Clinical trial NCT01519960
Conditions: Hepatitis B, Chronic
Sponsor: Hoffmann-La Roche
Start date: 2012-07-11; Completion date: 2021-10-18
Enrollment: 165 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This parallel group, open label study will evaluate the safety and efficacy of Pegasys (peginterferon alfa-2a) versus untreated control in children (age 3 years to \<18 years at baseline) with HBeAg positive chronic hepatitis B. Children without advanced fibrosis and without cirrhosis will be randomized 2:1 to treatment Group A, receiving Pegasys 45-180 mcg subcutaneously weekly for 48 weeks, or to the untreated control Group B. Children with advanced fibrosis will be assigned to treatment group C and receive 48 weeks of treatment with Pegasys. Children in the untreated control Group B who have not experienced seroconversion 48 weeks after randomization may enter the Switch Arm to receive 48 weeks of Pegasys treatment. This offer will be available for 1 year following 48 weeks from randomization. Anticipated time on study treatment is 48 weeks. All subjects will be followed up for 5 years after the end of treatment (A,C,Switch)/principal observation (B) period.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: peginterferon alfa-2a [Pegasys] intervention 2: peginterferon alfa-2a [Pegasys]
Intervention descriptions: intervention 1: Body surface area adapted doses of 45-180 mcg subcutaneously weekly for 48 weeks, Weeks 1- 48 intervention 2: Body surface area adapted doses of 45-180 mcg subcutaneously weekly for 48 weeks, after Week 48 for Group B patients who have not experienced HBeAg seroconversion

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Phase IIIb Parallel Group, Open Label Study of Pegylated 
Interferon alfa-2a Monotherapy (PEG-IFN, Ro 25-8310) Compared to 
Untreated Control in Children with HBeAg Positive Chronic Hepatitis 
B in the Immune Active Phase 
NCT Number: 
NCT01519960 
Document Date: 
Protocol Version E: 28-May-2014 
 
 


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Title
28-May-2014 15:03:27
Date and Time (UTC)
Company Signatory
Approver's Name
Pegylated Interferon alfa-2a—F. Hoffmann-La Roche Ltd 
Protocol YV25718, Version E  
1 
 
 
F. HOFFMANN-LA ROCHE LTD 
CLINICAL STUDY PROTOCOL 
PROTOCOL NUMBER YV25718 
RO 25-8310 
PEGASYS® 
EUDRACT NUMBER 2011-002732-70 
 
Sponsor:  F. HOFFMANN-LA ROCHE LTD 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
 
 
PROTOCOL APPROVAL
Protocol Number/Version:  YV25718 E    
Date:  See last date in electronic signature manifestation below. 
Protocol approved by:  See electronic signature manifestation 
below 
 
 
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property 
of F. Hoffmann-La Roche Ltd (or under its control), and therefore provided to you in 
confidence as an investigator, potential investigator or consultant, for review by you, 
your staff and an applicable Independent Ethics Committee/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 those persons to whom the drug may be administered. 


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PROTOCOL AMENDMENT, VERSION E: 
RATIONALE 
Protocol YV25718 has been amended as follows:  
• 
Negative hepatitis B surface antibody (anti-HBs) and hepatitis B envelope antibody 
(anti-HBe) results at screening has been removed as an inclusion critierion.  This is 
to avoid inappropriately excluding potential patients who have low level of anti-HBs 
or anti-HBe in the context of fulfilling all other eligibility criteria.  With the increasing 
sensitivity of laboratory assays, there have been several reports described with the 
coexistance of hepatitis B surface antigen (HBsAg) and anti-HBs antibodies in 10% 
to 25% of chronic hepatitis B (CHB) patients.  Some patients screened for this study 
have shown this.  In addition, current clinical guidelines (European Association for 
the Study of the Liver 2012, American Association for the Study of Liver Diseases 
2009, Asian Pacific Association for the Study of the Liver 2012) do not require 
negative results for anti-HBs and anti-HBe for the diagnosis of CHB. 
• 
For clarity and consistency, the exclusion criteria, switch exclusion criteria, and the 
stopping rule concerning hepatic decompensation have been updated. 
• 
The normal range of hemoglobin varies with age in pediatric patients; therefore the 
exclusion criterion and switch exclusion criterion for hemoglobin have been 
amended to below the lower limit of normal (< LLN) as opposed to using fixed cut-off 
values of <11 g/dL for females and <12 g/dL for males.  This may prevent 
unnecessary exclusion of some eligible patients. 
• 
The renal exclusion criterion has been amended to exclude patients with evidence 
of renal impairment. 
• 
Serum alanine aminotransferase (ALT) >10 × upper limit of normal (ULN) at switch 
baseline has been added into the switch exclusion criteria as treatment of 
Pegylated-Interferon Alfa-2a should normally not be initiated if ALT is >10 × ULN. 
• 
Changes have been made to the stopping rules to align with the current approved 
prescribing information, including removal of certain stopping rules, and separation 
of stopping rules into those where treatment must be discontinued and those where 
treatment discontinuation should be considered. 
• 
Scheuer Scoring system has been added in Appendix 1 (Liver Biopsy Scores) to 
help sites using this scoring system to classify the degree of liver fibrosis. 
Additional changes to the protocol are as follows: 
• 
The Medical Monitors’ details have been updated.  
• 
For clarity and consistency of occurrences of “post-treatment” have been changed 
to “post-end of treatment” 
• 
Additional rationale for the untreated control arm has been included, including 
procedures for minimizing the risk of bias in this open-label study. 
• 
Given the different schedule of assessments for the treatment group compared with 
the untreated group, it is practically not possible to blind the assessor within this 


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study. Therefore, the blinding of central laboratory to the treatment assignment has 
been removed. 
• 
Additional clarity has been included regarding administration of the Children’s 
Depression Inventory and assessment of patients with symptoms of major 
depression.  
• 
Additional clarity regarding the timepoint and contents of the primary safety analysis 
has been added.  In addition, following safety outcome measures until 1, 2, 3, 4, and 
5 years post-end of treatment have been added. 
• 
The schedule of assessments has been updated to clarify that the result of baseline 
pregnancy test must be available prior to randomization and commencement of 
treatment. 
• 
Additional text has been included regarding extensions of screening period, 
retesting of screening parameters, and circumstances for re-screening.  
• 
To fully evaluate the fundus of the eye and accurately detect any retinopathy, 
fundoscopic examination has been updated to specify that it should be with dilation.  
To facilitate a successful eye examination and minimize distress in this pediatric 
population, a Pediatric Ophthalmologist has been recommended.  To facilitate 
successful visual field testing in younger patients, confrontation has been 
recommended, as it is simpler than visual field test performed in automated machine 
and requires less collaboration of the child 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


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PROTOCOL AMENDMENT, VERSION E: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, 
where applicable. 
SECTION 3.1:  OVERVIEW OF STUDY DESIGN AND DOSING REGIMEN 
The screening period will be up to 35 days.All subjects will be followed up for 5 years after 
the end of treatment/principal observation period.  For Group A, Group B non-switch, and 
Group C subjects the study length is approximately 6 years (1-year treatment/principal 
observation period and 5 years of follow-up).  For Group B switch subjects the study 
length is up to approximately 8 years (1-year principal observation period, up to 1 year 
follow-up whilst deciding whether to switch, 1-year switch treatment period, and 5-year 
follow-up period). 
SECTION 3.1.1.1:  Use of Untreated Control Arm and Compassionate 
Switch 
An untreated control arm has been selected for this study as the use of a placebo control arm is 
not considered appropriate for several reasons.  Firstly, the use of placebo injections would not 
effectively blind treatment as the known adverse effects of IFN therapy, particularly influenza-like 
illness, would not occur.  It would therefore be likely that subjects/parents would become aware 
that the subject was not receiving IFN resulting in a potential risk of noncompliance.  Secondly, 
it would be unethical to administer weekly placebo injections for 48 weeks as administration 
requires an invasive procedure with an associated risk of injection-site infections and no 
associated benefit.  A further benefit of using an untreated control arm is that the study burden 
for the untreated subjects is reduced as their visit schedule is less frequent compared with that of 
the treated subjects, 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 central 
randomization, use of a central laboratory and standardized assays, and the choice of the intent-
to-treat (ITT) population for the primary analysis. 
SECTION 3.1.3:  End of Study 
The primary endpoint will be assessed 24 weeks after the end of treatment/principal 
observation period, with a further 4.5 years of extended long-term follow-up.  The end of 
study is defined as last subject last visit (LSLV).  
SECTION 4.1:  OVERVIEW 
The study population will be children aged 3 to < 18 years of age with CHB, who are 
HBeAg positive (+ve), HBsAg+ve, anti HBs negative ( ve), anti HBe ve, with detectable 
HBV-DNA (> 10,000 copies/mL [> 2,000 IU/mL]) by polymerase chain reaction (PCR) 


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and ALT > ULN but ≤ 10 × the ULN (using the reference range of the testing laboratory).  
Liver biopsy needs to have been performed within 2 years prior to baseline to confirm or 
exclude the presence of advanced fibrosis or cirrhosis (see Appendix 1).  For subjects 
with advanced fibrosis, a liver biopsy needs to have been performed within 9 months 
prior to baseline to ensure that the subject has not progressed to cirrhosis.  Subjects co-
infected with HCV, hepatitis D virus (HDV), human immunodeficiency virus (HIV) or who 
have received therapy for hepatitis B in the prior 6 months or who have de-compensated 
liver disease will be excluded.  
SECTION 4.2:  INCLUSION CRITERIA 
A subject may be included if the answer to all of the following statements is “yes”: 
• 
Male or female subjects aged 3 to < 18 years old at baseline 
• 
Positive HBsAg for more than 6 months 
• 
Positive HBeAg and detectable HBV-DNA at screening (subjects must have 
> 10,000 copies/mL [> 2,000 IU/mL] as measured by PCR)  
• 
Negative anti HBs and anti HBe at screening.  (Exception: subjects with positive antibodies 
based on central laboratory result but negative antibodies based on local laboratory result 
and who meet the other CHB inclusion criteria of positive HBsAg, positive HBeAg, 
detectable HBV DNA, and elevated ALT may be included.) 
• 
A liver biopsy performed within 2 years prior to baseline to confirm the presence of 
advanced fibrosis or exclude cirrhosis (see Appendix 1).  For subjects with 
advanced fibrosis, a liver biopsy needs to be performed within 9 months prior to 
baseline 
• 
Compensated liver disease (Child-Pugh Class A clinical classification; 
see Appendix 2) 
• 
Elevated serum ALT > ULN but ≤ 10 × the ULN as determined by two abnormal 
values taken ≥ 14 days apart during the 6 months before the first dose of study drug 
with at least one of the determinations obtained ≤ 35 days prior to the first dose.  
Reference range of the testing laboratory should be used 
• 
Signed informed consent from parent/legal guardian and willingness of parent/legal 
guardian to abide by the requirements of the study, and signed assent from child if 
appropriate.  Patients < 18 years of age at baseline who are legally adults according to 
national legislation must consent in their own right. 
SECTION 4.3:  EXCLUSION CRITERIA 
A subject will be excluded if the answer to any of the following statements is “yes”: 
• 
Subjects with cirrhosis (see Appendix 1) 


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• 
Subjects who have received investigational drugs or licensed treatments with 
anti-HBV activity within 6 months prior to baseline (e.g., IFNs, systemic 
corticosteroids, lamivudine, tenofovir, emtricitabine, adefovir, entecavir, telbivudine, 
systemic acyclovir, systemic famciclovir)  (Exception:  Subjects 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.)   
• 
Known hypersensitivity to PEG-IFN 
• 
Positive test results at screening for hepatitis A virus immunoglobulin M antibody 
(HAV IgM Ab), anti-HCV antibody (Ab), anti-HDV Ab, or anti-HIV Ab 
• 
History or other evidence of a medical condition associated with chronic liver 
disease other than CHB 
• 
History or other evidence of bleeding from esophageal varices 
• 
Decompensated liver disease (e.g., ascites, varices, Child-Pugh Class B or C clinical 
classification [see Appendix 2] or clinical evidence such as ascites or varices) 
• 
History or other evidence of metabolic liver disease 
• 
Suspicion of HCC on ultrasound or other liver imaging (all subjects to have 
ultrasound within 6 months prior to baseline) 
• 
Screening alfa-fetoprotein (AFP) ≥ 100 ng/mL 
• 
Screening neutrophil count < 1.5 × 109 cells/L, platelet count < 90 × 109 cells/L, 
or hemoglobin < 11 g/dL for females and < 12 g/dL for maleslower limit of normal (LLN) 
• 
Screening albumin < lower limit of normal or total bilirubin > ULN   
Exception: Subjects with non−hepatitis-related factors which may elevate 
bilirubin such as Gilbert’s disease 
• 
Screening serum creatinine concentration > 1.5 × the ULN for age or severee Evidence of 
renal impairment disease, e.g., glomerulonephritis 
• 
Autoimmune hepatitis 
• 
History of immunologically mediated disease to include, but not limited to: 
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 
• 
History or other evidence of chronic pulmonary or cardiac disease associated with 
clinically significant functional limitation 
• 
History of thyroid disease 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/or thyroxine-binding globulin [TBG]) at screening  
• 
Poorly controlled diabetes 


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• 
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 (international normalized ratio > 1.5), hemoglobinopathy, hemophilia, 
or history of severe illness or other blood disorders that would make subject 
unsuitable for the study 
• 
History of seizure disorder requiring treatment with anticonvulsant medication 
(excluding febrile seizures) 
• 
History or other evidence of severe retinopathy (all subjects to have 
ophthalmological examination within 6 months prior to baseline) 
• 
History or other evidence of severe illness or any other conditions that would make 
the subject, in the opinion of the investigator, unsuitable for the study 
• 
Active substance abuse within the last 6 months before the study 
• 
Sexually active females of childbearing potential and sexually active males who are 
not willing to utilize reliable contraception during the treatment/principal observation 
period and during the initial 24-week follow-up period 
• 
Females of childbearing potential who have a positive urine or serum pregnancy test 
result within 24 hours of baseline, or who are breast-feeding 
SECTION 4.6.1:  Withdrawal of Subjects from Study Treatment 
In the case that the subject decides to prematurely discontinue study treatment (“refuses 
treatment”), all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible preferably by returning to site to complete 
assessments as per the Week 48/Switch Week 48 visit (see Table 2 and Table 4) and 
the Treatment Completion eCRF.  The subject should then enter the post-end of 
treatment follow-up period.   
SECTION 4.8.2:  Switch Exclusion Criteria 
Subjects in Group B may not switch to treatment with PEG-IFN if the answer to any of 
the following statements is “yes”. 
• 
Cirrhosis (see Appendix 1) 
• 
Subjects who have received any anti-HBV treatment within 6 months prior to switch 
baseline 
• 
Positive test results within 6 months prior to switch baseline for HAV IgM Ab, anti-
HCV Ab, anti-HDV Ab, or anti-HIV Ab 


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• 
Evidence of decompensated liver disease (e.g., ascites, varices, Child−Pugh Class B 
or C clinical classification, see Appendix 2 or clinical evidence such as ascites or varices) 
at switch baseline 
• 
Serum ALT >10 ×the ULN at switch baseline.  Reference range of the testing laboratory 
should be used 
• 
International normalized ratio > 1.5 at switch baseline 
• 
Neutrophil count < 1.5 × 109 cells/L, platelet count <90  × 109 cells/L, or hemoglobin 
< 11 g/dL for females and < 12 g/dL for males lower limit of normal (LLN) at switch 
baseline  
• 
Evidence of Serum creatinine concentration > 1.5 × the ULN for age or severe renal 
impairement disease, e.g., glomerulonephritis, at switch baseline 
• 
Evidence of severe illness or any other conditions or contraindications that would 
make the subject, in the opinion of the investigator, unsuitable for commencing 
PEG-IFN 
• 
Clinically relevant abnormal thyroid function tests (TSH, FT3, FT4, TPO antibodies, 
and/or TBG) within 6 months prior to switch baseline  
• 
Sexually active females of childbearing potential and sexually active males who are 
not willing to use reliable contraception during the switch treatment period and initial 
24-week switch follow-up period 
• 
Females of childbearing potential who have a positive urine or serum pregnancy test 
result within 24 hours of switch baseline 
SECTION 5.1:  SCREENING EXAMINATION AND ELIGIBILITY SCREENING 
FORM 
The assessments in Table 5 mustshould  be obtained within a period of no more than 
35 days before the subject is randomized, except as noted.  Extensions to the screening 
period of up to 7 days may be permitted under exceptional circumstances if certain results 
concerning eligibility are not available within the 35 days and only upon approval from the 
Medical Monitor.  Subjects must fulfill all the entry criteria for participation in the study 
(see Sections 4.2 to 4.4).  An Eligibility Screening Form documenting the investigator’s 
assessment of each screened subject with regard to the protocol’s inclusion and 
exclusion criteria is to be completed by the investigator.  A screen failure log must be 
maintained by the investigator.   
If a subject 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 
below.  If the subject 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 retesting if blood samples have to be redrawn 
because of sample handling problems, breakage or sample integrity. 
Subjects who fail to meet the entry criteria may be re-screened on one more occasion 
provided that enrollment remains open and upon approval from the Medical Monitor.  If re


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screening occurs within the 35 day screening window for the original screening, then only the 
parameter that failed will need to be repeated.  If re screening will take the screening period 
beyond 35 days, thenIf re-screening is required, then the complete screening module should be 
repeated (except for those parameters indicated in Table 5).  Re-screening is required if a 
subject has not met all of the eligibility criteria within 35 days from the original screening visit.  
It will not be considered a re-screening if blood samples have to be redrawn because of sample 
handling problems, breakage, or sample integrity. 
SECTION 5.2:  PROCEDURES FOR ENROLLMENT OF ELIGIBLE SUBJECTS 
The enrollment of subjects in the rest of world will remain unchanged; patients aged 
3 to <18 years old at baseline will be enrolled. During study conduct, the Sponsor may 
postpone or stop the enrollment of subjects in certain age ranges in order to ensure that a 
broad maintain the age distribution balance in the study populationand representative dosing 
categories have been adequately studied. 
SECTION 5.3:  CLINICAL ASSESSMENTS AND PROCEDURES 
A baseline visit will be performed, and for subjects in Group A and Group C all baseline 
assessments and procedures must occur prior to administration of the first dose of 
PEG-IFN.  The first dose of PEG-IFN should be administered at the baseline visit.  Subjects will 
subsequently be seen for evaluation at the following timepoints: 
Group A and Group C 
• 
During treatment period:  Weeks 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, and 48 
• 
During initial 24 weeks of follow-up:  follow-up Weeks 4, 12, and 24 post-end of 
treatment 
• 
During extended long-term follow-up:  Years 1, 1.5, 2, 3, 4, and 5 post-end of 
treatment 
 
Group B⎯Switch 
• 
During principal observation period:  Weeks 12, 24, 36, and 48* 
• 
During initial 24 weeks of follow-up:  follow-up Weeks 12* and 24* post-principal 
observation period 
• 
During extended long-term follow-up:  Year 1* post−principal observation period 
• 
During switch treatment period:  Weeks 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, and 48 
• 
During initial 24 weeks of switch follow-up:  switch follow-up Weeks 4, 12, and 24 
post−principal observationend of treatment period 
• 
During extended long-term switch follow-up:  Years 1, 1.5, 2, 3, 4, and 5 
post-principal observationend of treatment period 


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Any subject who discontinues study treatment should return to complete assessments 
as per the Week 48/Switch Week 48 visit and enter the post-end of treatment follow-up 
period (see Section 4.6.1). 
SECTION 5.3.2:  Safety 
All subjects need to have an ophthalmological examination (including consisting of 
fundoscopic examination with dilation, visual acuity assessment, visual field testing 
(confrontation test is recommended for younger children), and color visual testing) by an 
ophthalmologist (pediatric ophthalmologist is recommended) within 6 months prior to 
baseline.  During the study, Thereafter, subjects treated with PEG-IFN will receive 
additional ophthalmological examination as per the schedules in Table 2 and Table 4.  
Any subject who develops ocular symptoms should receive a prompt eye examination by 
an ophthalmologist and additional examinations as necessary.   
SECTION 5.3.2.1:  Neuro-psychiatric Questionnaire 
As part of the overall assessment of subjects and their mental state, and collation of 
neurological and psychiatric AEs, the CDI [50] will be used in subjects ≥ 7 to 17 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 subject’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 subjects and then 
post-baseline for treated subjects as per the schedules in Table 2 to Table 4.  CDI 
should be performed prior to the completion of other study assessments. Note:  If 
a subject 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 17-year-old 
subjects who turn 18 years old during the study, the CDI should continue to be administered. 
The CDI Item Form will be provided in the subjects’ own language, if available.  All 
subjects should complete the form themselves.  For younger children or those with 
reading difficulties or who are are unable to read, the instructions and items should be 
read aloud to the child, then the child will select an answer themself.  If the CDI Item 
Form is not available in the subject’s own language, a translator may read the 
instructions and items to the child and then the child will select an answer themself. The 
mode of administration (self-administered or translator/caregiver administered) should be clearly 
documented in the clinical records. If subjects feel none of the sentences for an item applies 
to them, then they should be instructed to choose as best they can.  Subjects should be 
debriefed after the CDI has been completed to address any questions or concerns. 
Once the subject 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. Note:  If >10%of items 


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(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. 
Pathway of Referral for Follow up of Subjects Who Have with Symptoms of Major 
Depression or Potential CDI Scores > 19Indicators 
Whether the CDI is administered or not, investigators should still assess the mental state of their 
subjects per their standard clinical practice.  If any subject exhibits symptoms of major 
depression and/or if CDI total score is >19 and/or the subject fails to complete all items on the 
CDI, then the investigator will perform a more thorough evaluation to determine if major 
depression has developed.  If major depression is confirmed by the Investigator, then 
the subject will be referred to a mental health professional (e.g., counsellor).  If this is at 
screening or baseline, then the subject will be excluded from the study.  While in the 
study, the investigator will determine whether AE criteria have been met and report as an AE on 
the eCRF, if appropriate (see Section 7.1).  If whilst on study the subject is found to have 
severe depression, PEG-IFN should must be permanently discontinued and the subject 
referred for psychiatric intervention (as per Section 6.2.1 and Section 6.2.5.5). 
SECTION 5.4:  LABORATORY ASSESSMENTS 
All virological and serological efficacy parameters will be assessed by the central 
laboratory.  The central laboratory will not have access to clinical data or randomization 
information, and therefore is blinded to treatment assignment for the duration of the study. 
SECTION 6.2.1:  Stopping Rules 
Individual subject treatment with PEG-IFN will mustbe stopped in the event of any of the 
following: 
• 
Severe hypersensitivity reactions (e.g., anaphylaxis, angioedema, 
bronchoconstriction) 
• 
Evidence of hepatic decompensation, e.g., significant deterioration in hepatic function 
including those requiring alternative therapies (see also Section 6.2.5.3)  
• 
Severe depression (see also Section 6.2.5.5)  
• 
Convulsions  
• 
Thyroid abnormalities that cannot be adequately treated 
• 
Hypoglycemia, hyperglycemia, or diabetes mellitus that cannot be effectively controlled by 
medication 
• 
New or worsening visual disorders such as field deficits, decreased or loss of vision  
• 
Persistent or unexplained pulmonary infiltrates or pulmonary function impairment  
• 
Worsening of psoriatic lesion 
• 
Development of autoimmunity, including autoimmune hepatitis 
• 
Renal failure, including creatinine > 100 μmol/L  
• 
Severe symptoms e.g., rigors (see Sections 6.2.4 and 7.1.1) 


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• 
Absolute neutrophil count  < 0.25 × 109 cells/L or febrile neutropenia 
(see also Section 6.2.5.1)  
• 
Platelets < 25 × 109 cells/L (see also Section 6.2.5.2) 
• 
Pregnancy (see also Section 7.2.4) 
 
Discontinuation of individual patient treatment with Pegasys 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) (see also Section 6.2.5.3) 
• 
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 (see also Section 7.2.4) 
SECTION 6.2.4:  Dose Reduction Levels 
Moderate or severe adverse reactions (clinical and/or laboratory) may require dose 
reduction of PEG-IFN.  Decremental adjustments should be uniform across centers and 
subjects.  Toward this end, the following downward adjustments should be utilized: 
Starting Dose  
(μg) 
One Level Reduction 
(μg) 
Two Level Reduction 
(μg) 
Three Level Reduction 
(μg) 
45 
30 
20 
10 
65 
45 
30 
20 
90 
65 
45 
20 
135 
90 
65 
30 
180 
135 
90 
45 
 
Starting Dose  
One-Level Reduction 
Two-Level Reduction 
Three-Level Reduction 
(µg) 
(mL) 
(µg) 
(mL) 
(µg) 
(mL) 
(µg) 
(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 
 


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SECTION 6.2.5.4:  Dosage Adjustments for BSA Decrease/Increase 
Investigators will adjust the dose of PEG-IFN upward or downward to reflect the most 
current BSA.  BSA and dose will be provided by IXRS at Weeks 12, 24, and 36.  
Investigators may also assess the patient’s BSA (using the Mosteller formula) at other interim 
timepoints 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 a subject’s BSA falls below < 0.51 m2 during treatment, any dose adjustments should 
be made only after consultation between the investigator and Roche Clinical Science study 
personnel the Medical Monitor (Appendix 3 ) or delegate.  The recommended dose will be 
recorded in the SMD.   
SECTION 7.2.1:  Reporting of Adverse Events  
All AEs (related and unrelated) occurring during the treatment/principal observation 
period and initial 24 weeks of follow-up must be reported.  During the extended long-
term follow-up period, only persisting AEs, new-onset SAEs and, non-serious AEs of 
special interest related to PEG-IFN, and deaths will be reported. 
SECTION 7.2.2:  Reporting of Serious Adverse Events (immediately 
reportable) 
Related SAEs must be collected and reported regardless of the time elapsed from the 
last study drug administration, even if the study has been closed.  Every effort should be 
made to follow all SAEs considered to be related to the study drug or study-related procedures 
until a final outcome can be reported.  
SECTION 8.1.1:  Primary Endpoints 
• 
HBeAg seroconversion (loss of HBeAg and presence of anti-HBe) at the 24-week 
post-end of treatment/principal observation period follow-up visit 
SECTION 8.2.5.3:  Safety Data Analysis 
The primary safety analysis will compare safety in Group A with Group B at 24 weeks 
post-end of treatment/end of untreated observation.  The safety data of Group A and Group B 
will be qualitatively evaluated alongside subjects in Group C and the switch arm. 
• 
Incidence, nature, and severity of serious and non-serious AEs (including neurological and 
psychiatric events) 
• 
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 


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• 
Effect on growth (height and weight) 
The following safety outcome measures will be assessed using descriptive statistics at 1, 2, 3, 4, 
and 5 years post-end of 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 and weight) 
SECTION 10:  STUDY COMMITTEES 
A DSMB will review safety data on a routine basis (as persee DSMB charter).  Enrollment 
will be suspended and/or the study will be halted if serious concerns about safety are 
raised pending further analysis and review.  Enrollment and/or study re-start will resume 
only if the DSMB and the Sponsor areis satisfied with the safety of treatment. 
SECTION 12.2.1:  Main Study Informed Consent 
If children are old enough to understand the risks and benefits of the study, they should 
also be informed and should also provide their written assent.  Patients within the specified 
age range who are legally 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, if required by national legislation.  With regard to the 
donation of a specimen(s) by the minor that will be stored in the RCR this same principle 
will apply.  If the minor is not old enough to form an opinion or assess this information, 
the legal representative/guardian will replace the minor in recognizing his/her rights and 
responsibilities until he/she reaches legal age. 
TABLE 5:  Screening assessments  
Table 5 has been revised to reflect changes to medical history recording and 
ophthalmological examination: 
Medical history and physical 
examination 
Includes family history of HBV, concomitant medication 
(including for CHB), surgeries/procedures, and vital signs (blood 
pressure, heart rate, temperature). 
Ophthalmological examinationa 
Within 6 months prior to baseline; repeat at screening only if 
any change in medical condition.  By ophthalmologist 
(pediatric ophthalmologist is recommended) and including 
fundoscopic examination with dilation, visual acuity 
assessment, visual field testing (confrontation test is 
recommended for younger children), and color visual testing.  
Any subject who develops ocular symptoms should receive a 
prompt eye examination by an ophthalmologist and additional 
examinations as necessary.   
 


