, fatigue, depression, thyroid 
dysfunction, and bone marrow toxicity with no evidence of nucleoside resistance 
detected.  Effects on growth have been reported in a proportion of patients, and this is 
class effect reported with all interferons (see Section 5.1.1.4).
The incorporation of a pegylated interferon into this combination regimen would be 
expected to provide much improved tolerability for pediatric patients (one weekly 
injection compared with three weekly injections), in addition to more reliable exposures, 
and no change in the adverse event profile. 
The primary efficacy endpoint for Study NV25361 is HBsAg loss, which is the “ideal 
endpoint of treatment in patients with CHB with or without seroconversion to anti-HBs” 
(Papatheodoridis et al.2012).
Based on an evaluation of the recently disclosed data from the NIH, as well as data from 
other previous studies, the Sponsor considers that the NIH trial provides a more 
relevant and reliable assessment of the efficacy of Pegasys® in combination with a 
nucleoside analogue in pediatric patients with CHB in the immune-tolerant stage. 
Study NV25361 is expected to show similar efficacy results to those of the two NIH 
studies and the likelihood of patients achieving HBsAg loss is anticipated to be minimal. 
Therefore, the expected benefitrisk profile has changed in the immune-tolerant 
population treated with Pegasys® in combination with nucleoside analogue.  The 
minimal treatment benefit that is now expected should be weighed against the known
risks related to Pegasys® and nucleoside analogue treatment.
The assessment of current guidelines is that there is no urgency for treatment
intervention in patients with immune-tolerant CHB because of the low risk of disease 
progression and the minimal or no liver necroinflammation.  Moreover, patients in this 
phase of the disease can afford to wait for better treatment options with new agents that 
will become available in the near future (Sokal et al. 2013). 
For these reasons the Sponsor has prematurely terminated recruitment into Study 
NV25361. This decision was in accordance with the recommendation from the Data 
Safety Monitoring Board (DSMB) on 22 March 2018 to terminate recruitment on the 
basis of low efficacy and a changed benefitrisk assessment in light to the NIH studies, 
although no specific safety concerns were identified in their scheduled review of the 
study.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
30
2.
OBJECTIVES
Recruitment into the study was terminated prematurely (see Section 1.5); therefore, the 
data collected will be descriptively summarized. No formal statistical hypothesis 
testing or formal treatment group comparisons will be performed.
2.1
EFFICACY OBJECTIVES
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of Pegasys® lamivudine or entecavir for 48 weeks 
compared with an untreated control in children with CHB, as measured by loss of 
HBsAg 24 weeks post-treatment/end of untreated observation
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of Pegasys®lamivudine or entecavir compared with an 
untreated control in children with CHB, as measured by seroconversion to anti-HBs, 
seroconversion to anti-HBe, loss of HBeAg, and HBV DNA levels, at 24 weeks 
post- treatment/end of untreated observation 

To evaluate the efficacy of Pegasys®lamivudine or entecavir in children with CHB, 
as measured by seroconversion to anti-HBs, seroconversion to anti-HBe, loss of 
HBsAg, loss of HBeAg, HBV DNA levels, at 1 year post-treatment
2.2
SAFETY OBJECTIVE
The safety objective for this study is as follows:

To evaluate the safety of the Pegasys®lamivudine or entecavir group compared 
with the untreated control group in children with CHB, by assessment of adverse 
events (including neuropsychiatric assessment), laboratory test results (including 
thyroid function), vital signs and growth, up to 24 weeks post-treatment/end of 
untreated observation and up to 1 year post-treatment
2.3
PHARMACOKINETIC OBJECTIVE
The pharmacokinetic objective for this study is as follows:

To evaluate the pharmacokinetics of Pegasys® in children with CHB treated with 
Pegasys® lamivudine or entecavir following administration of a body surface area 
(BSA)based dosing regimen
2.4
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To explore the relationship between quantitative HBsAg/quantitative HBeAg and 
treatment response in children with CHB

To explore lamivudine or entecavir viral resistance in children with CHB 

To explore the incidence of anti-drug antibodies (ADAs) in children with CHB treated 
with Pegasys®lamivudine or entecavir

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
31
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
Study NV25361 was planned as a randomized, controlled, parallel group, open-label, 
multicenter superiority study in approximately 114 children, aged 3 to less than 18 years 
with immune-tolerant CHB.  
To allow for the varying response rates associated with different genotypes, patients will 
be stratified by HBV genotype A vs. B/C vs. D/other) and randomized 1:1 to one of 
two groups (see Figure 1):

Lamivudine or entecavir alone for 8 weeks followed by Pegasys®lamivudine or 
entecavir for 48 weeks

Untreated control
The screening period will be up to 6 weeks.  All treated patients will be followed for up to 
1 year after the end of treatment.  Primary analysis will be performed at 24 weeks 
post-treatment (follow-up Week 24)/end of untreated observation (Week 80).
Pegasys® will be given subcutaneously once weekly with dosing based on BSA 
categories.  Lamivudine or entecavir will be given as a film-coated tablet or oral solution 
once daily with dosing based on weight. Once the nucleoside analog is chosen, the 
patient must continue on that nucleoside analog throughout the study.
The study will comprise evaluation of efficacy (seroconversion to anti-HBe/anti-HBs, loss 
of HBeAg/HBsAg, and HBV DNA levels), safety (adverse events, laboratory 
abnormalities, dose modifications/discontinuations, vital signs, and growth), and 
pharmacokinetics (measurement of Pegasys® blood levels), as well as exploratory 
measures (quantitative HBsAg/HBeAg, lamivudine or entecavir viral resistance, and 
ADAs).
Patients will be enrolled from approximately 55 sites worldwide. 
A schedule of assessments is provided in Appendix 1.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
32
Figure 1
Schematic of Study Design
NAnucleoside analog (lamivudine or entecavir).
Notes:  The primary endpoint will be measured at 24 weeks after the end of the treatment period 
or the end of the untreated observation period.
3.1.2
Length of Study
The study originally commenced as a single-site investigatorled study 
(i.e., investigator-sponsored trial [IST]) in November 2006.  The length of the 
Roche-sponsored global multicenter study from screening of first patient to end of study 
will be approximately 10 years.  
For treated patients, the approximate study length is 2 years and 2 months (with up to 
6 weeks screening, 8 weeks of lamivudine or entecavir treatment, 48 weeks of 
Pegasys®lamivudine or entecavir treatment [i.e., 56 weeks of treatment], 24 weeks of 
initial follow-up, 28 weeks of additional follow-up [i.e., 52 weeks total or 1 year of
follow-up]). 
For untreated patients, the approximate study length is 1.5 years (with up to 6 weeks 
screening and 80 weeks untreated observation).
3.1.3
Data Safety Monitoring Board
An external DSMB will periodically review accrued safety data approximately every 
6 months on an advisory basis.  A separate DSMB Charter will be prepared that will 
define the DSMB membership and role, meeting outlines and schedule, communication 
plan, and data outputs to be provided to the DSMB.
3.1.4
Internal Monitoring Committee
To enhance safety monitoring in this study, an Internal Monitoring Committee (IMC) will 
review safety data on a routine basis (IMC Agreement).
The IMC will be an internal committee comprising study team members:  Biostatistician, 
Drug Safety Scientist, Statistical Programming Analyst, and Clinical Scientist.  The IMC 
will review the accumulating safety data for in this study population according to a 
predefined schedule.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
33
A separate IMC Agreement will be prepared, which defines the roles and responsibilities 
of the IMC, including its membership, scope, the timing of meetings, and communication 
plan.
3.1.5
Patients Previously Randomized to Investigator-Sponsored 
Trials including Pegasys® Monotherapy Group
The study originally commenced as a single-site IST with three arms (i.e., Pegasys®
monotherapy, Pegasys® lamivudine, and untreated control).  Safety data will be 
collected from all patients previously randomized to the IST; all other data will be 
collected only from those patients who subsequently consent to allow Roche to analyze 
those data.  In addition, any patients who have not yet completed the study will be asked 
to consent to continue in the Roche-sponsored study.  
Some differences exist between the IST Schedule of Assessments (Protocol NV25361, 
Version 5) and the Roche-sponsored study Schedule of Assessments, including certain 
assessments required as part of the IST study that were not required as part of the 
Roche-sponsored study.  However, all data collected on patients as part of the IST study,
which are also part of assessments defined in the Roche-sponsored study, will be 
recorded in the Roche electronic Case Report Form (eCRF).  Certain assessments 
included in the Roche-sponsored study may not have been undertaken as part of the 
IST (e.g., PK and ADA), hence data on these assessments will not be available for 
previous IST patients and will not be collected from previous IST patients continuing in 
the Roche-sponsored study.  
Patients in the Pegasys®lamivudine arm will follow the current protocol Schedule of 
Assessments for their remaining visits, with the caveats mentioned above.  All patients in 
the untreated have now completed the study, per the Roche-sponsored study design.
Any patient who was randomized to the Pegasys® monotherapy treatment arm under the 
IST and continuing in the Roche-sponsored study (all of whom have now completed 
treatment) will follow the Pegasys® monotherapy follow-up Schedule of Assessments in 
Appendix 1 for their remaining visits.  Where possible, the Pegasys® monotherapy 
Schedule of Assessments in Appendix 1, is consistent with the original IST Schedule of 
Assessments (Protocol NV25361, Version 5), while also incorporating differences 
required by the Roche-sponsored study. Details on how these data will be reported will 
be described in the data analysis plan (DAP).  
All laboratory data collected for patients to date as part of the IST have been collected 
by a local laboratory; local laboratory ranges will be provided to Roche.
3.2
END OF STUDY
The end of the study is defined as the date when the last patient, last visit (LPLV) for the 
final analysis occurs.  

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
34
LPLV for primary analysis was planned at 24 weeks after end of treatment/end of 
untreated observation is expected to occur approximately 1 year and 8 months after last 
patient is enrolled.
LPLV for final analysis at 1 year after the end of treatment is expected to occur 
approximately 2 years and 2 months after the last patient is enrolled.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Test Product Dosage
The NEPTUNE study (Study WV19432) was a Phase IV trial that examined two doses of 
Pegasys® (90 and 180 g/wk) and two durations (24 and 48 weeks) in adults with 
HBeAg-positive chronic HBV infection.  This trial incorporated a non-inferiority study 
design and demonstrated that the highest response rate was achieved in the 
180-g/48-week treatment group, confirming the registered dose and duration of 
180-g and 48-week treatment as the most efficacious regimen.  For the secondary 
endpoints tested, the overall trends were consistent with the primary endpoint, with the 
highest response rates being achieved in the 180-g/48-week treatment group.  The 
results confirmed that the overall safety profile of Pegasys® in patients with 
HBeAg-positive CHB was consistent with the currently approved label, with no new 
signals identified.  The dose confirmed by the NEPTUNE study has been modified for 
pediatric use in order to achieve similar exposures to the adult dosing of 180-g (see 
Section 3.3.1.1).
The present study aims to evaluate the efficacy and safety of treating children with 
immune-tolerant CHB disease in an open-label, randomized study of 
Pegasys®lamivudine or entecavir compared with untreated control in children with 
HBeAg-positive CHB.  Therapy duration in the treatment arm is based on those used in 
the 2 pilot studies where this particular treatment strategy was first tested and benefit 
shown (D’Antiga et al. 2006; Poddar et al. 2013).
3.3.1.1
Pediatric Dosing
This study will use the dose and duration of PEG-IFN established in the NEPTUNE 
study but modified for pediatric use.  Study NR16141 (Schwarz et al. 2006) 
demonstrated that adequate levels of PEG-IFN were achieved in a PK/PD study 
involving 14 children between 2 and 8 years of age infected with CHC when a PEG-IFN 
dose of 180 g/1.73 m2BSA was used for 48 weeks of treatment.  When pediatric PK 
data were compared with PK data in adults, it was revealed that mean predicted 
exposure (area under the curve [AUC0t]) to PEG-IFN in children was 25%70% higher 
than that observed in adults receiving a weekly dose of 180-g of PEG-IFN 
(5,667 ng h/mL vs. a range of mean values from 3,334 to 4,348 ng h/mL).  There was 
a higher incidence of neutropenia in children compared with adults, which may reflect 
the higher exposure in children.  However, predicted exposures in children were still 
within the range of individual adult exposures reported (maximum exposure of 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
35
11,125 ng h/mL), decreases in neutrophil counts reversed after the end of treatment, no 
patients had neutrophil counts less than 0.25109 cells/L, and neutropenia events were 
not associated with serious infections or premature withdrawal and were clinically 
manageable with appropriate dose modification.  In addition, dose modifications 
appeared to have no impact on sustained virological response (SVR), indicating that 
dosing may be slightly reduced to improve exposure-related adverse events while 
maintaining viral response.
The dosing regimen for this study is based on formula dosing of 180 g/1.73 m2BSA 
used in the pivotal Phase III HCV pediatric study (Study NV17424) and in the PK/PD 
Study NR16141 (Schwarz et al. 2006).  BSA categories, based on the formula 
180 g/1.73 m2BSA, have been provided to facilitate the calculation of the dose by 
clinicians and to minimize the risk of dosing errors (see Table 1).
This approach has been accepted by the EMA for Pegasys® pediatric dosing in HCV 
disease (EMEA-000298-PIP01-08).  This also aligns with the approved Pegasys® 
pediatric prescribing information in the United States, where the dose for children 
between the ages of 5 and 18 years is 180 gBSA/1.73 m2.  Utilizing the same dosing 
regimen and the same BSA categories will help align pediatric dose recommendations 
for Pegasys® across both HCV and HBV indications.
Since it has been established that there are no differences in the dosing regimen 
between hepatitis C versus and hepatitis B in adults, no differences are anticipated in 
the pediatric doses for the two indications.  Based on this assumption, it is reasonable to 
use the same bridging approach employed in treatment of HCV from adult to pediatric 
doses for hepatitis B.  The doses resulting from the BSA categories have deviations from 
20% to 19% from the formula dose.  This difference in doses relative to the formula 
dose is similar to the deviation in several adult HCV studies (17% to 24%).  The range 
of deviation in adults is computed from the variance resulting from a fixed dose given to 
adult patients of various sizes (BSAs) participating in six HCV clinical trials with 
Pegasys®.  It is calculated by comparing the ratio of the 180 g dose per adult BSA of 
the 5th and 95th percentile adult BSA (n1940) to the reference (180/median adult 
BSA). 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
36
Table 1
Pegasys® Pediatric Dosing Regimen
Dose
(g)
BSA Range
(m2)
45
0.51–0.53
65
0.54–0.74
90
0.75–1.08
135
1.09–1.51
180
1.51
The pediatric lamivudine dose of 3-mg/kg/day used in HBV was established in 212 year 
old children when this dose showed maximal antiviral effects in a dose-ranging study 
evaluating the pharmacokinetics, safety and efficacy of lamivudine monotherapy 
(Sokal et al. 2000).  In this study, adolescents from 12 years of age received 100 -mg 
daily doses.  Therefore, the recommended pediatric dosing is 3 mg/kg (maximum of 
100 mg daily).
The recommended once-daily dose of entecavir in pediatric patients weighing at least 10 
kg is presented in Table 2. Patients may be dosed with or without food. The oral solution 
should be used for patients with body weight less than 32.6 kg. Pediatric patients with 
body weight of at least 32.6 kg should be administered 10 mL (0.5 mg) of the oral 
solution or one 0.5 mg tablet once daily (BARACLUDE® SmPC).