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TABLE 6:  Laboratory assessments  
Table 6 has been revised to reflect the required availability of pregnancy test results: 
HCG pregnancy testb 
Urine or serum pregnancy test for females of childbearing 
potential at any time secondary amenorrhea of more than 
1 week occurs.  The result of the baseline pregnancy test must be 
available prior to randomization and commencement of treatment. 
 
Schedule of Assessments 
The Schedule of Assessments has been revised to reflect the changes to the protocol. 
APPENDIX 1:  Liver Biopsy Scores 
Appendix 1 has been revised to include Scheuer Fibrosis scores: 
Scores considered as advanced fibrosis will be Metavir fibrosis 3, Knodell fibrosis score 
3, Modified Ishak fibrosis score 4, or Batts & Ludwig score 3, or Scheuer score 3.  Subjects 
with these scores will be assigned to Group C. 
Scores considered as cirrhosis will be Metavir fibrosis 4, Knodell fibrosis score 4, 
Modified Ishak fibrosis score 5 and 6, or Batts & Ludwig score 4, or Scheuer score 4.  
Subjects with these scores are excluded from the study. 
 
SCHEUER FIBROSIS SCORE 
0. None 
1. Enlarged fibrotic portal tracts 
2. Periportal or portal -portal septa but intact architecture 
3. Fibrosis with architecture distortion but no cirrhosis 
4. Probable or definite cirrhosis 
APPENDIX 3:  ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
Appendix 3 has been revised to reflect changes to the medical monitor: 
ROCHE LOCAL COUNTRY CONTACT for SAEs:  Local Monitor:  
See provided forms for details of study administrative and contact information, including 
the Local Monitor.  
Note:  The Study Monitor should be contacted for any routine and administrative queries such as 
patient eligibility queries. 


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ROCHE HEADQUARTERS CONTACT for SAEs and Other Medical Emergencies:  
Clinical Operations/Clinical Science: 
Medical Monitor Contact Information 
Primary Contact 
Medical Monitor: 
, MD 
Telephone No.: 
Mobile Telephone No.: 
Secondary Contact 
Medical Monitor: 
, MD, PhD 
, MBChB Dip Pharm. Med 
Telephone No.: 
Mobile Telephone No.: 
 
24 HOUR MEDICAL COVERAGE:   
Identification of a contact for 24 hour medical coverage is mandatory to be compliant with 
worldwide regulatory agencies and to ensure the safety of study subjects. 
An Emergency Medical Call Center Help Desk will access the Roche Medical Emergency Contact 
List, escalate emergency medical calls, provide medical translation service (if necessary), connect 
the investigator with the Roche medical contact for this study and track all calls.  The Emergency 
Medical Call Center Help Desk will be manned 24 hours a day, 7 days a week, 52 weeks a year.  
Toll free numbers will be distributed to all investigators.  The Help Desk will be used for medical 
emergencies outside regular business hours, or when the regular Clinical Science or Clinical 
Pharmacology contact cannot be reached. 
Protocol Contact Information and Emergency Medical Call Center Help Desk toll free numbers 
will be provided.   
SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Forms have been revised to reflect the changes to the 
protocol. 
 
 


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SYNOPSIS OF PROTOCOL YV25718, VERSION E 
 
TITLE 
A Phase IIIb Parallel Group, Open Label Study of 
Pegylated Interferon alfa-2a Monotherapy (PEG-IFN, 
Ro 25-8310) Compared to Untreated Control in Children 
with HBeAg Positive Chronic Hepatitis B in the Immune 
Active Phase 
SPONSOR 
Hoffmann-La Roche  
CLINICAL 
PHASE 
IIIb 
INDICATION 
Treatment of hepatitis B envelope antigen (HBeAg) positive 
chronic hepatitis B (CHB) in children. 
OBJECTIVES  
• 
To compare efficacy and safety between a group 
treated with Pegylated-Interferon Alfa-2a (PEG-IFN) 
monotherapy and an untreated control group in HBeAg 
positive children with CHB virus infection in the immune 
active phase.  
• 
To evaluate the pharmacokinetics of PEG-IFN following 
administration of a new body surface area (BSA)-based 
dosing regimen in HBeAg positive PEG-IFN treated 
children with CHB virus infection. 
TRIAL DESIGN 
• 
A 2:1 randomized, controlled, parallel group, open 
label, multicenter study of PEG-IFN treatment 
(Group A) compared to an untreated control (Group B). 
• 
Subjects without advanced fibrosis and without 
cirrhosis (assessed by liver biopsy) will be randomized 
2:1 to PEG-IFN treatment (Group A) or untreated 
control (Group B) respectively.  That is for every 
2 subjects randomized to PEG-IFN only 1 will be 
randomized to the untreated control.  Subjects in 
Group A will receive PEG-IFN for 48 weeks.   
• 
Subjects with advanced fibrosis (assessed by liver 
biopsy) will be assigned to PEG-IFN treatment 
(Group C: Advanced Fibrotic arm).  Subjects in Group 
C will receive PEG-IFN for 48 weeks.   
• 
The first 48 weeks from randomization will be referred 
to as the treatment period for Group A and Group C 
and the principal observation period for Group B. 
• 
Forty-eight weeks after randomization, PEG-IFN will be 
offered to subjects in the Group B untreated control 
group who have not experienced HBeAg 
seroconversion.  This offer will be available for up to 
one year following Week 48.  If eligible, these subjects 
will enter the Switch arm and receive PEG-IFN for 
48 weeks.  
• 
All subjects will be followed up for 5 years after the end 
of treatment/principal observation period.  
• 
Liver elastography will be performed in at least 
50 subjects as a site specific sub-study. 
NUMBER OF SUBJECTS 
N = 160 


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TARGET POPULATION 
• 
Children aged 3 to < 18 years of age with CHB, 
HBeAg+ve, hepatitis B surface antigen (HBsAg)+ve, 
detectable hepatitis B virus (HBV) DNA (> 10,000 
copies/mL [> 2,000 IU/mL]) by polymerase chain 
reaction and alanine aminotransferase (ALT) > upper 
limit of normal (ULN) but  ≤ 10 × ULN (using the 
reference range of the testing laboratory). 
• 
Liver biopsy needs to have been performed within 
2 years prior to baseline, or within 9 months prior to 
baseline for subjects with advanced fibrosis.  Subjects 
with advanced fibrosis will be assigned to PEG-IFN 
treatment (Group C), and those without advanced 
fibrosis or cirrhosis will be randomized.  Cirrhotic 
subjects will be excluded from the study.   
• 
Subjects co-infected with hepatitis C virus, hepatitis D 
virus, human immunodeficiency virus or who have 
received therapy for hepatitis B in the prior 6 months or 
who have de-compensated liver disease will be 
excluded. 
LOCATION (Regions)  
Americas, Europe, Asia-Pacific. 
LENGTH OF STUDY  
• 
For Group A, Group B non-switch and Group C 
subjects the study length is 6 years (1 year 
treatment/principal observation period, 5 years follow-
up). 
• 
For Group B switch subjects the study length is up to 
8 years (1 year principal observation period, up to 
1 year to decide whether to receive treatment, 1 year 
treatment, 5-year follow-up). 
END OF STUDY 
• 
Primary endpoint is assessed 24 weeks after the end of 
treatment/principal observation period, with a further 
4.5 years of follow- up. 
• 
End of study is defined as last subject last visit.  
INVESTIGATIONAL MEDICAL 
PRODUCT(S) 
DOSE/ ROUTE/ REGIMEN 
PEG-IFN for 48 weeks subcutaneously once weekly with 
dosing based on the following 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 
NON-INVESTIGATIONAL 
MEDICAL PRODUCT(S) 
N/A 
COMPARATOR “DRUG” (or 
STANDARD OF CARE) 
DOSE/ ROUTE/ REGIMEN 
N/A (Untreated control) 
ASSESSMENTS OF: 
 


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- 
EFFICACY 
Primary:  
HBeAg seroconversion (loss of HBeAg and presence of 
hepatitis B envelope antibody [anti-HBe]) at 24 weeks 
post-end of treatment/principal observation period. 
 
Secondary:  
• 
Loss of HBeAg, HBsAg seroconversion (loss of HBsAg 
and presence of hepatitis B surface antibody), loss of 
HBsAg, quantitative serum ALT, proportion of normal 
ALT, quantitative HBV DNA, suppression of HBV 
DNA < 100,000 copies/mL (< 20,000 IU/mL),< 10,000 
copies/mL (< 2,000 IU/mL), undetectable and change 
from baseline, combined endpoint of HBeAg 
seroconversion and HBV DNA < 100,000 copies/mL 
( < 20,000 IU/mL), and combined endpoint of HBeAg 
seroconversion and HBV DNA  < 10,000 copies/mL 
( < 2,000 IU/mL) at the end of treatment/principal 
observation period, at 24 weeks after end of 
treatment/principal observation period, and at 1, 2, 3, 4 
and 5 years after end of treatment/principal 
observation period. 
• 
Persistence of HBeAg seroconversion (loss of HBeAg 
and presence of anti-HBe) at the end of 
treatment/principal observation period, and at 1, 2, 3, 4 
and 5 years after end of treatment/principal observation 
period. 
• 
Descriptive change from baseline in liver elasticity (in 
liver elasticity site specific sub-study subjects) at end of 
treatment/principal observation period, and at 24 weeks 
and 2 years after end of treatment/principal observation 
period. 
- 
SAFETY 
Safety during the treatment/principal observation period 
and initial 24 weeks of follow-up: 
• 
Serious and non-serious adverse events (AEs) 
(including neurological and psychiatric events, and 
non-serious AEs of special interest, and monitoring 
with neuro-psychiatric questionnaire for PEG-IFN 
treated subjects). 
• 
Laboratory test results (including thyroid function). 
• 
Vital signs. 
• 
Growth: weight and height. 
 
Safety during the 4.5 year extended, long-term follow up 
period: 
• 
All persisting AEs initially reported prior to follow-up 
Week 24 (including neuro-psychiatric events). 
• 
New-onset serious AEs (including neuro-psychiatric 
events) and non-serious AEs of special interest related 
to PEG-IFN. 
• 
Deaths 
• 
Thyroid function. 
• 
Growth: weight and height. 


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- 
PHARMACOKINETICS/
 
PHARMACODYNAMICS  
• 
Site-specific sub-study 
• 
Blood samples will be collected in PEG-IFN treated 
subjects to evaluate the pharmacokinetics of PEG-IFN 
following administration of a new BSA-based dosing 
regimen.  
 
• 
Samples should be collected during weeks 1 and 24 at 
pre-dose (0 hour) and 24-48, 72-96, and 168 hours 
post-dose.  Additional pre-dose samples should be 
collected at weeks 4, 8 and 12 within 6 hours prior to 
administration. 
- 
EXPLORATORY  
 
BIOMARKERS 
Optional Roche Clinical Repository (RCR) samples, 
including plasma and whole blood RNA and whole blood 
DNA (baseline only), will be taken from 
consenting/assenting subjects at Baseline, Weeks 12, 24 
and 48, 24 weeks after end of treatment/principal 
observation period, and at 1, 2, 3, 4 and 5 years after end 
of treatment/principal observation period.  These 
specimens will be used for research purposes, for example 
to help to better understand the pharmacogenetics, 
pathogenesis, course and outcome of CHB and related 
diseases, and identify dynamic biomarkers that are 
predictive of response to PEG-IFN treatment (in terms of 
dose, safety and tolerability).  These specimen(s) may be 
stored for up to 15 years after the end of Study YV25718. 
INTERIM ANALYSES AND 
STOPPING RULES  
 
Individual subject treatment with PEG-IFN must be 
discontinued in the event of any of the following: 
• 
Severe hypersensitivity reactions (e.g., anaphylaxis, 
angioedema, bronchoconstriction) 
• 
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  
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 
 
A data safety monitoring board (DSMB) will review safety 
data on a routine basis (as per DSMB charter).  Enrollment 


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will be suspended and/or the study will be halted if serious 
concerns about safety are raised pending further analysis 
and review.  Enrollment and/or study re-start will resume 
only if the DSMB and the Sponsor are satisfied with the safety 
of treatment. 
PROCEDURES (Summary):   
After signing informed consent/assent and meeting screening parameters, subjects 
without advanced fibrosis and without cirrhosis (assessed by liver biopsy performed 
within 2 years prior to baseline) will be randomized 2:1 into the PEG-IFN treatment 
(Group A) or untreated control (Group B) respectively.  Stratification will be performed by 
genotype (A versus non-A) and ALT (< and ≥5 × ULN).  Subjects with advanced fibrosis 
(assessed by liver biopsy performed within 9 months prior to baseline) will be assigned 
to PEG-IFN treatment (Group C).  Subjects in Group A and Group C will receive 
PEG-IFN for 48 weeks. 
Subjects treated with PEG-IFN (Group A and Group C) will be seen for evaluation at 
Weeks 1, 2, 4, 8, 12 and then every 6 weeks during the treatment period, and during the 
initial 24 weeks of follow-up at follow-up Weeks 4, 12, and 24.  
Subjects in the untreated arm (Group B) will be seen for evaluation at 12 weekly 
intervals during the principal 48-week observation period and during the initial 24 weeks 
of the follow-up period.   
For consenting/assenting subjects in the site specific liver elasticity sub-study, liver 
elastography will be performed at baseline, end of treatment/principal observation period, 
follow-up Week 24, and follow-up Year 2.   
Forty-eight weeks after randomization, PEG-IFN will be offered to subjects in the 
Group B untreated control group who have not experienced HBeAg seroconversion.  
This offer will be available for up to 1 year following 48 weeks from randomization.  If 
eligible, these subjects will enter the switch arm, where they will start the Switch 
schedule of assessments and receive PEG-IFN for 48 weeks. 
For consenting/assenting subjects in the site specific pharmacokinetic (PK) sub-study, 
additional visits will also be required for PK blood sampling.  When adequate PK data 
have been collected over the first 24 weeks for at least 15 PEG-IFN-treated subjects, 
ideally with representation from all BSA categories, exposure will be analyzed and if 
necessary an adjustment will be made to the dosing regimen.  Once PK data up to 
Week 24/switch Week 24 are available for at least 5 to 10 subjects in each BSA 
category, subject PK sampling will be stopped.  However, the sub-study may be stopped 
even if data from a minimum of 5 subjects in each BSA category are not obtained in the 
case of excessively long recruitment times. 
Those subjects that do not complete the treatment period should still return for all 
follow-up visits.  As well as evaluation during the initial 24 weeks post-end of 


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treatment/principal observation period, all subjects will be followed up annually for 
5 years after the end of treatment/principal observation period.  Safety assessments at 
these extended long-term follow-up visits will include evaluation of persisting AEs which 
were initially reported prior to follow-up Week 24, assessment of new-onset serious 
adverse events (SAEs) (including neuro-psychiatric events) and non-serious AEs of 
special interest related to PEG-IFN, deaths, thyroid function, and growth (weight and 
height). 
Standard measures will be taken in this study to minimize the pediatric subjects’ possible 
pain and distress. 
STATISTICAL ANALYSES 
Sample Size 
Sample size is based on the χ2 test statistic.  Assuming a 32% HBeAg seroconversion 
rate for Group A (PEG-IFN) and 10% for Group B (untreated control), a total sample size 
of 145 subjects provides at least 80% power at the 0.05 level of significance with a 
two-sided χ2 test.  The sample size shall be increased by 10% and rounded to 
160 subjects to allow for advanced fibrotics (Group C) and withdrawals.   
Populations 
Intent to treat (ITT) population:  For Group A, the ITT population shall include all subjects 
who receive at least one dose of study drug.  For the untreated Group B the ITT 
population shall include all subjects with at least the baseline efficacy or safety data.  For 
the ITT population subjects will be analyzed according to the groups to which they were 
randomized.  Subjects in Group B who switched to receive PEG-IFN after Week 48 and 
prior to 24 weeks post-observation period will be counted as non-responders. 
Switch Population:  The switch population shall be those subjects randomized to 
Group B who opt to switch to initiating treatment with PEG-IFN after Week 48.   
Group C: Subjects who have advanced fibrosis (diagnosed on liver biopsy) will receive 
PEG-IFN in an advanced fibrotic arm (Group C).  
Efficacy 
• 
The primary efficacy analysis will compare efficacy in Group A with Group B.  
Subjects with missing values will be considered as non-responders.  The efficacy 
data of Group A and Group B will be qualitatively evaluated alongside subjects in 
Group C and the switch arm. 
• 
The primary analysis of the response rate variables will be with the Cochran-Mantel-
Haenszel test (χ2) stratified by genotype (A versus non-A) and ALT (< and ≥5 × ULN).  
Fisher’s exact test will be used as a secondary analysis.  The response rates for 


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HBeAg seroconversion will be analyzed at the end of the initial 24-week follow-up 
period.  
• 
Several secondary analyses are planned, including descriptive statistics of 
secondary endpoints, and exploratory p-values between Group A and Group B. 
 
Safety 
• 
The primary safety analysis will compare safety in Group A with Group B at 24 weeks 
post-end of treatment/end of untreated observation.  The safety data of Group A and 
Group B will be qualitatively evaluated alongside subjects in Group C and the 
Switch Arm. 
• 
Adverse events: AEs will be assigned preferred terms and categorized into body 
systems according to the Medical Dictionary for Regulatory Activities (MedDRA) 
classification of the World Health Organization (WHO) terminology.  Descriptive 
statistics will be used to summarize safety parameters by group.  Neurological and 
psychiatric AEs will be assessed in further detail, including persistence and duration, 
as well as new onset of SAEs and non-serious AEs of special interest related to 
PEG-IFN reported during the extended long-term follow-up period of this study. 
• 
Laboratory Safety Data: The laboratory data will be analyzed according to Roche’s 
“International Guideline for the Handling and Reporting of Laboratory Data”. 
• 
Growth (weight and height): The continuous growth will be analyzed with residual 
maximum likelihood, or analysis of covariance.  The assumptions of the analysis 
such as normally distributed residuals will be assessed.  If necessary rectifying 
transformations shall be applied.  Growth (height) velocity will be explored. 
 
Pharmacokinetic 
• 
PK parameters (e.g., CL/F, V/F, AUC, Cmax, etc,) of PEG-IFN will be estimated using 
non-compartmental analysis and/or a population PK modeling approach.  All PK 
parameters will be presented descriptively including arithmetic means, standard 
deviations, geometric means, coefficient of variation, medians, and ranges. 
• 
The relationship between clinical endpoints and PEG-IFN serum exposure may be 
explored.  
• 
The relationship between pharmacokinetic and pharmacodynamic parameters may 
be explored. 


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TABLE OF CONTENTS 
1. 
BACKGROUND AND RATIONALE............................................................. 34 
1.1 
Background ........................................................................... 34 
1.1.1 
Disease.................................................................................. 34 
1.1.2 
Study Drug............................................................................. 36 
1.2 
Rationale for the Study .......................................................... 37 
2. 
OBJECTIVES.............................................................................................. 39 
2.1 
Primary Objective .................................................................. 39 
2.2 
Secondary Objectives............................................................ 40 
2.3 
Exploratory Objectives........................................................... 40 
3. 
STUDY DESIGN ......................................................................................... 41 
3.1 
Overview of Study Design and Dosing Regimen................... 41 
3.1.1 
Rationale for Study Design.................................................... 43 
3.1.1.1 
Use of Untreated Control Arm and 
Compassionate Switch .......................................................... 43 
3.1.1.2 
Use of Advanced Fibrotic Arm and Exclusion of 
Cirrhotic Subjects .................................................................. 44 
3.1.1.3 
Liver Elasticity Sub-study....................................................... 44 
3.1.2 
Rationale for Dose Selection ................................................. 44 
3.1.2.1 
Establishment of Optimal Dose and Duration of 
PEG-IFN in CHB.................................................................... 44 
3.1.2.2 
Pediatric Dosing of PEG-IFN................................................. 45 
3.1.3 
End of Study.......................................................................... 46 
3.2 
Number of Subjects/Assignment to Treatment 
Groups................................................................................... 46 
3.3 
Centers.................................................................................. 47 
4. 
STUDY POPULATION................................................................................ 47 
4.1 
Overview................................................................................ 47 
4.1.1 
Recruitment Procedures........................................................ 47 
4.2 
Inclusion Criteria.................................................................... 47 
4.3 
Exclusion Criteria................................................................... 48 
4.4 
Concomitant Medication and Treatment................................ 50 
4.5 
Minimizing Pain and Distress................................................. 51 


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4.6 
Criteria for Premature Withdrawal ......................................... 51 
4.6.1 
Withdrawal of Subjects from Study Treatment....................... 51 
4.6.2 
Withdrawal of Subjects from the Study.................................. 51 
4.6.3 
Withdrawal of Subjects from the Roche Clinical 
Repository (RCR) .................................................................. 52 
4.7 
Replacement Policy (Ensuring Adequate 
Numbers of Evaluable Subjects) ........................................... 53 
4.7.1 
For Subjects .......................................................................... 53 
4.7.2 
For Centers............................................................................ 53 
4.8 
Switch Criteria ....................................................................... 53 
4.8.1 
Switch Inclusion Criteria ........................................................ 53 
4.8.2 
Switch Exclusion Criteria ....................................................... 53 
5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES............................ 55 
5.1 
Screening Examination and Eligibility Screening 
Form ...................................................................................... 67 
5.2 
Procedures for Enrollment of Eligible Subjects...................... 68 
5.3 
Clinical Assessments and Procedures .................................. 69 
5.3.1 
Efficacy.................................................................................. 71 
5.3.1.1 
Main Efficacy Assessments................................................... 71 
5.3.1.2 
Liver Elasticity........................................................................ 71 
5.3.2 
Safety .................................................................................... 71 
5.3.2.1 
Neuro-psychiatric Questionnaire ........................................... 72 
5.4 
Laboratory Assessments ....................................................... 73 
5.4.1 
Serum Bank and Exploratory HBV Markers........................... 75 
5.4.2 
Pharmacokinetic Assessments.............................................. 75 
5.4.3 
Roche Clinical Repository Specimen(s)................................. 77 
5.5 
Subject Medication Diary Review .......................................... 78 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT............................................. 78 
6.1 
Dose and Schedule of Investigational Medicinal 
Product and Comparator ....................................................... 78 
6.2 
Dose Modifications, Interruptions, and Delays....................... 79 
6.2.1 
Stopping Rules ...................................................................... 79 
6.2.2 
Missing Consecutive Doses................................................... 80 
6.2.3 
Dose Delay............................................................................ 80 