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
37
Table 2
Entecavir Dosing for Nucleoside Naïve Pediatric Patients Aged 2 
to < 18 Years
Body Weight a
Recommended Once Daily Dose of Oral 
Solution b
10.0 – 14.1 kg
4.0 mL
14.2 – 15.8 kg
4.5 mL
15.9 – 17.4 kg
5.0 mL
17.5 – 19.1 kg
5.5 mL
19.2 – 20.8 kg
6.0 mL
20.9 – 22.5 kg
6.5 mL
22.6 – 24.1 kg
7.0 mL
24.2 – 25.8 kg
7.5 mL
25.9 – 27.5 kg
8.0 mL
27.6 – 29.1 kg
8.5 mL
29.2 – 30.8 kg
9.0 mL
30.9 – 32.5 kg
9.5 mL
At least 32.6 kg
10 mL 
a Body weight should be rounded to the nearest 0.1 kg
b Children with body weight at least 32.6 kg should receive 10 mL (0.5 
mg) or oral solution or one 0.5 mg tablet once daily
3.3.2
Rationale for Patient Population
Hepatitis B is a major public health problem, with infected children being at risk of 
serious complications in later life as well as posing a risk of spread of infection to others.  
Most children with chronic HBV are in the immune-tolerant phase of infection and have 
high viral loads as well as no or minimal signs of liver disease. 
Historically, the consensus among clinicians has been to avoid treating children infected 
with certain baseline characteristics (e.g., patients with normal transaminase levels, high 
HBV DNA, or mild changes on liver biopsy) on the grounds that the published results in 
these children did not justify the cost and the particularly demanding nature of 
non-pegylated IFN treatment (i.e., three injections per week) (Jara and Bortolotti 1999).  
However, despite the low reported rates of success historically using IFN and/or 
lamivudine treatment in immune-tolerant HBV patients, two small studies 
(D’Antiga et al. 2006; Poddar et al. 2013) have shown impressive HBeAg and HBsAg 
seroconversion and sustained virological responses, both compared with controls and 
compared historical spontaneous seroconversion rates, when sequential and then 
combination therapy using non-pegylated interferon and lamivudine were evaluated.  
These data suggest this novel strategy is a promising alternative strategy for 
management of pediatric immune-tolerant HBV disease, since an increased chance of 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
38
both HBeAg and HBsAg seroconversion through lowering viral load in a proportion of 
patients has been reported in both studies.  
Any treatment that can speed up the HBeAg/HBsAg loss and seroconversion rate would 
avoid the long-term complications of chronic infection such as cirrhosis, cancer, and 
have a major impact on reducing the spread of infection of hepatitis B in the population.  
Successful treatment in the immune-tolerant population would bring added benefits of
reducing the stigma of carrying an infectious disease, and would avoid the other 
potential social sequelae of impaired career choices, and an impact on personal 
relationships/marriages.
3.3.3
Rationale for Untreated Control Group
This study will use an untreated control group in order to assess the benefit-risk balance 
of anti-HBV treatment in this immune-tolerant population, across a treated group 
(Pegasys® and lamivudine or entecavir sequential combination) versus an untreated 
observation control group.  
An untreated control will be used, because the use of a placebo control is not considered 
appropriate for several reasons.  First, the use of placebo injections would not effectively 
blind treatment, because the known adverse effects of IFN therapy would not occur, 
particularly influenza-like illness.  It would therefore be likely that patients/parents would 
become aware the patient is not receiving IFN resulting in a potential risk of
noncompliance.  Secondly, it would be unethical to administer weekly placebo injections 
for 48 weeks, because there is an associated risk of injection-site infections without any 
associated benefit.  A further benefit of using an untreated control arm is that the study 
burden for the untreated patients is reduced because their visit schedule is less frequent 
compared with that of the treated patients, which they would have to match in a 
placebo-controlled study.  Importantly, an openlabel study design does not introduce 
significant bias in the primary analyses, because the primary efficacy endpoints are 
objective and unaffected by presence of blinding.  The risk of bias being introduced is 
further minimized with current procedures, including use of a central randomization, use 
of a central laboratory and standardized assays, and the choice of intent-to-treat (ITT) 
population for the primary analysis.
Because treatment up until now has been reserved for those with immune-active HBV 
disease, there is no standard-of-care therapy for the immune-tolerant HBV population 
(Murray et al. 2008; Kurbegov and Sokol 2009; Jonas et al. 2010).  Therefore, any 
evaluation of treatment strategies requires a comparison with an untreated control in 
order to clearly assess the benefit risk of the treatment strategy.  Use of an untreated 
control group has advantages over use of a historical control since randomization can 
reduce differences in baseline factors, and provide a robust assessment of the benefit 
risk of the treatment, thereby increasing the chance that the research question will be 
satisfactorily answered.  The untreated control group will not be at any disadvantage as 
treatment of pediatric patients is not normally required in this group.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
39
The analysis planned a superiority assessment of loss of HBsAg of sequential 
combination Pegasys®lamivudine or entecavir treatment against the control group.  
The study design allowed a comparison of various serological and virological markers 
across the groups during treatment and at the primary endpoint.
3.4
OUTCOME MEASURES
3.4.1
Efficacy Outcome Measures
The primary efficacy outcome measure for this study at 24 weeks post- treatment/end of 
untreated observation is as follows:

Loss of HBsAg 
The secondary efficacy outcome measures for this study at 24 weeks 
posttreatment/end of untreated observation are as follows:

Loss of HBeAg

Seroconversion to anti-HBs (loss of HBsAg and presence of anti-HBs) 

Seroconversion to anti-HBe (loss of HBeAg and presence of anti-HBe)

HBV DNA 20,000 IU/mL, <2000 IU/mL, undetectable and change from baseline 
(by polymerase chain reaction [PCR] or hybridization)

Combined endpoints:  HBeAg seroconversion and HBV DNA 20,000 IU/mL

Combined endpoints:  HBeAg seroconversion and HBV DNA 2000 IU/mL
The secondary efficacy outcome measures for this study at 1 year post-treatment are as 
follows:

Loss of HBeAg

Loss of HBsAg

Seroconversion to anti-HBs (loss of HBsAg and presence of anti-HBs)

Seroconversion to anti-HBe (loss of HBeAg and presence of anti-HBe)

HBV DNA 20,000 IU/mL< 2000 IU/mL, undetectable and change from baseline (by 
PCR or hybridization)

Combined endpoints:  HBeAg seroconversion and HBV DNA 20,000 IU/mL

Combined endpoints:  HBeAg seroconversion and HBV DNA 2000 IU/mL
3.4.2
Safety Outcome Measures
The safety outcome measures for this study at 24 weeks posttreatment/end of 
untreated observation are as follows:

Incidence, nature, and severity of serious and non-serious adverse events (including 
neuropsychiatric assessment)

Reasons for the discontinuation of any study medication

Dose modifications for laboratory abnormalities and clinical adverse events

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
40

Changes in vital signs and laboratory tests from screening/baseline, including 
thyroid function

Effect on growth (height, weight and sexual maturity status)
The safety outcome measures for this study at 1 year posttreatment are as follows:

Incidence, nature, and severity of persisting adverse events, new-onset related 
serious adverse events/non-serious adverse events of special interest

Changes in thyroid function from screening/baseline

Effect on growth (height, weight and sexual maturity status)
3.4.3
Pharmacokinetic Outcome Measures
Pharmacokinetic samples will be collected from all patients treated with 
Pegasys®lamivudine or entecavir for measurement of Pegasys®.
3.4.4
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Quantitative HBsAg and quantitative HBeAg 

Presence of lamivudine or entecavir viral resistance

Incidence of ADAs from all patients treated with Pegasys®lamivudine or 
Pegasys®+entecavir
4.
MATERIALS AND METHODS
4.1
PATIENTS
Patients in this study will be children 3 to less than 18 years of age with immune-tolerant 
CHB of any genotype, with positive HBsAg and HBeAg, and detectable HBV DNA 
(20,000 IU/mL).  Patients who have had any previous anti-HBV treatment, or who are 
co-infected with hepatitis A virus (HAV), HCV, hepatitis D virus (HDV), HIV, or who have 
decompensated liver disease will be excluded.
During study conduct, the Sponsor may postpone or stop the enrollment of patients in 
certain age ranges in order to ensure that a broad age distribution and representative 
dosing categories be adequately studied.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Male and female patients age 3 to less than 18 years of age at baseline 
(12 to18 years of age at baseline in Russia and India)

Positive for HBsAg and HBeAg for more than 6 months prior to baseline 

Detectable HBV-DNA (20,000 IU/mL, as measured by PCR or hybridization) on at 
least 2 occasions at least one month apart with the latest determination obtained 
42 days prior to baseline.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
41

Compensated liver disease (Child-Pugh Class A clinical classification 
[see Appendix 2])

Either 
Liver biopsy performed within 2 years prior to baseline showing no or minimal 
fibrosis (Liver Biopsy Scores [see Appendix 3]) and stable normal ALT levels 
(upper limit of normal [ULN]) during the 6 months leading up to baseline 
(including two separate occasions at least 1 month apart over the 6 months prior 
to baseline). Screening ALT levels must be normal (ULN). 
OR
Stable normal ALT levels (ULN), during the 1-year leading up to baseline 
(including three separate occasions at least 1 month apart over the 1 year prior to 
baseline) and no signs of HCC, advanced fibrosis/cirrhosis, or splenomegaly on 
liver abdominal ultrasound at screening. Screening ALT levels must be normal 
(ULN).

Signed informed consent from parent/legal guardian and willingness of parent/legal 
guardian to abide by the requirements of the study, and signed informed consent or 
assent from child where appropriate.  Patients 18 years of age at baseline who are 
legally considered to be adults according to their national legislation must consent in 
their own right if required.  
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Patients who have received investigational drugs or licensed treatments with 
anti-HBV activity (e.g., IFNs, lamivudine, tenofovir, emtricitabine, adefovir, entecavir, 
telbivudine, systemic acyclovir, systemic famciclovir) (Exception: Patients who have 
had a limited [7-day] course of acyclovir for herpetic lesions more than 1 month 
before the study baseline visit are not excluded)  

Patients who have participated in any other clinical trial or who have received any 
investigational drug within 6 months prior to baseline

Known hypersensitivity to IFN, Pegasys®, lamivudine, or entecavir

BSA 0.51 m2 (based on Mosteller formula; see Appendix 4)

Positive test results at screening for HAV immunoglobulin M (IgM) antibody (Ab), 
anti-HCV Ab, anti-HDV Ab, or anti-HIV Ab

History or other evidence of bleeding from esophageal varices

Decompensated liver disease (e.g., Child-Pugh Class B or C clinical classification 
[see Appendix 2] or clinical evidence such as ascites or varices)

Advanced fibrosis or cirrhosis (assessed by liver biopsy or ultrasound)

Suspicion of HCC on liver abdominal ultrasound (all patients to have liver abdominal 
ultrasound within 6 months prior to baseline)

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
42

History or other evidence of a medical condition associated with chronic liver 
disease other than CHB, including metabolic liver diseases such as 
hemochromatosis, Wilson’s disease, or -1 anti-trypsin deficiency

Screening alfa-fetoprotein (AFP) ULN

Screening neutrophil count 1.5109 cells/L, platelet count 90109 cells/L, or 
hemoglobin lower limit of normal (LLN)

Screening albumin of LLN or direct and indirect bilirubin of ULN (Exception: 
patients with non-hepatitis related factors which may elevate bilirubin such as 
Gilbert’s disease where screening indirect bilirubin must be 3.0 mg/dL.)

Evidence of renal impairment

History of immunologically mediated disease to include, but not limited to 
autoimmune hepatitis, inflammatory bowel disease, idiopathic thrombocytopenic 
purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe 
psoriasis, or clinical evidence of rheumatoid arthritis

Major depression or history of psychiatric disorder, such as major psychoses, 
suicidal ideation, and/or suicide attempt, for which clinical trial participation would be 
inappropriate

Evidence or history of chronic pulmonary or cardiac disease associated with 
clinically significant functional limitation

History of thyroid disease that was poorly controlled on prescribed medications, or 
clinically relevant abnormal thyroid function tests (thyroid-stimulating hormone [TSH], 
free triiodothyronine [FT3], free thyroxin [FT4], thyroid peroxidase [TPO] antibodies, 
and TBG) at screening 

Poorly controlled diabetes

History of solid organ or bone marrow transplantation

Evidence of an active or suspected cancer or a history of malignancy in which the 
risk of recurrence was/is 20% within 2 years

History of having received any systemic anti-neoplastic (including radiation) or 
immunomodulatory treatment (including systemic corticosteroids) 6 months prior to 
the study baseline visit or the expectation that such treatment will be needed at any 
time during the study (Exception: topical corticosteroids, corticosteroids prescribed 
as physiological replacement therapies, or short courses [7 days] of systemic 
corticosteroids)

Coagulopathy (screening international normalized ratio 1.5), hemoglobinopathy, 
hemophilia, or history of severe illness or other blood disorders that would make 
patient unsuitable for the study

History of seizure disorder requiring treatment with anticonvulsant medication 
(excluding febrile seizures)

History or other evidence of severe retinopathy

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
43

History or other evidence of severe illness or any other conditions that would make 
the patient, in the opinion of the investigator, unsuitable for the study

Active substance abuse within 6 months prior to screening

Sexually active females of childbearing potential and sexually active males who are 
not willing to utilize effective contraceptive measures (with abstinence being 
considered a satisfactory method), during treatment and for 90 days following the 
end of treatment   

Females who are pregnant or breastfeeding.  (Females of childbearing potential 
who have a positive urine or serum pregnancy test result at screening or at the 
baseline visit are excluded).
4.2
METHOD OF TREATMENT ASSIGNMENT 
This is an open-label study.  Assignment to study arms will be performed by use of an 
interactive voice or web-based response system (IxRS).  Patients will be stratified by 
HBV genotype A vs. B/C vs. D/other and randomized in a 1:1 ratio.  
The choice of nucleoside analog (lamivudine or entecavir) to be used in combination 
with Pegasys® (if applicable) will be made by the investigator and prior to the 
assignment to study arms by IxRS. Once the nucleoside analog is chosen, the patient 
must continue on that nucleoside analog throughout the study (8-week lead-in phase 
and the subsequent 48-week Pegasys®-combination phase).
Although this study is open-label, dummy randomization groups will be assigned in a 
ratio 2:1 for the development of statistical outputs to limit availability of aggregated data 
summaries during study conduct. 
As of 28 March 2018, recruitment into the study was terminated and no additional 
patients have been randomized.
4.3
STUDY TREATMENT 
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Pegasys®
Formulation:  180 μg/mL; 1 mL solution in 2-mL vials
Packaging:  Two vials of Pegasys® will be packed per box
Storage:  Refrigerate at 2C8C (36F46F).
For further details, see the local prescribing information for Pegasys®.
4.3.1.2
Lamivudine
Tablets
Formulation:  100 mg tablets 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
44
Packaging:  Each kit will contain one blister pack with 14 tablets.
Storage:  Do not store above 30C (86F).
Oral Solution
Formulation:  10 mg/mL oral solution 
Packaging:  Each kit will contain one bottle with 240 mL oral solution, one syringe 
adapter, and one 10 mL oral dosing syringe.
Storage:  Do not store above 25C (77F). 
For further details, see the local prescribing information for lamivudine.
4.3.1.3
Entecavir
Tablets
Formulation:  0.5 mg film-coated tablets 
Packaging:  Each kit will contain blistered pack with 10 tablets.
Storage:  Do not store above 30C (86F).
Oral Solution
Formulation:  0.05 mg/mL oral solution 
Packaging:  Each kit will contain one bottle with 210 mL oral solution, with a measuring 
spoon.
Storage:  Do not store above 30C (86F). Keep the bottle in the outer carton in order to 
protect from light.
For further details, see the local prescribing information for entecavir.
4.3.2
Dosage, Administration, and Compliance
Treated patients will receive lamivudine as a film-coated tablet or oral solution once daily 
at a dose of 3 mg/kg (maximum daily dose 100 mg) or entecavir as a film-coated tablet 
or oral solution at a dose of 0.015 mg/kg once daily (maximum dose of 0.5 mg), given 
alone for 8 weeks then in combination with Pegasys® for 48 weeks.  A single nucleoside 
analogue (lamivudine or entecavir) must be administered throughout the study treatment 
period and must not be used interchangeably. The first dose of lamivudine or entecavir 
should be taken at the study site during the baseline visit.  Pegasys® will be given
subcutaneously once weekly with dosing based on BSA categories.  Pegasys® injection 
instructions will be provided for the parent/legal guardian and patients, if applicable.  A 
container will also be provided for disposal of all used needles.  The first dose of 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
45
Pegasys® should be taken at the study site during the Week 8 visit (after approximately 
8 weeks of lamivudine or entecavir monotherapy).  
Prior to starting treatment and at the time points indicated in the Schedule of 
Assessments (see Appendix 1), a system will be in place to confirm the patient’s 
intended dose of Pegasys® based on the patient’s weight and height provided by the 
investigator.  Investigators may reassess the patient’s dose at other interim time points if 
they are concerned that the BSA and therefore Pegasys® dose may have changed (see 
Appendix 4).
As for Pegasys®, investigators may reassess the patient’s dose of lamivudine or 
entecavir at other interim time points if they are concerned that weight and therefore 
lamivudine or entecavir dose may have changed (see Appendix 4).
Each patient will be provided with a medication diary.  It is mandatory that each weekly 
Pegasys® injection is recorded in the diary (date and volume/dose) and initialed by the 
person administering the treatment.  Any modified/missed doses of Pegasys®, 
lamivudine, or entecavir must be recorded in the diary, including the reason.  Patients 
must bring completed drug diaries to each visit during the treatment period and it will be 
reviewed by the investigator.  Each modified/missed dose of Pegasys®, lamivudine or 
entecavir must be entered onto the eCRF.
All trial medication should be returned at the next scheduled visit (see Appendix 1) and 
reconciled against the patient’s diary. The quantities returned should be documented in 
the drug accountability forms. Please note that any unused lamivudine or entecavir 
blister pack or bottles can be redispensed if unopened and will not expire. Please note 
that once a lamivudine bottle is opened it should not be used after 30 days. A new bottle 
should be opened and used.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 4.6.1.2 and Appendix 4.
4.3.3
Study Treatment Accountability
All study treatments required for completion of this study (Pegasys® and lamivudine or 
entecavir) will be provided by the Sponsor.  The investigational site will acknowledge 
receipt of study treatments, using the IxRS to confirm the shipment condition and 
content.  Any damaged shipments will be replaced. 
Study treatments will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to the Sponsor with the 
appropriate documentation.  The site's method of study treatment destruction must be 
agreed upon by the Sponsor.  The site must obtain written authorization from the 
Sponsor before any study treatment is destroyed, and study treatment destruction must 
be documented on the appropriate form.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
46
Accurate records of all study treatments received at, dispensed from, returned to, and 
disposed of by the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Pegasys®
The Sponsor does not have any plans to provide the Roche IMP Pegasys® or any other 
study treatments or interventions to patients who have completed the study.  
4.3.4.1
Patients who Become Immune Active
Patients treated in the active arm of the study and untreated control patients who 
complete the study  and subsequently meet the criteria for immune-active disease 
(sustained ALT elevation for at least 6 months), should be managed per investigators 
judgment and standard of care.  
4.4
CONCOMITANT THERAPY
4.4.1
Permitted Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, nutritional supplements) used by a patient up to 
follow-up Week 24/end of untreated observation.  All concomitant medications should be 
reported to the investigator and recorded on the Concomitant Medications eCRF, 
including any significant concomitant medications taken within 2 years prior to baseline.  
During follow-up of treated patients (i.e., after follow-up Week 24), only concomitant 
medications for CHB need to be recorded, which includes licensed or investigational 
immunomodulatory or antiviral therapy, and herbal, botanical, and other agents (e.g., 
ursodeoxycholic acid) that are traditionally used for CHB.
Topical corticosteroids, or corticosteroids prescribed as physiological replacement 
therapies are permitted.
Short courses (7 days) of systemic corticosteroids are permitted.
Short courses (1 month) of topically applied acyclovir are permitted.
Herbal, botanical, and other agents (e.g., ursodeoxycholic acid) that are traditionally 
used for chronic HBV disease are discouraged.
Patients who use oral contraceptives should continue their use.
4.4.2
Prohibited Therapy
Use of the following therapies is prohibited:

Any investigational drugs as a result of participation in another clinical study during 
the study including the follow-up period.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
47

Any other investigational drugs (e.g., compassionate use), immunomodulatory 
treatments (e.g., interferons, systemic corticosteroids), growth factors 
(e.g., erythropoietin, granulocyte colony-stimulating factor [G-CSF]) or 
antiviral treatments with anti HBV activity (e.g., tenofovir, emtricitabine, adefovir, 
telbivudine, systemic acyclovir, systemic famciclovir) other than those specifically 
allowed by this protocol prior to follow-up Week 24/end of untreated observation.  
(Exception: patients with significant deterioration in hepatic function [e.g., 
decompensation] who permanently discontinue study treatment and need to 
consider alternative therapies).
4.5
STUDY ASSESSMENTS 
4.5.1
Description of Study Assessments
Patients will be assessed according to the Schedule of Assessments (see Appendix 1).  
Baseline assessments are those assessments taken on the first day of administration of 
study drug and should be performed prior to administration of study drug, unless 
otherwise noted in the Schedule of Assessments.
Demographic data to be collected will include age, sex, and race/ethnicity (as reported 
by parent/legal guardian).  The racial and ethnic differences in drug responses have now 
been well described for a range of drugs and appear to be based on the varying 
distributions of polymorphisms in drug receptors or drug-metabolizing enzymes among 
different racial and ethnic groups.
In order to help estimate the patients’ growth potential, height will be collected from 
consenting biological parents.  This information may be entered directly onto the eCRF,
and the eCRF may be considered as the source document. Sexual maturity status will
be monitored by collecting the date of menarche for female patients and assessing
Tanner Staging for both male and female patients (see Appendix 6).  
If feasible and upon agreement with the investigator, certain visits, as indicated in the 
Schedule of Assessments (see Appendix 1), may be conducted by appropriately 
qualified personnel (e.g., mobile nurse) in the patient’s home, if this is more convenient 
for the patient.  The investigator will still remain responsible for all trial-related medical 
decisions.  If weight measurement is required at the visit, then the same brand of scales 
must be used by both the site and the mobile nurse.  If height measurement is required 
at the visit, then a stadiometer must still be used.  
The total volume of blood taken throughout the whole study is up to approximately 
340 mL (excluding Roche Clinical Repository [RCR] samples) depending on the age of 
the child and the study group.  Monovette tubes will be used in younger children to 
reduce blood draws, and less blood will be taken from the untreated control group since 
they have fewer study visits.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
48
4.5.1.1
Safety Assessments
Assessments of safety are summarized in Table 3, including those required for study 
entry.  
Any abnormality identified during screening or baseline assessments should be recorded 
on the General Medical History and Baseline Conditions eCRF.  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant 
abnormalities from baseline should be recorded as adverse events on the adverse event 
eCRF (see Sections 5.2.1 and 5.3.5.8).  

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
49
Table 3
Safety Assessments
Assessment
Parameter
Medical history
Clinically significant diseases within the previous 2 years and HBV 
history
Concomitant 
medication
All significant medications (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, nutritional supplements), including 
any significant concomitant medications taken within 2 years prior to 
baseline.  During follow-up of treated patients, only concomitant 
medications for CHB need to be recorded (see Section 4.4).
Surgeries/procedures
All surgeries/procedures, including any significant surgeries/procedures 
prior to baseline; during follow-up of treated patients, only 
surgeries/procedures associated with reportable adverse events (see 
Section 5.3.1).
Complete physical 
examination
Should include an evaluation of the head, eye, ear, nose, and throat, and 
the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  
Symptom-directed 
physical examination
Signs, symptoms, and concerns reported by the parent/legal 
guardian/patient should be considered.
Liver biopsy
If applicable (Section 4.1.1).  
Liver abdominal 
ultrasound a
Must show no signs of HCC; for patients without study entry liver biopsy,
must also show no signs of cirrhosis or splenomegaly
Vital signs
Blood pressure, heart rate, temperature
Electrocardiogram a
Section 4.5.1.3.  
Growth
Weight (kg) and height (cm), using the same instruments in the same 
individual b.  A stadiometer with mean of three readings should be used 
for height measurement.  Collect the date of menarche for female 
patients and assess Tanner Staging for both male and female patients.
Ophthalmological 
examination a
Completed by an ophthalmologist; includes fundoscopic examination with 
dilation, visual acuity assessment, visual field testing, and color visual 
testing.  Eye examination by a pediatric ophthalmologist is 
recommended.  Visual field testing by confrontation is recommended in 
younger patients.  Any patient who develops ocular symptoms should 
receive a prompt eye examination by an ophthalmologist and additional 
examinations as necessary.  
Neuropsychiatric 
questionnaire
Section 4.5.1.2
Adverse events
Section 5.3.1
CHBchronic hepatitis B; HBVhepatitis B virus; HCChepatocellular carcinoma 
a Within 6 months prior to baseline; repeat at screening only if any change in the medical 
condition.  Assessment does not need to be repeated at re-screening if performed within 
6 months prior to baseline, unless dictated by a change in the patient’s medical condition or 
the assessment accounted for the original screen failure.
b Exception to using the same instruments in the same individuals is if patients are measured at 
home by a mobile nurse (see Section 4.5.1).

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
50
4.5.1.2
Neuropsychiatric Questionnaire
As part of the overall assessment of patients and their mental state, and collation of 
neurological and psychiatric adverse events, the Children’s Depression Inventory (CDI) 
(Kovacs 2010) will be used in patients 7 years of age to evaluate the presence and 
severity of specific depressive symptoms.  It is stressed that use of the CDI should not 
replace the overall assessment of patient’s mental state that should be undertaken 
before and during treatment, and investigators should consider these assessments in 
the context of previous medical and psychiatric history.  The CDI will be performed at 
screening and baseline for all patients and then post-baseline for treated patients as per 
the schedules in Appendix 1.  CDI should be performed prior to the completion of other 
study assessments.  If a patient is 7 years old, but turns 7 years old during the study 
and within the scheduled CDI administration period, the CDI should be administered 
from that point onward.  For 
-year-old patients who turn 
 years old during the study, 
the CDI should continue to be administered.
Parents or patients may not be comfortable with certain sentences or question the 
sensitive or personal nature of some sentences; therefore, it should be clearly explained 
that the CDI is just a tool that all patients in the study are required to complete as part of 
the assessment of mood disorder problems.  
The CDI Item Form will be provided in the patient’s own language, if available.  All 
patients should complete the form themselves.  For younger children or those with 
reading difficulties or who are unable to read, the instructions and items should be read 
aloud to the child, and then the child will select an answer by themselves.  If the CDI 
Item Form is not available in the patient’s own language, a translator may read the 
instructions and items to the child and then the child will select an answer by themselves.  
The mode of administration (self-administered or translator/caregiver administered) 
should be clearly documented in the clinical records.  If patients feel none of the 
sentences for an item applies to them, then they should be instructed to choose as best 
they can.  Patients should be debriefed after the CDI has been completed to address 
any questions or concerns.
Once the patient has finished the item form, investigational site staff will then complete 
the CDI Scoring Page and transfer the five subscale scores to the eCRF.  Site staff will 
then add up the five subscale scores to obtain the total CDI score.  If 10% of items 
(i.e., more than 3 items) are unanswered, the assessment should be considered 
invalid/incomplete, and the data should not be entered onto the eCRF.  
Follow-up of Patients with Symptoms of Major Depression or Potential 
Children’s Depression Inventory Indicators
Whether the CDI is administered or not, investigators should still assess the mental state 
of their patients per their standard clinical practice.  If any patient exhibits symptoms of 
major depression, and/or if CDI total score is 19 and/or the patient fails to complete all 
items on the CDI, then the investigator will perform a more thorough evaluation to 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
51
determine if major depression has developed.  If major depression is confirmed by the 
investigator, then the patient will be referred to a mental health professional (e.g., 
counselor).  If this is at screening or baseline, then the patient will be excluded from the 
study.  While in the study, the investigator will determine whether adverse event criteria 
have been met and report as an adverse event on the eCRF, if appropriate (see 
Section 5.2.1).  If while in the study the patient is found to have severe depression 
Pegasys® must be permanently discontinued and the patient referred for psychiatric 
intervention (Section 5.3.5.12).
4.5.1.3
Electrocardiograms
Single 12-lead ECGs will be collected locally and assessed at screening.  For safety 
monitoring purposes, ECG abnormalities will be documented on the eCRF General 
Medical History and Baseline Conditions.  The investigator or designee must review, 
sign, and date all ECG tracings.  Paper copies will be kept as part of the patient’s 
permanent study file at the site.  Digital recordings will be stored at site.
4.5.1.4
Laboratory Assessments
The list of laboratory tests is provided in Table 4.  Except where specified, samples will 
be sent to one or more central laboratories or to the Sponsor for analysis.
At certain visits outlined in the Schedule of Assessments in Appendix 1, and at any 
unscheduled visit that is required for safety reasons, hematology and biochemistry may 
be undertaken at the patient’s primary physician clinic/local hospital/home, if this is 
feasible and more convenient for the patient, and upon agreement with the investigator.  
The primary physician/local hospital laboratory must be accredited and local laboratory 
ranges must be provided.  If the visit occurs at the primary physician clinic/local hospital, 
adverse events will then be recorded via a telephone call from investigator site to 
patient’s parent/legal guardian.
Upon agreement with the Sponsor, samples can be analyzed by local laboratories if 
deemed required by local regulations.
Prior to screening, local laboratory test values will be used. The following parameters are 
required to be recorded in CRF: 

ALTs results within 6 months (for patients with liver biopsy) and within 1 year prior to 
baseline 

HBsAg results with more than 6 months prior to baseline

HBeAg results with more than 6 months prior to baseline

HBV DNA results prior to screening
Normal ranges (age-specific where available) for the local site study laboratory 
parameters must be supplied to Roche prior to study initiation.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
52
Table 4
Laboratory Assessments
Laboratory 
Assessment
Parameters
Hematology and 
coagulation
Complete blood count [hemoglobin, hematocrit, reticulocytes, total WBC 
count, differential WBC count (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils), platelet count], INR
Serum chemistry
ALT, AST, GGT, bilirubin (total, direct and indirect), alkaline phosphatase, 
total protein, albumin, BUN/urea, creatinine a, uric acid, total calcium, 
phosphorus, cholesterol, triglycerides, random glucose, sodium, chloride, 
potassium, lactate b
Urinalysis c
Dipstick with subsequent microscopic evaluation if positive for blood.
Pregnancy test c
Females of childbearing potential will have a serum pregnancy test at 
screening.  Urine pregnancy tests may be performed at subsequent visits.  
If a urine pregnancy test result is positive, it must be confirmed by a 
serum pregnancy test.  The result of the baseline pregnancy test must be 
available prior to randomization and commencement of treatment. Urine 
pregnancy test to be performed by site.
Thyroid function 
tests d
FT3, FT4, TSH, TPO antibodies, TBG
HBV serology and 
virology d
HBsAg, HBeAg, anti-HBs, anti-HBe, HBV DNA, HBV genotype
Special chemistry d
AFP, anti-HAV IgM Ab, anti-HCV Ab, anti-HDV Ab, anti-HIV Ab
Plasma samples for PK analysis (Section 4.5.1.5) 
Immunoglobulins 
and autoantibodies d
ASMA, ALKM1, ANA, A1AT
Exploratory testing d
Quantitative HBsAg, quantitative HBeAg, lamivudine or entecavir viral 
resistance b (Section 4.5.1.6), ADA e
A1AT-1 antitrypsin; ADAanti-drug antibody; AFP-fetoprotein; ALKM1antiliver-kidney 
microsome-1 antibody; ANAanti-nuclear antibody, ASMAanti-smooth muscle antibodies 
FT3free triiodothyronine; FT4free thyroxin ; GGTgamma-glutamyl transpeptidase; 
HAVhepatitis A virus; TBGthyroxine-binding globulin; TPOthyroid peroxidase; 
TSHthyroid-stimulating hormone.
a Estimated creatinine clearance to be calculated by sites during lamivudine or entecavir
treatment any time creatinine is abnormal (see Appendix 5) and internally by Roche at 
baseline and end of treatment/Week 48 of untreated observation.
b Treated patients only post-baseline. 
c To be performed by site/local laboratory.
d Parameters do not need to be repeated at re-screening if performed within 6 months prior to 
baseline, unless dictated by a change in the patient’s medical condition or the parameter 
accounted for the original screen failure.
e Patients treated with Pegasys®lamivudine or entecavir only.
Additional serum bank samples will be collected during the course of this study in order 
to perform or repeat any scheduled laboratory tests should there be a problem with the 
original sample.  If patients have consented to a RCR sample collection, any serum bank 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
53
samples that are no longer required for repeat testing will be converted to RCR serum 
samples at the end of the study (see Section 4.5.1.7).
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
4.5.1.5
Pharmacokinetic Analysis
Blood samples will be collected in all patients treated with Pegasys® lamivudine or 
entecavir to evaluate the pharmacokinetics of Pegasys® following administration of a 
BSA-based dosing regimen.  See Section 4.5.2.5 for timing of PK assessments. 
The exact date and time of Pegasys® dosing and collection of PK blood samples will be 
recorded in the source document (see Section 4.5.2.4).  The procedure for the collection 
and handling of blood samples for PK analysis is specified in the laboratory manual.  
The serum concentrations of Pegasys® will be assessed by a quantitative enzyme-linked 
immunosorbent assays (ELISA).  PK parameters, such as Cmax, AUC, clearance (CL/F) 
and volume of distribution (V/F), if possible, will be estimated using a population 
approach.
4.5.1.6
Lamivudine and Entecavir Resistance
Blood samples will be collected from all patients for lamivudine or entecavir viral
resistance testing (sequencing of the HBV polymerase reverse transcriptase region 
where the YMDD motif and other resistance mutations are located).  For untreated 
patients, a blood sample for lamivudine or entecavir viral resistance testing will be taken 
at baseline only.  For treated patients, a blood sample for lamivudine or entecavir viral
resistance testing will be taken at baseline (prior to the first dose of lamivudine or 
entecavir) and Week 8 (end of lamivudine or entecavir monotherapy treatment and prior 
to dose of lamivudine or entecavir during that visit), per the Schedule of Assessments in 
Appendix 1.  Samples will be batched and sent to the sequencing laboratory.  Therefore, 
results from baseline and Week 8 lamivudine or entecavir viral resistance testing may 
not be obtained before the start of the lamivudine or entecavir monotherapy and the 
Pegasys® lamivudine or entecavir combination, respectively.  In the event of baseline 
lamivudine or entecavir viral resistance or emergence of lamivudine or entecavir viral
resistance after 8 weeks of monotherapy, the investigator will be informed.  After 
consultation with the Medical Monitor, the decision to continue treatment will be at the 
discretion of the investigator.
A blood sample for lamivudine or entecavir viral resistance testing will be taken at 
follow-up Week 4 for all treated patients.  If lamivudine or entecavir viral resistance is 
detected or the test is unsuccessful, a blood sample to assess for lamivudine or 
entecavir viral resistance should be taken at follow-up Week 24.  If lamivudine or 
entecavir viral resistance is detected at follow-up Week 24, then testing should continue
up to the last time point of the follow-up period.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
54
If HBV DNA measurement was negative at follow-up Week 4 but becomes positive at 
follow-up Week 24, an unscheduled blood sample may be requested for lamivudine or 
entecavir viral resistance testing, preferably within 2 to 4 weeks. If lamivudine or 
entecavir viral resistance is detected before the last time point of follow up, lamivudine 
or entecavir viral resistance testing should be performed at the last time point of the 
follow-up period 
The procedure for the collection and handling of blood samples for lamivudine or 
entecavir viral resistance is specified in the laboratory manual.  
Population sequencing will be used as the primary methodology for the detection of the 
lamivudine or entecavir viral resistance mutation(s).  For the purposes of sequence 
determination, an HBV DNA 200 IU/mL is required.  Additional sequencing analyses 
may be performed on those samples for which viral resistance mutation(s) cannot be 
detected by population sequencing.
4.5.1.7
Samples for Roche Clinical Repository
Overview of the Roche Clinical Repository
The RCR is a centrally administered group of facilities for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent/assent 
to participate in this optional research (provided parents/legal guardians also provide 
consent).  RCR specimens will be used to achieve the following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
Approval by the Institutional Review Board or Ethics Committee
Sampling for the RCR is contingent upon the review and approval of the exploratory 
research and the RCR portion of the Informed Consent/Assent Form by each site's 
Institutional Review Board or Ethics Committee (IRB/EC) and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for RCR sampling, 
this section of the protocol will not be applicable at that site.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
55
Sample Collection
The following samples will be collected as per the Schedule of Assessments (see 
Appendix 1) for identification of dynamic (non-inherited) biomarkers:

Serum samples (if patients consent/assent to RCR samples, residual serum bank 
samples will be converted into RCR serum samples at the end of the study) 

Whole blood samples for RNA extraction 
The following sample will be collected at baseline for identification of genetic (inherited) 
biomarkers:

Whole blood samples for DNA extraction 
The total volume of blood taken for RCR samples is up to approximately 29 mL 
depending on the study group.  
For all samples, dates of consent/assent and specimen collection should be recorded on 
the associated RCR page of the eCRF.  For sampling procedures, storage conditions, 
and shipment instructions, see the laboratory manual.  
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens, which includes any residual serum bank samples,
will be subject to the confidentiality standards described in Section 8.4.  The genetic 
biomarker specimens will undergo additional processes to ensure confidentiality, as 
described below.  
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
56
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR specimens is confidential and may only 
be disclosed to third parties as permitted by the Informed Consent/Assent Form 
(or separate authorization for use and disclosure of personal health information) signed 
by the parent/legal guardian/patient, unless permitted or required by law.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
Consent to Participate in the Roche Clinical Repository
The Informed Consent and Assent Form will contain a separate section that addresses 
participation in the RCR.  The investigator or authorized designee will explain to each 
patient and their parent/legal guardian the objectives, methods, and potential hazards of 
participation in the RCR.  Patients will be told that they are free to refuse to participate 
and may withdraw their specimens at any time and for any reason during the storage 
period.  A separate, specific signature will be required to document a patient's and their 
parent/legal guardian’s agreement for provision of optional RCR specimens.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient and their parent/legal 
guardian has given consent/assent to participate by completing the RCR Research 
Sample Informed Consent/Assent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
Withdrawal from the Roche Clinical Repository
Patients who give consent/assent to provide RCR specimens have the right to withdraw 
their specimens from the RCR at any time for any reason.  If a parent/legal guardian or 
patient wishes to withdraw consent/assent to the testing of the patients specimens, the 
investigator must inform the Medical Monitor in writing of the patient's wishes using the 
RCR Subject Withdrawal Form and, if the trial is ongoing, must enter the date of 
withdrawal on the RCR Research Sample Withdrawal of Informed Consent/Assent eCRF.  
The parent/legal guardian/patient will be provided with instructions on how to withdraw 
consent/assent after the trial is closed.  A patient's withdrawal from Study NV25361 does 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
57
not, by itself, constitute withdrawal of specimens from the RCR.  Likewise, a patient's 
withdrawal from the RCR does not constitute withdrawal from Study NV25361.
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent/Assent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples.
4.5.2
Timing of Study Assessments
4.5.2.1
Screening and Pretreatment Assessments
Written informed consent signed by the patient’s parent/legal guardian and written 
informed consent or assent (if applicable) signed by the patient, for participation in the 
study must be obtained before performing any study-specific screening tests or 
evaluations.  Informed Consent/Assent Forms for enrolled patients and for patients who 
are not subsequently enrolled will be maintained at the study site.  
Screening tests and evaluations should be performed within 6 weeks prior to baseline 
(Day 1), unless otherwise specified.  Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent/assent and within 6 weeks prior to 
baseline (Day 1) may be used; such tests do not need to be repeated for screening.  
Extensions to the screening period of up to 7 days may be permitted under exceptional 
circumstances if information concerning eligibility is outstanding and upon approval from 
the Medical Monitor.  All screening evaluations must be completed and reviewed to 
confirm that patients meet all eligibility criteria before randomization.  The investigator 
will maintain a screening log to record details of all patients screened and to confirm 
eligibility or record reasons for screening failure, as applicable.
Assessments scheduled for baseline (Day 1) should be performed prior to administration 
of study treatment, unless otherwise noted in the Schedule of Assessments.
Please see Appendix 1 for the schedule of screening and pretreatment assessments.
4.5.2.2
Re-Testing Laboratory Inclusion/Exclusion
If a patient fails any laboratory Inclusion/Exclusion criteria at screening, the investigator 
may repeat the test twice within the screening period.  (This will not be considered as 
re-screening; see Section 4.5.2.3)  If the patient fails the laboratory criteria on the third 
assessment, he or she will not be able to enter the study.  It will not be considered a 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
58
retesting if blood samples have to be redrawn because of sample handling problems, 
breakage or sample integrity.
4.5.2.3
Re-Screening
Patients who fail to meet the entry criteria may be screened on one more occasion, 
provided that enrollment remains open.  Rescreening refers to repeating the whole 
screening process (except potentially for those assessments/parameters indicated in 
Table 3 and Table 4).  Rescreening is required if a patient has not met all of the eligibility 
criteria within 6 weeks from the original screening visit.  Prior to rescreening, approval 
from the Medical Monitor is required. It will not be considered a rescreening if blood 
samples have to be redrawn because of sample handling problems, breakage or sample 
integrity. Only the data for a successful screening visit will be recorded in the eCRF.
4.5.2.4
Assessments during Treatment and Untreated Observation
All assessments must be performed on the day of the specified visit, unless a time 
window is specified in the Schedule of Assessments (see Appendix 1).  Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the Schedule of 
Assessments.  CDI should be performed prior to the completion of other study 
assessments.
Please see Appendix 1 for the Schedule of Assessments performed during the treatment 
and untreated observation period.
4.5.2.5
Pharmacokinetic Assessments
A PK blood sample will be taken at baseline (prior to the first dose of lamivudine or 
entecavir) and on Day 1 of subsequent PK sampling weeks as per the Schedule of 
Assessments in Appendix 1.  The pre-dose PK sample will be collected prior to (anytime 
between 6 hours to immediately before) administration of Pegasys® and lamivudine or 
entecavir on that day.  Pegasys® dosing (if scheduled to occur) on the day of PK 
sampling should happen in the clinic. If a particular visit is taking place outside the clinic 
via mobile nursing then the mobile nurse will ensure the dosing takes place after PK 
sampling. The exact date and time of Pegasys® dosing and collection of PK blood 
samples will be recorded.
At Week 32 samples will be taken at pre-dose (any time between 6 hours to immediately 
before), and at post doses at 2448 hours, 7296 hours, and 168 hours. For scheduling 
purposes, time windows are provided for the first two post-dose blood samples. The first 
post-dose blood sample should be collected within 24 to 48 hours after the dose.  The 
second post-dose blood sample should be collected between 72 and 96 hours after the 
dose.  There must be at least 48 hours between the two blood samples.  The 168-hour 
blood sample will be collected within 6 hours before the next dose is administered.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
59
The procedure for the collection and handling of blood samples for PK analysis 
is specified in the Lab Manual and Lab Flowchart.  The exact date and time of dosing 
and collection of blood samples will be recorded in the source document and eCRF.  If 
an unscheduled PK sample is taken, the exact day and time that the sample was taken 
relative to the latest dose of Pegasys® needs to be recorded in the source document.
4.5.2.6
Lamivudine or Entecavir Viral Resistance Assessments
A blood sample for lamivudine or entecavir viral resistance testing will be taken at 
baseline for all patients (prior to the first dose of lamivudine or entecavir for treated 
patients) and at subsequent weeks per the Schedule of Assessments in Appendix 1 and 
as described in Section 4.5.1.6.
4.5.2.7
Assessments at Study Drug Discontinuation
For patients in the Pegasys®lamivudine or entecavir group who prematurely 
discontinue study drug, the assessments as per the Week 56 visit should be completed.
All patients should then continue onto the follow-up visit schedule (see Appendix 1).
4.5.2.8
Assessments at Study Completion or Early Termination
Patients who complete the study will be those treated patients who complete the full 
1-year follow-up and those untreated patients who complete the full 80-week untreated 
observation.  All patients who withdraw from the study early will be asked to return to the 
clinic for a final visit.
For treated patients withdrawing from the study prior to the end of treatment, the 
assessments as per the Week 56 visit should be completed.
For treated patients withdrawing from the study after the end of treatment but prior to 
follow-up Week 24, the assessments as per the follow-up Week 24 visit should be 
completed.
For treated patients withdrawing after follow-up Week 24, the assessments as per 
follow-up Year 1 visit should be completed.
For patients in the untreated control group withdrawing prior to Week 80, the 
assessments as per the Week 80 visit should be completed.
Please see Appendix 1 for the Schedule of Assessments performed at the study 
completion/early termination visit.
4.5.2.9
Follow-Up Assessments
Please see Appendix 1 for the Schedule of Assessments for initial and follow-up of 
treated patients.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
60
After the study completion or early termination visit, adverse events should be followed 
(see Section 5.5 and 5.6).
4.5.2.10
Assessments at Unplanned Visits
Assessments at unplanned visits should be clinically indicated as determined by the 
investigator.
4.5.3
Assessment of Sexual Maturity
The age of onset of menarche will be collected for all female patients.  Depending on 
approval by the Institutional Review Board / Ethics Committee (IRB/EC), the relevant 
health authority, and patient/guardian consent, Tanner Stage for all patients will be 
determined at baseline.  Patients deemed to be at Tanner Stage 5 at baseline will 
require no further Tanner Stage assessments.  Patients deemed to be below Tanner 
Stage 5 at baseline will be assessed annually as outlined in the schedule of 
assessments (see Appendix 1).  Guidance on the Tanner Stages is provided in 
Appendix 6.  
4.6
PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Reasons 
for discontinuation of study drug or withdrawal from the study may include but are not 
limited to the following:

Parent/legal guardian or patient withdrawal of consent/assent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance with study requirements
4.6.1.1
Untreated Control Patients who become Immune-Active
Untreated control patients who progress to immune-active disease (sustained ALT 
elevation for at least 6 months) should remain in the study until their completion 
(Week 80), per investigator’s judgment.  If the investigator wishes to initiate treatment 
per standard of care, this should first be discussed with the Medical Monitor. If such 
treatment is started, the patient would have been deemed to have been withdrawn from 
the study (see also Section 1.1).
4.6.1.2
Discontinuation from Study Drug
Individual patient treatment with Pegasys®lamivudine or entecavir must be 
discontinued in the event of any of the following:  

Severe hypersensitivity reactions (e.g., anaphylaxis, angioedema, 
bronchoconstriction)

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
61

Severe depression

Absolute neutrophil count0.25109 cells/L or febrile neutropenia 

Platelets 25109 cells/L 
Discontinuation of individual patient treatment with Pegasys®lamivudine or entecavir
should be considered in the event of any of the following:

Evidence of hepatic decompensation (e.g., Child-Pugh Class B or C clinical 
classification [Appendix 2] or clinical evidence such as ascites or varices)

Thyroid abnormalities that cannot be effectively controlled by medication

Hypoglycemia, hyperglycemia, or diabetes mellitus that cannot be effectively 
controlled by medication

New or worsening visual disorders such as field deficits, decrease or loss of vision 

Persistent or unexplained pulmonary infiltrates or pulmonary function impairment 

Worsening of psoriatic lesion

Development of autoimmunity, including autoimmune hepatitis

Pregnancy 
Discontinuation of individual patient treatment with lamivudine or entecavir should be 
considered in the event of the following:  

Clinical or laboratory findings suggestive of lactic acidosis or pronounced 
hepatotoxicity (which may include hepatomegaly and steatosis even in the absence 
of marked transaminase elevations)
In the event that Pegasys® treatment has to be permanently discontinued, patients must 
also cease lamivudine or entecavir.  
In the event that lamivudine or entecavir treatment has to be discontinued, patients may 
continue to receive Pegasys® monotherapy for the rest of the planned treatment period.
Patients who discontinue study drug permanently will be asked to return to the clinic for 
a study drug discontinuation visit (see Section 4.5.2.7) and should continue into 
follow-up.  The primary reason for premature study drug discontinuation should be 
documented on the appropriate eCRF.
4.6.1.3
Withdrawal from Study
Every effort should be made to obtain information on patients who withdraw from the 
study (see Section 4.5.2.7).  The primary reason for withdrawal from the study should be 
documented on the appropriate eCRF.  Patients will not be followed for any reason after 
consent/assent has been withdrawn.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
62
4.6.2
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the study is placed on hold, or if the Sponsor 
decides to discontinue the study or development program. 
As of 28 March 2018, recruitment into the study was terminated due to questionable 
efficacy and a change in the benefitrisk profile of the trial, although no specific safety 
concerns were identified in the DSMB scheduled review of the study (see Section 1.5).
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include but are not limited to the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonization (ICH) guideline 
for Good Clinical Practice
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Pegasys® is associated with adverse effects such as neuropsychiatric events, 
cytopenias (including neutropenia, lymphopenia, and thrombocytopenia), influenza-like 
symptoms, infections, and cardiovascular, thyroid, metabolic, autoimmune, respiratory, 
ophthalmic, and other conditions.  Significant adverse effects of Pegasys® are 
highlighted in Section 5.1.1.  
The safety profiles of lamivudine and entecavir are summarized in Section 5.1.2 and 
Section 5.1.3, respectively. 
For other adverse effects associated with lamivudine or entecavir, see local prescribing 
information.  
Specific exclusion criteria aim to exclude patients who are at risk for increased toxicity 
based on the potential and identified risks of Pegasys® and lamivudine or entecavir, such 
as patients with pre-existing cardiac disease, significant anemia, abnormal thyroid 
function, severe retinopathy, and severe mood or psychiatric disorder.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
63
Regular monitoring of laboratory parameters, growth parameters, vital signs, and 
adverse events will occur as per the Schedule of Assessments in Appendix 1 and will 
ensure that any adverse effects are detected early and treated promptly.  Appropriate 
study drug and study stopping rules based on safety will be instituted (see 
Sections 4.6.1.2 and 4.6.2).
Dose adjustment guidance for Pegasys® is provided in Appendix 4, including guidance 
for management of the specific effects listed below.  All missed, reduced, or withheld 
doses of Pegasys® or lamivudine or entecavir, including the reason, must be recorded 
on the eCRF.

Neutropenia

Thrombocytopenia

Elevated serum ALT

Severe mood or psychiatric disorder

Change of BSA category
A DSMB and IMC will review the safety data at regular intervals (see Sections 3.1.3 and 
3.1.4). 
5.1.1
Risks Associated with Pegasys®
5.1.1.1
Neutropenia, Lymphopenia, and Thrombocytopenia
Pegasys® is associated with the development of neutropenia, lymphopenia, and 
thrombocytopenia through dose-related suppression of the bone marrow.  Neutropenia 
is the most common reason for dose modification of Pegasys® and is managed clinically 
with dose reduction in approximately one quarter of patients.  
5.1.1.2
Elevated ALT
Transient elevations in ALT (2-fold to 5-fold above baseline) have been observed in 
some patients receiving Pegasys® and were not associated with deterioration of other 
liver function tests.
5.1.1.3
Thyroid
-interferons, including Pegasys®, may cause or aggravate hypothyroidism and 
hyperthyroidism.  The most common thyroid function abnormalities during studies with 
Pegasys® were hypothyroidism (low T3 and elevated TSH) as well as hyperthyroidism 
(elevated T4).  Female patients appear to be more likely than male patients to develop 
significant thyroid abnormalities with Pegasys® treatment.  Most patients who developed 
thyroid abnormalities during treatment were generally adequately managed with 
medication without the need for stopping Pegasys® treatment, and in most, thyroid 
function had normalized or improved by the end of an untreated follow-up period.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
64
5.1.1.4
Growth
Growth inhibition was observed in pediatric patients.  Pediatric patients with HCV treated 
with Pegasys® plus ribavirin combination therapy (Study NV17424, [PEDS-C] Phase III 
study) showed a delay in weight and height increases after 48 weeks of therapy 
compared with baseline.  Both weight and height for age z-scores as well as the 
percentiles of the normative population for patient weight and height decreased during 
treatment.  At the end of 2 years of follow-up after treatment, most patients had returned 
to baseline normative growth curve percentiles for weight and height (mean weight for 
age percentile was 64% at baseline and 60% at 2 years after the end of treatment; mean 
height percentile was 54% at baseline and 56% at 2 years after the end of treatment).  
At the end of treatment, 43% of patients experienced a weight percentile decrease of 
15 percentiles or more and 25% of patients experienced a height percentile decrease of 
15 percentiles or more on the normative growth curves.  At 2 years after the end of 
treatment, 16% of patients remained 15 percentiles or more below their baseline weight 
curve and 11% of patients remained 15 percentiles or more below their baseline height 
curve.  In addition, 38 of 114 patients who participated in Study NV17424 continued into 
the long-term follow-up study, whose data demonstrated that recovery in growth at the 
2-year follow-up was maintained at 56 years after treatment.  In the few patients who 
did not return to baseline height for age percentiles by 56 years post-treatment, an 
alternative causative factor was identified.  
5.1.1.5
Neuropsychiatric
Effects on mood have been reported in adults treated with interferons.  In 
Study NV17424 (PEDS-C), a Phase III study of HCV-infected children treated with 
Pegasys®, insomnia, depression, and anxiety were reported.
Life-threatening or fatal neuropsychiatric reactions may manifest in patients receiving 
therapy with Pegasys® and include suicide, suicidal ideation, homicidal ideation, 
depression, relapse of drug addiction, and drug overdose.  These reactions may occur in 
patients with and without previous psychiatric illness.
Neuropsychiatric AEs observed with Pegasys® treatment include aggressive behavior, 
psychoses, hallucinations, bipolar disorders, and mania.  Physicians should use their 
clinical judgment to monitor young pediatric patients for evidence of depression and 
other psychiatric symptoms.
5.1.1.6
Ophthalmic
Decrease or loss of vision, retinopathy (including macular edema), retinal artery or vein 
thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, and papilledema 
are induced or aggravated by treatment with Pegasys® or other -interferons.
5.1.1.7
Fertility
Pegasys® has not been studied for its effect on fertility and should not be used in 
pregnant women.  