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6.2.4 
Dose Reduction Levels.......................................................... 80 
6.2.5 
Specific Dose Reduction Guidance ....................................... 82 
6.2.5.1 
Dose Adjustments for Low Absolute 
Neutrophil Counts.................................................................. 82 
6.2.5.2 
Dose Adjustments for Low Platelet Counts............................ 82 
6.2.5.3 
Dose Adjustments for Elevated Serum ALT .......................... 83 
6.2.5.4 
Dosage Adjustments for BSA Decrease/Increase ................. 83 
6.2.5.5 
Dosage Adjustments for Depression ..................................... 83 
6.3 
Formulation, Packaging and Labeling ................................... 83 
6.4 
Blinding and Unblinding......................................................... 84 
6.5 
Accountability of Investigational Medicinal 
Product and Assessment of Compliance............................... 84 
6.5.1 
Accountability of Investigational Medicinal 
Product .................................................................................. 84 
6.5.2 
Assessment of Compliance ................................................... 85 
6.6 
Destruction of the Investigational Medicinal 
Product/Comparator .............................................................. 85 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE.............................................. 86 
7.1 
Adverse Events and Laboratory Abnormalities...................... 86 
7.1.1 
Clinical Adverse Events......................................................... 86 
7.1.1.1 
Intensity ................................................................................. 86 
7.1.1.2 
Drug−Adverse Event Relationship......................................... 86 
7.1.1.3 
Serious Adverse Events (Immediately Reportable 
to Roche)............................................................................... 87 
7.1.1.4 
Other Safety Findings Requiring Expedited 
Reporting............................................................................... 87 
7.1.2 
Treatment and Follow-up of Adverse Events......................... 87 
7.1.3 
Laboratory Test Abnormalities............................................... 88 
7.1.3.1 
Follow-up of Abnormal Laboratory Test Values..................... 88 
7.2 
Handling of Safety Parameters.............................................. 89 
7.2.1 
Reporting of Adverse Events................................................. 89 
7.2.2 
Reporting of Serious Adverse Events 
(immediately reportable)........................................................ 89 
7.2.3 
Reporting of Non-serious Events of Special 
Interest................................................................................... 90 


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7.2.4 
Pregnancy ............................................................................. 90 
7.3 
Warnings and Precautions..................................................... 91 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .................. 92 
8.1 
Primary and Secondary Study Endpoints .............................. 92 
8.1.1 
Primary Endpoints ................................................................. 92 
8.1.2 
Secondary Endpoints ............................................................ 92 
8.1.3 
Safety .................................................................................... 92 
8.1.4 
Pharmacokinetic .................................................................... 92 
8.2 
Statistical and Analytical Methods ......................................... 92 
8.2.1 
Statistical Model .................................................................... 92 
8.2.1.1 
Primary Variables .................................................................. 92 
8.2.1.2 
Secondary Variables ............................................................. 93 
8.2.2 
Sample Size .......................................................................... 93 
8.2.3 
Hypothesis Testing ................................................................ 93 
8.2.4 
Analysis Populations ............................................................. 93 
8.2.4.1 
ITT Population ....................................................................... 93 
8.2.4.2 
Switch Population .................................................................. 94 
8.2.4.3 
Group C................................................................................. 94 
8.2.5 
Efficacy Analysis.................................................................... 94 
8.2.5.1 
Exclusion of Data from Analysis ............................................ 95 
8.2.5.2 
Interim Analysis ..................................................................... 95 
8.2.5.3 
Safety Data Analysis ............................................................. 95 
8.2.6 
Other Analyses...................................................................... 96 
8.2.6.1 
Pharmacokinetic Analysis...................................................... 96 
9. 
DATA COLLECTION, MANAGEMENT, AND 
QUALITY ASSURANCE ............................................................................. 96 
9.1 
Assignment of Preferred Terms and Original 
Terminology........................................................................... 97 
10.  STUDY COMMITTEES............................................................................... 97 
11.  REFERENCES ........................................................................................... 98 
12.  ETHICAL ASPECTS ................................................................................. 102 
12.1 
Local Regulations/Declaration of Helsinki............................ 102 


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12.2 
Informed Consent/Assent .................................................... 102 
12.2.1 
Main Study Informed Consent ............................................. 102 
12.2.2 
RCR Informed Consent ....................................................... 103 
12.3 
Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB)............................................................. 103 
12.4 
Role of the Science and Ethics Advisory Group .................. 104 
13.  CONDITIONS FOR MODIFYING THE PROTOCOL................................. 104 
14.  CONDITIONS FOR TERMINATING THE STUDY .................................... 104 
15.  STUDY DOCUMENTATION, CASE REPORT FORMS AND 
RECORD KEEPING.................................................................................. 105 
15.1 
Investigator's Files / Retention of Documents...................... 105 
15.2 
Source Documents and Background Data........................... 105 
15.3 
Audits and Inspections ........................................................ 106 
15.4 
Electronic Case Report Forms............................................. 106 
15.5 
Financial Disclosure ............................................................ 106 
16.  MONITORING THE STUDY ..................................................................... 106 
17.  CONFIDENTIALITY OF TRIAL DOCUMENTS AND 
SUBJECT RECORDS............................................................................... 107 
18.  CLINICAL STUDY REPORT..................................................................... 108 
19.  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS................................................................................................. 108 
 


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LIST OF TABLES 
Table 1 
Pediatric Dosing Regimen........................................................... 46 
Table 2 
Schedule of Assessments and Procedures⎯Group A (PEG-
IFN) and Group C (Advanced Fibrotic PEG-IFN)........................ 55 
Table 3 
Schedule of Assessments and Procedures⎯Group B 
(Untreated Control) ..................................................................... 59 
Table 4 
Schedule of Assessments and Procedures⎯Switch (PEG-
IFN)............................................................................................. 63 
Table 5 
Screening Assessments ............................................................. 67 
Table 6 
Laboratory Assessments ............................................................ 74 
Table 7 
PK Sampling Schedule ............................................................... 77 
Table 8 
Dosing Categories ...................................................................... 78 
 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design......................................................... 42 
 
 
LIST OF APPENDICES 
Appendix 1 
 Liver Biopsy Scores ................................................................. 109 
Appendix 2 
 Child-Pugh Classification of Severity of Liver Disease............. 111 
Appendix 3 
 ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 .. 112 


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GLOSSARY OF ABBREVIATIONS 
 
AASLD 
American 
Association 
for 
the 
Study 
of 
Liver Diseases 
Ab 
Antibody 
AE 
Adverse event 
AFP 
Alpha-fetoprotein 
A1AT 
Alpha-1 antitrypsin 
ALKM1 
Anti−liver-kidney microsome-1 antibody 
ALT 
Alanine aminotransferase 
AMA 
Anti-mitochondrial antibody 
ANA 
Anti-nuclear antibody 
Anti-HBe 
Hepatitis B envelope antibody 
Anti-HBs 
Hepatitis B surface antibody  
ASMA 
Anti-smooth muscle antibody 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0−τ 
Area under the curve from 0 hours to a given time 
point 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CA 
Competent Authority 
CDI 
Children’s Depression Inventory 
CHB 
Chronic hepatitis B 
CHC 
Chronic hepatitis C 
CL/F 
Clearance/bioavailability 
Cmax 
Maximum concentration 
CSR 
Clinical Study Report 
DSMB 
Data Safety Monitoring Board 
EASL 
European Association for the Study of the Liver 


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GLOSSARY OF ABBREVIATIONS 
 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EEA 
European Economic Area 
EEG 
Electroencephalogram 
eform 
Electronic form (page) 
ELISA 
Enzyme-linked immunosorbent assay 
EMEA 
European Medicines Agency 
EU 
European Union 
FT3 
Free triiodothyronine 
FT4 
Free thyroxin 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transpeptidase 
HAV IgM Ab 
Hepatitis A virus Immunoglobulin M antibody 
HBeAb 
Hepatitis B envelope antibody 
HBeAg 
Hepatitis B envelope antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HBV-DNA 
Hepatitis B DNA 
HCC 
Hepatocellular carcinoma 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HDV 
Hepatitis D virus 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee  
IFN 
Interferon  


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GLOSSARY OF ABBREVIATIONS 
 
IgM 
Immunoglobulin M 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IXRS 
Interactive voice or web response system 
LLN 
lower limit of normal 
LSM 
Liver Stiffness Measure 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PEG 
polyethylene glycol 
PEG-IFN 
Pegylated-interferon α-2a 
PK 
Pharmacokinetic 
RCR 
Roche Clinical Repository 
REVEAL 
Risk Evaluation of Viral Load Elevation and 
Associated Liver Disease 
RNA 
ribonucleic acid 
SAE 
Serious adverse event 
SMD 
Subject Medication Diary 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
SW 
switch week 
TBG 
Thyroxine-binding globulin 
TPO 
Thyroid peroxidase 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 


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GLOSSARY OF ABBREVIATIONS 
 
US 
United States 
+ve 
Positive 
-ve 
Negative 
V/F 
Volume of distribution/bioavailability 
WBC 
White blood cell 
WHO 
World Health Organization 


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PART I: 
STUDY DESIGN AND CONDUCT 
1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND 
1.1.1 
Disease 
Despite the availability of effective vaccination in the western world, hepatitis B is one of 
the most common infectious diseases in the world.  Of the 2 billion individuals infected 
by the hepatitis B virus (HBV), more than 350 million are chronically infected [1].  Over a 
million individuals die annually of HBV-related chronic liver disease [2]. 
The prevalence of chronic hepatitis B (CHB) varies widely in different parts of the world.  
In areas of low prevalence such as Northern Europe, infection is typically acquired 
during adulthood via intravenous drug abuse or sexual transmission.  In the United 
States, although prevalence of CHB is low, around 1.25 million people are infected.  
Moreover, in certain areas and populations in the United States, such as in Alaskan 
natives, Pacific Islanders, and infants of first-generation immigrant mothers from highly 
endemic areas, prevalence of HBV infection is high.  The majority of individuals in areas 
with a high prevalence of CHB infection, where > 5% of the population are HBV-infected 
carriers, are infected either at the time of birth by vertical transmission from mother to 
child or during early childhood [3].  
The natural history of CHB is highly variable with respect to the course, outcome, and 
complications.  This is partly attributable to the timing of infection e.g., whether acquired 
in childhood, as occurs in Asia and developing countries, or in adulthood, as occurs in 
western countries.  Viral strain and genotype as well as sex, age, racial/ethnic 
background, and other host factors also influence the natural history of CHB infection.  
The onset of CHB is characterized by the persistence of hepatitis B virus DNA (HBV-
DNA), hepatitis B surface antigen (HBsAg), and hepatitis B envelope antigen (HBeAg) in 
serum for more than 6 months after acute infection.  During the early phase of CHB, 
the underlying disease is generally subclinical and often mild.  In some cases, the virus 
can further evolve variants that either do not show or show markedly reduced expression 
of HBeAg, thereby evading the immune control and a further late phase of reactivated, 
HBeAg-negative disease can occur.  Both HBeAg-positive and HBeAg-negative CHB 
can lead to cirrhosis and end-stage liver disease.  CHB is generally milder in children 
compared with adults and is almost always asymptomatic.  Despite effective vaccination 
being available in some countries of the world, perinatal infection still occurs, and about 
1% of children of those who are infected around the time of birth will spontaneously clear 
the infection in the first decade of life [4].  
The natural history of CHB infection in children differs from that of adults, particularly in 
those infected vertically.  The key differences between children and adults are the high 
rate of chronic infection that develops with infection in childhood and the long 
immunotolerant phase.  After exposure to HBV, the probability of becoming chronically 


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infected is inversely proportional to the age at infection:  90% to 95% of neonates, 
80% of children, and 30% of adolescents become persistently infected.  Rates of 
spontaneous seroconversion are variable, depending on age at onset of infection, 
genotype, lower viral load at onset of infection, mode of acquisition, elevated alanine 
aminotransferase (ALT) level and higher histological inflammatory score on liver biopsy 
[4, 5, 6].   
Chronic disease in children is typically characterized by three phases: 
the immunotolerant phase, the immunoactive phase, and the inactive carrier state.  
A large majority of pediatric subjects with perinatally acquired HBV infection with HBeAg-
positive disease are considered to be immunotolerant.  This phase is associated with 
minimal or no evidence of clinical symptoms, normal ALT levels, and high serum HBV-
DNA.  This phase can persist throughout childhood, with disease only becoming active 
with consequent liver damage in a proportion of subjects later in life.  Therefore, severe 
disease with significant fibrosis is very rarely found in children and adolescents, although 
instances of hepatocellular carcinoma (HCC) and decompensated cirrhosis have been 
reported [4, 7].   
The immunoactive phase normally follows the immunotolerant phase.  Early in this 
phase, there may be high HBV-DNA levels, but then during this phase, the HBV-DNA 
levels may decrease to < 10,000 copies/mL.  It is characterized by varying degrees of 
liver inflammation and fibrosis and increased levels of aspartate aminotransferase (AST) 
and ALT.  Seroconversion of HBeAg to hepatitis B envelope antibody (HBeAb) occurs 
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.  
Rates of spontaneous HBeAg seroconversion are much higher in the immunoactive 
phase than in the immunotolerant phase varying between 8% and 12%.  As in adults, a 
further late phase of reactivated, HBeAg-negative disease can occur.  Such patients 
tend to be older and have more advanced liver disease, however, as this represents a 
later stage in the natural history of CHB infection.   
In adults, the risk with CHB is of progression to advanced liver disease, and histologic 
progression to cirrhosis has a cumulative incidence of 5%−20% of chronically infected 
individuals over 5 years.  This carries the further risk of HCC, which has an annual 
incidence of 2%−5% when cirrhosis is established [8].  CHB is thought to be responsible 
for 75% of the cases of HCC on a global level.  In adults who acquired CHB infection as 
an infant or as a child, approximately 15%−25% will die from liver-related causes [9, 10, 
11, 12].  It is now established that the risk factors for cirrhosis and HCC include a longer 
immunoactive phase of infection, earlier age of infection (particularly perinatal acquisition 
is associated with the highest risk of HCC), prolonged elevation of HBV-DNA, elevated 
ALT, presence of HBeAg, family history of HCC, genotype C in Asia (although HCC in 


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younger patients is more often genotype B), co-infection with hepatitis C and D virus, 
and male sex [13, 14, 15, 16, 17, 18, 19].   
Furthermore, the Risk Evaluation of Viral Load Elevation and Associated Liver 
Disease/Cancer Hepatitis B Virus (REVEAL-HBV) study suggested that during the 
immunoactive phase, high HBV-DNA and elevated ALT levels were associated with 
greater risk of cirrhosis and HCC [16, 17, 18].  These findings have prompted a new and 
more aggressive approach to treatment of adults during the immunoactive phase and 
heightened awareness amongst some pediatric liver specialists that treatment during a 
prolonged immunoactive phase is important for decreasing an infected child’s risk of 
developing cirrhosis and/or cancer later in life.  
Therefore, given the medium- to long-term risk of chronic infection and liver disease with 
perinatal infection, treatment of children with CHB represents an opportunity to minimize 
and avoid the risk of long-term complications such as cirrhosis and HCC in later life.  
1.1.2 
Study Drug  
A development program exploring the use of pegylated interferon alfa-2a (PEG-IFN) in 
the treatment of CHB was initiated with a Phase II study using 90, 180, and 270-μg 
doses of PEG-IFN doses, which were compared against the licensed dose of 
conventional interferon (IFN) alfa for 24 weeks of therapy [20].  This pilot trial showed a 
two-fold improvement in efficacy of PEG-IFN over unpegylated IFN and the 270-μg dose 
did not show any indication of additional benefit over the 180-μg dose.  Two large 
Phase III studies were performed and showed that 180 μg of PEG-IFN was superior to 
lamivudine in both HBeAg-positive and -negative disease when assessed 24 weeks after 
stopping 48 weeks of therapy.  Furthermore, both studies contained a third arm 
containing the combination of PEG-IFN with lamivudine, which while showing 
significantly greater HBV-DNA suppression on treatment than lamivudine monotherapy, 
did not show any improvement over PEG-IFN monotherapy at 24 weeks after the end of 
therapy [21, 22].  These HBV studies included more than 1500 subjects and led to 
regulatory approval of PEG-IFN use in CHB in the European Union (EU), United States 
(US), and many other countries with high incidence of HBV disease.  The safety profile 
of 180 μg of PEG-IFN in subjects with CHB was no worse and possibly a little better 
tolerated than that in subjects with hepatitis C virus (HCV) treated with PEG-IFN, 
particularly with regards to the incidence of depression. 
The NEPTUNE study was a Phase IV trial which examined two doses of PEG-IFN 
(90 and 180 μg/wk), and two durations (24 and 48 weeks) in adults with HBeAg-positive 
chronic HBV infection [23].  This trial incorporated a non-inferiority study design and 
showed that the highest response rate was achieved in the 180-μg/wk 48-week 
treatment group, confirming the registered dose and duration of 180 μg/wk 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-μg/wk 48-week treatment group.  The results confirmed that 


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the overall safety profile of PEG-IFN in subjects with HBeAg-positive CHB was 
consistent with the currently approved label, with no new signals identified.  
The present study aims to evaluate the efficacy and safety of treating children with 
immunoactive CHB disease with PEG-IFN in a prospective, open-label, randomized 
study of PEG-IFN monotherapy compared with untreated control in children with 
HBeAg-positive CHB.  The dose and duration of PEG-IFN are based on the results of 
the NEPTUNE study, which showed clearly that the best response rates were in those 
treated with the licensed dose of 180 μg of PEG-IFN for 48 weeks.  This is discussed in 
Section 3.1.2.  
1.2 
RATIONALE FOR THE STUDY  
The principal rationale for conducting a controlled study in pediatric subjects with CHB is 
to establish the risk−benefit balance of treatment in this immunoactive population, given 
that there is no consensus established among experts with regard to the most 
appropriate treatment and timing of therapy for pediatric HBV infection, or with regard to 
the appropriate pediatric HBV target population(s).  Pediatric subjects with immunoactive 
disease may have no signs or symptoms of disease, other than raised transaminases 
(e.g., ALT).  While some experts prefer not to treat and allow for natural resolution of the 
infection, spontaneous seroconversion, and viral clearance, others believe that 
promoting childhood treatment of HBV infection reduces the risk of transmission and 
progression to cirrhosis and HCC.  
There are several arguments in favor of not delaying treatment in pediatric subjects with 
CHB.  For example, children are more likely than adults to develop chronic HBV and 
therefore have higher risk of long-term complications.  Earlier HBeAg seroconversion, 
and a higher chance of HBsAg seroconversion with IFN-based treatment, therefore may 
reduce the risk of long-term complications of liver disease, and also the risks of 
horizontal secondary infection.  In addition, children above the age of 3 years old appear 
to tolerate IFN therapy better than adults, with few persisting serious adverse events 
(SAEs).  Of note, safety concerns in treating children under the age of 3 years with IFN 
therapy exist, and therefore treatment of such infants is not recommended [24, 25, 26, 
27, 28].  
Although anti-HBV treatment using small molecules (nucleos[t]ide therapy) is available 
to suppress levels of HBV-DNA, IFN-based therapies have the advantage that a defined 
duration of treatment is required, rather than apparent life-long treatment, and also that 
interferons lack the development of drug resistance.  PEG-IFN is a long-acting IFN alfa-
2a that has been successfully used for treating CHB in adults and chronic hepatitis C 
(CHC).  Its reduced frequency of injection (once per week) has an advantage over 
conventional IFN-alfa 2a particularly in children.  
The available literature data suggest and support a positive benefit−risk balance for the 
treatment of pediatric subjects with IFN-based therapy.  Treatment with 24 weeks of IFN 


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[29] showed similar or better response rates to adult studies with pegylated alfa 
interferon, with HBeAg loss and HBV-DNA negativity in 26% of treated patients versus 
11% of controls (p = 0.03), loss of HBsAg in 10% of treated patients versus 1% of 
controls at 48 weeks.  A publication reporting two combined IFN-treated cohorts and an 
untreated control group reported that 32% of IFN-treated pediatric subjects and 13.5% of 
control patients achieved HBeAg seroconversion (p < 0.05) 12 months after finishing 
therapy [30].  Data suggest that IFN appears to accelerate an early HBeAg 
seroconversion rate compared with controls, whereas untreated children may have 
similar overall rates of HBeAg seroconversion as treated children, but the 
seroconversion lags behind by 2−3 years in terms of timing [30, 31].  Shifting the time to 
seroconversion by 12−36 months could therefore be helpful in preventing long-term 
damage to the liver, although this has not been demonstrated in clinical studies to date.  
Of note, however, HBeAg seroconversion frequencies among treated children with 
raised ALT at baseline (ALT was ≥ 2 × the upper limit of normal [ULN]) were almost twice 
that of the untreated children or children with baseline of ALT ≤ 2 × the ULN, showing an 
enhanced response in those patients with a higher degree of hepatic injury at baseline.  
Pediatric subjects treated with IFN have higher rates of HBsAg seroconversion than 
untreated controls (10% vs. 1.2%, respectively; p = 0.03) [29], supporting the idea that 
treatment enhances cure rates in terms of loss of HBsAg and production of hepatitis B 
surface antibodies (anti-HBs).   
A review in 2003 [32] identified factors predictive of IFN response in the pediatric CHB 
population, including higher baseline ALT levels, lower DNA levels, higher histological 
activity on biopsy in children [33] and younger age [34].  In addition, genotypes A and B 
appeared to respond better to IFN than types C and D with standard therapy [35, 36, 37].  
PEG-IFN data have suggested that genotype C responded similarly to genotype B [37, 
38].   
Pawlowska et al. [37] reported on the treatment of 13 children (9 boys and 4 girls), aged 
11–17 years with CHB, who were treated with PEG-IFN (100 μg/m2/wk; doses ranged 
from 135 to 180 μg/wk) for 48 weeks.  There were 5 HBeAg-positive and 8 HBeAg-
negative children.  Five children achieved sustained virological response (undetectable 
serum HBV-DNA 24 weeks after the end of treatment) and continued to sustain this 
response 48 weeks after the end of treatment; 2 children had HBsAg loss at the end of 
48 weeks of treatment.  
A study conducted in China evaluated the safety and efficacy of extended PEG-IFN 
therapy in children with HBeAg-positive CHB [39].  Forty-two children, aged 8–16 years, 
were treated with PEG-IFN 104 μg/m2 body surface area (BSA) once weekly.  Treatment 
duration was extended from 48 weeks to a maximum of 96 weeks with a subsequent 
follow-up of 24 weeks.  All response rates were higher at Week 96 and at 24 weeks after 
end of treatment compared with responses at 48 weeks with HBeAg seroconversion rate 
at Week 96 being significantly higher than at Week 48 (83.8% vs. 19.1%, respectively; 
p < 0.005).  These data indicate that extension of PEG-IFN may improve response rates 


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for those with poorer predictors of response, e.g., genotype C, and appears to be 
tolerated in children. 
The major adverse events (AEs) seen in children treated with non-pegylated or 
pegylated alfa interferon were similar to those seen in adults and included fever, fatigue, 
headaches, muscle aches, dizziness, irritability, arthralgia, anorexia, nausea, abdominal 
discomfort, injection-site reactions, neutropenia, and thrombocytopenia.  The AEs which 
seem to be more prominent in children than in adults were hair loss, personality changes, 
and transient growth suppression [29, 30, 37, 38, 39, 40].  Changes in height and growth 
percentiles over time were assessed at the end of treatment and at 2 years of follow-up 
in 114 subjects with CHC who were treated with PEG-IFN as part of the PEDS-C trial 
[41].  Although reductions in weight and height were observed compared to the 
normative population at the end of treatment, these had returned to baseline by Year 2 
of follow-up.  
Therefore, the available data involving treatment with both non-pegylated and pegylated 
interferon alfa suggest that the risk−benefit balance of not delaying treatment may be 
positive.  While there may be an emerging consensus from pediatricians that the 
potential therapeutic benefit of treatment might outweigh the risks in most children to 
avoid the risk of long-term liver disease, opinion and practice still diverge, and there is a 
need to assess the benefit−risk balance of treatment against observed untreated 
controls.   
2. 
OBJECTIVES 
This controlled study in children with HBeAg positive CHB in the immune active phase 
will compare efficacy and safety between a group treated with PEG-IFN monotherapy 
and an untreated control group, and evaluate pharmacokinetics (PK) of PEG-IFN 
following administration of a new BSA-based dosing regimen. 
2.1 
PRIMARY OBJECTIVE 
To compare HBeAg seroconversion (loss of HBeAg and presence of hepatitis B 
envelope antibody [anti-HBe]) between a group treated with PEG-IFN monotherapy and 
an untreated control group.  The primary endpoint will be assessed 24 weeks after the 
end of treatment/principal observation period, with a further 4.5 years of follow-up 
(see Section 8.1.1). 