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
65
5.1.2
Risks Associated with Lamivudine
The safety profile of lamivudine has been established in adult patients with HBV, and 
also in adult and pediatric patients with HIV.  The dose of lamivudine used to treat adults 
with HIV as part of combination therapy is 150 mg twice daily, whereas in adults with 
chronic HBV the dose is 100 mg four times daily.  Similarly a lower lamivudine dose is 
recommended for pediatric patients with HBV than in pediatric patients with HIV, and 
therefore it is anticipated that the safety profile in pediatric patients with HBV will be no 
worse given the lower exposure, and very likely better, than that observed in pediatric 
patients with HIV who have been treated with regimens containing lamivudine.  Some 
safety data are available on lamivudine use in pediatric HBV treatment (Sokal et al. 2000, 
2006; Jonas et al. 2002, 2008), and most reported events were not different from 
placebo and included ear, nose, and throat symptoms, gastrointestinal symptoms, and 
non-specific AEs such as malaise and fatigue.  Few safety issues, other than the 
development of lamivudine viral resistance with long-term monotherapy, have been 
reported relating to lamivudine.  
In a review of therapies used in pediatric HBV (Jonas et al. 2010), it was concluded that 
the safety profile of nucleoside and nucleotide analogues used in pediatrics was 
generally well tolerated, while serious sequelae such as lactic acidosis were rare.  Cases 
of lactic acidosis, sometimes fatal, and usually associated with severe hepatomegaly 
with steatosis, have been reported rarely with the use of nucleoside analogues.  
Investigators should refer to the prescribing information for lamivudine indicated for HBV 
for additional information on the safety profile of lamivudine in HBV.
5.1.3
Risks Associated with Entecavir
The safety profile of entecavir has been established in adult and pediatric patients with 
HBV. In clinical studies in adult patients with compensated liver disease, the most 
common adverse reactions of any severity with at least a possible relation to entecavir 
were headache (9%), fatigue (6%), dizziness (4%) and nausea (3%). Exacerbations of 
hepatitis during and after discontinuation of entecavir therapy have also been reported.
Assessment of adverse reactions in adults is based on experience from postmarketing 
surveillance and four clinical studies in which 1720 patients with chronic hepatitis B 
infection and compensated liver disease received double-blind treatment with entecavir 
(n862) or lamivudine (n858) for up to 107 weeks. In these studies, the safety profiles, 
including laboratory abnormalities, were comparable for entecavir 0.5 mg daily 
(679 nucleoside-naive HBeAg positive or negative patients treated for a median of 
53 weeks), entecavir 1 mg daily (183 lamivudine-refractory patients treated for a median 
of 69 weeks), and lamivudine.
Cases of lactic acidosis have been reported, often in association with hepatic 
decompensation, other serious medical conditions or drug exposures.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
66
The safety of entecavir in pediatric patients from 2 to 18 years of age is based on two 
clinical trials in subjects with chronic HBV infection: one Phase II PK trial and one 
Phase III trial. These trials provide experience in 173 HBeAg-positive nucleoside-analog 
treatment-naïve subjects treated with entecavir for a median duration of 60 weeks. The 
adverse reactions observed in pediatric subjects who received treatment with entecavir 
were consistent with those observed in clinical trials of entecavir in adults
(BARACLUDE® SmPC).
Adverse drug reactions reported in greater than 1% of pediatric subjects included 
abdominal pain, rash events, poor palatability (“product taste abnormal”), nausea, 
diarrhea, and vomiting (BARACLUDE®. U.S. Package Insert).
Investigators should refer to the prescribing information for entecavir for additional 
information on the entecavir safety profile.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording AEs, including serious 
adverse events (SAEs) and non-serious AEs of special interest, measurement of 
protocol-specified safety laboratory assessments, measurement of protocol-specified 
vital signs, measurement of height and weight, and other protocol-specified tests that are 
deemed critical to the safety evaluation of the study.
Certain types of events require immediate reporting to the Sponsor (see Section 5.4).
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product, regardless of causal attribution.  An AE can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition [see Section 5.3.5.9]).

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., invasive screening procedures such as 
biopsies)

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
67
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
An SAE is any AE that meets any of the following criteria:

Fatal (i.e., the AE actually causes or leads to death)

Life-threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death)
This does not include any AE that had it occurred in a more severe form or was 
allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions)

Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an AE (rated as mild, moderate, or severe, or according to the Division of AIDS [DAIDS] 
criteria [see Section 5.3.3]); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF.
SAEs are required to be reported by the investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; [see Section 5.4.2]).
5.2.3
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)
In addition to SAEs, non-serious AEs of special interest must be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the
event; see Section 5.4.2]).  AEs of special interest for this study include the following:

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug. Any organism, 
virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.  
A transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory findings that indicate an infection in a patient exposed to a medicinal 
product.  This term applies only when a contamination of the study drug is 
suspected.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
68
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all AEs (see Section 5.2.1) are recorded 
on the AE eCRF and reported to the Sponsor in accordance with instructions (see 
Sections 5.4 and 5.6).
For each AE recorded on the AE eCRF, the investigator will make an assessment of 
seriousness (see Section 5.2.2), severity (see Section 5.3.3), and causality (see 
Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the AE eCRF.
After informed consent/assent has been obtained but prior to initiation of study drug 
/baseline visit, only SAEs caused by a protocol-mandated intervention should be 
reported (e.g., SAEs related to invasive procedures such as biopsies).
After initiation of study drug/baseline visit, all AEs, regardless of relationship to study 
drug, will be reported until follow-up Week 24/end of untreated observation.  After this 
period (i.e., during follow-up for treated patients), investigators should report any 
persisting AEs, new-onset SAEs or non-serious AEs of special interest that are believed 
to be related to prior treatment with study drug, and any deaths (see Section 5.6).  
At certain visits outlined on the Schedule of Assessments in Appendix 1, AEs may be 
recorded via a telephone call from investigator site to the patient or the patient’s 
parent/legal guardian as appropriate.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation time points.  Examples of non-directive questions 
include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?” 
5.3.3
Assessment of Severity of Adverse Events
The DAIDS Table for Grading the Severity of Adult and Pediatric AEs should be used to 
assist in the assessment of severity:  
http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Table_for_ 
Grading_Severity_of_Adult_Pediatric_Adverse_Events.pdf

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
69
Note that events that are considered life-threatening should be reported as an SAE (see 
Section 5.2.2), and the severity would be reported as “severe” on the eCRF.
Table 5 will be used for assessing severity for AEs that are not specifically listed in the 
DAIDS Table.
Table 5
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of an SAE (see Section 5.2.2). 
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an AE is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording AEs on 
the AE eCRF; the use of colloquialisms and abbreviations should be avoided.
Only one AE term should be recorded in the event field on the AE eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the AE eCRF rather than individual signs 
and symptoms (e.g., record only appendicitis rather than abdominal pain, vomiting, 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
70
sweating and elevated white blood cell count).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the AE eCRF.  If a 
diagnosis is subsequently established, all previously reported AEs based on signs and 
symptoms should be nullified and replaced by one AE report based on the single 
diagnosis, with a starting date that corresponds to the starting date of the first symptom 
of the eventual diagnosis.
5.3.5.2
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  However, medically significant AEs occurring secondary to 
an initiating event that are separated in time should be recorded as independent events 
on the AE eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.
All AEs should be recorded separately on the AE eCRF if it is unclear as to whether the 
events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points.  Such events should be recorded only once on the AE eCRF.  
The initial severity of the event should be recorded in the initial severity field of the AE 
eCRF page, and the most extreme severity field should be updated to reflect the most 
extreme severity any time the event worsens.  If the event becomes serious, the AE 
eCRF should be updated to reflect it.
A recurrent AE is one that resolves between patient evaluation time points and 
subsequently recurs.  Each recurrence of an AE should be recorded separately on the 
AE eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an AE.  In this study, a laboratory test 
result should be reported as an AE if it meets any of the following criteria:

Considered an SAE 

Results in a discontinuation of study treatment 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
71

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE.
If a laboratory abnormality meeting the above criteria is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholecystitis), only the 
diagnosis (i.e., cholecystitis) should be recorded on the AE eCRF.
If a laboratory abnormality meeting the above criteria is not a sign of a disease or 
syndrome, the abnormality itself should be recorded on the AE eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE.  For example, a decreased neutrophil level below 0.6 x 109
cells/L should be recorded as “Neutropenia”.  
Observations of the same laboratory abnormality from visit to visit should not be 
repeatedly recorded on the AE eCRF, unless the etiology changes.  The initial severity 
of the event should be recorded, and the severity or seriousness should be updated any 
time the event worsens.
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE if it meets any of the following criteria:

Accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the AE eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the AE eCRF, unless the etiology changes.  The 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
72
initial severity of the event should be recorded, and the severity or seriousness should 
be updated any time the event worsens.
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3 baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the AE eCRF (see Section 5.3.5.1) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event), either as an SAE or a non-serious AE of special interest (see Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the study including follow-up of treated patients (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the AE 
eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This includes death 
attributed to progression of CHB.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the AE eCRF.  Generally, only one such event should be reported.  The term 
“sudden death” should only be used for the occurrence of an abrupt and unexpected 
death due to presumed cardiac causes in a patient with or without preexisting heart 
disease, within 1 hour of the onset of acute symptoms or, in the case of an unwitnessed 
death, within 24 hours after the patient was last seen alive and stable.  If the cause of 
death is unknown and cannot be ascertained at the time of reporting, “unexplained 
death” should be recorded on the AE eCRF.  If the cause of death later becomes 
available (e.g., after autopsy), “unexplained death” should be replaced by the 
established cause of death.
If the death is attributed to progression of CHB, "Chronic hepatitis B progression” should 
be recorded on the AE eCRF.  
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
73
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the AE eCRF, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”).
5.3.5.9
Lack of Efficacy or Worsening of CHB
Medical occurrences or symptoms of deterioration that are anticipated as part of CHB 
should be recorded as an AE if judged by the investigator to have unexpectedly 
worsened in severity or frequency or changed in nature at any time during the study.  
When recording an unanticipated worsening of CHB on the AE eCRF, it is important to 
convey the concept that the condition has changed by including applicable descriptors 
(e.g., “worsening of chronic hepatitis B”).
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE (per the definition of SAE in Section 5.2.2), except as outlined 
below.  
The following hospitalization scenarios are not considered to be SAEs:

Hospitalization for respite care

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not suffered an AE.
5.3.5.11
Overdoses
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.
All overdoses or incorrect administration of study drug should be recorded on the AE 
eCRF.  If the associated AE fulfils serious criteria, the event should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event 
[Section 5.4.2]).
5.3.5.12
Patient-Reported Outcome Data 
AE reports will not be derived from patient-reported outcome (PRO) data (CDI [see 
Section 4.5.1.2]).  However, if any patient responses are suggestive of a possible AE 
and are identified during site review of the CDI questionnaires, site staff will alert the 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
74
investigator, who will determine if the criteria for an AE have been met and will document 
the outcome of this assessment in the patient's medical record per site practice.  If the 
event meets the criteria for an AE, it will be reported on the AE eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

SAEs

Non-serious AEs of special interest

Pregnancies
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Note:  The Study Monitor should be contacted for any routine and administrative queries 
such as patient eligibility queries. 
Medical Monitor Contact Information
Medical Monitor (UTC+01):
, Ph.D.
Telephone No.:
Mobile Telephone No.:
Medical Monitor:
, M.D. (Secondary)
Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
be available to access the appointed Roche Medical Monitors, escalate emergency 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
75
medical calls, provide medical translation service (if necessary), connect the investigator 
with a Roche Medical Monitor, and track all calls.  The Help Desk will be available 
24 hours per day, 7 days per week, 52 weeks per year.  Help Desk numbers will be 
distributed to all investigators.
5.4.2
Reporting Requirements for Serious Adverse Events and
Non-Serious Adverse Events of Special Interest 
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Drug Administration
For reports of SAEs and non-serious AEs of special interest, investigators should record 
all case details that can be gathered immediately (i.e., within 24 hours) on the AE eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, a paper SAE/Non-Serious AE of 
Special Interest Case Report Form (CRF) and Fax Coversheet should be completed and 
faxed to Roche Safety Risk Management or its designee immediately (i.e., no more than 
24 hours after learning of the event), using the fax numbers provided to investigators.  
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.  
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant at any time during the study or within 90 days after 
the last dose of study drug for any treated patients that withdraw from the study early.  A 
Clinical Trial Pregnancy Reporting Form should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Pregnancy should not be recorded on the 
AE eCRF.  
The investigator should discontinue study drug and counsel the patient, discussing the 
risks of the pregnancy and the possible effects on the fetus.  Monitoring of the patient 
should continue until conclusion of the pregnancy.  Any SAEs associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
76
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
AE eCRF.
In addition, the investigator should submit a Clinical Trial Pregnancy Reporting Form 
when updated information on the course and outcome of the pregnancy becomes 
available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent/Assent Form to 
immediately inform the investigator if their partner becomes pregnant during the 
treatment period or within 90 days after the last dose of study drug.  A Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Attempts should be made to collect and report details 
of the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug.  The pregnant partner will be required to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow up on her pregnancy.  
After the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.  
5.4.3.3
Abortions
Any spontaneous abortion should be classified as an SAE (as the Sponsor considers 
spontaneous abortions to be medically significant events), recorded on the AE eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; [see Section 5.4.2]).  
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as an SAE, recorded on the 
AE eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; [see Section 5.4.2]).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow-up, 
or the patient withdraws consent/assent.  Every effort should be made to follow all SAEs 
considered to be related to study drug or trial-related procedures until a final outcome 
can be reported.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
77
During the study period, resolution of AEs (with dates) should be documented on the AE 
eCRF and in the patient’s medical record to facilitate source data verification.  If, after 
follow-up, return to baseline status or stabilization cannot be established, the appropriate 
AE outcome should be recorded on the AE eCRF and in the patient’s medical record. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
5.5.2
Sponsor Follow-Up
For SAEs, non-serious AEs of special interest, and pregnancies, the Sponsor or a 
designee may follow-up by telephone, fax, electronic mail, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
At the study completion/early termination visit, the investigator should instruct each 
patient to report to the investigator any subsequent AEs that the patient’s personal 
physician believes could be related to prior study drug treatment or study procedures.  
The investigator should notify the Sponsor of any death, SAE, or non-serious AE of 
special interest occurring at any time after a patient has discontinued study participation 
if the event is believed to be related to prior study drug treatment or study procedures.  
The Sponsor should also be notified if the investigator becomes aware of the 
development of cancer or a congenital anomaly/birth defect in a subsequently conceived 
offspring of a treated patient that participated in this study.
The investigator should report these events to Roche Safety Risk Management on the 
AE eCRF.  If the AE eCRF is no longer available, the investigator should report the 
event directly to Roche Safety Risk Management using the telephone number provided.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all SAEs and non-serious AEs of special interest 
against cumulative product experience to identify and expeditiously communicate 
possible new safety findings to investigators, IRBs, ECs, and applicable health 
authorities based on applicable legislation.
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents:

Pegasys® Investigator's Brochure

Local prescribing information for lamivudine and entecavir

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
78
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Recruitment into the study was terminated prematurely (see Section 1.5). Therefore, 
the data collected will be summarized using descriptive statistics.  No formal statistical 
hypothesis testing or formal treatment group comparisons will be performed. The data 
from this study will be descriptively summarized and reported in a clinical study report 
after the last patient has completed the last study visit at 1 year post-end of treatment.
The efficacy analyses and summaries will be presented for the ITT population, which will 
comprise all randomized patients who receive at least one dose of study medication and 
patients randomized to no treatment who report any efficacy or safety data.  Patients will 
be analyzed according to the group assigned at randomization.
Patients with missing data for the primary endpoint will be considered non-responders 
for the purpose of statistical analysis.  
The safety population will be used for the reporting of all safety information and will 
comprise all patients who report any safety data.  For safety summaries, patients will be 
summarized according to treatment received.
6.1
DETERMINATION OF SAMPLE SIZE
Taking into account the comparable entecavir and lamivudine early viral kinetics and the 
low resistance rates observed during Pegasys®-combination therapy with entecavir or 
lamivudine, the efficacy of Pegasys®lamivudine and Pegasys®entecavir regimens in 
this study are expected to be comparable. The assumptions for the expected loss of 
HBsAg rates after 24 weeks after the end of treatment/end of untreated observation are 
17% in the Pegasys®lamivudine arm and 0.6% in the untreated control group.  These 
assumptions are based on the observed rate on conventional Interferon in a pilot study 
(D’Antiga et al. 2006) and observed spontaneous rates (Hsu 1992), respectively.  
With a two-sided 5% significance level, Fisher’s Exact test would have 80% power to 
detect a difference between a treated group and untreated control with 50 evaluable 
patients per group.  Approximately 114 patients were planned to be recruited (57 per 
group) to ensure at least 50 evaluable patients in each group.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
79
6.2
SUMMARIES OF CONDUCT OF STUDY
Study drug administration, patient disposition, and important protocol deviations will be 
summarized by group.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics will be summarized descriptively by group.  
Continuous variables will be summarized by the number of observations, mean, 
standard deviation, median, minimum and maximum values.  Categorical variables will 
be summarized using frequencies and percentages. 
6.4
EFFICACY ANALYSES
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is defined as loss of HBsAg at 24 weeks post-treatment 
(follow-up Week 24)/end of untreated observation (Week 80).  The number of 
observations, percentage of responders (response rate) and 95% CI (using the 
Clopper-Pearson method) for the response rate will be presented for each group.  
The primary analysis was planned as the comparison of the response rate in the 
Pegasys®lamivudine or entecavir group with that in the untreated control group.  
Testing of the primary endpoint was planned as a superiority test based on the ITT 
population, which would comprise all randomized patients who received at least one 
dose of study medication and patients randomized to no treatment. The test would be 
using Fisher’s exact test, stratified by HBV genotype (A vs. B/C vs. D/other), and the 
significance level taken at 5% two-sided.  Patients with missing data will be treated as 
non-responders.  Sensitivity analyses would include a last observation carried forward
approach for missing data.  The Cochran Mantel Haenszel test stratified by genotype 
would also be provided.  
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints for this study at 24 weeks post-treatment/end of 
untreated observation are as follows:

Seroconversion to anti-HBs (loss of HBsAg and presence of anti-HBs)

Seroconversion to anti-HBe (loss of HBeAg and presence of anti-HBe)

Loss of HBeAg

HBV DNA 20,000 IU/mL 2000 IU/mL, undetectable and change from baseline (by 
PCR or hybridization)

Combined endpoints:  HBeAg seroconversion and HBV DNA 20,000 IU/mL

Combined endpoints:  HBeAg seroconversion and HBV DNA 2000 IU/mL
Categorical endpoints will be summarized and analyzed in the same way as the primary 
efficacy endpoint.  Continuous endpoints will be summarized using descriptive statistics 
(n, mean, median, SD, minimum, and maximum) and comparisons between the treated 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
80
and untreated control groups were planned using an analysis of variance, adjusted for 
HBV genotype (A vs. B/C vs. D/other).
In order to control the Type I error rate for the multiple secondary endpoints, a 
hierarchical testing approach would be used.  
The secondary efficacy endpoints for this study at 1 year post-treatment are as follows:

Seroconversion to anti-HBs (loss of HBsAg and presence of anti-HBs)

Seroconversion to anti-HBe (loss of HBeAg and presence of anti-HBe)

Loss of HBsAg

Loss of HBeAg

HBV DNA 20,000 IU/mL, 2000 IU/mL, undetectable and change from baseline 
(by PCR or hybridization)

Combined endpoints:  HBeAg seroconversion and HBV DNA 20,000 IU/mL

Combined endpoints: HBeAg seroconversion and HBV DNA 2000 IU/mL
These secondary efficacy endpoints will be summarized descriptively at 1 year
post-treatment for the Pegasys®lamivudine or entecavir treatment group.
6.5
SAFETY ANALYSES
The following safety outcome measures will be compared between groups using 
descriptive statistics at 24 weeks post-treatment/end of untreated observation:

Incidence, nature, and severity of serious and non-serious AEs (including 
neuropsychiatric assessment)

Reasons for the discontinuation of any study medication

Dose modifications for laboratory abnormalities and clinical AEs

Changes in vital signs and laboratory tests from screening/baseline, including 
thyroid function

Effect on growth (height, weight, and sexual maturity)
The following safety outcome measures will be assessed using descriptive statistics at 
1 year post-treatment:

Incidence, nature, and severity of persisting AEs, new-onset related SAEs/ 
non-serious AEs of special interest

Changes in thyroid function from screening/baseline

Effect on growth (height, weight, and sexual maturity)
AEs will be assigned preferred terms and categorized into body systems according to 
the Medical Dictionary for Regulatory Activities classification of the World Health 
Organization terminology.  AEs will be summarized by body system and preferred term 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
81
for each group.  AE summaries will be presented for events with an onset date during up 
to 24 weeks post treatment (follow-up Week 24)/end of untreated observation (Week 80) 
by group and for events with an onset at any time up to the end of the 1-year safety 
follow-up for the Pegasys®lamivudine or entecavir treatment group only.
Neurological and psychiatric AEs will be assessed in further detail, including persistence 
and duration, as well as new onset of related SAEs reported during the follow-up period 
of this study for the Pegasys®lamivudine or entecavir treatment group.
Laboratory Safety Data:  Laboratory data will be descriptively summarized by treatment 
group over time. The Division of AIDS (DAIDS) Table for Grading the Severity of Adult 
and Pediatric Adverse Events (version 2.0, Nov 2014, or more recent) will be used to 
assess the severity of laboratory abnormalities.
Growth (weight, height and sexual maturity):  Descriptive summaries of weight and 
height will be presented by group over time.  Sexual maturity data will be summarized as 
appropriate.  
The number of patients who discontinued study medication and reason for 
discontinuation will be summarized.
6.6
PHARMACOKINETIC ANALYSES
Individual and mean serum Pegasys® concentration versus time data will be tabulated.
Additional PK analyses will be conducted as appropriate.
6.7
EXPLORATORY ANALYSES
The exploratory outcome measures for this study are as follows:

Quantitative HBsAg and quantitative HBeAg 

Presence of lamivudine or entecavir resistance mutations

Incidence of ADAs from all patients treated with Pegasys®lamivudine or 
Pegasys®+entecavir
Exploratory analyses may not be reported in the Clinical Study Report. 
6.8
INTERIM ANALYSES
No interim analysis is planned for the primary efficacy endpoint.
The primary efficacy analysis was planned when the last patient reaches the end of the 
24-week after the end of treatment (follow-up Week 24)/end of untreated observation 
(Week 80).  
Due to the early termination of recruitment and consequent reduction in both sample 
size and statistical power, the study data will be summarized using descriptive 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
82
statistics and reported in a clinical study report after the last patient has completed the 
last study visit at 1-year post end of treatment. 
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC using eCRFs.  
Sites will be responsible for data entry into the EDC system.  In the event of discrepant 
data, the Sponsor will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
Data from paper CDI questionnaires will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have access to a manual for appropriate eCRF completion.  eCRFs will be 
submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
83
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
study treatments, including eCRFs, Informed Consent/Assent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for at least 15 years after completion or discontinuation of the study, or for the length of 
time required by relevant national or local health authorities, whichever is longer.  After 
that period of time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
84
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union (EU)/European Economic Area will comply with the 
EU Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent/Assent Forms or any alternate 
consent/assent forms proposed by the site (collectively, the “consent forms”) before 
IRB/EC submission.  The final IRB/EC-approved consent forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s 
parent/legally authorized representative before his or her participation in the study.  The 
case history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained prior to participation in the study.  
Patients within the specified age range who are legally considered to be adults 
according to national legislation must consent in their own right.  Patients enrolled as 
minors who attain legal adulthood during the course of the study must consent in their 
own right at that time and if required by national legislation.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
85
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
parent/legally authorized representative.  All signed and dated Consent Forms must 
remain in each patient’s study file or in the site file and must be available for verification 
by study monitors at any time.
For sites in the United States, each Consent Form may also include patient 
authorization to allow use and disclosure of personal health information in compliance 
with the U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  
If the site utilizes a separate Authorization Form for patient authorization for use and 
disclosure of personal health information under the HIPAA regulations, the review, 
approval, and other processes outlined above apply except that IRB review and approval 
may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent/Assent Forms, any information to be given to the 
patient, and relevant supporting information must be submitted to the IRB/EC by the 
Principal Investigator and reviewed and approved by the IRB/EC before the study is 
initiated.  In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local health authority and IRB/EC.  
Investigators may receive written IND safety reports or other safety-related 
communications from the Sponsor.  Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with health authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file. 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
86
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data 
and used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted clinical study reports and other summary reports will be provided 
upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV).

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
87
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, informed consent/assent forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
patient data, which includes an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The 
investigator should promptly report any deviations that might have an impact on 
patient safety and data integrity to the Sponsor and to the IRB/EC in accordance with 
established IRB/EC policies and procedures.  The Sponsor will review all protocol 
deviations and assess whether any represent a serious breach of Good Clinical Practice 
guidelines and require reporting to health authorities.  As per the Sponsor's standard 
operating procedures, prospective requests to deviate from the protocol, including 
requests to waive protocol eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
The overall procedures for quality assurance of clinical study data are described in the 
Roche Standard Operational Procedures.
This study will be sponsored and managed by F. Hoffman-La Roche.  Approximately 
55 centers worldwide may participate in the study and will enroll approximately 114 
patients.
A system will be in place to confirm patients intended dose of Pegasys®, based on 
patient’s weight and height provided by the investigator, at the time points indicated in 
Appendix 1.  
Central laboratories will be used for study assessments, including PK samples (see 
Table 4).  If local laboratories are used for hematology and biochemistry assessments, 
local laboratory ranges will be collected.  The RCR will receive all RCR samples at the 
end of the study.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
88
Data for this study will be recorded via an EDC system using eCRFs.  Except where 
specified (see Section 4.5.1), in no case will the eCRF be considered source data for 
this trial.  
The study will be overseen by the Study Management Team (SMT).  During the study 
the SMT will review study data according to the Data Quality Plan.  
A DSMB and IMC will be utilized (see Sections 3.1.3 and 3.1.4).  Information regarding 
the structure and role of the DSMB and IMC will be provided in a separate DSMB 
Charter and IMC Agreement.  
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries of the U.S. National Institutes of Health and the 
European Medicines Agency, and in peer-reviewed journals.  The Sponsor will comply 
with all requirements for publication of study results.  Study data may be shared with 
others who are not participating in this study, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 8.4 for more details).  
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific meetings.  For all 
clinical trials in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical trial results within 6 months after the 
availability of the respective Clinical Study Report.  In addition, for all clinical trials in 
patients involving an IMP for which a marketing authorization application has been 
filed or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and 
statistically sound.
The investigator agrees to submit all manuscripts or abstracts to the Sponsor prior to 
submission.  This allows the Sponsor to protect proprietary information and to provide 
comments based on information from other studies that may not yet be available to the 
investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
89
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
90
10.
REFERENCES
Akarsu M, Sengonul A, Tankurt E, et al. YMDD motif variants in inactive hepatitis B 
carriers detected by Inno-Lipa HBV DR assay. J Gastroenterol Hepatol 
2006;21:17838.
Baraclude (entecavir 0.5 mg film-coated tablets) Summary of Product 
Characteristics 
Baraclude (entecavir 0.5 mg film-coated tablets) U.S. Package Insert Bristol-Myers 
Squibb 
Beasley RP, Hwang LY, Lin CC, et al. Incidence of hepatitis B virus infections in 
preschool children in Taiwan. J Inf Dis 1982;146:198204.
Bortolotti F, Calzia R, Cadrobbi P, et al. Liver cirrhosis associated with chronic 
hepatitis B virus infection in childhood. J Pediatr 1986;108:2247.
Chang MH, Sung JL, Lee CY, et al. Factors affecting clearance of hepatitis B e 
antigen in hepatitis B surface antigen carrier children. J Pediatr 1989;115:38590.
Chayama K, Suzuki Y, Kobayashi M, et al. Emergence and takeover of YMDD motif 
mutant hepatitis B virus during long-term lamivudine therapy and re-takeover by wild 
type after cessation of therapy. Hepatology 1998;27:1711-6. 
Chu CM, Karayiannis P, Fowler MJ, et al. Natural history of chronic hepatitis B virus 
infection in Taiwan: studies of hepatitis B virus DNA in serum. Hepatology 
1985;5:4314.
D'Antiga L, Aw M, Atkins M, et al. Combined lamivudine/interferon-treatment in 
'immunotolerant' children perinatally infected by hepatitis B: a pilot study. J Pediatr 
2006;148:2283.
De Potter CR, Robberecht E, Laureys G, et al. Hepatitis B related childhood 
hepatocellular carcinoma. Childhood hepatic malignancies. Cancer 1987;60:4148.
EMEA-000298-PIP01-08.
Epivir-HBV (lamivudine tablets for oral use) U.S. Package Insert GlaxoSmithKline.
Papatheodoridis G, Buti M, Cornberg M, et al. European Association for the Study of 
the Liver Clinical practice guidelines: management of chronic hepatitis B. J Hepatol 
2012;57:16785.
Feld JJ, Terrault N, Belle SH, et al. The combination of entecavir and peginterferon 
alfa-2a in HBeAg-positive immune tolerant (IT) adults with chronic hepatitis B 
virus (HBV) infection: results of the HBRN IT trial. Abstract 910. American 
Association for the Study of Liver Diseases Congress. 2017 Washington, DC.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
91
Giacchino R, Cappelli B. Treatment of viral hepatitis B in children. Expert Opin 
Pharmacother 2010;11:889903.
Hsu HC, Wu MZ, Chang MH, et al. Childhood hepatocellular carcinoma develops 
exclusively in hepatitis B surface antigen carriers in three decades in Taiwan: a 
report of 51 cases strongly associated with rapid development of cirrhosis. J Hepatol 
1987;5:2607.
Hsu HC, Lin YH, Chang MH, et al. Pathology of chronic hepatitis B virus infection in 
children: with special reference to the intrahepatic expression of hepatitis virus 
antigens. Hepatology 1988;8:37882.
Hsu HY, Chang MH, Lee CY, et al. Spontaneous loss of HBsAg in children with 
chronic hepatitis B virus infection. Hepatology 1992;15:3826.
Jara P, Bortolotti F. Interferon-alpha treatment of chronic hepatitis B in childhood: a 
consensus advice based on experience in European children. J Pediatr 
Gastroenterol Nutr. 1999;29:16370.
Jonas MM, Mizerski J, Badia IB, et al. Clinical trial of lamivudine in children with 
chronic hepatitis B. N Engl J Med 2002;346:170613.
Jonas MM, Little NR, Gardner SD, et al. Long-term lamivudine treatment of children 
with chronic hepatitis B: durability of therapeutic responses and safety. J Viral Hepat 
2008;15:207.
Jonas MM, Block JM, Haber BA, et al. Treatment of children with chronic hepatitis B 
virus infection in the United States: patient selection and therapeutic options. 
Hepatology 2010;52:2192205.
Kiire CF. Hepatitis B infection in sub-Saharan Africa. The African Regional Study 
Group. Vaccine 1990;8:S10712.
Kovacs M, Multi-Health Systems (MHS) Staff. Children’s Depression Inventory (CDI) 
Technical Manual Update, New York: Multi-Health Systems Inc., 1992, 2003. 
Printed December 2010.
Kurbergov AC, Sokol RJ. Hepatitis B therapy in children. Expert Rev Gastroenterol 
Hepatol 2009;3:3949.
Lai CL, Dienstag J, Schiff E, et al. Prevalence and clinical correlates of YMDD 
variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect 
Dis 2003;36:68796.
Lai CL, Lok AS, Lin HJ, et al. Placebo-controlled trial of recombinant 2-interferon in 
Chinese HBsAg-carrier children. Lancet 1987;2:87780.
Lai CL, Lin HJ, Lau JN, et al. Effect of recombinant alpha 2 interferon with or without 
prednisone in Chinese HBsAg carrier children. Q J Med 1991;78:15563.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
92
Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the 
combination for HBeAg-positive chronic hepatitis B. N Engl J Med 
2005;352:2682-95
Lee SH, Kim HS, Byun IS, et al. Pre-existing YMDD mutants in treatment-naïve 
patients with chronic hepatitis B are not selected during lamivudine therapy. J Med 
Virol 2012;84:21722.
Leuschner I, Harms D, Schmidt D. The association of hepatocellular carcinoma in 
childhood with hepatitis B virus infection. Cancer 1988;62:23639.
Liaw YF, Jia JD, Chan HL, et al. Shorter durations and lower doses of peginterferon 
alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in 
hepatitis B virus genotypes B or C. Hepatology. 2011;54:15919.
Lok AS, Wu PC, Lai CL, et al. A controlled trial of interferon with or without 
prednisone priming for chronic hepatitis B. Gastroenterology 1992;102:20917.
Lok AS, McMahon BJ. American Association for the Study of Liver Diseases, 
Chronic Hepatitis B:update 2009. Hepatology 2009;50:6612.
Maynard JE, Kane MA, Alter MJ, et al. Control of hepatitis B by immunization: global 
perspective. In: Zuckerman AJ (ed). Viral hepatitis and liver disease. Alan R Liss, 
New York 1988 pp 96769.
Moyes CD, Milne A, Waldon J. Liver function of hepatitis B carriers in childhood. 
Pediatr Infect Dis J 1993;12:1205.
Murray KF, Shah U, Mohan N, et al. Chronic Hepatitis. J Pediatr Gastroenterol Nutr 
2008;47:22533.
Natsuizaka M, Hige S, Ono Y, et al. Long-term follow-up of chronic hepatitis B after 
the emergence of mutations in the hepatitis B virus polymerase region. J Viral Hepat 
2005;12:1549.
Park HJ, Chu MA, Hong SJ, et al. The rate of conversion to the Immune Reactive 
Phase from the Immune Tolerant Phase in Children with Chronic Hepatitis B. Oral 
Presentation (OP-1-4-3 [#06021]) 4th World Congress of Pediatric Gastroenterology, 
Hepatology, and Nutrition 2012, Taipei, Taiwan.
Pegasys/Copegus Investigator’s Brochure. Version 15. July 2012.
Poddar U, Yachha SK, Agarwal J, et al. Cure for immune-tolerant hepatitis B in 
children: is it an achievable target with sequential combo therapy with lamivudine 
and interferon? J Viral Hepat 2013;20:3116.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
93
Rosenthal P, Ling SC, Belle SH, et al. The combination of entecavir and 
peginterferon alfa-2a in HBeAg-positive immune-tolerant (IT) children and 
adolescents with chronic hepatitis B virus (HBV) infection: results of the HBRN 
pediatric IT trial. Abstract 910. American Association for the Study of Liver 
Diseases Congress. 2017 Washington, DC.
Salpini R, Svicher V, Cento V, et al. Characterization of drug-resistance mutations in 
HBV D-genotype chronically infected patients, naïve to antiviral drugs. Antiviral Res. 
2011;92:3825.
Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the 
management of hepatitis B: a 2015 update.  Hepatol Int. 2015 Nov 13 (epub ahead 
of print).
Schwarz KB, Mohan P, Narkewicz MR, et al. Safety, efficacy and pharmacokinetics 
of peginterferon 2a(40 kd) in children with chronic hepatitis C. J Ped Gastroenterol 
Nutr 2006;43:499505.
Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in 
children with CKD. J Am Soc Nephrol 2009;20:629–37.
Seto WK, Hui AJ, Wong VW, et al. Treatment cessation of entecavir in hepatitis B e 
antigen-negative chronic hepatitis B Asian patients: a multicenter prospective study. 
Gut 2015;64:667–672
Sokal EM, Roberts EA, Mieli-Vergani G, et al. A dose ranging study of the 
pharmacokinetics, safety, and preliminary efficacy of lamivudine in children and 
adolescents with chronic hepatitis B. Antimicrob Agents Chemother 2000;44:5907.
Sokal EM, Kelly DA, Mizerski J,et al. Long-term lamivudine therapy for children with 
HBeAg-positive chronic hepatitis B. Hepatology 2006;43:22532.
Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of 
chronic hepatitis B. Hepatology. 2016;63:261-83. 
Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma by exchange blood 
transfusion. N Engl J Med 1966; 274:47381.
Wirth S, Zhang H, Hardikar, W, et al. Efficacy and safety of peginterferon alfa-2a 
(40KD) in children with chronic hepatitis B: the PEG-B_ACTIVE study. 
Hepatology 2018; doi: 10.1002/hep.30050. [Epub ahead of print].
Zhao J, Guo Y, Yan Z, et al. The natural YMDD mutations of hepatitis B virus in 
Western China. Scand J Infect Dis 2012;44:447.
Zöllner B, Petersen J, Puchhammer-Stöckl E, et al. Viral features of lamivudine 
resistant hepatitis B genotypes A and D. Hepatology 2004;39:4250.
Zoulim F, Locarnini S. Optimal management of chronic hepatitis B patients with 
treatment failure and antiviral drug resistance. Liver Int 2013;33(Suppl. 1):116–124