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2.2 
SECONDARY OBJECTIVES 
To examine the short and longer term effects on various efficacy and safety measures 
between a group treated with PEG-IFN monotherapy and an untreated control group, 
and to evaluate PK in PEG-IFN−treated subjects (see Section 8.1.2), as follows:  
Efficacy 
• 
Loss of HBeAg, HBsAg seroconversion (loss of HBsAg and presence of anti-HBs), 
loss of HBsAg, quantitative serum ALT, proportion of normal ALT, quantitative 
HBV-DNA, suppression of HBV-DNA < 100,000 copies/mL (< 20,000 IU/mL), 
< 10,000 copies/mL (< 2,000 IU/mL), undetectable and change from baseline, 
combined endpoint of HBeAg seroconversion and HBV-DNA < 100,000 copies/mL 
(< 20,000 IU/mL), and combined endpoint of HBeAg seroconversion and HBV-DNA 
< 10,000 copies/mL (< 2,000 IU/mL)  
• 
Persistence of HBeAg seroconversion (loss of HBeAg and presence of anti-HBe) 
over extended long-term follow-up  
• 
Descriptive change from baseline in liver elasticity (in liver elasticity sub-study 
subjects⎯see Section 5.3.1.2) 
 
Safety 
• 
AEs (including neurological and psychiatric events), serious and non-serious, and 
non-serious AEs of special interest 
• 
Laboratory test results (including thyroid function) 
• 
Vital signs (blood pressure, heart rate, temperature) 
• 
Growth:  weight and height 
 
Pharmacokinetic 
• 
PK of PEG-IFN following administration of a new BSA-based dosing regimen in 
PEG-IFN−treated subjects 
 
2.3 
EXPLORATORY OBJECTIVES 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities for 
the long-term storage of human biological specimens including body fluids, solid tissues 
and derivatives thereof (e.g., DNA, RNA proteins/peptides; see Section 5.4.3).  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.  RCR specimens will be used to 
achieve the following objectives: 
• 
To study the association of biomarkers with efficacy, AEs, or other effects 
associated with medicinal products 
• 
To increase knowledge and understanding of disease biology 


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• 
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 
 
3. 
STUDY DESIGN 
3.1 
OVERVIEW OF STUDY DESIGN AND DOSING REGIMEN  
This is a 2:1 randomized, controlled, parallel-group, open-label, multicenter study of 
PEG-IFN treatment compared to an untreated control (Figure 1).  Subjects without 
advanced fibrosis/cirrhosis will be randomized 2:1 to PEG-IFN treatment (Group A) or 
untreated control (Group B), respectively.  Subjects with advanced fibrosis will be 
assigned to PEG-IFN treatment (Group C).  Subjects in Groups A and C will receive 
PEG-IFN for 48 weeks.  The first 48 weeks from randomization will be referred to as the 
treatment period for Groups A and C and the principal observation period for Group B.  
The primary endpoint will be assessed 24 weeks after the end of treatment/principal 
observation period. 
Forty-eight weeks after randomization, PEG-IFN will be offered to subjects in the 
Group B untreated control group who have not experienced HBeAg seroconversion.  
This offer will be available for up to 1 year following Week 48.  If eligible, these subjects 
will enter the switch arm, where they will receive PEG-IFN for 48 weeks.  
The screening period will be up to 35 days.  For Group A, Group B non-switch, and 
Group C subjects the study length is approximately 6 years (1-year treatment/principal 
observation period and 5 years of follow-up).  For Group B switch subjects the study 
length is up to approximately 8 years (1-year principal observation period, up to 1 year 
follow-up whilst deciding whether to switch, 1-year switch treatment period, and 5-year 
follow-up period). 


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Figure 1 Schematic of Study Design 
 
 
 


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3.1.1 
Rationale for Study Design 
3.1.1.1 
Use of Untreated Control Arm and Compassionate Switch  
Experts have debated whether a need exists for treatment during childhood, since the 
majority of children infected with HBV are in the immunotolerant phase [11], and only a 
minority of subjects might fulfill the criteria to be considered for antiviral therapy on 
grounds of absolute clinical need.  The current European Association for the Study of the 
Liver (EASL) guidance recommends consideration of treatment in children with CHB in 
those with immunoactive disease i.e., those with persistently elevated ALT greater than 
the ULN for 6 months [42].   
It is acknowledged that few children with immunoactive disease show any signs or 
symptoms of disease.  Some experts take the view that treatment should be delayed in 
children with chronic HBV disease given the lack of clinical signs, the possible natural 
resolution of infection, the uncertainties around treatment effectiveness, the AEs 
reported during treatment, and the possible development of newer more effective, less 
toxic therapies [43].  This has led to a lack of consensus among experts with regard to 
the most appropriate treatment and timing of therapy for pediatric HBV infection, or with 
regard to the appropriate pediatric HBV target population(s).  The inclusion of an 
untreated control arm for 48 weeks in the study design therefore takes account of this 
area of uncertainty by allowing a period of direct comparison of efficacy and safety with 
untreated subjects.   
The study design also takes into account these management uncertainties by ensuring 
that all subjects randomized to the untreated control arm who request it and who have 
not seroconverted will be offered treatment with PEG-IFN at the end of the 48-week 
observation period and up to 1 year after this point.   
An untreated control arm has been selected for this study as the use of a placebo control arm is 
not considered appropriate for several reasons.  Firstly, the use of placebo injections would not 
effectively blind treatment as the known adverse effects of IFN therapy, particularly influenza-like 
illness, would not occur.  It would therefore be likely that subjects/parents would become aware 
that the subject was not receiving IFN resulting in a potential risk of noncompliance.  Secondly, 
it would be unethical to administer weekly placebo injections for 48 weeks as administration 
requires an invasive procedure with an associated risk of injection-site infections and no 
associated benefit.  A further benefit of using an untreated control arm is that the study burden 
for the untreated subjects is reduced as their visit schedule is less frequent compared with that of 
the treated subjects, 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 central 
randomization, use of a central laboratory and standardized assays, and the choice of the intent-
to-treat (ITT) population for the primary analysis. 


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The objective of this study would be therefore to establish the benefit−risk balance for 
treatment using PEG-IFN in this immunoactive pediatric population, by comparing the 
safety and efficacy of 48 weeks treatment with an untreated control group.  
3.1.1.2 
Use of Advanced Fibrotic Arm and Exclusion of Cirrhotic 
Subjects 
This study will also evaluate the efficacy and safety of PEG-IFN−based treatment in a 
small subgroup of pediatric subjects with advanced fibrosis (see Appendix 1) and 
compensated liver disease.  When these subjects are recruited they will be allocated to 
treatment arm (Group C; 48 weeks treatment with PEG-IFN), rather than being 
randomized to treatment or untreated control.  This is because a majority of specialists 
surveyed on the clinical and ethical risk-benefit gave the opinion that it would be 
clinically and ethically unacceptable to them to delay treatment in subjects with 
advanced disease (advanced fibrosis/cirrhosis) by potentially randomizing them to an 
untreated control arm.  Instead, subjects with advanced fibrosis will receive guaranteed 
immediate treatment. 
The data from these subjects with more advanced fibrosis will therefore be analyzed 
descriptively and separately from the main comparison.   
Subjects with cirrhosis will be excluded from this study.  The current treatment guidance 
from the European and US experts (EASL and American Association for the Study of 
Liver Diseases [AASLD]) does not recommend interferon treatment for cirrhotic patients 
with CHB due to the risk of hepatic decompensation associated with IFN-related flares of 
hepatitis.  Long-term treatment with nucleos(t)ides analogues are recommended for this 
patient population [42, 44].  
3.1.1.3 
Liver Elasticity Sub-study 
Liver elasticity using liver elastography will also be assessed as a sub-study at specific 
sites in both treated and untreated subjects.  Liver elastography is a non-invasive 
procedure used in some countries to assess liver fibrosis.  It is a measure of liver 
elasticity as a Liver Stiffness Measure (LSM) that has been shown to correlate 
significantly with the degree of hepatic fibrosis [45, 46, 47].  Liver elastography is a 
potentially useful method of diagnosing degrees of fibrosis, and therefore will be utilized 
in this sub-study to assess progression and improvement in liver fibrosis.  In addition, 
this sub-study will explore the association of baseline liver biopsy score with LSM in a 
proportion of subjects.   
3.1.2 
Rationale for Dose Selection 
3.1.2.1 
Establishment of Optimal Dose and Duration of PEG-IFN 
in CHB 
The NEPTUNE study was a Phase IV trial that examined two doses of PEG-IFN (90 and 
180 μg/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 


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that the highest response rate was achieved in the 180-μg/48-week treatment group, 
confirming the registered dose and duration of 180 μg and 48 weeks 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-μg/48-week treatment group.  The results confirmed that the overall safety 
profile of PEG-IFN in patients with HBeAg-positive CHB was consistent with the 
currently approved label, with no new signals identified.  
The present study aims to evaluate the efficacy and safety of treating children with 
immunoactive CHB disease with PEG-IFN in an open-label, randomized study of 
PEG-IFN monotherapy compared with untreated control in children with HBeAg-positive 
CHB.  The dose and duration of PEG-IFN are based on the results from the NEPTUNE 
study. 
3.1.2.2 
Pediatric Dosing of PEG-IFN 
This study will use the dose and duration of PEG-IFN established in the NEPTUNE 
study but modified for pediatric use.  Study NR16141 (Schwarz PK/pharmacodynamic 
[PD] 2006 study) [48] demonstrated 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 μg/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 from 0 hours to a given time point 
[AUC0−τ]) to PEG-IFN in children was 25% to 70% higher than that observed in adults 
receiving a weekly dose of 180 μg of PEG-IFN (5667 ng • h/mL vs. a range of mean 
values from 3334 to 4348 ng • h/mL).  There was a high 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 11125 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, indicating that dosing may be slightly reduced to improve exposure-related 
AEs while maintaining viral response.  
The dosing regimen for this study is based on  formula dosing of 180 μg/1.73 m2
 × BSA 
used in the pivotal Phase III HCV pediatric study (NV17424 PEDS-C Study) [41] and in 
the PK/PD Study NR16141 (Schwarz PK/PD [2006] study) [48].  BSA categories, based 
on the formula 180 μg/1.73 m2
 × BSA, have been provided to facilitate the calculation of 
the dose by clinicians and to minimize the risk of dosing errors (Table 1).   


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Table 1 
Pediatric Dosing Regimen 
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 
 
This approach has been accepted by the European Medicines Agency (EMEA) for 
Pegasys pediatric dosing in HCV disease [49]. This also aligns with the approved 
Pegasys pediatric label in the United States, where the dose for children between the 
ages of 5 to 18 years is 180 μg × 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 hepatitis B in adults, similarly 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 hepatitis C from adult to pediatric doses 
to 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 subjects of various sizes (BSAs) participating in six HCV clinical trials with Pegasys.  
It is calculated by comparing the ratio of the 180-μg dose per adult BSA of the 5th and 
95th percentile adult BSA (n = 1940) to the reference (180/ median adult BSA).  
Treated subjects will receive PEG-IFN subcutaneously once weekly for 48 weeks with 
dosing based on BSA categories.   
3.1.3 
End of Study 
The primary endpoint will be assessed 24 weeks after the end of treatment/principal 
observation period, with a further 4.5 years of extended long-term follow-up.  The end of 
study is defined as last subject last visit (LSLV).  
3.2 
NUMBER OF SUBJECTS/ASSIGNMENT TO TREATMENT 
GROUPS 
One-hundred-sixty subjects will be recruited.  At least 145 subjects without advanced 
fibrosis or cirrhosis (assessed by liver biopsy performed within 2 years prior to baseline) 
will be randomized in a 2:1 ratio to PEG-IFN treatment (Group A) or untreated control 
(Group B), respectively.  That is for every 2 subjects randomized to PEG-IFN only, 1 will 
be randomized to the untreated control.  Stratification will be performed by genotype (A 


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vs. non-A) and ALT (< 5 × the ULN vs. ≥ 5 × the ULN).  Subjects with advanced fibrosis 
(assessed by liver biopsy performed within 9 months prior to baseline), will be assigned 
to PEG-IFN treatment (Group C: advanced fibrotic arm).  Group and dose, if applicable, 
will be assigned by an interactive voice or web response system (IXRS [see 
Section 5.2]). 
Forty-eight weeks after randomization, PEG-IFN will be offered to subjects in the 
Group B untreated control group who have not experienced HBeAg seroconversion.  
This offer will be available for up to 1 year following Week 48.  If eligible, these subjects 
will enter the switch arm, where they will receive PEG-IFN for 48 weeks. 
3.3 
CENTERS 
Subjects will be enrolled from approximately 40-70 centers globally.  There will be a 
mean number of 2−4 subjects per center, with the majority of subjects being in 
Asia−Pacific regions. 
4. 
STUDY POPULATION 
Under no circumstances are subjects who enroll in this study permitted to be 
re-randomized to this study and enrolled for a second course of treatment. 
4.1 
OVERVIEW 
The study population will be children aged 3 to < 18 years of age with CHB, who are 
HBeAg positive (+ve), HBsAg+ve, with detectable HBV-DNA (> 10,000 copies/mL 
[> 2,000 IU/mL]) by polymerase chain reaction (PCR) and ALT > ULN but ≤ 10 × the ULN 
(using the reference range of the testing laboratory).  Liver biopsy needs to have been 
performed within 2 years prior to baseline to confirm or exclude the presence of 
advanced fibrosis or cirrhosis (see Appendix 1).  For subjects with advanced fibrosis, a 
liver biopsy needs to have been performed within 9 months prior to baseline to ensure 
that the subject has not progressed to cirrhosis.  Subjects co-infected with HCV, hepatitis 
D virus (HDV), human immunodeficiency virus (HIV) or who have received therapy for 
hepatitis B in the prior 6 months or who have de-compensated liver disease will be 
excluded.  
4.1.1 
Recruitment Procedures 
Subjects will be identified for potential recruitment using pre-screening enrollment logs, 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB)-approved 
newspaper/radio advertisements, and/or mailing lists prior to consenting/assenting to 
take place in this study.   
4.2 
INCLUSION CRITERIA  
A subject may be included if the answer to all of the following statements is “yes”: 
• 
Male or female subjects aged 3 to < 18 years old at baseline 


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• 
Positive HBsAg for more than 6 months 
• 
Positive HBeAg and detectable HBV-DNA at screening (subjects must have 
> 10,000 copies/mL [> 2,000 IU/mL] as measured by PCR)  
• 
A liver biopsy performed within 2 years prior to baseline to confirm the presence of 
advanced fibrosis or exclude cirrhosis (see Appendix 1).  For subjects with 
advanced fibrosis, a liver biopsy needs to be performed within 9 months prior to 
baseline 
• 
Compensated liver disease (Child-Pugh Class A clinical classification; 
see Appendix 2) 
• 
Elevated serum ALT > ULN but ≤ 10 × the ULN as determined by two abnormal 
values taken ≥ 14 days apart during the 6 months before the first dose of study drug 
with at least one of the determinations obtained ≤ 35 days prior to the first dose.  
Reference range of the testing laboratory should be used 
• 
Signed informed consent from parent/legal guardian and willingness of parent/legal 
guardian to abide by the requirements of the study, and signed assent from child if 
appropriate.  Patients < 18 years of age at baseline who are legally adults according to 
national legislation must consent in their own right. 
 
4.3 
EXCLUSION CRITERIA 
A subject will be excluded if the answer to any of the following statements is “yes”: 
• 
Subjects with cirrhosis (see Appendix 1) 
• 
Subjects who have received investigational drugs or licensed treatments with 
anti-HBV activity within 6 months prior to baseline (e.g., IFNs, systemic 
corticosteroids, lamivudine, tenofovir, emtricitabine, adefovir, entecavir, telbivudine, 
systemic acyclovir, systemic famciclovir)  (Exception:  Subjects 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.)   
• 
Known hypersensitivity to PEG-IFN 
• 
Positive test results at screening for hepatitis A virus immunoglobulin M antibody 
(HAV IgM Ab), anti-HCV antibody (Ab), anti-HDV Ab, or anti-HIV Ab 
• 
History or other evidence of a medical condition associated with chronic liver 
disease other than CHB 
• 
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) 
• 
History or other evidence of metabolic liver disease 
• 
Suspicion of HCC on ultrasound or other liver imaging (all subjects to have 
ultrasound within 6 months prior to baseline) 
• 
Screening alfa-fetoprotein (AFP) ≥ 100 ng/mL 


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• 
Screening neutrophil count < 1.5 × 109 cells/L, platelet count < 90 × 109 cells/L, 
or hemoglobin < lower limit of normal (LLN) 
• 
Screening albumin < lower limit of normal or total bilirubin > ULN   
Exception: Subjects with non−hepatitis-related factors which may elevate 
bilirubin such as Gilbert’s disease 
• 
Evidence of renal impairment  
• 
Autoimmune hepatitis 
• 
History of immunologically mediated disease to include, but not limited to: 
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 
• 
History or other evidence of chronic pulmonary or cardiac disease associated with 
clinically significant functional limitation 
• 
History of thyroid disease 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/or thyroxine-binding globulin [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 (international normalized ratio > 1.5), hemoglobinopathy, hemophilia, 
or history of severe illness or other blood disorders that would make subject 
unsuitable for the study 
• 
History of seizure disorder requiring treatment with anticonvulsant medication 
(excluding febrile seizures) 
• 
History or other evidence of severe retinopathy (all subjects to have 
ophthalmological examination within 6 months prior to baseline) 
• 
History or other evidence of severe illness or any other conditions that would make 
the subject, in the opinion of the investigator, unsuitable for the study 
• 
Active substance abuse within the last 6 months before the study 


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• 
Sexually active females of childbearing potential and sexually active males who are 
not willing to utilize reliable contraception during the treatment/principal observation 
period and during the initial 24-week follow-up period 
• 
Females of childbearing potential who have a positive urine or serum pregnancy test 
result within 24 hours of baseline, or who are breast-feeding 
 
4.4 
CONCOMITANT MEDICATION AND TREATMENT 
• 
Use of any investigational drugs as a result of participation in another clinical study 
is prohibited during the study including the extended long-term follow-up period. 
• 
Concomitant use of any other investigational drugs (e.g., compassionate use), 
immunomodulatory treatments (e.g., interferons, systemic corticosteroids), growth 
factors (e.g., erythropoietin, granulocyte colony-stimulating factor) or antiviral 
treatments with anti-HBV activity (e.g., lamivudine, tenofovir, emtricitabine, adefovir, 
entecavir, telbivudine, systemic acyclovir, systemic famciclovir) other than those 
specifically allowed by this protocol are prohibited during either the 
treatment/principal observation period or initial 24 weeks of follow-up, in order to 
minimize the confounding effects of such treatments in determining treatment 
responses.  
Exceptions to this are as follows:  
Subjects with significant deterioration in hepatic function (e.g., decompensation) 
who permanently discontinue study drug and need to consider alternative therapies 
In Group C, treatments with anti-HBV activity will not be prohibited during the 
24-week follow-up period. 
• 
Commencing any anti-HBV treatment between follow-up Week 24 and follow-up 
Year 1 will make Group B subjects ineligible for entering the switch arm. 
• 
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. 
 
All concomitant medications should be reported to the investigator and recorded on the 
appropriate electronic Case Report Form (eCRF), including details of any previous 
anti-HBV treatment, as well as any other previous concomitant medications taken within 
2 years prior to baseline.   
During extended long-term follow-up, only concomitant medications for CHB will 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 chronic HBV disease. 


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4.5 
MINIMIZING PAIN AND DISTRESS 
As per the International Conference on Harmonisation (ICH) Guideline for Clinical 
Investigation of Medicinal Products in the Pediatric Population, Topic E11, measures will 
be taken in this study to minimize the pediatric subjects’ possible pain and distress. 
This study has been designed specifically for a pediatric population. 
Considerations to ensure that subjects’ experiences in the study are positive and to 
minimize discomfort and distress will include the following: 
• 
Investigators will be experienced and skilled in the treatment of pediatric subjects 
and in dealing with the pediatric population and its age-appropriate needs, including 
skill in performing pediatric procedures. 
• 
Investigator sites will provide a physical setting with furniture, play equipment, 
activities, and food appropriate for age. 
• 
Investigator sites will be the hospitals or clinics where subjects normally receive 
their care and hence will provide a familiar environment. 
• 
Approaches to minimize discomfort of procedures will be utilized, e.g., topical 
anesthesia to place IV catheters, indwelling catheters rather than repeated 
venepuncture for blood sampling. 
• 
Blood draws will be kept to those absolutely necessary for the study, and volumes 
will be minimized. 
• 
Subjects have the right to withdraw from the study at any time for any reason (see 
Section 4.6). 
 
4.6 
CRITERIA FOR PREMATURE WITHDRAWAL 
4.6.1 
Withdrawal of Subjects from Study Treatment 
Subjects have the right to withdraw from study treatment at any time for any reason.  
Specific rules for stopping study treatment also apply (see Section 6.2.1). 
In the case that the subject decides to prematurely discontinue study treatment (“refuses 
treatment”), all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible preferably by returning to site to complete 
assessments as per the Week 48/Switch Week 48 visit (see Table 2 and Table 4) and 
the Treatment Completion eCRF.  The subject should then enter the post-end of 
treatment follow-up period.   
4.6.2 
Withdrawal of Subjects from the Study 
Subjects have the right to withdraw from the study at any time for any reason. 
In the case that the subject decides not to enter the follow-up period or 
prematurely discontinues from the follow-up period, he/she should be asked if he/she 
can still be contacted for further information.  The outcome of that discussion should be 


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documented in the medical records.  If the subject is lost to follow-up, the investigator 
should contact the subject or a responsible relative by telephone followed by registered 
mail or through a personal visit to establish as completely as possible the reason for the 
withdrawal.  In all cases, the Study Completion eCRF must be completed.   
If possible, a complete final evaluation at the time of the subject’s withdrawal from the 
study should be made with an explanation of why the subject is withdrawing from the 
study.  For subjects withdrawing prior to Week 48, the assessments as per the Week 48 
visit should be completed.  For subjects withdrawing post−Week 48 but prior to follow-up 
Week 24, the assessments as per the follow-up Week 24 visit should be completed.  For 
subjects withdrawing after follow-up Week 24, the assessments as per the follow-up 
Year 5 visit should be completed. 
When applicable, subjects should be informed of circumstances under which 
their participation may be terminated by the investigator without the subject’s 
consent/assent.  The investigator may withdraw subjects from the study in the event of 
intercurrent illness, AEs, lack of compliance with the study and/or study procedures (e.g., 
dosing instructions, study visits) or any reason where it is felt by the investigator that 
further follow-up of the subject is impossible or it is in the best interest of the subject to 
be terminated from the study.  Any administrative or other reasons for withdrawal must 
be documented and explained to the subject. 
If the reason for removal of a subject from the study is an AE, the principal specific event 
will be recorded on the eCRF.  The subject should be followed until the AE has resolved, 
if possible. 
An excessive rate of withdrawals can render the study non-interpretable; therefore, 
unnecessary withdrawal of subjects should be avoided.  Should a subject decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
See Section 7.2.4 for withdrawal due to pregnancy. 
4.6.3 
Withdrawal of Subjects from the Roche Clinical Repository 
(RCR) 
Subjects 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 subject wishes to 
withdraw consent/assent to the testing of his or her specimens, the investigator must 
inform the Roche monitor in writing of the subject'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 eCRF.  The subject will be 
provided with instructions on how to withdraw consent/assent after the trial is closed.  
A subject’s withdrawal from Study YV25718 does not, by itself, constitute withdrawal 


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of specimens from the RCR.  Similarly, a subject’s withdrawal from the RCR does not 
constitute withdrawal from Study YV25718. 
4.7 
REPLACEMENT POLICY (ENSURING ADEQUATE NUMBERS 
OF EVALUABLE SUBJECTS) 
4.7.1 
For Subjects 
No subject prematurely discontinued from the study for any reason will be replaced.  
4.7.2 
For Centers 
A center may be replaced for the following administrative reasons:   
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
 
4.8 
SWITCH CRITERIA 
Forty-eight weeks after randomization, PEG-IFN will be offered to subjects in the 
Group B untreated control group who have not experienced HBeAg seroconversion.  
This offer will be available for up to 1 year following Week 48.  Subjects must meet the 
following switch inclusion and exclusion criteria. 
4.8.1 
Switch Inclusion Criteria 
Subjects in Group B may switch to treatment with PEG-IFN if the answer to all of the 
following statements is “yes.” 
• 
Positive HBeAg and positive HBsAg within 6 months prior to switch baseline 
• 
Either 
A liver biopsy performed within 2 years prior to switch baseline to exclude cirrhosis 
(see Appendix 1) or 
Clinical, laboratory, and ultrasound data which together exclude cirrhosis 
4.8.2 
Switch Exclusion Criteria 
Subjects in Group B may not switch to treatment with PEG-IFN if the answer to any of 
the following statements is “yes”. 
• 
Cirrhosis (see Appendix 1) 
• 
Subjects who have received any anti-HBV treatment within 6 months prior to switch 
baseline 
• 
Positive test results within 6 months prior to switch baseline for HAV IgM Ab, anti-
HCV Ab, anti-HDV Ab, or anti-HIV Ab 
• 
Evidence of decompensated liver disease (e.g., Child−Pugh Class B or C clinical 
classification, see Appendix 2 or clinical evidence such as ascites or varices) at switch 
baseline 
• 
Serum ALT >10 ×the ULN at switch baseline.  Reference range of the testing laboratory 
should be used 


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• 
International normalized ratio > 1.5 at switch baseline 
• 
Neutrophil count < 1.5 × 109 cells/L, platelet count <90  × 109 cells/L, or hemoglobin 
< lower limit of normal (LLN) at switch baseline  
• 
Evidence of renal impairement  
• 
Evidence of severe illness or any other conditions or contraindications that would 
make the subject, in the opinion of the investigator, unsuitable for commencing 
PEG-IFN 
• 
Clinically relevant abnormal thyroid function tests (TSH, FT3, FT4, TPO antibodies, 
and/or TBG) within 6 months prior to switch baseline  
• 
Sexually active females of childbearing potential and sexually active males who are 
not willing to use reliable contraception during the switch treatment period and initial 
24-week switch follow-up period 
• 
Females of childbearing potential who have a positive urine or serum pregnancy test 
result within 24 hours of switch baseline 
 


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5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
Table 2 
Schedule of Assessments and Procedures⎯Group A (PEG-IFN) and Group C (Advanced Fibrotic 
PEG-IFN) 
Screen
(days) 
BL
(days)
Treatment Period  
(weeks) 
Initial Follow-Up 
(weeks Post-End 
of Treatment) 
Long-Term  
Follow-Up  
(years Post-End of  
Treatment Period) 
Assessment/Procedure 
−35 to −1
1 
1
2
4
8 12 18 24 30 36 42 48 a
4 a 
12 a
24 a
1 a 1.5 a, 
b 
2 a 
3 a 
4 a 
5 a 
Informed Consent/Assent c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete medical history, including 
family history of HBV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
Vital signs  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Weight d 
x 
x f 
x 
x 
x 
x x f
x 
xf
x x f
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
Height d, e 
x 
x f 
 
 
 
 
x f
 
xf
 
x f
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
Parental height g  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ultrasound h, j 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology exam i, j 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
a 
Or upon and following study treatment withdrawal. 
b 
By telephone. 
c 
Informed Consent obtained from legal guardian, and assent obtained from child if appropriate.  
d 
Measurements must be taken using the same instruments in the same individual. 
e 
Using stadiometer and taking the mean of three readings. 
f 
Weight and height to be provided to IXRS. 
g 
From consenting biological parents. 
h 
To rule out hepatocellular carcinoma.  Further liver imaging assessment may be performed if necessary.  
i 
By ophthalmologist (pediatric ophthalmologist recommended) and including fundoscopic examination with dilation, visual acuity assessment, visual field testing 
(confrontation test is recommended for younger children), and color visual testing.  Any subject who develops ocular symptoms should receive a prompt eye 
examination by an ophthalmologist and additional examinations as necessary. 
j 
Within 6 months prior to baseline; repeat only if any change in the subject’s medical condition. 