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
94
Appendix 1A
Schedule of AssessmentsPegasys® Monotherapy for Previous IST Patients Only
Assessment/Procedure
Screen 
Week
-6 to -1
Pegasys® Treatment Week
Initial 
Follow-up 
Week
Long-term Follow-up 
Year a
BL
1
2
4
6
8
12
24
36
48
4
26
1
2
3
4
5 b
Informed consent/assent c
x
Medical history d
x
x
Demography
x
Concomitant medications e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Physical examination
x
x
Symptom-directed PE
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG
x
Vital signs f
x
x
x
x
x
x
x
x
x
x
x
x
x n
x n
x n
Height (cm) g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Weight (kg) g
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Ophthalmology h
x
x
Liver biopsy m
x
AEs i
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispense study drug
x
x
x
x
x
x
Hematology j, l
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x n
x n
x n
Chemistry k, l
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x n
x n
x n
FT3, FT4, TSH l,
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x n
x n
x n
ASMA, ALKM1, ANA, A1AT 
x
x
x
x
x
x
x
x
x
x
x
x
x n
x n
x n

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
95
Appendix 1A
Schedule of AssessmentsPegasys® Monotherapy for Previous IST Patients Only (cont.)
Assessment/Procedure
Screen 
Week
-6 to -1
Pegasys® Treatment Week
Initial 
Follow-up 
Week
Long-term Follow-up 
Year a
BL
1
2
4
6
8
12
24
36
48
4
26
1
2
3
4
5 b
AFP
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x n
x n
x n
Pregnancy test
x
x
x
x
x
x
x
x
x
x
x
Anti-HCV, anti-HIV, and anti-
HDV
x
HBV genotype
x
HBsAg, HBeAg, (anti-HBe, 
anti-HBs)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
HBV DNA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Lamivudine or entecavir viral
resistance 
x
x
A1AT = -1-antitrypsin; AFP = -fetoprotein; ALKM1 = anti-liver-kidney microsome-1 antibody; ANA = antinuclear antibody; ASMA = anti–smooth 
muscle antibody; BL = baseline; FT3 = free triiodothyronine; FT4 = free thyroxin; f/u = follow-up; HBeAg = hepatitis B envelope antigen; HBsAg = 
hepatitis B surface antigen; HBV hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; PE = physical examination; TSH = 
thyroid-stimulating hormone; YMDD = tyrosine-methionine-aspartate-aspartate.
Notes:  For description of Pegasys® Monotherapy group see Section 3.1.5.
On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.
a.
For visits after follow-up Week 26, the visit window is 28 days.
b.
For patients withdrawing after follow-up Week 26, the assessments as per follow-up year 5 visit should be completed.
c.
Informed consent signed by the patient’s parent/legal guardian and informed consent or assent (if applicable) signed by the patient.
d.
Clinically significant diseases within the previous 2 years and HBV history.  After baseline, new or worsening abnormalities should be 
recorded on the AE eCRF.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
96
Appendix 1A
Schedule of AssessmentsPegasys® Monotherapy for Previous IST Patients Only (cont.)
e.
Including any significant concomitant medications taken within 2 years prior to baseline.  During long term follow-up only concomitant 
medications (including herbal agents) for HBV need to be recorded. Including any significant surgeries/procedures prior to baseline.  During 
long-term follow-up, only surgeries/procedures associated with reportable adverse events need to be recorded (see Section 5.3.1).
f.
Blood pressure, heart rate, temperature.
g.
Measurements to be taken using the same instruments in the same individual.  A stadiometer with mean of three readings should be used for 
height measurement.
h.
By ophthalmologist and including fundoscopic examination, visual acuity assessment, visual field testing, and color visual testing.  Any patient 
who develops ocular symptoms should receive a prompt eye examination by an ophthalmologist and additional examinations as necessary.
i.
After informed consent has been obtained but prior to initiation of study drug, only SAEs caused by a protocol mandated intervention should 
be reported.  Beyond follow-up Week 26 investigators should report persisting AEs, new-onset SAEs, including AEs of concern, that are 
believed to be 
j.
Complete blood count (hemoglobin, hematocrit, reticulocytes, total WBC count, differential WBC count [neutrophils, lymphocytes, monocytes, 
eosinophils, basophils], platelet count), INR.  
k.
ALT, AST, GGT, bilirubin (total, direct and indirect), alkaline phosphatase, total protein, albumin, BUN/urea, creatinine, uric acid, total calcium, 
phosphorus, cholesterol, triglycerides, random glucose, sodium, chloride, potassium.  Estimated creatinine clearance to be calculated 
internally by Roche at baseline and Week 48.
l.
If there are clinically significant laboratory abnormalities, repeat no less frequently than every 2 weeks or as clinically indicated, with 
appropriate toxicity management, until values return to normal or baseline.
m.
If applicable (see Section 4.1.1).  Where available the biopsy score should be reported in the CRF.
n.
Assessment does not need to be performed by any previous IST patients who are continuing into follow-up as part of the Roche-sponsored 
study.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
97
Appendix 1B
Schedule of Assessments:  Pegasys® + Lamivudine or Entecavir
Assessment/Procedure
Screen 
Week
Lamivudine or 
Entecavir
Treatment 
Week a
Pegasys®Lamivudine or Entecavir Treatment Week a
Initial 
Follow-up 
Week b
Follow-up 
(Year Post End 
of Treatment) c
-6 to -1
BL
1d
4d
8
9d 10d 12d 14d 16d 20 26d 32 38d 44 50d 56e
4
24f
1 g
Informed consent/assent h
x
Medical history i
x
x
Demography
x
Concomitant medications j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Surgeries/procedures k
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Physical examination
x
x
x
x
Symptom-directed PE
x
x
x
x
x
x
x
x
x
x
x
x
ECG l
x
Vital signs m
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Height (cm) n
x
x o
x o
x o
x o
x o
x
x
x
Weight (kg) n
x
x o
x
x o
x
x
x o
x
x o
x
x o
x
x
x
x
x
Parental height p
x
Date of menarche for females
q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tanner Stage r
x
x
x
Ophthalmology l, s
x
x
x
x
Liver abdominal ultrasound l, t
x
Liver biopsy u
x
CDI v
x
x
x
x
x
x
x
x
AEs w
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Patient medication diary 
x
x
x
x
x
x
x
x
x
x
x
x
Dispense study drug
x
x
x
x
x
x
x
x
x
x
x
Urinalysis x, aa
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematology, coagulation y, aa
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Chemistry z, aa
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x

Appendix 1B
Schedule of Assessments – Pegasys Lamivudine/Entecavir (cont.)
Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
98
Assessment/Procedure
Screen 
Week
Lamivudine or 
Entecavir
Treatment 
Week a
Pegasys®Lamivudine or Entecavir Treatment Week a
Initial 
Follow-up 
Week b
Follow-up 
(Year Post End 
of Treatment) c
-6 to -1
BL
1d
4d
8
9d 10d 12d 14d 16d 20 26d 32 38d 44 50d 56e
4
24f
1 g
Lactate
x
x
x
x
x
x
FT3, FT4, TSH l, aa
x
x
x
x
x
x
x
x
TBG l
x
TPO antibodies l
x
x
x
ASMA, ALKM1, ANA l
x
x
x
x
x
x
x
x
AFP, A1AT l
x
Pregnancy test bb
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Anti-HAV IgM, anti-HCV, anti-
HIV, and anti-HDV l
x
HBV genotype l
x
HBsAg, HBeAg, (anti-HBe, 
anti-HBs) l
x
x
x
x
x
x
x
x
x
x
Quantitative HBsAg/HBeAg l
x
x
x
x
x
x
x
HBV DNA l
x
x
x
x
x
x
x
x
x
x
Serum bank sample cc
x
x
x
x
x
x
x
Lamivudine or entecavir viral 
resistance
x
x
x
x dd
x dd
RCR samples (optional) ee
x
x
x
x
x
x
x
x
A1AT = -1-antitrypsin; Ab = antibody; AFP = -fetoprotein; ALKM1 = anti-liver-kidney microsome-1 antibody; ANA = antinuclear antibody; ASMA 
= anti–smooth muscle antibody; BL = baseline (Day 1); BSA = body surface area; CDI = Children’s Depression Inventory; eCRF = electronic Case 
Report Form; FT3 = free triiodothyronine; FT4 = free thyroxin; f/u = follow-up; HAV = hepatitis A virus; HBeAg = hepatitis B envelope antigen; 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HDV = hepatitis D virus; IgM = immunoglobulin M; PE = physical examination; RCR 
= Roche Clinical Repository; SAE = serious adverse event; TBG = Thyroxine-binding globulin; TPO = Thyroid peroxidase; TSH = thyroid-

Appendix 1B
Schedule of Assessments – Pegasys Lamivudine/Entecavir (cont.)
Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
99
stimulating hormone.
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified.
a For visits during the treatment period the visit window is 3 days.
b For visits during the initial f/u period (24 week period post-treatment), up to and including follow-up Week 24, the visit window is 7 days.
c For visits after f/u Week 24, the visit window is 28 days.
d Visit may be undertaken at the patient’s primary physician clinic/local hospital (Visit 1, 9, 10, or 14 only) or patient’s home (e.g., by mobile 
nurse), if this is feasible and more convenient for the patient, and upon agreement with the investigator.  The primary physician/local hospital 
laboratory must be accredited and local laboratory ranges must be provided.  If the visit occurs at the primary physician clinic/local hospital, AEs 
will then be recorded via a telephone call from investigator site to patient’s parent/legal guardian. 
e Week 56 assessments should be completed for patient’s prematurely discontinuing treatment.  Patient’s remaining in the study should then 
continue onto the follow-up visit schedule.
f
For patients withdrawing after the end of treatment but prior to follow-up 24, the assessments as per the follow-up Week 24 visit should be 
completed. 
g For patients withdrawing after follow-up Week 24, the assessments as per follow-up Year 1 visit should be completed.
h Informed consent signed by the patient’s parent/legal guardian and informed consent or assent (if applicable) signed by the patient.
i
Clinically significant diseases within the previous 2 years and HBV history.  After baseline, new or worsening abnormalities should be recorded 
on the adverse events eCRF
j
Including any significant concomitant medications taken within 2 years prior to baseline.  During follow-up only concomitant medications 
(including herbal agents) for HBV need to be recorded.
k Including any significant surgeries/procedures prior to baseline.  During follow-up, only surgeries/procedures associated with reportable adverse 
events need to be recorded (see Section 5.3.1).
l
Within 6 months prior to baseline; repeat at screening only if any change in the medical condition.  Parameters do not need to be repeated at 
rescreening if performed within 6 months prior to baseline, unless dictated by a change in the patient’s medical condition or the parameter 
accounted for the original screen failure  
m Blood pressure, heart rate, temperature.
n Measurements to be taken using the same instruments in the same individual.  A stadiometer with mean of three readings should be used for 
height measurement.  Exception to using the same instruments in the same individual is if patients are measured at home by a mobile nurse, in 
which case the same brand of scales must be used by both the site and the mobile nurse for weight, and a stadiometer must still be used for 
height.  

Appendix 1B
Schedule of Assessments – Pegasys Lamivudine/Entecavir (cont.)
Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
100
o A system will be in place to confirm the patient’s BSA and intended dose of Pegasys® based on the patient’s weight and height.  
p From consenting biological parents.  May be collected at any point during the study.
q Date of menarche should be assessed at each visit as appropriate. 
r
If the patient/guardian agrees, Tanner Stage for all patients will be determined at baseline.  Once a patient is deemed to have reached Tanner 
Stage 5, no further assessments are required.
s
By ophthalmologist and including fundoscopic examination with dilation, visual acuity assessment, visual field testing and color visual testing.  
Eye examination by a pediatric ophthalmologist is recommended.  Visual field testing by confrontation is recommended for younger patients.  
Any patient who develops ocular symptoms should receive a prompt eye examination by an ophthalmologist and additional examinations as 
necessary.
t
Must show no signs of HCC, and for patients without study entry liver biopsy must also show no signs of cirrhosis or splenomegaly.
u If applicable (see Section 4.1.1).  Where available, the liver biopsy score should be reported on the CRF
v Children 7 years of age only.  Should be performed prior to the completion of other study assessments.
w After informed consent has been obtained but prior to initiation of study drug, only SAEs caused by a protocol mandated intervention should be 
reported.  Beyond follow-up Week 24 investigators should report persisting AEs, new-onset SAEs or, non-serious AEs of special interest that 
are believed to be related to prior treatment with study drugs and any deaths.
x Dipstick with subsequent microscopic evaluation if positive for blood.  To be performed by site/local laboratory.  
y Complete blood count (hemoglobin, hematocrit, reticulocytes, total WBC count, differential WBC count [neutrophils, lymphocytes, monocytes,
eosinophils, basophils], platelet count), INR.  
z ALT, AST, GGT, bilirubin (total, direct and indirect), alkaline phosphatase, total protein, albumin, BUN/urea, creatinine, uric acid,  total calcium, 
phosphorus, cholesterol, triglycerides, random glucose, sodium, chloride, potassium.  Estimated creatinine clearance to be calculated by sites 
during lamivudine or entecavir treatment any time creatinine is abnormal (see formula in Appendix 5), and internally by Roche at baseline and 
Week 56.
aa If there are clinically significant laboratory abnormalities, repeat no less frequently than every 2 weeks or as clinically indicated, with appropriate 
toxicity management, until values return to normal or baseline.  
bb Females of child bearing potential only (Tanner stage 2, where available, or onset of menarche).  Test as per schedule and any time 
secondary amenorrhea of more than 1 week occurs.  Serum pregnancy test at screening.  Urine pregnancy tests may be performed at 
subsequent visits.  Result of baseline pregnancy test must be available prior to randomization and commencement of treatment. If a urine 
pregnancy test result is positive, it must be confirmed by a serum pregnancy test.  Urine pregnancy test to be performed by site.  
cc Sample will be retained frozen at the central laboratory in the event that repeat testing is required. If patient provides consent/assent to RCR 