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Table 2 
Schedule of Assessments and Procedures⎯Group A (PEG-IFN) and Group C (Advanced Fibrotic 
PEG-IFN) (cont.) 
 
Screen 
(days) 
BL 
(days)
Treatment Period  
(weeks) 
Initial Follow-Up 
(weeks Post-End 
of Treatment) 
Long-Term  
Follow-Up  
(years Post-End of  
Treatment Period) 
Assessment/Procedure 
−35 to −1 
1 
1
2
4
8 12 18 24 30 36 42 48 a
4 a 
12 a
24 a
1 a 1.5 a, b 2 a
3 a 
4 a 
5 a 
Urine or serum HCG pregnancy 
test (selected subjects) c, d 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Alfa-fetoprotein e,h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-HAV IgM, anti-HCV, 
anti-HIV, anti-HDV h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV genotypeh 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ceruloplasmin, A1AT, AMA, 
ASMA, ALKM1 h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-nuclear antibody (ANA) h 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Hematology  f, i  
x 
x 
x
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Chemistry f, i 
x 
x 
x
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Urinalysis d, f, g 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
a 
Or upon and following study treatment withdrawal. 
b 
By telephone. 
c 
For females of childbearing potential, a pregnancy test will be performed within 24 hours prior to baseline, and at any time secondary amenorrhea of more than 
1 week occurs.  Result of baseline pregnancy test must be available prior to randomization and commencement of treatment. 
d 
To be performed by local laboratory. 
e 
Subjects need to have serum alfa-fetoprotein assessed during the screening period to rule out hepatocellular carcinoma. 
f 
If there are clinically significant laboratory abnormalities, repeat no less frequently than every 2 weeks or as clinically indicated, with appropriate toxicity 
management, until they return to normal or baseline values.   
g 
Urinalysis to be performed via dipstick, with subsequent microscopic evaluation if positive for blood at the discretion of the investigator. 
h 
Parameter does not need to be repeated at re-screening if performed within 6 months prior to baseline, unless dictated by a change in the subject’s medical 
condition or the parameter accounted for the original screen failure. 
i 
To be performed by a local laboratory in countries activated prior to April 2013, and by a central laboratory in countries activated after April 2013. 


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Table 2 
Schedule of Assessments and Procedures⎯Group A (PEG-IFN) and Group C (Advanced Fibrotic 
PEG-IFN) (cont.) 
 
Screen
(days) 
BL 
(days)
Treatment Period  
(weeks) 
Initial Follow-Up 
(weeks Post-End 
of Treatment) 
Long-Term  
Follow-Up  
(years Post-End of  
Treatment Period) 
Assessment/Procedure 
−35 to −1
1 
1 
2 4
8 12 18 24 30 36 42 48 a
4 a 
12 a
24 a 
1 a 1.5 a,b 2 a
3 a 
4 a 
5 a 
FΤ3, FΤ4, TSH c 
xl 
 
 
 
 
 
x
 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
TBG 
xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TPO antibodies 
xl 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Population PK d 
 
x 
x 
 
x
x x
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBeAg, anti-HBe e 
xl 
x 
 
 
 
 
x
 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
HBV DNA e  
xl 
x 
 
 
 
 
x
 
x 
 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
HBsAg, anti-HBs e 
xl 
x 
 
 
 
 
x
 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
Quantitative HBsAg and HBeAg e 
 
x 
 
 
 
 
x
 
x 
 
x 
 
x 
 
 
x 
 
 
 
 
 
 
Serum bank f 
 
x 
 
 
 
 
x
 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
RCR plasma & RNA specimen 
 
x 
 
 
 
 
x
 
x 
 
 
 
x 
 
 
x 
x 
 
x 
x 
x 
x 
RCR DNA specimen 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
x 
x 
x x
x x
x
x 
x x 
x 
x 
x 
x 
x 
x g 
x g 
x g 
x g 
x g 
x g 
Concomitant medications 
(including for CHB h) 
x 
x 
x 
x x
x x
x
x 
x x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Concomitant medications for 
CHB only h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Subject study drug diary 
 
 
x 
x x
x x
x
x 
x x 
x 
x 
 
 
 
 
 
 
 
 
 
Dispense study drug 
 
x 
 
 
x
x x
x
x 
x x 
x 
 
 
 
 
 
 
 
 
 
 
Compliance 
 
 
x 
x x
x x
x
x 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Neuro-Psychiatric Questionnaire i 
x 
x 
 
 
 
 
x
 
x 
 
x 
 
x 
x 
 
 
 
 
 
 
 
 
Liver biopsy 
x j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver elastography k 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
a 
Or upon and following study treatment withdrawal. 
b 
By telephone. 
c 
If there are clinically significant laboratory abnormalities, repeat no less frequently than every 2 weeks or as clinically indicated, with appropriate toxicity 
management, until they return to normal or baseline values. 


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Table 2 
Schedule of Assessments and Procedures⎯Group A (PEG-IFN) and Group C (Advanced Fibrotic 
PEG-IFN) (cont.) 
 
d 
Specific sites.  Blood samples should be collected for PK analysis during Weeks 1 and 24 at pre-dose (0 hour) and 24−48, 72−96, and 168 hours post-dose.  
Additional pre-dose samples should be collected at Weeks 4, 8, and 12 within 6 hours prior to PEG-IFN administration.  The time of PEG-IFN administration on 
PK sampling days must be recorded on the eCRF. 
e 
Frozen for central processing.   
f 
Sample to be retained frozen at site in the event that any tests need to be repeated.  From RCR-consenting subjects, they also may be used for exploratory HBV 
biomarker analyses (DNA and/or non-DNA).  Sample to be retained frozen at site in the event that any tests need to be repeated. 
g 
During the 5-year follow-up period, only persistent AEs initially reported prior to follow-up Week 24, new-onset SAEs and non-serious AEs of special interest 
related to PEG-IFN, and deaths will be collected. 
h 
Concomitant medications for CHB include licensed or investigational immunomodulatory or antiviral therapy, and herbal, botanical and other agents 
(e.g., ursodeoxycholic acid) that are traditionally used for chronic HBV disease.  
i 
Not required for children < 7 years of age. 
j 
Within 2 years prior to baseline or within 9 months prior to baseline for subjects with advanced fibrosis. 
k 
Subjects in site-specific liver elasticity sub-study only.  
l 
Parameter does not need to be repeated at re-screening if performed within 6 months prior to baseline, unless dictated by a change in the subject’s medical 
condition or the parameter accounted for the original screen failure. 


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Table 3 
Schedule of Assessments and Procedures⎯Group B (Untreated Control) 
Screen
(days) 
BL 
(days) 
Principal 
Observation Period 
(weeks) 
Initial  
Follow-up (weeks 
Post-End of Principal 
Observation Period) 
Long-Term Follow-Up  
(years Post-End of Principal  
Observation Period) 
Assessment/Procedure 
−35 to 
−1 
1 
12 
24 
36 48 a
12a 
24 a 
1 a 
1.5 b 
2 
3 
4 
5 
Informed Consent/Assent c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete medical history, including family 
history of HBV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
Symptom-directed physical examination 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
Vital signs  
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Weight d 
x 
x f 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
Height d, e 
x 
x f 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
Parental height g 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Ultrasound h,i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology exam i, j 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
Eligible subjects may switch at any time between Week 48 and 1 year following Week 48 at which time subjects will continue on the Switch Schedule of 
Assessments and Procedures. 
b 
By telephone. 
c 
Informed Consent obtained from legal guardian, and assent obtained from child if appropriate.  
d 
Measurements must be taken using the same instruments in the same individual.  
e 
Using stadiometer and taking the mean of three readings. 
f 
Weight and height to be provided to IXRS. 
g 
From consenting biological parents. 
h 
To rule out hepatocellular carcinoma.  Further liver imaging assessment may be performed if necessary. 
i 
Within 6 months prior to baseline; repeat only if any change in medical condition.  
j 
By ophthalmologist (pediatric ophthalmologist is recommended) and including fundoscopic examination with dilation, visual acuity assessment, visual field testing 
(confrontation test is recommended for younger children), and color visual testing.  Any subject who develops ocular symptoms should receive a prompt eye 
examination by an ophthalmologist and additional examinations as necessary. 


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Table 3 
Schedule of Assessments and Procedures⎯Group B (Untreated Control) (cont.) 
 
Screen
(days) 
BL 
(days)
Principal 
Observation 
Period  
(weeks) 
Initial  
Follow-up (weeks 
Post-End of Principal 
Observation Period) 
Long-Term Follow-Up  
(years Post-End of Principal  
Observation Period) 
Assessment/Procedure 
−35 to 
−1 
1 
12 
24 
36 48 a
12a 
24 a 
1 a 
1.5 b 
2 
3 
4 
5 
Urine or serum HCG pregnancy test 
(selected subjects) c, d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alfa-fetoprotein e, h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-HAV IgM, anti-HCV, anti-HIV, and 
anti-HDV h  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV genotype h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ceruloplasmin, A1AT, AMA, ANA, ASMA, 
ALKM1 h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology f,i  
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
 
Chemistry f,i 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
 
Urinalysis d, f, g 
x 
x 
 
 
 
x 
 
x 
 
 
 
 
 
 
FΤ3, FΤ4, TSH f, h 
x 
 
 
 
 
x 
 
x 
x 
 
x 
x 
x 
x 
TPO antibodies, TBG h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
Eligible subjects may switch at any time between Week 48 and 1 year following Week 48 at which time subjects will continue on the Switch Schedule of 
Assessments and Procedures. 
b 
By telephone. 
c 
For females of childbearing potential, a pregnancy test will be performed within 24 hours prior to baseline, and at any time secondary amenorrhea of more than 1 
week occurs. Result of baseline pregnancy test must be available prior to randomization and commencement of treatment. 
d 
To be performed by local laboratory. 
e 
Subjects need to have serum alfa-fetoprotein assessed during the screening period to rule out hepatocellular carcinoma. 
f 
If there are clinically significant laboratory abnormalities, repeat no less frequently than every 2 weeks or as clinically indicated, with appropriate toxicity 
management, until they return to normal or baseline values.   
g 
Urinalysis to be performed via dipstick, with subsequent microscopic evaluation if positive for blood at the discretion of the investigator. 
h 
Parameter does not need to be repeated at re-screening if performed within 6 months prior to baseline, unless dictated by a change in the subject’s medical 
condition or the parameter accounted for the original screen failure. 
i 
To be performed by a local laboratory in countries activated prior to April 2013, and by a central laboratory in countries activated after April 2013. 


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Table 3 
Schedule of Assessments and Procedures⎯Group B (Untreated Control) (cont.) 
 
Screen
(days) 
BL 
(days)
Principal 
Observation Period 
(weeks) 
Initial  
Follow-up (weeks 
Post-End of 
Principal 
Observation 
Period) 
Long-Term Follow-Up  
(years Post-End of Principal  
Observation Period) 
Assessment/Procedure 
−35 to −1
1 
12 
24 
36 48 a
12 a 
24 a 
1 a 
1.5 b 
2 
3 
4 
5 
HBeAg, anti-HBe c 
x j 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
HBV-DNA c 
x j 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
HBsAg, anti-HBs c 
x j 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
Quantitative HBsAg and HBeAg c, j 
 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
 
Serum bank d 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
RCR plasma and RNA specimen 
 
x 
x 
x 
 
x 
 
x 
x 
 
x 
x 
x 
x 
RCR-DNA specimen 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x e 
x e 
x e 
x e 
x e 
x e 
Concomitant medications (including for  
CHB f) 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Concomitant medications for CHB only f 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Compliance 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Neuro-Psychiatric Questionnaire g 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Liver biopsy  
x h 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver elastography i 
 
x 
 
 
 
x 
 
x 
 
 
x 
 
 
 
a 
Eligible subjects may switch at any time between Week 48 and 1 year following Week 48 at which time subjects will continue on the Switch Schedule of 
Assessments and Procedures. 
b 
By telephone. 
c 
Frozen for central processing.   
d 
Sample to be retained frozen at site in the event that any tests need to be repeated.  From RCR-consenting subjects, they also may be used for exploratory HBV 
biomarker analyses (DNA and/or non-DNA). 
e 
During the 5-year follow-up period, only persistent AEs initially reported prior to follow-up Week 24 and deaths. 
f 
Concomitant medications for CHB include licensed or investigational immunomodulatory or antiviral therapy, and herbal, botanical and other agents 
(e.g., ursodeoxycholic acid) that are traditionally used for chronic HBV disease.  


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Table 3 
Schedule of Assessments and Procedures⎯Group B (Untreated Control) (cont.) 
 
g 
Not required for children < 7 years of age. 
h 
Within 2 years prior to baseline or within 9 months prior to baseline for subjects with advanced fibrosis. 
i 
Subjects in site-specific liver elasticity sub-study only.   
j 
Parameter does not need to be repeated at re-screening if performed within 6 months prior to baseline, unless dictated by a change in the subject’s medical 
condition or the parameter accounted for the original screen failure. 


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Table 4 
Schedule of Assessments and Procedures⎯Switch (PEG-IFN) 
Switch 
BL a 
Treatment Period  
(weeks) 
Initial  
Follow-up (weeks 
Post-End of 
Principal 
Observation 
Period) 
Long-Term Follow-Up  
(years Post-End of Principal  
Observation Period) 
Assessment/Procedure 
 
SW
1
SW
2
SW
4
SW
8 SW
12
SW 
18
SW 
24
SW 
30
SW 
36
SW 
42
SW 
48 b 
SW 
4 b 
SW 
12 b 
SW 
24 b 
SW
1 b 
SW
1.5 b, c SW
2 b 
SW
3 b 
SW
4 b 
SW
5 b 
Physical examination 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
Vital signs  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Weight d 
x f 
x 
x 
x 
x x f
x x f
x x f
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
Height d, e 
x f 
 
 
 
 
x f
 
x f
 
x f
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
Ophthalmology exam g 
xj 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
Urine or serum HCG pregnancy test 
(selected subjects) h, i 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Anti-HAV IgM, anti-HCV, anti-HIV, 
and anti-HDV j  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANA 
xj 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
a 
Switch baseline will take place at the time of the final visit of the pre-switch schedule.  Results from all switch baseline assessments must be available and 
subjects must meet all switch criteria prior to commencing PEG-IFN. 
b 
Or upon and following study treatment withdrawal. 
c 
By telephone. 
d 
Measurements must be taken using the same instruments in the same individual. 
e 
Using stadiometer and taking the mean of three readings. 
f 
Weight and height to be provided to IXRS. 
g 
By ophthalmologist (pediatric ophthalmologist is recommended) and including fundoscopic examination with dilation, visual acuity assessment, visual field testing 
(confrontation test is recommended for younger children), and color visual testing.  Any subject who develops ocular symptoms should receive a prompt eye 
examination by an ophthalmologist and additional examinations as necessary. 
h 
For females of childbearing potential, a pregnancy test will be performed within 24 hours prior to switch baseline, and at any time secondary amenorrhea of 
more than 1 week occurs. Result of baseline pregnancy test must be available prior to randomization and commencement of treatment. 
i 
To be performed by local laboratory. 
j 
Parameter does not need to be repeated at switch baseline if performed within 6 months prior to switch baseline, unless dictated by a change in the subject’s 
medical condition. 


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Table 4 
Schedule of Assessments and Procedures⎯Switch (PEG-IFN) (cont.) 
 
Treatment Period  
(weeks) 
Initial  
Follow-up (weeks 
Post-End of 
Principal 
Observation 
Period) 
Long-Term Follow-Up  
(years Post-End of Principal  
Observation Period) 
Assessment/Procedure 
Switch 
BL a 
SW
1 
SW
2 
SW
4 
SW 
8 SW 
12
SW 
18
SW 
24
SW 
30
SW 
36
SW 
42
SW 
48 b 
SW 
4 b 
SW 
12 b 
SW 
24b 
SW
1 b 
SW
1.5 b,c SW
2 b 
SW
3 b 
SW
4 b 
SW
5 b 
Hematology d,j  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Chemistry d,j 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Urinalysis d, e, f 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
FΤ3, FΤ4, TSH d 
xi 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
TPO antibodies 
xi 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
TBG 
xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Population PK g 
x 
x 
 
x 
x 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBeAg, anti-HBe h 
xi 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
HBV-DNA h  
xi 
 
 
 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
HBsAg, anti-HBs h 
xi 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
a 
Switch baseline will take place at the time of the final visit of the pre-switch schedule.  Results from all switch baseline assessments must be available and 
subjects must meet all switch criteria prior to commencing PEG-IFN. 
b 
Or upon and following study treatment withdrawal. 
c 
By telephone. 
d 
If there are clinically significant laboratory abnormalities, repeat no less frequently than every 2 weeks or as clinically indicated, with appropriate toxicity 
management, until they return to normal or baseline values.   
e 
Urinalysis to be performed via dipstick, with subsequent microscopic evaluation if positive for blood at the discretion of the investigator. 
f 
To be performed by local laboratory. 
g 
Specific sites.  Blood samples should be collected for PK analysis during switch Weeks 1 and 24 at pre-dose (0 hour) and 24−48, 72−96, and 168 hours post-
dose.  Additional pre-dose samples should be collected at switch Weeks 4, 8 and 12 within 6 hours prior to PEG-IFN administration.  The time of PEG-IFN 
administration on PK sampling days must be recorded on the eCRF. 
h 
Frozen for central processing.   
i 
Parameter does not need to be repeated at switch baseline if performed within 6 months prior to switch baseline, unless dictated by a change in the subject’s 
medical condition. 
j 
To be performed by a local laboratory in countries activated prior to April 2013, and by a central laboratory in countries activated after April 2013. 


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Table 4 
Schedule of Assessments and Procedures⎯Switch (PEG-IFN) (cont.) 
 
Switch 
BLa 
Treatment Period  
(weeks) 
Initial  
Follow-up (weeks 
Post-End of 
Principal 
Observation 
Period) 
Long-Term Follow-Up  
(years Post-End of Principal  
Observation Period) 
Assessment/Procedure 
 
SW 
1
SW
2
SW 
4
SW 
8 SW 
12
SW 
18
SW 
24
SW 
30
SW 
36
SW 
42
SW 
48 b 
SW 
4 b 
SW 
12 b 
SW 
24 b 
SW 
1 b 
SW 
1.5 b,c SW
2 b 
SW
3 b 
SW
4 b 
SW
5 b 
Quantitative HBsAg and HBeAg d 
xk 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
 
x 
 
 
 
 
 
 
Serum bank e 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
RCR plasma and RNA specimen 
x 
 
 
 
 
x 
 
x 
 
 
 
x 
 
 
x 
x 
 
x 
x 
x 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xf 
xf 
xf 
xf 
xf 
xf 
Concomitant medications (including for 
CHB g) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Concomitant medications for CHB only 
g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Subject study drug diary 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Dispense study drug 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
Compliance 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Neuro-Psychiatric Questionnaire h 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
x 
 
 
 
 
 
 
 
 
Liver biopsy i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ultrasound i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver elastography j 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
a 
Switch baseline will take place at the time of the final visit of the pre-switch schedule.  Results from all switch baseline assessments must be available and 
subjects must meet all switch criteria prior to commencing PEG-IFN. 
b 
Or upon and following study treatment withdrawal. 
c 
By telephone. 
d 
Frozen for central processing.   
e 
Sample to be retained frozen at site in the event that any tests need to be repeated.  From RCR-consenting subjects, they also may be used for exploratory HBV 
biomarker analyses (DNA and/or non-DNA). 
f 
During the 5-year follow-up period, only persistent AEs initially reported prior to follow-up Week 24, new-onset SAEs and non-serious AEs of special interest 
related to PEG-IFN, and deaths will be collected. 


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Table 4 
Schedule of Assessments and Procedures⎯Switch (PEG-IFN) (cont.) 
 
g 
Concomitant medications for CHB include licensed or investigational immunomodulatory or antiviral therapy, ursodeoxycholic acid, and herbal, botanical and 
other agents (e.g., ursodeoxycholic acid) that are traditionally used for chronic HBV disease. 
h 
Not required for children < 7 years of age. 
i 
Either a liver biopsy performed within 2 years prior to switch baseline to exclude cirrhosis, OR clinical, laboratory, and ultrasound data within 6 months prior to 
switch baseline which together exclude cirrhosis. 
j 
Subjects in site-specific liver elasticity sub-study only. 
k 
Parameter does not need to be repeated at switch baseline if performed within 6 months prior to switch baseline, unless dictated by a change in the subject’s 
medical condition. 
 


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5.1 
SCREENING EXAMINATION AND ELIGIBILITY SCREENING 
FORM 
All legal guardians/subjects must sign and date the most current IRB/IEC-approved 
written informed consent/assent (where appropriate) before any study-specific 
assessments or procedures are performed.   
The assessments in Table 5 should be obtained within a period of no more than 35 days 
before the subject is randomized, except as noted.  Extensions to the screening period of up 
to 7 days may be permitted under exceptional circumstances if certain results concerning 
eligibility are not available within the 35 days and only upon approval from the Medical Monitor.  
Subjects must fulfill all the entry criteria for participation in the study (see Sections 4.2 to 
4.4).  An Eligibility Screening Form documenting the investigator’s assessment of each 
screened subject with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator.  A screen failure log must be maintained by the 
investigator.   
If a subject 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 
below.  If the subject 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 retesting if blood samples have to be redrawn 
because of sample handling problems, breakage or sample integrity. 
Subjects who fail to meet the entry criteria may be re-screened on one more occasion 
provided that enrollment remains open and upon approval from the Medical Monitor.  If 
re-screening is required, then the complete screening module should be repeated (except for 
those parameters indicated in Table 5).  Re-screening is required if a subject has not met all 
of the eligibility criteria within 35 days from the original screening visit.  It will not be considered 
a re-screening if blood samples have to be redrawn because of sample handling problems, breakage, 
or sample integrity. 
Table 5 
Screening Assessments 
Medical history and physical 
examination 
Includes family history of HBV, concomitant medication 
(including for CHB), surgeries/procedures, and vital signs (blood 
pressure, heart rate, temperature). 
Ophthalmological examinationa 
Within 6 months prior to baseline; repeat at screening only if 
any change in medical condition.  By ophthalmologist 
(pediatric ophthalmologist is recommended) and including 
fundoscopic examination with dilation, visual acuity 
assessment, visual field testing (confrontation test is 
recommended for younger children), and color visual testing.  
Any subject who develops ocular symptoms should receive a 
prompt eye examination by an ophthalmologist and additional 
examinations as necessary.   
Neuro-psychiatric Questionnaire 
Children’s Depression Inventory (CDI) 
Growth 
Weight and height 


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Ultrasounda 
Within 6 months prior to baseline; repeat at screening only if 
any change in medical condition.  To rule out hepatocellular 
carcinoma.  Further liver imaging assessment may be 
performed if necessary. 
Liver biopsy 
Only if no previous histology available within 2 years prior to 
baseline or within 9 months prior to baseline for subjects with 
advanced fibrosis.   
Liver elastography 
For subjects taking part in site specific liver elasticity 
sub-study only 
HCG pregnancy testb 
For females of childbearing potential, a negative urine or 
serum HCG test needs to be documented within 24 hours 
prior to baseline.  Note that the test may be performed at the 
baseline visit, provided that the result is available prior to 
randomization and commencement of treatment. 
Hematologyc 
Complete blood count (hemoglobin, hematocrit, total white 
blood cell [WBC] count, differential WBC count [neutrophils, 
lymphocytes, monocytes, eosinophils, basophils]), platelet 
count, international normalized ratio (INR) 
Clinical chemistryc 
ALT, AST, GGT, total bilirubin, alkaline phosphatase, total 
protein, albumin, blood urea nitrogen (BUN)/urea, creatininee, 
uric acid, total calcium, phosphorus, cholesterol, triglycerides, 
random glucose, sodium, chloride, potassium 
Urinalysisb 
Dipstick with subsequent microscopic evaluation if positive 
for blood 
Immunology and special 
chemistry a,d 
Alfa-fetoprotein, ceruloplasmin, A1AT, anti-mitochondrial 
antibody (AMA), ANA, anti-smooth muscle antibody (ASMA), 
anti–liver-kidney microsome-1 antibody (ALKM1), anti-HAV 
IgM, anti-HCV, anti-HIV, anti-HDV 
HBV serology and virologya,d 
HBeAg, anti-HBe, HBsAg, anti-HBs, quantitative HBsAg and 
HBeAg, HBV-DNA, HBV genotype 
Thyroid function testsa,d 
FT3, FT4, TSH, TPO antibodies, TBG 
a Parameter does not need to be repeated at re-screening if performed within 6 months prior to 
baseline, unless dictated by a change in the subject’s medical condition or the parameter 
accounted for the original screen failure. 
b To be performed by local laboratory. 
c To be performed by a local laboratory in countries activated prior to April 2013, and by a 
central laboratory in countries activated after April 2013. 
d To be performed by central laboratory. 
e Estimated creatinine clearance will be calculated internally at baseline/switch baseline. 
 
5.2 
PROCEDURES FOR ENROLLMENT OF ELIGIBLE SUBJECTS  
A subject will be enrolled in the study and assigned a screening number after the subject 
has given informed consent/assent.  Once a subject has fulfilled the entry criteria they 
may be randomized or assigned, as applicable.  Upon contacting IXRS, the investigator 
or designee must confirm/provide the following: 
• 
Whether the subject has advanced fibrosis 
• 
The subject’s height and weight 


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• 
If the site is taking part in either the PK sub-study or the liver elastography sub-study, 
whether the subject will take part in these sub-studies 
 
Advanced fibrotic subjects will be assigned to Group C.  Non-advanced 
fibrotic/non-cirrhotic subjects will be randomized to Group A or Group B and stratified by 
genotype and ALT.  Based on the height and weight provided, IXRS will confirm the 
dose for treated subjects. 
In accordance with a request from the China Food and Drug Administration Clinical Trial 
Permit (CTP File No: 2013L00401), at sites in China only, this study will start with 
enrolling older pediatric patients first (aged 7 to <18 years old at baseline) in order to 
assess safety in this population before extending enrollment to younger patients. A Data 
Safety Monitoring Board (DSMB) will review the safety data from older pediatric patients 
enrolled in China together with all other available safety data from pediatric patients 
enrolled in rest of world, to support appropriate subsequent enrollment of the younger 
age group in China. The recruitment of younger patients at sites in China will only start if 
review of the data by the DSMB determines that there are no safety concerns. 
The enrollment of subjects in the rest of world will remain unchanged; patients aged 
3 to <18 years old at baseline will be enrolled. During study conduct, the Sponsor may 
postpone or stop the enrollment of subjects in certain age ranges in order to ensure that a 
broad age distribution and representative dosing categories have been adequately studied. 
The subject randomization numbers will be generated by Roche or its designee and 
incorporated into a set of subject numbers and associated study group which will be 
given to the investigator over the telephone at the time of individual subject enrollment.  
The investigator or designee will use the eCRF with the assigned subject number and 
enter the corresponding number for allocation to the study groups in the appropriate 
place on each subject’s eCRF. 
The subject randomization numbers are to be allocated sequentially in the order in which 
the subjects are enrolled according to the specification document agreed with the 
external randomization company/center.  A subject Enrollment and Identification Code 
List must be maintained by the investigator. 
5.3 
CLINICAL ASSESSMENTS AND PROCEDURES 
A baseline visit will be performed, and for subjects in Group A and Group C all baseline 
assessments and procedures must occur prior to administration of the first dose of 
PEG-IFN.  The first dose of PEG-IFN should be administered at the baseline visit.  Subjects will 
subsequently be seen for evaluation at the following timepoints: 
Group A and Group C 
• 
During treatment period:  Weeks 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, and 48 


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• 
During initial 24 weeks of follow-up:  follow-up Weeks 4, 12, and 24 post-end of 
treatment 
• 
During extended long-term follow-up:  Years 1, 1.5, 2, 3, 4, and 5 post-end of 
treatment 
 
Group B⎯Non-Switch 
• 
During principal observation period:  Weeks 12, 24, 36, and 48 
• 
During initial 24 weeks of follow-up:  follow-up Weeks 12 and 24 post-principal 
observation period 
• 
During extended long-term follow-up:  Years 1, 1.5, 2, 3, 4, and 5 post-principal 
observation period 
 
Group B⎯Switch 
• 
During principal observation period:  Weeks 12, 24, 36, and 48* 
• 
During initial 24 weeks of follow-up:  follow-up Weeks 12* and 24* post-principal 
observation period 
• 
During extended long-term follow-up:  Year 1* post−principal observation period 
• 
During switch treatment period:  Weeks 1, 2, 4, 8, 12, 18, 24, 30, 36, 42, and 48 
• 
During initial 24 weeks of switch follow-up:  switch follow-up Weeks 4, 12, and 24 
post− end of treatment period 
• 
During extended long-term switch follow-up:  Years 1, 1.5, 2, 3, 4, and 5 post- end of 
treatment period 
 
*Subjects may switch at any time between Week 48 and 1 year following Week 48.  Switch 
baseline will take place at the time of the final visit of the pre-switch schedule.  Results from all 
switch baseline assessments must be available and subjects must meet all switch criteria prior 
to commencing PEG-IFN. 
 
The extended long-term follow-up visit at Year 1.5 will be by telephone. 
For assessments and procedures required at each visit refer to Table 2 to Table 4.  
For visits up to and including Week 48, the visit window is ± 3 days. 
For visits after Week 48 and up to and including follow-up Week 24, the visit window is 
± 7 days. 
For visits after follow-up Week 24, the visit window is ± 28 days. 
Any subject who discontinues study treatment should return to complete assessments 
as per the Week 48/Switch Week 48 visit and enter the post-end of treatment follow-up 
period (see Section 4.6.1). 


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5.3.1 
Efficacy  
5.3.1.1 
Main Efficacy Assessments 
Efficacy (see Section 8.1 for primary and secondary endpoints) will be determined from 
assessment of HBeAg and HBsAg seroconversion, loss of HBeAg and HBsAg, 
HBV-DNA, and ALT (see Section 5.4 for laboratory assessment details).   
5.3.1.2 
Liver Elasticity 
At least 50 consenting/assenting subjects at specific sites will take part in a liver 
elasticity sub-study.  For these subjects, liver elastography will be performed at baseline, 
end of treatment/principal observation period, follow-up Week 24, and follow-up Year 2. 
Change in the LSM over time will be assessed comparing treated and untreated subjects.   
Baseline liver elasticity will also be explored for association with the screening liver 
biopsy result in these sub-study subjects. 
5.3.2 
Safety 
Safety assessments will include symptom directed physical examination, vital signs, 
growth, neuro-psychiatric questionnaire (PEG-IFN−treated subjects only, post-baseline), 
review of concomitant medications, reported AEs and specified safety laboratory 
assessments of hematology, clinical chemistry, thyroid function, and urinalysis.  
Additional safety assessments will be determined from tabulations of dose adjustments 
and premature withdrawals from treatment for safety or tolerability reasons.   
All subjects need to have an ophthalmological examination (consisting of fundoscopic 
examination with dilation, visual acuity assessment, visual field testing (confrontation test 
is recommended for younger children), and color visual testing) by an ophthalmologist 
(pediatric ophthalmologist is recommended) within 6 months prior to baseline.  During the 
study, subjects treated with PEG-IFN will receive additional ophthalmological examination 
as per the schedules in Table 2 and Table 4.  Any subject who develops ocular 
symptoms should receive a prompt eye examination by an ophthalmologist and 
additional examinations as necessary.   
For females of childbearing potential, a pregnancy test will be performed within 24 hours 
prior to baseline or switch baseline.  This could be performed at the baseline visit, 
provided that the result is available prior to randomization and commencement of 
treatment.  Pregnancy testing will also be performed at any time secondary amenorrhea 
of more than 1 week occurs. In addition, subjects treated with PEG-IFN will have 
pregnancy tests performed as per the schedules in Table 2 and Table 4.  
Measurements of growth must be taken using the same instruments in the same 
individual.  A stadiometer with mean of three readings should be used for height 
measurement.  For Group A and C subjects, at Weeks 12, 24, and 36, and for switch 
subjects at switch baseline, switch week (SW)12, SW24, and SW36 the investigator or 


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designee will provide IXRS with the subject’s height and weight so that the BSA and 
dose can be provided. 
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. 
During the extended long-term follow-up period, only the following safety data will be 
collected: 
• 
Persisting AEs initially reported prior to follow-up Week 24 (including neurological 
and psychiatric events) 
• 
New-onset SAEs (including neuro-psychiatric events) and non-serious AEs of 
special interest related to PEG-IFN 
• 
Deaths 
• 
Growth:  weight and height 
• 
Thyroid function 
 
5.3.2.1 
Neuro-psychiatric Questionnaire 
As part of the overall assessment of subjects and their mental state, and collation of 
neurological and psychiatric AEs, the CDI [50] will be used in subjects ≥ 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 subject’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 subjects and then post-baseline for 
treated subjects as per the schedules in Table 2 to Table 4.  CDI should be performed 
prior to the completion of other study assessments. Note:  If a subject 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 17-year-old subjects who turn 18 years old 
during the study, the CDI should continue to be administered. 
Parents or subjects may not be comfortable with certain sentences, or question the 
sensitive or personal nature of some sentences, and therefore it should be clearly 
explained that the CDI is just a tool that all subjects 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 subjects’ own language, if available.  All 
subjects should complete the form themselves.  For younger children or those with 
reading difficulties or who are are unable to read, the instructions and items should be 
read aloud to the child, then the child will select an answer themself.  If the CDI Item 
Form is not available in the subject’s own language, a translator may read the 
instructions and items to the child and then the child will select an answer themself. The 
mode of administration (self-administered or translator/caregiver administered) should be clearly 


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documented in the clinical records. If subjects feel none of the sentences for an item applies 
to them, then they should be instructed to choose as best they can.  Subjects should be 
debriefed after the CDI has been completed to address any questions or concerns. 
Once the subject 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. Note:  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 Subjects with Symptoms of Major Depression or Potential CDI 
Indicators 
Whether the CDI is administered or not, investigators should still assess the mental state of their 
subjects per their standard clinical practice.  If any subject exhibits symptoms of major 
depression and/or if CDI total score is >19 and/or the subject fails to complete all items on the 
CDI, then the investigator will perform a more thorough evaluation to determine if major 
depression has developed.  If major depression is confirmed by the Investigator, then 
the subject will be referred to a mental health professional (e.g., counsellor).  If this is at 
screening or baseline, then the subject will be excluded from the study.  While in the 
study, the investigator will determine whether AE criteria have been met and report as an AE on 
the eCRF, if appropriate (see Section 7.1).  If whilst on study the subject is found to have 
severe depression, PEG-IFN must be permanently discontinued and the subject referred 
for psychiatric intervention (as per Section 6.2.1 and Section 6.2.5.5). 
5.4 
LABORATORY ASSESSMENTS 
Laboratory assessments post-screening are noted in Table 6 and will be carried out as 
per the schedules in Table 2 to Table 4.  


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Table 6 
Laboratory Assessments 
Hematologya 
Complete blood count (hemoglobin, hematocrit, total WBC count, 
differential WBC count [neutrophils, lymphocytes, monocytes, 
eosinophils, basophils]), platelet count], INR 
Clinical chemistrya  
ALT, AST, GGT, total bilirubin, alkaline phosphatase, total protein, 
albumin, BUN/urea, creatinined, uric acid, total calcium, 
phosphorus, cholesterol, triglycerides, random glucose, sodium, 
chloride, potassium 
Urinalysisb 
Dipstick with subsequent microscopic evaluation if positive 
for blood. 
HCG pregnancy testb 
Urine or serum pregnancy test for females of childbearing 
potential at any time secondary amenorrhea of more than 
1 week occurs.  The result of the baseline pregnancy test must be 
available prior to randomization and commencement of treatment. 
Thyroid function testsc 
FT3, FT4, TSH, TPO antibodies e 
Immunologyc 
ANA e 
HBV serology and 
virologyc 
HBeAg, anti-HBe, HBsAg, anti-HBs, quantitative HBsAg and 
HBeAg, HBV-DNA 
a To be performed by a local laboratory in countries activated prior to April 2013, and by a 
central laboratory in countries activated after April 2013. 
b To be performed by local laboratory. 
c To be performed by central laboratory. 
d Estimated creatinine clearance will be calculated by the Sponsor at Week 24/SW 24. 
e PEG-IFN−treated subjects only. 
 
Samples for central analysis will be sent to one or more central laboratories or to the 
Sponsor for analysis. 
Where any analysis is performed by a local laboratory, normal ranges for the local 
laboratory parameters must be supplied to Roche or designee before the study starts 
and at any point that the normal ranges are changed.   
The results from all hematology and clinical chemistry investigations should be available 
and reviewed by the investigator or his/her authorized designee before instructing the 
subject on whether PEG-IFN dosing should continue unchanged or be modified.   
See Section 6.2.5  and 7.1.3.1 for follow-up of laboratory abnormalities. 
All virological and serological efficacy parameters will be assessed by the central 
laboratory.   


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The total volume of blood loss for laboratory assessments (excluding PK and RCR) will 
be approximately as follows: 
• 
Group A and Group C:  228 mL 
• 
Group B non-switch:  158 mL 
• 
Group B switch:  up to 312 mL 
 
The procedures for the collection, handling, and shipping of laboratory samples are 
specified in the Sample Handling and Logistics Manual for this study.  All remaining 
blood samples will be destroyed no later than 18 months after the final closure of the 
study database. 
The samples for this study should be classified, packed, and shipped as UN3373 
Biological Substance, Category B. 
5.4.1 
Serum Bank and Exploratory HBV Markers 
Additional serum bank samples (included in the blood volumes in Section 5.4) will be 
collected during the course of this study (as per the schedules in Table 2 to Table 4).  
The primary purpose of these samples is to repeat laboratory tests outlined in the 
Schedule of Assessments should there be a problem with the original sample.  In the 
event that repeat testing is required, sites will be informed whether the sample should be 
transferred to the central laboratory for retesting (e.g., HBV serology) or whether it is a 
test that should be repeated locally (e.g., ALT).  
The secondary intention is to use residual serum bank samples for exploratory HBV 
biomarker analyses.  This secondary use of serum bank samples is optional and 
only applies to subjects who have consented to RCR sample collection and analyses 
(see Section 5.4.3).  After confirmation that serum bank samples are no longer required 
for repeat testing, any remaining serum bank samples, either at investigational sites or at 
the central laboratory, may be used for DNA and/or non−DNA biomarker analyses.  
Samples still at the site may remain stored at the site or can be transferred to the central 
laboratory for storage until required for biomarker analyses.  Example biomarker 
analyses include viral factors and sequencing and host response factors to infection and 
treatment.  Protection of subject confidentiality will extend to any data generated from 
the assaying of these samples (see Section 17).  
All remaining serum bank samples, either at the site or central laboratory, will be 
destroyed no later than 18 months after the final closure of the study database. 
5.4.2 
Pharmacokinetic Assessments 
For sites taking part in the PK sub-study, consenting/assenting subjects assigned, 
randomized or switching to PEG-IFN will have blood samples (approximately 1 mL) 
collected to evaluate the PK of PEG-IFN during Weeks 1 and 24 pre-dose (0), and 
24−48, 72−96, and 168 hours after administration of PEG-IFN.  (See also footnote to 


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Table 7.)  Blood samples designated as pre-dose must be collected within 6 hours prior 
to PEG-IFN administration.   
For scheduling purposes, time windows are provided for the first two post-dose samples 
during Weeks 1 and 24.  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. 
Pre-dose samples will also be collected at Weeks 4, 8, and 12 within 6 hours prior to 
PEG-IFN administration (Table 7).  Subjects should take all doses of PEG-IFN 
associated with both pre- and post-dose PK sampling at the clinic. 
The procedure for the collection and handling of blood samples for PK analysis 
is specified in the Sample Handling and Logistics Manual.  The exact date and 
time of dosing and collection of blood samples will be recorded in the source document 
and eCRF.  The serum concentrations of PEG-IFN will be assessed by a quantitative 
enzyme-linked immunosorbent assay (ELISA).  PK parameters, such as the maximum 
concentration (Cmax), area under the curve (AUC), clearance (CL/F) and volume of 
distribution (V/F), if possible, will be estimated using either non-compartmental analysis 
or a population approach. 
The target exposure is based on the mean exposure observed in adults treated 
at 180 μg in clinical studies (3334 to 4348 ng • h/mL) and the mean exposure observed 
in children in Study NR16141 treated at a dose of 180 μg/1.73 m2
 × BSA (5667 ng • h/mL).  
When adequate PK data have been collected over the first 24 weeks for at least 
15 PEG-IFN−treated subjects, ideally with representation from all BSA categories, PK 
analysis will be undertaken to ensure exposure is in the appropriate therapeutic range.  
If data suggest that the exposure is not in the appropriate range, an adjustment to the 
dosing regimen will be made to meet the target exposure range. 
Once PK data up to Week 24/switch Week 24 are available for at least 5 to 10 subjects 
in each BSA category, PK sampling will be stopped.  However, the sub-study may be 
ceased even if data from a minimum of 5 subjects in each BSA category are not 
obtained in the case of excessively long recruitment times. 
The relationship between PK and PD parameters may also be explored. 
Any PK sample residues may be used for analysis of exploratory HBV markers (see 
Section 5.4.1). 
The total volume blood loss for PK assessments will be approximately 14 mL.  


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Table 7 
PK Sampling Schedule 
 
Baseline/ 
Switch 
Baseline 
Week 4/ 
Switch 
Week 4 
Week 8/ 
Switch 
Week 8 
Week 12/ 
Switch 
Week 12 
Week 24/ 
Switch 
Week 24 
0 hour (pre-dose) 
x 
 
 
 
x 
Pre-dose 
 
x 
x 
x 
 
24−48 hours post-dose 
x 
 
 
 
x 
72−96 hours post-dose a 
x 
 
 
 
x 
168 hours post-dose 
x b 
 
 
 
x 
a At least 48 hours after the previous blood sample. 
b Equates to Week 1 visit. 
 
5.4.3 
Roche Clinical Repository Specimen(s) 
For sites opting to take part, specimens for the RCR will be collected from subjects who 
give specific consent/assent to participate in this optional research.  The results of 
specimen analysis from the RCR will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for subjects. 
RCR samples will be collected as per the schedule in Table 2 to Table 4.  For all RCR 
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 Sample Handling and Logistics 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/IEC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
Specimens for dynamic (non-inherited) biomarker discovery and validation will be used 
for research purposes to help to better understand the pathogenesis, course, and 
outcome of CHB and related diseases, and identify dynamic biomarkers that are 
predictive of response to PEG-IFN treatment (in terms of dose, safety, and tolerability).  
Specimens for dynamic biomarker discovery will be subject to the confidentiality 
standards described in Section 17.  The following samples will be collected for 
identification of dynamic (non-inherited) biomarkers: 
• 
Whole blood for isolation of plasma 
• 
Whole blood for RNA expression analysis 
 
Specimens for genetic (inherited) biomarker discovery and validation will be used for 
research purposes to hopefully help improve subject outcome by predicting which 
subjects are more likely to respond to specific drug therapies, predicting which subjects 
are susceptible to developing adverse side effects and/or predicting which subjects are 


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likely to progress to more severe disease states.  Such genetic biomarker specimens will 
undergo additional processes to ensure confidentiality, as described in Section 17.  The 
following samples will be collected for identification of genetic (inherited) biomarkers: 
• 
One time whole blood sample for DNA isolation  
 
Total blood volume collected for RCR sampling will be approximately as follows: 
• 
Group A and Group C:  36 mL 
• 
Group B non-switch:  36 mL  
• 
Group B switch:  up to 54 mL 
 
5.5 
SUBJECT MEDICATION DIARY REVIEW 
Subjects treated with PEG-IFN will complete a Subject Medication Diary (SMD), which 
the family will bring to each study visit.  The information will be reviewed with the family 
by the Clinic Coordinator at each study visit.  It is mandatory that each PEG-IFN injection 
dose be recorded in the SMD.  The parent/guardian will be instructed to record the date 
and dose of PEG-IFN.  The person giving the PEG-IFN injection must initial the SMD.  
During the diary review, the reviewer will correct unreadable information and ask the 
subject to supply missing information.  Reviewers will report missing doses, dose 
adjustments, and treatments stops or restarts on the eCRF.  Subject diaries will be 
maintained with the source documents at each site.  See also Section 6.5.2. 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT 
PEG-IFN is a chemically modified alpha interferon formed by the covalent attachment of 
a 40-kD single branched methoxy polyethylene glycol (PEG) moiety to recombinant 
IFN alfa-2a.  Clinical PK studies have shown that PEG-IFN alfa-2a exhibits sustained 
absorption and low systemic clearance, enabling the maintenance of therapeutic serum 
concentrations in adults for at least 1 week after a subcutaneous injection of 180 μg of 
PEG-IFN. 
6.1 
DOSE AND SCHEDULE OF INVESTIGATIONAL MEDICINAL 
PRODUCT AND COMPARATOR 
Treated subjects will receive PEG-IFN subcutaneously once weekly for 48 weeks with 
dosing based on the following BSA categories: 
Table 8 
Dosing 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 
 


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6.2 
DOSE MODIFICATIONS, INTERRUPTIONS, AND DELAYS 
The intention of the protocol is that subjects remain on PEG-IFN until the completion of 
the allocated treatment period.  However, it is possible that some subjects will encounter 
transient or prolonged adverse effects at some juncture during their participation in the 
trial leading to adjustment of the PEG-IFN dosage.  To minimize the effects of these 
modifications on the eventual evaluation of the safety, tolerability, and efficacy of test 
drug regimens, the principles in the following sections will be used to adjust the dose of 
PEG-IFN. 
If consistent with subject safety, doses should not be held or eliminated.  This 
recommendation stems from concerns that extended periods of lowered drug 
concentrations in the blood may lead to a failure of virological and immunological control 
reducing the chance of HBeAg seroconversion and sustained response at the 
conclusion of therapy.  When the investigator considers it prudent to hold a dose, 
consideration needs to be given to informing the Sponsor of the missed scheduled dose 
and the reasons the dose was withheld.  Investigators should consider if adjusting the 
dose, either transiently or permanently, might be appropriate rather than holding a dose. 
6.2.1 
Stopping Rules 
Individual subject treatment with PEG-IFN must be stopped in the event of any of the 
following: 
• 
Severe hypersensitivity reactions (e.g., anaphylaxis, angioedema, 
bronchoconstriction) 
• 
Severe depression (see also Section 6.2.5.5)  
• 
Absolute neutrophil count  < 0.25 × 109 cells/L or febrile neutropenia 
(see also Section 6.2.5.1)  
• 
Platelets < 25 × 109 cells/L (see also Section 6.2.5.2) 
 
Discontinuation of individual patient treatment with Pegasys 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) (see also Section 6.2.5.3) 
• 
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 (see also Section 7.2.4) 


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In the event of discontinuation from treatment, subjects will be encouraged to remain in 
the 5-year follow-up period (see Section 4.6.1). 
6.2.2 
Missing Consecutive Doses 
If four or more consecutive doses of PEG-IFN are held or otherwise not administered 
(i.e., the subject has not received study drug for more than 28 days), the subject will be 
considered intolerant of the study drug or noncompliant, whichever is more appropriate 
to the clinical situation.  No additional study drug may be administered to such subjects 
without explicit permission from the Sponsor. 
6.2.3 
Dose Delay 
If a PEG-IFN 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., the 
next dose may be administered as usual on Monday). 
• 
Dose delayed 3−5 days:  administer subsequent doses every 5th or 6th day until the 
subject 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 subject 
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 subject every 5th or 6th day until the subject resumes weekly 
dosing on his or her usual scheduled day. 
 
6.2.4 
Dose Reduction Levels 
Moderate or severe adverse reactions (clinical and/or laboratory) may require dose 
reduction of PEG-IFN.  Decremental adjustments should be uniform across centers and 
subjects.  Toward this end, the following downward adjustments should be utilized: 
Starting Dose  
One-Level Reduction 
Two-Level Reduction 
Three-Level Reduction 
(µg) 
(mL) 
(µg) 
(mL) 
(µg) 
(mL) 
(µg) 
(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 
 


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Specific dose adjustment guidance for PEG-IFN is provided in Section 6.2.5 for 
post-treatment neutropenia, thrombocytopenia, elevated serum ALT, BSA change, and 
depression.   
When practical, abnormal laboratory results should be confirmed as soon as possible 
following notification of the investigator.  If appropriate, downward adjustments in 
one-level decrements should be considered.  It should be kept in mind that, whereas 
these guidelines should be generally followed to promote consistency across centers, 
other responses by an investigator may be more appropriate in some circumstances.  
See Section 7.1.1.1 for definitions of intensity of AEs.  For laboratory and vital signs 
abnormalities, “severe” may be considered as any value requiring intervention, further 
work-up, or more frequent follow-up. 