Appendix 1B
Schedule of Assessments – Pegasys Lamivudine/Entecavir (cont.)
Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
101
samples, residual serum bank samples will be converted into additional RCR serum samples at the end of the study.
dd If lamivudine or entecavir viral resistance is detected at follow-up Week 4 or the test is unsuccessful, a blood sample to assess for lamivudine or 
entecavir viral resistance should be collected at follow-up Week 24; if lamivudine or entecavir viral resistance is detected at follow-up Week 24, 
then testing should continue up to the last time point of the follow-up period.  If HBV DNA measurement was negative at follow-up Week 4 but 
becomes positive at follow-up Week 24, an unscheduled blood sample may be requested for lamivudine or entecavir viral resistance testing, 
preferably within 24 weeks; if lamivudine or entecavir viral resistance is detected, lamivudine or entecavir viral resistance testing should be 
performed at the last time point of the follow-up period.
ee Not applicable for a site that has not been granted approval for RCR sampling. RCR sample for DNA extraction at baseline only.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
102
Appendix 1C
Schedule of Assessments:  Untreated Control
Assessment/Procedure
Screen 
Week
Untreated Observation Week a
-6 to -1
BL
32w
56w
80b
Informed consent/assent c
x
Medical history d
x
x
Demography
x
Concomitant medications e
x
x
x
x
x
Surgeries/procedures f
x
x
x
x
x
Physical examination
x
x
x
Symptom-directed PE
x
x
ECG g
x
Vital signs h
x
x
x
x
x
Height (cm) i
x
x
x
x
x
Weight (kg) i
x
x
x
x
x
Parental height j
x
Date of menarche for females 
x
x
x
x
x
Tanner Stage x
x
x
Ophthalmology k, g
x
Liver abdominal ultrasound l, g
x
Liver biopsy m
x
CDI n
x
x
AEs o
x
x
x
x
x
Urinalysis p, s
x
x
x
x
x
Hematology, coagulation s, q
x
x
x
x
x
Chemistry r, s
x
x
x
x
x
Lactate
x
FT3, FT4, TSH s, g
x
x
x
x
TPO antibodies, TBG g
x
ASMA, ALKM1, ANA g
x
x
x
x
x
AFP, A1AT g
x
Pregnancy test t
x
x
Anti-HAV IgM, anti-HCV, anti-HIV, 
and anti-HDV g
x
HBV genotype g
x
HBsAg, HBeAg, (anti-HBe, 
anti-HBs) g
x
x
x
x
x
Quantitative HBsAg/HBeAg g
x
x
x
x
HBV DNA g
x
x
x
x
x
Serum bank sample u
x
x
x
x
Lamivudine or entecavir viral
resistance
x
RCR samples (optional) v
x
x
x
x
AEadverse event, A1AT = -1-antitrypsin; Ab = antibody; AFP = -fetoprotein; ALKM1 = 
anti-liver-kidney microsome-1 antibodies; ANA = antinuclear antibody; ASMA = anti–smooth 
muscle antibody; anti-HBe = hepatitis B envelope antibody; anti-HBs = hepatitis B surface 
antibody; BL = baseline (Day 1); BSA = body surface area; CDI = Children’s Depression 
Inventory; eCRF = electronic Case Report Form; FT3 = free triiodothyronine; FT4 = free thyroxin; 
f/u = follow-up; HAV = hepatitis A virus; HBeAg = hepatitis B envelope antigen; HBsAg = hepatitis 
B surface antigen; HCV = hepatitis C virus; HDV = hepatitis D virus; IgM = immunoglobulin M, PE 
= physical examination; PK = pharmacokinetic; RCR = Roche Clinical Repository; 

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
   103
Appendix 1C
Schedule of Assessments – Untreated Control (cont.)
SAE = serious adverse event; TBG = Thyroxine-binding globulin; TPO = Thyroid peroxidase; TSH 
= thyroid stimulating hormone.
a.
For visits up to and including Week 80, the visit window is 7 days.
b.
For patients withdrawing prior Week 80, the assessments as per the Week 80 visit should be 
completed. 
c.
Informed consent signed by the patient’s parent/legal guardian and informed consent or 
assent (if applicable) signed by the patient.
d.
Clinically significant diseases within the previous 2 years and HBV history.  After baseline, new 
or worsening abnormalities should be recorded on the AE eCRF
e.
Including any significant concomitant medications taken within 2 years prior to baseline.
f.
Including any significant surgeries/procedures prior to baseline.  
g.
Within 6 months prior to baseline; repeat at screening only if any change in the medical 
condition.  Parameters do not need to be repeated at rescreening if performed within 6 months 
prior to baseline, unless dictated by a change in the patient’s medical condition or the 
parameter accounted for the original screen failure  
h.
Blood pressure, heart rate, temperature.
i.
Measurements to be taken using the same instruments in the same individual.  A stadiometer 
with mean of three readings should be used for height measurement.  Exception to using the 
same instruments in the same individual is if patients are measured at home by a mobile 
nurse, in which case the same brand of scales must be used by both the site and the mobile 
nurse for weight, and a stadiometer must still be used for height.
j.
From consenting biological parents.  May be collected at any point during the study.
k.
By ophthalmologist and including fundoscopic examination with dilation, visual acuity 
assessment, visual field testing, and color visual testing.  Eye examination by a pediatric 
ophthalmologist is recommended.  Visual field testing by confrontation is recommended for 
younger patients.  Any patient who develops ocular symptoms should receive a prompt eye 
examination by an ophthalmologist and additional examinations as necessary.
l.
Must show no signs of HCC, and for patients without study entry liver biopsy must also show 
no signs of cirrhosis or splenomegaly.
m.
If applicable (Section 4.1.1).  Where available, the liver biopsy score should be reported on the 
CRF. 
n.
Children 7 years of age only.
o.
After informed consent has been obtained but prior to baseline, only SAEs caused by a 
protocol mandated intervention should be reported.  
p.
Dipstick with subsequent microscopic evaluation if positive for blood. To be performed by 
site/local laboratory. 
q.
Complete blood count (hemoglobin, hematocrit, reticulocytes, total WBC count, differential 
WBC count [neutrophils, lymphocytes, monocytes, eosinophils, basophils], platelet count), INR.  
r.
ALT, AST, GGT, bilirubin (total, direct and indirect), alkaline phosphatase, total protein, 
albumin, BUN/urea, creatinine, uric acid, total calcium, phosphorus, cholesterol, triglycerides, 
random glucose, sodium, chloride, potassium.  Estimated creatinine clearance to be calculated 
internally by Roche at baseline and Week 56.
s.
If there are clinically significant laboratory abnormalities, repeat no less frequently than every 
2 weeks or as clinically indicated, with appropriate toxicity management, until values return to 
normal or baseline.  
t.
Females of child bearing potential only.  Test any time secondary amenorrhea of more than 
1 week occurs.  Serum pregnancy test at screening.  Urine pregnancy tests may be performed 
at subsequent visits.  Result of baseline pregnancy test must be available prior to 
randomization and commencement of treatment.  If a urine pregnancy test result is positive, it 
must be confirmed by a serum pregnancy test.  Urine pregnancy test to be performed by local 
laboratory.  

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
   104
Appendix 1C
Schedule of Assessments – Untreated Control (cont.)
u.
Sample will be retained frozen at the central laboratory in the event that repeat testing is 
required. If patient provides consent/assent to additional RCR samples, residual serum bank 
samples will be converted into RCR serum samples at the end of the study.  Not applicable for 
a site that has not been granted approval for RCR sampling.  
v.
Not applicable for a site that has not been granted approval for RCR sampling.  RCR sample 
for DNA extraction at baseline only.
w.
Visit may be conducted at the patient’s home (e.g., by a mobile nurse), if this is feasible and 
more convenient for the patient, and upon agreement with the investigator. 
x.
Depending on IRB/EC and HA approval, and if the patient/guardian agrees, Tanner stage for 
all patients will be determined at baseline. Once a patient is deemed to have reached Tanner 
stage 5, no further assessments are required.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
   105
Appendix 2
Child Pugh Classification of Severity of Liver Disease
Clinical and Biochemical Measurements
Points Scored for Increasing Abnormality
1
2
3
Encephalopathy (grade) a
None
1 or 2
3 or 4
Ascites b
Absent
Slight
Moderate
Bilirubin (mol/L)
34
34–50
50
Albumin (g/L)
35
28–35
28
Prothrombin time prolongation (seconds prolonged)
OR
4
4–6
6
Prothrombin time (International Normalized Ratio)
1.7
1.7–2.3
2.3
a According to grading of Trey et al.1966.
b As determined by physical examination alone.
1, 2, or 3 points are scored for increasing abnormality of each of the 5 parameters 
measured.
Class A:  5 or 6
Class B:  7 to 9
Class C:  10 to 15

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
106
Appendix 3
Liver Biopsy Scores
Various liver biopsy classification systems may be used for entry into this study.  Some 
examples are included below.  
Scores considered as minimal or mild fibrosis will be Metavir Fibrosis Score 02; 
Knodell Fibrosis Score 01; Modified Ishak Fibrosis Score 03; Batts & Ludwig Fibrosis 
Score 02; or Scheuer Fibrosis Score 02.  
Scores considered as advanced fibrosis and cirrhosis will be Metavir Fibrosis Score 34; 
Knodell Fibrosis Score 34; Modified Ishak Fibrosis Score 46; Batts & Ludwig Fibrosis 
Score 34; or Scheuer Fibrosis Score 34.  Patients with these scores are excluded 
from the study.
METAVIR FIBROSIS SCORE
0.
No fibrosis
1.
Stellate enlargement of portal tract but without septa formation
2.
Enlargement of portal tract with rare septa formation
3.
Numerous septa without cirrhosis
4.
Cirrhosis
KNODELL FIBROSIS SCORE
5.
No fibrosis
6.
Fibrous portal expansion
7.
Bridging fibrosis (portal-portal or portal-central linkage)
8.
Cirrhosis
MODIFIED ISHAK FIBROSIS SCORE
9.
No fibrosis
10. Fibrous expansion of some portal areas, with or without short fibrous septa
11. Fibrous expansion of most portal areas, with or without short fibrous septa
12. Fibrous expansion of most portal areas, with occasional portal to portal 
(P-P) bridging
13. Fibrous expansion of portal areas, with marked bridging (P-P) as well as portal-
central (P-C)
14. Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis)
15. Cirrhosis, probable or definite

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
107
Appendix 3
Liver Biopsy Scores (cont.)
BATTS & LUDWIG FIBROSIS SCORE
0. No fibrosis; normal connective tissue
1. Portal fibrosis; fibrous portal expansion
2. Periportal fibrosis; periportal or rare portal-portal septa
3. Septal fibrosis; fibrous septa with architectural distortion; no obvious cirrhosis
4. Cirrhosis
SCHEUER FIBROSIS SCORE
0.
None
1.
Enlarged by fibrosis
2.
Portal-portal linkage
3.
Distortion, not cirrhotic
4.
Cirrhosis (or probable)

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
108
Appendix 4
Pegasys® Dose Modification Guidance
The intention of the protocol is that patients remain on study treatment until the 
completion of the allocated treatment period.  However, it is possible that some patients 
will encounter transient or prolonged adverse effects at some juncture during their
participation in the study leading to adjustment of study drug dosage.  To minimize the 
effects of these modifications on the eventual evaluation of the safety, tolerability, and 
efficacy of test drug regimens, dose adjustment guidance is provided in this Appendix, 
including guidance for management of specific effects.  It should be kept in mind that, 
whereas this guidance should be generally followed to promote consistency across 
centers, other responses by an investigator may be more appropriate in some 
circumstances.  
Moderate or severe adverse reactions (clinical and/or laboratory) may require dose 
reduction.  Decremental adjustments should be uniform across centers and patients.  
When practicable, abnormal laboratory results should be confirmed as soon as possible 
following notification of the investigator.  For laboratory and vital signs abnormalities, 
“severe” may be considered as any value requiring intervention, further work up, or more 
frequent follow-up (Section 5.3.3).
If consistent with patient safety, doses should not be held or eliminated.  This 
recommendation stems from concerns that extended periods of lowered drug 
concentrations in the blood may be associated with the replication of the more resistant 
clones of the virus, resulting in a lack of sustained response at the conclusion of therapy.  
Investigators should consider if adjusting the dose, either transiently or permanently, 
might be appropriate rather than holding a dose.
The investigator will record the patient’s recommended dose of study medication on the 
medication diary.
Missing Consecutive Doses
If four or more consecutive doses of Pegasys® are held or otherwise not administered 
(i.e., the patient has not received test medication for more than 28 days), the patient will 
be considered intolerant of the test medication or non-compliant, whichever is more 
appropriate to the clinical situation.  No additional test drug may be administered to such 
patients, without explicit permission from the sponsor.  

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
109
Appendix 4
Pegasys® Dose Modification Guidance (cont.)
Dose Delay
If a Pegasys® dose is delayed but eventually administered, the following guidelines 
should be utilized for the next scheduled dose(s):

Dose delayed 1 or 2 days:  administer on usual dosing day of the week (e.g., if 
Monday is the usual dosing day and the dose is delayed until Wednesday, the next 
dose may be administered as usual on Monday).

Dose delayed 3 to 5 days:  administer subsequent doses every fifth or sixth day until 
the patient is back to his or her original schedule (e.g., if Monday is the usual dosing 
day and the dose is delayed until Saturday, the next dose should be administered 
on Thursday, the following dose on Tuesday, then the dose after that as usual on 
Monday).

Dose delayed 6 days:  hold the dose for that week then continue on the usual 
schedule the following week (e.g., if Monday is the usual dosing day but the patient 
is not ready to be dosed until the following Sunday, the dose is considered to have 
been held and the next injection should be for the following week’s dose on 
Monday).

Dose delayed 7 days:  the investigator may reintroduce test drug at any time and, 
if necessary, dose the patient every fifth or sixth day until the patient resumes 
weekly dosing on their usual scheduled day.
Dose Reduction Levels
The downward adjustments in Table 1 below should be utilized.  If appropriate, 
downward adjustments in one level decrements should be considered.  
Table 1
Pegasys® Dose Reduction Levels
Starting Dose 
One-Level Reduction
Two-Level Reduction
Three-Level Reduction
(g)
(mL)
(g)
(mL)
(g)
(mL)
(g)
(mL)
45
0.25
30
0.17
20
0.11
10
0.06
65
0.36
45
0.25
30
0.17
20
0.11
90
0.50
65
0.36
45
0.25
20
0.11
135
0.75
90
0.50
65
0.36
30
0.17
180
1.00
135
0.75
90
0.50
45
0.25

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
110
Appendix 4
Pegasys® Dose Modification Guidance (cont.)
Once the patient’s unit dose has been decreased, the investigator may attempt to 
increase the dose back to or toward that which was originally assigned only if the 
following conditions are satisfied:

The event or circumstance responsible for the dosage adjustment has resolved or 
improved

Patients who have received more than four consecutive or six total doses at the 
lower dose level should not generally have their dosage regimen readjusted upward.
Specific Dose Reduction Guidance
Neutropenia, Thrombocytopenia and Elevated Serum ALT
Table 2
Neutropenia
ANC 
(x 109 cells/L)
Response
0.75
None
0.5–0.749
Immediate one-level adjustment and monitor
0.25–0.499
Delay or hold dose until 1.0 then resume dose with two-level adjustment and 
monitor
<0.25 or febrile 
neutropenia
PERMANENTLY DISCONTINUE STUDY TREATMENT
Table 3
Thrombocytopenia
Platelets
(x 109 cells/L)
Response
<50
Two-level dose reduction
<25
PERMANENTLY DISCONTINUE STUDY TREATMENT
Table 4
Elevated Serum ALT
ALT
Response
Persistent or 
increasing 
elevations 5 
but 10ULN
Reduce dose with a 1 level adjustment and monitor weekly ALT level to 
ensure it is stable or decreasing
Persistent ALT 
values 
10ULN
PERMANENTLY DISCONTINUE STUDY TREATMENT

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
111
Appendix 4
Pegasys® Dose Modification Guidance (cont.)
Severe Mood or Psychiatric Disorder
In cases of severe mood or psychiatric disorder, study treatment must be permanently 
discontinued and the patient referred for psychiatric intervention. 
Table 5
Recommended PEGASYS® Dosage Modifications and Psychiatric 
Visits Due to Depression 
Depression 
Severity
Initial Depression 
Management 4-8 Weeks
Depression Management after 8 Weeks
Dosage 
Modification
Visit 
Schedule
Depression 
Severity 
Remains 
Stable
Depression 
Severity 
Improves
Depression 
Severity 
Worsens
Mild
No change
Evaluate 
once 
weekly by 
visit 
and/or 
phone
Continue 
weekly visit 
schedule
Resume 
normal visit 
schedule
Consider 
psychiatric 
consultation. 
Discontinue 
Pegasys® or 
one or two 
level dose 
reduction
Moderate
One or two 
level dose 
reduction
Evaluate 
once 
weekly 
(office visit 
at least 
every 
other 
week)
Consider 
psychiatric 
consultation. 
Continue 
reduced 
dosing
If symptoms 
improve and 
are stable for 
4 weeks, 
may resume 
normal visit 
schedule. 
Continue 
reduced 
dosage or 
return to 
normal 
dosage
Obtain 
immediate 
psychiatric 
consultation 
Discontinue 
Pegasys®
permanently.

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
112
Appendix 4
Pegasys® Dose Modification Guidance (cont.)
Depression 
Severity
Initial Depression 
Management 4-8 Weeks
Depression Management after 8 Weeks
Dosage 
Modification
Visit 
Schedule
Depression 
Severity 
Remains 
Stable
Depression 
Severity 
Improves
Depression 
Severity 
Worsens
Severe
Discontinue 
Pegasys®
Permanently
Obtain 
immediate 
psychiatric 
consultation 
Psychiatric therapy necessary 
Change of Body Surface Area Category
Investigators will adjust the dose of Pegasys® upward or downward to reflect the most 
current Body Surface Area (BSA) category.  A system will be in place to confirm BSA 
and dose based on the patient’s weight and height at the time points indicated in the 
Schedule of Assessments (see Appendix 1).  Investigators may also assess the patient’s 
BSA (using the Mosteller formula) at other interim time points if they are concerned that 
the BSA and therefore Pegasys® dosing category may have changed.  It is 
recommended that an online calculator is utilized for the BSA calculation.
Mosteller Formula:
BSA (m²) = √[Height(cm) Weight(kg)] / 3600
If BSA falls below <0.51m2 during treatment, any dose adjustments should be made only 
after consultation between the Investigator and Medical Monitor.  The recommended 
dose will be recorded on the medication diary.  

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
113
Appendix 5
Estimated Creatinine Clearance
Schwartz Formula 2009 
Estimated creatinine clearance (mL/min/1.73 m²)= 
0.413Height (cm)
Serum Creatinine (mg/dL)
(Formula reproduced from Schwartz et al 2009)

Pegasys®—F. Hoffmann-La Roche Ltd
Protocol NV25361, Version 13
114
Appendix 6
Tanner Stages