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Once the subject’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. 
• 
Subjects 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. 
 
6.2.5 
Specific Dose Reduction Guidance 
6.2.5.1 
Dose Adjustments for Low Absolute Neutrophil Counts 
Absolute 
neutrophil count
(× 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 
 
6.2.5.2 
Dose Adjustments for Low Platelet Counts 
Platelets 
(cells/L) 
Response 
< 50 × 109 
Two-level dose reduction 
< 25 × 109 
PERMANENTLY DISCONTINUE 
 
 


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6.2.5.3 
Dose Adjustments for Elevated Serum ALT 
ALT 
Response 
< 5 × the ULN 
No change. 
5−10 × the ULN 
Repeat in 1 week.   
i. 
If decreased to < 5 × the ULN, continue dose but monitor to ensure stability.
ii. If persistently 5−10 × the ULN on two occasions over 2 weeks, continue 
dose with one-level adjustment, and monitor ALT until stable or 
decreasing, then return to full dose 
iii. If further increased to > 10 × the ULN, follow advice under point (ii) below 
> 10 × the ULN 
Repeat in 1 week. 
i. 
If decreased to 5−10 × the ULN, continue dose with 1 level adjustment, 
and monitor ALT until stable or decreasing, then return to full dose. 
ii. If persistently > 10 × the ULN, hold dose, and carefully monitor ALT and 
assess for signs of decompensation. a 
• 
If there is significant evidence of ALT recovery b and there are no signs 
of decompensation, restart dose with one-level reduction. 
• 
PERMANENTLY DISCONTINUE if there are signs of decompensation.
a Decompensation is a clinical diagnosis and may be defined as a using a mixture of clinical 
signs and signs leading to a Child-Pugh score of more than 6 (see Appendix 2), or the 
presence of oesophageal varices. 
b Significant decrease in ALT levels may be defined as a progressive decrease in ALT on 
two serial determinations, with a decline of at least 50% from peak. 
 
6.2.5.4 
Dosage Adjustments for BSA Decrease/Increase  
Investigators will adjust the dose of PEG-IFN upward or downward to reflect the most 
current BSA.  BSA and dose will be provided by IXRS at Weeks 12, 24, and 36.  
Investigators may also assess the patient’s BSA (using the Mosteller formula) at other interim 
timepoints 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 a subject’s BSA falls below < 0.51 m2 during treatment, any dose adjustments should 
be made only after consultation between the investigator and the Medical Monitor 
(Appendix 3 ) or delegate.  The recommended dose will be recorded in the SMD.   
6.2.5.5 
Dosage Adjustments for Depression 
In severe cases of depression, PEG-IFN should be permanently discontinued and the 
subject referred for psychiatric intervention. 
6.3 
FORMULATION, PACKAGING AND LABELING 
Pegasys®: 
180 µg/mL; 1-mL solution in 2-mL vials 
Packaging: 
TBD 


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Storage: 
Refrigerate at 2°−8°C (36°−46°F) 
Study drug packaging will be overseen by the Roche Clinical Trial Supplies Department 
and bear a label with the identification required by local law, the protocol number, drug 
identification, and vial contents.  The investigator will inform the subject of the dose they 
are required to take based on their BSA, and this will be recorded in the SMD.   
The packaging and labeling of the study medication will be in accordance with Roche 
standards and local regulations. 
The study drug must be stored according to the details on the product label.  The drug 
label indicates the storage temperature. 
Local packaging in some countries may be different. 
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals, and temperature 
conditions, and report any deviations or product complaints to the monitor upon 
discovery. 
6.4 
BLINDING AND UNBLINDING 
The study is open label. 
6.5 
ACCOUNTABILITY OF INVESTIGATIONAL MEDICINAL 
PRODUCT AND ASSESSMENT OF COMPLIANCE 
6.5.1 
Accountability of Investigational Medicinal Product 
The investigator is responsible for the control of drugs under investigation.  Adequate 
records for the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug 
Dispensing Log) of the study drug must be maintained.  Accountability will be assessed 
by maintaining adequate drug dispensing and return records.  
Accurate records must be kept for each study drug provided by the Sponsor.  These 
records must contain the following:  
• 
Documentation of drug shipments received from the Sponsor (date received and 
quantity). 
• 
Disposition of unused study drug not dispensed to subject. 
 
Study drug will be dispensed according to the schedules in Table 2 and Table 4.  A Drug 
Dispensing Log must be kept current and should contain the following information: 
• 
The identification of the subject to whom the study drug was dispensed 
• 
The date(s) and quantity of the study drug dispensed to the subject 
• 
The date(s) and quantity of the study drug returned by the subject 
 


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All records and drug supplies must be available for inspection by the Monitor at every 
monitoring visit. 
Subjects will be asked to return all used drug supply containers at each visit and 
all unused drug supply containers at the end of treatment as a measure of compliance.  
When the study is terminated, the investigator will return any used and unused study 
drug (i.e., empty, partially used, and unused containers) to the Monitor.  The completed 
Drug Dispensing Log and Drug Return Record(s) will be returned to Roche, unless 
alternate destruction has been authorized by Roche, or required by local or institutional 
regulations (Section 6.6).  The investigator's copy of the Drug Return Record(s) must 
accurately document the return of all study drug supplies to Roche. 
6.5.2 
Assessment of Compliance 
At each visit, compliance with the study requirements will be reinforced. 
Subject compliance with taking study drug as required will be assessed by maintaining 
adequate study drug dispensing records and review of the SMD.  The investigator is 
responsible for ensuring that dosing is administered in compliance with the protocol.  
Delegation of this task must be clearly documented and approved by the investigator. 
It is mandatory that each injection (date and volume) be recorded in the drug diary and 
initialed by the person giving the injection (see Section 5.5).  Subjects will be asked to 
return used drug containers at each visit, along with the drug diary.  Returned drug 
containers will be counted and justified against the diary entries by study site personnel.  
Each verified injection will be recorded on the eCRF at each visit.  Unused study drug 
should be returned at the end of the treatment period (i.e., Week 48).  Under no 
circumstances should the treatment period for any subject extend beyond the allocated 
48 weeks. 
6.6 
DESTRUCTION OF THE INVESTIGATIONAL MEDICINAL 
PRODUCT/COMPARATOR 
Local or institutional regulations may require immediate destruction of used 
investigational medicinal product (IMP) for safety reasons.  In these cases, it may be 
acceptable for investigational site staff to destroy dispensed IMP before a monitoring 
inspection provided that source document verification is performed on the remaining 
inventory and reconciled against the documentation of quantity shipped, dispensed, 
returned, and destroyed.  Written authorization must be obtained from the Sponsor at 
study start up before destruction. 
If there are any issues with the drug, it should be returned to the appropriate Roche 
clinical trial supplies department for long-term storage and not destroyed. 


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Written documentation of destruction must contain the following: 
• 
Identity of IMP(s) (and comparators [if applicable]) destroyed 
• 
Quantity of IMP(s) destroyed 
• 
Date of destruction 
• 
Method of destruction 
• 
Name and signature of responsible person who destroyed investigational products(s) 
 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE 
7.1 
ADVERSE EVENTS AND LABORATORY ABNORMALITIES 
7.1.1 
Clinical Adverse Events 
According to the ICH, an AE is any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product.  Preexisting 
conditions that worsen during a study are to be reported as AEs. 
7.1.1.1 
Intensity 
All clinical AEs encountered during the clinical study will be reported on the AE eCRF.  
Intensity of AEs will be graded (mild, moderate, severe) and reported in detail on the 
eCRF.   
Mild 
discomfort noticed but no disruption of normal daily activity 
Moderate 
discomfort sufficient to reduce or affect daily activity 
Severe 
inability to work or perform normal daily activity 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events should be used to assist in the assessment of intensity.   
– 
http://rsc.tech-
res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of
_Adult_Pediatric_Adverse_Events.pdf 
Note that events that are considered as life threatening should be reported as an SAE 
(see Section 7.1.1.3) and the intensity would be reported as “severe” on the eCRF. 
7.1.1.2 
Drug−Adverse Event Relationship 
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event 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 


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• 
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 subject 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 
 
7.1.1.3 
Serious Adverse Events (Immediately Reportable to Roche) 
An SAE is any experience that suggests a significant hazard, contraindication, side 
effect, or precaution.  It is any AE that at any dose fulfils at least one of the following 
criteria: 
• 
Is fatal (results in death**; note: death is an outcome, not an event) 
• 
Is life-threatening (Note:  the term “life-threatening” refers to an event in which the 
subject was at immediate risk of death at the time of the event; it does not refer to 
an event which could hypothetically have caused a death had it been more severe) 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
**The term sudden death should be used only when the cause is of a cardiac origin as per 
standard definition.  The terms death and sudden death are clearly distinct and must not 
be used interchangeably. 
The study will comply with all local regulatory requirements and adhere to the full 
requirements of the ICH Guideline for Clinical Safety Data Management, Definitions and 
Standards for Expedited Reporting, Topic E2.  
7.1.1.4 
Other Safety Findings Requiring Expedited Reporting  
Other safety findings may require expedited reporting depending on local legislation, e.g., 
a major safety finding from a newly completed animal study (such as carcinogenicity). 
7.1.2 
Treatment and Follow-up of Adverse Events 
Subjects experiencing AEs should be treated by accepted clinical procedures.  If the use 
of medications excluded by protocol is deemed necessary, the subject may need to be 
discontinued from the test regimen after consultation with Roche.  All AEs should be 
followed until resolved or stabilized. 


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7.1.3 
Laboratory Test Abnormalities 
Laboratory test results will be recorded on the laboratory results electronic form page 
([eForm]) of the eCRF, or appear on electronically produced laboratory reports submitted 
directly from the central laboratory, if applicable.  
Any laboratory result abnormality fulfilling the criteria for an SAE should be reported as 
such on the AE eForm (see Section 7.2.2). 
Any treatment-emergent abnormal laboratory result which is clinically significant, 
i.e., meeting one or more of the following conditions, should be recorded as a single 
diagnosis on the AE eForm in the eCRF: 
• 
Is considered an SAE 
• 
Results in discontinuation from study treatment 
• 
Results in a requirement for a change in concomitant therapy (e.g., addition of, 
interruption of, discontinuation of, or any other change in a concomitant medication, 
therapy or treatment) 
 
This applies to any protocol and non−protocol-specified safety and efficacy laboratory 
result from tests performed after the first dose of study drug, which falls outside the 
laboratory reference range and meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result which falls outside the laboratory 
reference range but which does not meet the clinical significance criteria [these will be 
analyzed and reported as laboratory abnormalities]; those which are considered AEs of 
the type explicitly exempted by the protocol; or those which are a result of an AE that 
has already been reported. 
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) or 
• 
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 and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event), either as an SAE 
(Section 7.2.2) or a non-serious AE of special interest (Section 7.2.3). 
7.1.3.1 
Follow-up of Abnormal Laboratory Test Values 
Clinically significant laboratory abnormalities should prompt a repeat measure no less 
frequently than every 2 weeks or as clinically indicated, with appropriate clinical 


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management, until they return to normal or baseline levels, and/or an adequate 
explanation of the abnormality is found.  If a clear explanation is established it should be 
recorded on the eCRF.  See also Section 6.2.5 for specific guidance. 
7.2 
HANDLING OF SAFETY PARAMETERS 
7.2.1 
Reporting of Adverse Events  
All AEs (related and unrelated) occurring during the treatment/principal observation 
period and initial 24 weeks of follow-up must be reported.  During the extended long-
term follow-up period, only persisting AEs, new-onset SAEs and non-serious AEs of 
special interest related to PEG-IFN, and deaths will be reported. 
7.2.2 
Reporting of Serious Adverse Events (immediately reportable) 
Any clinical AE or abnormal laboratory test value that is serious (as defined in 
Section 7.1.1.3) and that occurs during the study, regardless of the treatment arm, 
occurring from the enrollment visit (start of study screening procedures), including 
extended long-term follow-up must be reported to Roche within 1 working day of the 
investigator becoming aware of the event (expedited reporting).   
For initial reports of serious adverse events, investigators should record all case details 
that can be gathered within 1 working day on the Adverse Event eCRF and submit the 
report via the Electronic Data Capture (EDC) system.  A report will be generated and 
sent to Roche Safety by the EDC system. 
In the event that the EDC system is unavailable, a paper Serious Adverse Event CRF 
and Fax Cover Page should be completed and faxed immediately to Roche Safety.  
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.   
After informed consent/assent, but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected (e.g., SAEs related to 
invasive procedures such as biopsies, medication washout, or no treatment run-in).  
After first study drug, all SAEs must be reported.  
Unrelated SAEs must be collected and reported during the study treatment/principal 
observation period and initial 24 weeks of follow-up. 
Related SAEs must be collected and reported regardless of the time elapsed from the 
last study drug administration, even if the study has been closed.  Every effort should be 
made to follow all SAEs considered to be related to the study drug or study-related procedures 
until a final outcome can be reported.  
Suspected Unexpected Serious Adverse Reactions (SUSARs) are reported to 
investigators at each site and associated IRB/IEC when the following conditions occur: 
• 
The event must be an SAE.  


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• 
There must be a certain degree of probability that the event is an adverse reaction 
from the administered drug.  
• 
The adverse reaction must be unexpected, that is to say, not foreseen in the SPC 
text (Summary of Product Characteristics [for an authorized medicinal product]) or 
the Investigator’s Brochure (for an unauthorized medicinal product).  
 
When all subjects at a particular site are off treatment as defined by the protocol:  
• 
Only individual SUSAR reports originating in that particular trial will be forwarded to 
the site and associated IRB/IEC on an expedited basis; 
• 
Individual SUSARs considered to be a significant safety issue and/or which result in 
Roche recommending a change to the Informed Consent Form/assent, will be 
reported in an expedited manner to all investigators and IRBs/IECs; 
• 
SUSAR reports originating from other trials using the same IMP will be provided as 
six monthly SUSAR Reports to investigators and IRBs/IECs where long-term follow-
up studies are carried out, unless they are considered significant. 
 
This study adheres to the definition and reporting requirements of ICH Guideline for 
Clinical Safety Data Management, Definitions and Standards for Expedited Reporting, 
Topic E2.  Complete information can be found in Appendix 3. 
7.2.3 
Reporting of Non-serious Events of Special Interest  
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; as per SAE 
reporting procedure in Section 7.2.2).  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 (Section 7.1.3) 
• 
Suspected transmission of an infectious agent by the study drug 
 
7.2.4 
Pregnancy 
A female subject must be instructed to stop taking the study medication and immediately 
inform the investigator if she becomes pregnant during the study.  The investigator 
should report all pregnancies within 24 hours to the Sponsor, using the Pregnancy 
Report eCRF.  The investigator should counsel the subject, and discuss the risks of 
continuing with the pregnancy and the possible effects on the fetus.  Monitoring of the 
subject should continue until conclusion of the pregnancy.  Pregnancies occurring up to 
90 days after the completion of the study medication must also be reported to the 
investigator. Subjects that become pregnant during the treatment period will be 
withdrawn from the treatment period and continue into the follow-up period. 
Pregnancy occurring in the partner of a male subject participating in the study should be 
reported to the investigator and the Sponsor.  The partner should be counseled, the risks 


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of continuing the pregnancy discussed, as well as the possible effects on the fetus.  
Monitoring of the subject should continue until conclusion of the pregnancy. 
NOTE:  The investigator should fill out a Pregnancy Report eCRF only if the pregnant 
partner has signed a Pregnant Partner Data Release Form. 
In the event that the EDC system is unavailable, a Pregnancy Report worksheet and 
Pregnancy Fax Coversheet should be completed and faxed to Roche Safety or its 
designee within 1 working day after learning of the pregnancy. 
7.3 
WARNINGS AND PRECAUTIONS 
Alpha interferons, including PEG-IFN, may cause or aggravate fatal or life-threatening 
neuropsychiatric, autoimmune, ischemic, and infectious disorders.  Subjects should be 
monitored closely with periodic clinical and laboratory evaluations.  Therapy should be 
withdrawn from subjects with persistently severe or worsening signs or symptoms of 
these conditions.  In many, but not all cases, these disorders resolve after stopping 
PEG-IFN therapy. 
To date, no teratology or reproduction studies have been conducted in humans with 
PEG-IFN.  Primate teratology studies indicate an increased incidence of spontaneously 
aborted fetuses in pregnant rhesus monkeys (Macaca mulatta) receiving high doses of 
intramuscular Roferon®-A [51].  Studies with Roferon®-A in non-pregnant rhesus 
monkeys have shown menstrual cycle irregularities, including prolonged menstrual 
periods.  Male fertility and teratological evaluations have yielded no significant adverse 
effects to date.  However, sexually active males will be excluded or discontinued from 
this study if not utilizing reliable contraception during the treatment/principal observation 
period and during the initial 24-week follow-up period. 
Interferons are human proteins that show a substantial degree of species specificity, 
making extrapolation of animal study data to humans of questionable value.  
Investigations have been conducted in normally cycling healthy females using non-
recombinant human leukocyte interferon.  Results demonstrate a significant reduction of 
serum estradiol and progesterone concentrations during the treatment interval [52].   
There are no adequate, controlled studies of any IFN in pregnant females.  Therefore, 
extreme care must be taken to avoid pregnancy during the study in female subjects, and 
female partners of male subjects taking PEG-IFN.  Sexually active females will be 
excluded/discontinued from this study if not utilizing effective contraception at enrollment 
and will be discontinued from study treatment if not using effective contraception during 
the initial 24-week follow-up period.  Females who are pregnant or breast-feeding will 
also be excluded.  A pregnancy test will be performed for each female of childbearing 
potential prior to baseline and switch baseline, and at any time secondary amenorrhea of 
more than 1 week occurs.  In addition, subjects treated with PEG-IFN will have a 
pregnancy test performed according to the schedules in Table 2 and Table 4.  If 


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pregnancy occurs in a subject or partner of a subject during the PEG-IFN treatment 
period or up to 3 months after PEG-IFN treatment, the cases should be handled as 
described in Section 7.2.4. 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
8.1 
PRIMARY AND SECONDARY STUDY ENDPOINTS 
8.1.1 
Primary Endpoints 
• 
HBeAg seroconversion (loss of HBeAg and presence of anti-HBe) at the 24-week 
post-end of treatment/principal observation period follow-up visit 
 
8.1.2 
Secondary Endpoints 
• 
Loss of HBeAg, HBsAg seroconversion (loss of HBsAg and presence of anti-HBs), 
loss of HBsAg, quantitative serum ALT, proportion of normal ALT, quantitative 
HBV-DNA, suppression of HBV-DNA < 100,000 copies/mL (< 20,000 IU/mL), 
< 10,000 copies/mL (< 2,000 IU/mL), undetectable and change from baseline, 
combined endpoint of HBeAg seroconversion and HBV-DNA < 100,000 copies/mL 
(< 20,000 IU/mL), and combined endpoint of HBeAg seroconversion and HBV-DNA 
<10,000 copies/mL (< 2,000 IU/mL) at the end of treatment/principal observation 
period, 24 weeks after end of treatment/principal observation period, and 1, 2, 3, 4 
and 5 years after end of treatment/principal observation period. 
• 
Persistence of HBeAg seroconversion (loss of HBeAg and presence of anti-HBe) at 
the end of treatment/principal observation period, and 1, 2, 3, 4, and 5 years after 
end of treatment/principal observation period. 
• 
Descriptive change from baseline in liver elasticity (for subjects enrolled in the liver 
elasticity sub-study) at the end of treatment/principal observation period, and 
24 weeks and 2 years after end of treatment/principal observation period. 
 
8.1.3 
Safety 
Safety of the treatment will be evaluated by AEs (including SAEs and non-serious AEs of 
special interest), laboratory tests, vital signs (blood pressure, heart rate, temperature), 
and growth (weight and height).   
8.1.4 
Pharmacokinetic 
PK parameters (e.g., CL/F, V/F, AUC, Cmax, etc.) of PEG-IFN will be evaluated in 
subjects following administration of a new BSA-based dosing regimen over the first 
24 weeks of treatment. 
8.2 
STATISTICAL AND ANALYTICAL METHODS 
8.2.1 
Statistical Model 
8.2.1.1 
Primary Variables 
The primary efficacy parameter is HBeAg seroconversion (defined as absence of HBeAg 
and presence of HBeAb) determined 24 weeks after the end of treatment/principal 


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observation period.  Subjects with missing values for this parameter will be considered 
non-responders. 
8.2.1.2 
Secondary Variables 
All secondary variables will be determined at 24 weeks after the end of 
treatment/principal observation period and at 1, 2, 3, 4, and 5 years after the end of 
treatment/principal observation period. 
• 
Loss of HBeAg (defined as absence of HBeAg) 
• 
HBsAg seroconversion (defined as loss of HBsAg and presence of anti-HBs) 
• 
Loss of HBsAg (defined as absence of HBsAg) 
• 
Quantitative serum ALT  
• 
Proportion of normal serum ALT (defined as ALT measure ≤ ULN) 
• 
Quantitative HBV-DNA  
• 
Suppression of HBV-DNA < 100,000 copies/mL (< 20,000 IU/mL), 
< 10,000 copies/mL (< 2,000 IU/mL), undetectable, and change from baseline 
• 
Combined endpoints:  HBeAg seroconversion and HBV-DNA < 100,000 copies/mL 
(< 20,000 IU/mL)  
• 
Combined endpoints:  HBeAg seroconversion and HBV-DNA < 10,000 copies/mL 
(< 2,000 IU/mL)  
• 
HBeAg seroconversion (defined as absence of HBeAg and presence of HBeAb) 
 
8.2.2 
Sample Size 
Sample size is based on the χ2 test statistic.  Assuming a 32% HBeAg seroconversion 
rate for Group A (PEG-IFN) and 10% for Group B (untreated control), a total sample size 
of 145 subjects provides at least 80% power at the 0.05 level of significance with a 
two-sided χ2 test.  The sample size shall be increased by 10% and rounded to 
160 subjects to allow for advanced fibrotics (Group C) and withdrawals.   
8.2.3 
Hypothesis Testing 
Testing of the primary endpoint consists of a superiority test for the ITT population of 
HBeAg seroconversion determined 24 weeks after the end of treatment in Group A 
compared with HBeAg seroconversion determined 24 weeks after the principal 
observation period in Group B.  The primary analysis will be done using a 
Cochran-Mantel-Haenszel test using stratification factors of genotype (A vs. non-A) and 
ALT (< 5 × the ULN and ≥ 5 × the ULN). 
8.2.4 
Analysis Populations 
8.2.4.1 
ITT Population 
For Group A, the ITT population shall include all subjects who receive at least one dose 
of study medication.  For the untreated Group B, the ITT population shall include all 
subjects with at least the baseline efficacy or safety data.  For the ITT population, 


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subjects will be analyzed according to the groups to which they were randomized.  
Subjects in Group B who switched to receive PEG-IFN after Week 48 and prior to 
24 weeks post-observation period will be counted as non-responders. 
8.2.4.2 
Switch Population 
The Switch population shall be those subjects randomized to Group B who opt to switch 
to initiating treatment with PEG-IFN after Week 48.  Efficacy and safety data will be 
reported from all subjects entering the switch arm if at least one dose of study 
medication was taken.   
8.2.4.3 
Group C 
Subjects who have advanced fibrosis (diagnosed on liver biopsy, see Appendix 1) which 
is not decompensated will receive PEG-IFN in an advanced fibrotic arm (Group C).  
Efficacy and safety data will be reported from all subjects in Group C if at least one dose 
of study medication was taken.   
8.2.5 
Efficacy Analysis 
The primary efficacy analysis will compare efficacy in Group A with Group B.  The 
efficacy data of Group A and Group B will be qualitatively evaluated alongside subjects 
in Group C and the switch arm. 
The primary analysis of the response rate variables will be with the Cochran-Mantel-
Haenszel test (χ2) stratified by genotype (with strata of A and non-A) and ALT (< 5 × the 
ULN and ≥ 5 × the ULN).  Fisher’s exact test will be used as a secondary analysis.  The 
response rates for HBeAg seroconversion will be analyzed at the end of the initial 
24-week follow-up period. 
Several secondary analyses are planned.  Descriptive statistics of secondary endpoints 
loss of HBeAg, HBsAg seroconversion, loss of HBsAg, proportion of normal serum ALT, 
suppression of HBV-DNA, and combined endpoints will be summarized by Groups A, B, 
and C separately.  Exploratory p-values will be presented using Fisher’s exact test.  
Quantitative serum ALT and quantitative HBV-DNA will be summarized by timepoints 
numerically and graphically over time.  No formal statistical tests are planned. Graphs of 
secondary endpoints and corresponding 95% confidence intervals over time by group 
will be displayed. 
For subjects in the liver elasticity sub-study, LSM will be measured at baseline, end of 
treatment/principal observation period, and at 24 weeks and 2 years after the end of 
treatment to assess change in liver elasticity over time.  These results in subjects 
receiving treatment (Group A) will be compared with parallel measurements in the 
untreated control arm (Group B).  For the comparison with liver biopsy at baseline, 
associations with liver stiffness will be explored using liver biopsy fibrosis score.  
Continuous outcomes will be studied using Pearson correlation, and potential 


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categorizations will be investigated as well.  Confidence intervals will be provided as 
needed.  No formal statistical tests will be carried out. 
8.2.5.1 
Exclusion of Data from Analysis 
8.2.5.1.1 
Intent-to-Treat Population 
All subjects randomized will be included in the ITT population, as defined 
in Section 8.2.4.1. 
Subjects will be assigned to groups as randomized for analysis purposes. 
Subjects will be excluded if they do not meet ITT criteria, as defined in Section 8.2.4.1.  
8.2.5.2 
Interim Analysis 
No efficacy interim analyses are planned.   
When adequate PK data have been collected over the first 24 weeks for at least 
15 PEG-IFN−treated subjects, ideally with representation from all BSA categories, PK 
analysis will be undertaken to ensure exposure is in the appropriate therapeutic range.  
If data suggest that the exposure is not in the appropriate range, an adjustment to the 
dosing regimen will be made to meet the target exposure range (see Section 5.4.2). 
See Section 10 on review of safety data by a Data Safety Monitoring Board (DSMB).   
8.2.5.3 
Safety Data Analysis 
The primary safety analysis will compare safety in Group A with Group B at 24 weeks 
post-end of treatment/end of untreated observation.  The safety data of Group A and Group B 
will be qualitatively evaluated alongside subjects in Group C and the switch arm. 
• 
Incidence, nature, and severity of serious and non-serious AEs (including neurological and 
psychiatric events) 
• 
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 and weight) 
The following safety outcome measures will be assessed using descriptive statistics at 1, 2, 3, 4, 
and 5 years post-end of 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 and weight) 


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AEs:  AEs will be assigned preferred terms and categorized into body systems according 
to the Medical Dictionary for Regulatory Activities (MedDRA) classification of the World 
Health Organization (WHO) terminology.  Descriptive statistics will be used to 
summarize safety parameters by group.  Neurological and psychiatric AEs will be 
assessed in further detail, including persistence and duration, as well as new onset of 
SAEs and non-serious AEs of special interest related to PEG-IFN reported during the 
extended long-term follow-up period of this study. 
Laboratory Safety Data:  The laboratory data (including thyroid function) will be analyzed 
according to Roche’s “International Guideline for the Handling and Reporting of 
Laboratory Data”. 
Growth (weight and height):  The continuous growth will be analyzed with Residual 
Maximum Likelihood, or analysis of covariance.  The assumptions of the analysis such 
as normally distributed residuals will be assessed.  If necessary, rectifying 
transformations shall be applied.  Growth (height) velocity will be explored. 
8.2.6 
Other Analyses 
8.2.6.1 
Pharmacokinetic Analysis 
PK parameters (e.g., CL/F V/F, AUC, Cmax, etc,) of PEG-IFN will be estimated using non-
compartmental analysis and/or a population PK modeling approach.  
All PK parameters will be presented descriptively including arithmetic means, standard 
deviations, geometric means, coefficients of variation, medians, and ranges. 
The relationship between clinical endpoints and PEG-IFN serum exposure may be 
explored. 
The relationship between PK and PD parameters may be explored. 
9. 
DATA COLLECTION, MANAGEMENT, AND 
QUALITY ASSURANCE 
The overall procedures for quality assurance of clinical study data are described in the 
Roche standard operational procedures. 
Data for this study will be recorded via an EDC system using eCRF.  It will be 
transcribed by the site from the paper source documents onto the eCRF.  In no case is 
the eCRF to be considered as source data for this trial except where stated in this 
protocol.  Sites will receive training and a manual for appropriate eCRF completion.  
(See also Section 15.4.)  Accurate and reliable data collection will be assured by 
verification and cross-check of the eCRFs against the investigator’s records by the study 
monitor (source document verification), and the maintenance of a drug dispensing log by 
the investigator. 


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A comprehensive validation check program utilizing front-end checks in the eCRF and 
back-end checks in the Roche database will verify the data and discrepancies will be 
generated accordingly.  These are transferred electronically to the eCRF at the site for 
resolution by the investigator. 
Throughout the study the Study Management Team will review data according to the 
integrated Data Review Plan. 
9.1 
ASSIGNMENT OF PREFERRED TERMS AND ORIGINAL 
TERMINOLOGY 
For classification purposes, the lowest level terms will be assigned by the Sponsor to the 
original terms entered on the eCRF, using the most up-to-date version of the MedDRA 
terminology for AEs and diseases and Genentech’s Drug Dictionary for treatments. 
10. 
STUDY COMMITTEES 
A DSMB will review safety data on a routine basis (as per DSMB charter).  Enrollment will 
be suspended and/or the study will be halted if serious concerns about safety are raised 
pending further analysis and review.  Enrollment and/or study re-start will resume only if 
the DSMB and the Sponsor are satisfied with the safety of treatment. 


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11. 
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2. 
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and emerging prevention and control measures. J Viral Hepat 2004;11:97–107. 
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Wright TL. Introduction to chronic hepatitis B infection. Am J Gastroenterol 
2006;101:S1−S6. 
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Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000⎯summary 
of a workshop. Gastroenterology 2001;120:1828–53. 
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Kim H, et al. Predictive factors for early HBeAg seroconversion in acute 
exacerbation of HBeAg-positive chronic hepatitis B patients. Gastroenterology 
2009;136:505−12. Epub 27 Nov 2008. 
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Sanchez-Taspias JM, et al.  Analysis of factors predicting early seroconversion to 
anti-HBe in HBeAg-positive chronic hepatitis B. J Hepatol 1988;6:15−22. 
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Gonzalez Peralta RP, et al. Hepatocellular carcinoma in 2 young adolescents with 
chronic hepatitis C. J Pediatr Gastroenterol Nutr 2009;48:630−5. 
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Clinical Practice Guidelines. European Association for the Study of the Liver. J 
Hepatol 2009;50:227–42. 
9. 
Beasley RP, et al. Hepatocellular carcinoma and hepatitis B virus. A prospective 
study of 22 707 men in Taiwan. Lancet 1981; 21;2(8256):1129−33. 
10. Evans A, et al. Eight-year follow-up of the 90,000-person haimen city cohort: I. 
hepatocellular carcinoma mortality, risk factors, and gender differences. Cancer 
Epidemiol Biomarkers Prev 2002;11:369–76. 
11. Fattovich G, et al. Natural history of chronic hepatitis B: special emphasis on 
disease progression and prognostic factors. J Hepatol 2008; 48:335−52. 
12. Fattovich G, et al. Long-term outcome of chronic hepatitis B in Caucasian patients: 
mortality after 25 years. Gut 2008;57:84−90.  
Epub 22 Aug 2007. 
13. Fwu CW, et al. Hepatitis B virus infection and hepatocellular carcinoma among 
parous Taiwanese women: nationwide cohort study. J Natl Cancer Inst 
2009;101(14):1019–27. 
14. Sorrel M. NIH Consensus development statement on management of hepatitis B. 
Ann Intern Med 2009;150:104−10.  
15. Lok A. AASLD practice guidelines. Hepatology 2009, Vol 50, no.3. 
16. Chen C-J, et al. Long-term outcomes in hepatitis B: the reveal-HBV study. Clin Liver 
Dis 2007;11:797–816. 
17. Chen C-J, et al. Risk of hepatocellular carcinoma across a biological gradient of 
serum hepatitis B virus DNA level. JAMA 2006;295:65–73. 


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18. Lai CL, et al. The natural history and treatment of chronic hepatitis B: a critical 
evaluation of standard treatment criteria and end points. Ann Intern Med 
2007;147:58–61. 
19. Ni Y, et al. Clinical relevance of hepatitis B virus genotype in children with chronic 
infection and hepatocellular carcinoma. Gastroenterology 2004;127:1733–38. 
20. Clinical Study Report⎯Protocol NV16037: A phase II, open-label, randomized, 
multicenter, parallel-group study evaluating the safety and efficacy of PEG-
Interferon alfa-2a (PEG-IFN, Ro 25-8310) versus interferon alfa-2a (IFN, Roferon®-A) 
in interferon naïve patients with chronic hepatitis B (CHB). Research Report 
1005189, February 8, 2002.  
21. Clinical Study Report⎯Protocol WV16240: A phase III partially double blinded study 
evaluating the efficacy and safety of 40kD pegylated interferon alfa-2a (PEG-IFN Ro 
25-8310) combined with placebo or lamivudine versus Lamivudine in HBeAg-
positive patients with chronic hepatitis B. Research Report 1011914, June 2004.   
22. Clinical Study Report⎯Protocol WV16241: A phase III partially double blinded study 
evaluating the efficacy and safety of Pegasys® (pegylated interferon alpha-2a) 
combined with placebo or lamivudine versus lamivudine in anti-HBe positive 
patients with chronic hepatitis B. Research Report 1007770, February 2004. 
23. Clinical Study Report⎯Protocol WV19432: A phase IV, 2 × 2 factorial, double blind 
study of 24 versus 48 weeks and 90 versus 180 mcg doses of pegylated interferon 
alfa-2a 40KD (PEG-IFN, Ro 25-8310) in adult patients with HBeAg positive chronic 
hepatitis B. Research Report 1040108, November 2010. 
24. Dubois J, et al. Toxicity profile of interferon alfa-2b in children: a prospective 
evaluation. J Pediatr 1999 Dec;135:782–5. 
25. Worle H, Maass E, Kohler B, et al. Interferon alpha-2a therapy in haemangiomas of 
infancy: spastic diplegia as a severe complication. Eur J Pediatr 1999;158:344. 
26. Sin NC, Li CK, Shing MK, et al. Spastic diplegia as a complication of interferon 
alpha treatment of Kasabach-Merritt syndrome. HK J Paediatr 2002;7:220–2. 
27. Barlow CF, Priebe CJ, Mulliken JB, et al. Spastic diplegia as a complication of 
interferon alfa-2a treatment of hemangiomas of infancy. J Pediatr 1998;132:527–30. 
28. Contraindications in Pegasys® Package Insert (24 May 2010) and Summary of 
Product Characteristics (2 July 2010). 
29. Sokal E, et al. Interferon alfa therapy for chronic hepatitis B in children: a 
multinational randomized controlled trial. Gastroenterology 1998; 114: 988–95. 
30. Bortolotti F, et al. Long term effect of alpha interferon in children with chronic 
hepatitis B. Gut 2000;46:715–8. 
31. Diem H, et al. Chronic hepatitis B infection: Long term comparison of children 
receiving interferon α and untreated controls. J Pediatr Gastroenterol Nutr 2005; 
40(2):141–5. 
32. Bortolotti F. Treatment of chronic hepatitis B in children. J Hepatology 
2003;39:S200–5. 


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33. Hou J, et al. Genetic characteristics of hepatitis B virus genotypes as a factor for 
interferon-induced HBeAg clearance. J Med Virol 2007; 79:1055–1063. 
34. Zhao H, et al. Genotype B and younger patient age associated with better response 
to low-dose therapy: a trial with pegylated/nonpegylated interferon-α-2b for hepatitis 
BeAg-positive patients with chronic hepatitis B in China. Clin Infect Dis 2007; 
44;541−7. 
35. Lau G, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-
positive chronic hepatitis B. N Engl J Med 2005; 352:2682−95. 
36. Marcellin P, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in 
combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 
2004;351:1206−17. 
37. Pawlowska M, Halota W. Virological response to treatment with pegylated interferon 
alfa-2a of chronic hepatitis B in children. AASLD Poster No.701; Oct−Nov 2009. 
38. Hsu H-Y, Tsai H-Y, Wu T-C, et al. Interferon-α treatment in children and young 
adults with chronic hepatitis B: a long-term follow-up study in Taiwan. Liver Inter 
2008;28:1288−97.  
39. Zhu et al. Data on file. 2010. 
40. Chang M-H. Natural history and clinical management of chronic hepatitis B virus 
infection in children. Hepatol Int 2008;2:S28−S36. 
41. Protocol NV17424.  Pegylated inteferon +/- ribavirin for children with HCV (PEDS-C). 
42. EASL Clinical practice guidelines: management of chronic hepatitis B. J Hepatol 
2009;50:227−42. 
43. Kurbergov A, Sokol RJ. Hepatitis B therapy in children. Expert Rev Gastroenterol 
Hepatol 2009;3:39−49. 
44. AASLD Practice Guidelines for Management of Chronic Hepatitis B: Update 2009. 
Hepatol 2009;50:661−2.  
45. Ziol M, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in 
patients with chronic hepatitis C. Hepatology 2005; 41:48−54. 
46. Degos F et al. Diagnostic accuracy of FibroScan and comparison to liver fibrosis 
biomarkers in chronic viral hepatitis: a multicenter prospective study (the 
FIBROSTIC study). J Hepatol 2010;53:1013−21. 
47. Friedrich–Rust M, et al. Performance of transient elastography for the staging of 
liver fibrosis: a meta-analysis. Gastroenterology 2008; 134:960−74. 
48. Schwarz KB, 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. 
49. Roche Pediatric Investigation Plan. EMEA-000298-PIP01-08-M03. March 2013. 
50. Kovacs, Maria, Multi-Health Systems (MHS) Staff. Children’s Depression Inventory 
(CDI) Technical Manual Update, New York: Multi-Health Systems Inc.,© 1992, 2003. 
Printed December 2010. 
51. PEGASYS® Core Data Sheet Version 12. November 2009. 


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52. Kauppila A, Cantell K, Janne O, et al. Serum sex steroid and peptide hormone 
concentration and endometrial estrogen and progestin receptor levels during 
administration of human leukocyte interferon. Int J Cancer 1982;29:291. 
 
 


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PART II: 
ETHICS AND GENERAL STUDY ADMINISTRATION 
12. 
ETHICAL ASPECTS 
12.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual.  The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline or with local law if it affords greater protection 
to the subject.  For studies conducted in the EU/European Economic Area (EEA) 
countries, the investigator will ensure compliance with the EU Clinical Trial Directive 
(2001/20/EC).  For studies conducted in the United States of America or under a U.S. 
Investigational New Drug (IND), the investigator will additionally ensure adherence to the 
basic principles of “Good Clinical Practice” as outlined in the current version of 21 Code 
of Federal Regulations, subchapter D, part 312, “Responsibilities of Sponsors and 
Investigators”, part 50, “Protection of Human Subjects,” and part 56, “Institutional Review 
Boards”. 
In other countries where a “Guideline for Good Clinical Practice” exists, Roche and the 
investigators will strictly ensure adherence to the stated provisions. 
12.2 
INFORMED CONSENT/ASSENT  
12.2.1 
Main Study Informed Consent 
It is the responsibility of the investigator, or a person designated by the investigator (if 
acceptable by local regulations), to obtain signed informed consent from each 
parent/legal guardian of subjects prior to participating in this study after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of the 
study. 
If children are old enough to understand the risks and benefits of the study, they should 
also be informed and should also provide their written assent.  Patients within the specified 
age range who are legally 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, if required by national legislation.  With regard to the 
donation of a specimen(s) by the minor that will be stored in the RCR this same principle 
will apply.  If the minor is not old enough to form an opinion or assess this information, 
the legal representative/guardian will replace the minor in recognizing his/her rights and 
responsibilities until he/she reaches legal age. 
The investigator or designee must also explain that the subjects are completely free to 
refuse to enter the study or to withdraw from it at any time, for any reason.   
The eCRFs for this study contain a section for documenting informed consent/assent, 
and this must be completed appropriately.  If new safety information results in significant 


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changes in the risk/benefit assessment, the informed consent/assent should be reviewed 
and updated if necessary.  All subjects (including those already being treated) and their 
parent/legal guardian should be informed of the new information, given a copy of the 
revised informed consent/assent and give their consent/assent to continue in the study. 
12.2.2 
RCR Informed Consent 
The Informed Consent/Assent Form will contain a separate section that addresses 
participation in the RCR.  It also covers use of serum bank samples for exploratory HBV 
biomarker analyses.  The investigator or authorized designee will explain to each subject 
the objectives, methods, and potential hazards of participation in the RCR.  Subjects 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 subject's agreement to provide optional RCR specimens.  
Subjects who decline to participate will check a “no” box in the appropriate section and 
will not provide a separate signature. 
The investigator should document whether or not the subject has given consent/assent 
to participate by completing the RCR Research Sample Informed Consent 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. 
12.3 
INDEPENDENT ETHICS COMMITTEE (IEC)/INSTITUTIONAL 
REVIEW BOARD (IRB) 
The protocol, informed consent/assent, and any accompanying material provided to the 
subject in the United States will be submitted by the investigator to an IRB for review.  
For EEA member states, the Sponsor will submit to the Competent Authority (CA) and 
IEC, the protocol and any accompanying material provided to the subject.  In both the 
United States and EEA member states, the accompanying material may include subject 
information sheets, descriptions of the study used to obtain informed consent/assent, 
and terms of any compensation given to the subject as well as advertisements for the 
trial. 
An approval letter or certificate (specifying the protocol number and title) from the 
IEC/IRB must be obtained before study initiation by the investigator specifying the date 
on which the committee met and granted the approval.  This applies whenever 
subsequent amendments/modifications are made to the protocol. 
Any modifications made to the protocol, informed consent/assent, or material provided to 
the subject after receipt of the IEC/IRB approval must also be submitted by the 
investigator in the United States and by the Sponsor in the EEA member states in 
accordance with local procedures and regulatory requirements. 


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When no local review board exists, the investigator is expected to submit the protocol to 
a regional committee.  If no regional committee exists, Roche will assist the investigator 
in submitting the protocol to the European Ethics Review 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 
IRB/EC and, if applicable, an appropriate regulatory body.  If a site is not granted 
approval for RCR sampling, this section of the protocol will not be applicable at that site. 
Roche shall also submit an Annual Safety Report once a year to the IEC and CAs 
according to local regulatory requirements and timelines of each country participating in 
the study.  In the United States, Roche submits an IND Annual Report to the Food and 
Drug Administration according to local regulatory requirements and timelines. 
12.4 
ROLE OF THE SCIENCE AND ETHICS ADVISORY GROUP 
In addition to an internal review body, an independent Science and Ethics Advisory 
Group, consisting of experts in the fields of biology, ethics, sociology, and law, will 
advise Roche regarding the use of RCR specimens and on the scientific and ethical 
aspects of handling genetic information.  
13. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Requests from investigators to modify the protocol to ongoing studies will be considered 
only by consultation between an appropriate representative of the Sponsor and the 
investigator (investigator representative[s] in the case of a multicenter trial).  Protocol 
modifications must be prepared by a representative of the Sponsor and initially reviewed 
and approved by the Associate PD Group Medical Director/Clinical Pharmacologist and 
Biostatistician. 
All protocol modifications must be submitted to the appropriate IEC or IRB for 
information and approval in accordance with local requirements, and to regulatory 
agencies if required.  Approval must be obtained before any changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to trial 
subjects, or when the change(s) involves only logistical or administrative aspects of the 
trial (e.g., change in monitor[s], change of telephone number[s]). 
14. 
CONDITIONS FOR TERMINATING THE STUDY 
Both the Sponsor and the investigator reserve the right to terminate the study at any 
time.  Should this be necessary, both parties will arrange the procedures on an individual 
study basis after review and consultation.  In terminating the study, Roche and the 
investigator will assure that adequate consideration is given to the protection of the 
subjects’ interests.  The appropriate IRB/IEC and regulatory agencies should be 
informed accordingly. 


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15. 
STUDY DOCUMENTATION, CASE REPORT FORMS AND 
RECORD KEEPING 
15.1 
INVESTIGATOR'S FILES / RETENTION OF DOCUMENTS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified.  These 
documents should be classified into two different separate categories 1) Investigator's 
Study File, and 2) subject clinical source documents. 
The Investigator's Study File will contain the protocol/amendments, schedule of 
assessments, IEC/IRB and governmental approval with correspondence, sample 
informed consent/assent, drug records, staff curriculum vitae, and authorization forms 
and other appropriate documents/correspondence, etc. 
Subject clinical source documents (usually defined by the project in advance to record 
key efficacy/safety parameters independent of the eCRFs) would include subject 
hospital/clinic records, physician's and nurse's notes, appointment book, original 
laboratory reports, electrocardiogram (ECG), electroencephalogram (EEG), X-ray, 
pathology and special assessment reports, signed informed consent/assent forms, 
consultant letters, and subject screening and enrollment logs.  The investigator must 
keep the documents as described above on file for at least 15 years after completion or 
discontinuation of the study.  After that period of time the documents may be destroyed, 
subject to local regulations. 
Should the Investigator wish to assign the study records to another party or move them 
to another location, Roche must be notified in advance. 
If the investigator cannot guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
Investigator and Roche to store these in a sealed container(s) outside of the site so that 
they can be returned sealed to the Investigator in case of a regulatory audit.  Where 
source documents are required for the continued care of the subject, appropriate copies 
should be made for storing outside of the site. 
ICH Good Clinical Practice (GCP) guidelines require that Investigators maintain 
information in the study subject’s records which corroborate data collected on the 
eCRF(s).  Completed eCRFs will be forwarded to Roche. 
15.2 
SOURCE DOCUMENTS AND BACKGROUND DATA 
The investigator shall supply the Sponsor on request with any required background data 
from the study documentation or clinic records.  This is particularly important when 
errors in data transcription are suspected.  In case of special problems and/or 
governmental queries or requests for audit inspections, it is also necessary to have 
access to the complete study records, provided that subject confidentiality is protected. 


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15.3 
AUDITS AND INSPECTIONS 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Roche Pharma Development 
Quality Assurance Unit or its designees, or to health authority inspectors after 
appropriate notification.  The verification of the eCRF data must be by direct inspection 
of source documents. 
15.4 
ELECTRONIC CASE REPORT FORMS   
eCRFs are to be completed using the RAVE EDC system.  Sites will receive training and 
a manual for appropriate eCRF completion.  eCRFs will be submitted electronically to 
Roche and should be handled in accordance with instructions from Roche. 
All eCRFs should be completed by designated, trained examining personnel or the study 
coordinator as appropriate.  The eCRF should be reviewed and electronically signed and 
dated by the investigator. 
In addition, at the end of the study, the investigator will receive subject data for his or her 
site in a readable format on a compact disc that must be kept with the study records. 
15.5 
FINANCIAL DISCLOSURE 
The investigator(s) will provide the Sponsor with sufficient accurate financial information 
to allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the appropriate regulatory authorities.  The investigator is responsible to 
promptly update any information provided to the Sponsor if relevant changes occur in 
the course of the investigation and for 1 year following the completion of the study 
(LSLV). 
16. 
MONITORING THE STUDY 
It is understood that the responsible Roche monitor [or designee] will contact and visit 
the investigator regularly and will be allowed, on request, to inspect the various records 
of the trial (eCRFs and other pertinent data) provided that subject confidentiality is 
maintained in accord with local requirements. 
It will be the monitor's responsibility to inspect the eCRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them.  The monitor must verify that the subject 
received the study drug assigned by the randomization center (by controlling the written 
confirmation of the randomization by IXRS).  The monitor should have access to 
laboratory test reports and other subject records needed to verify the entries on the 
eCRF.  The investigator [or deputy] agrees to cooperate with the monitor to ensure that 
any problems detected in the course of these monitoring visits are resolved. 


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RCR specimens will be tracked in a manner consistent with GCP 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 subject participation in the RCR for the purposes of verifying the data 
provided to Roche.  The site will permit monitoring, audits, IRB/IEC review, and health 
authority inspections by providing direct access to source data and documents related to 
the RCR samples. 
17. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND 
SUBJECT RECORDS 
The investigator must assure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On eCRFs or other documents 
submitted to the Sponsor, subjects should not be identified by their names, but by an 
identification code.  The investigator should keep a subject enrollment log showing 
codes, names, and addresses.  The investigator should maintain documents not for 
submission to Roche, e.g., subjects’ written consent/assent forms, in strict confidence. 
Roche already maintains rigorous confidentiality standards for clinical studies by 
“coding” (i.e., assigning a unique subject ID number at the investigator site) all subjects 
enrolled in Roche clinical studies.  This means that subject names are not included in 
data sets that are transmitted to any Roche location. 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure subject confidentiality for RCR specimens (see Section 5.4.3).  These 
processes also apply to any central laboratory carrying out biomarker analysis on serum 
bank samples (see Section 5.4.1).  Upon receipt by the RCR, all specimens are “single-
coded” then each genetic specimen is “double-coded” by replacing the subject 
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 subject 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. 
Data generated from RCR or any other biomarker specimens must be available for 
inspection upon request by representatives of national and local health authorities, and 
Roche monitors, representatives, and collaborators, as appropriate. 


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Subject medical information associated with RCR or any other biomarker 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 subject, unless permitted or required by law. 
18. 
CLINICAL STUDY REPORT 
A clinical study report (CSR) will be written and distributed to health authorities as 
required by applicable regulatory requirements.   
Note:  EU Regulation (EC) No.1901/2006, states: For pediatric studies the CSR must be 
distributed to the applicable health authorities within 6 months of completion of the study. 
19. 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Roche will comply with the requirements for publication of study results. 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to Roche 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, Roche 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. 
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 Roche personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Roche personnel.  
Data derived from RCR or any other biomarker specimen analysis on individual subjects 
will not be provided to study investigators, except where explicitly stipulated in a study 
protocol (e.g., if the result is an enrollment criterion).  Exceptions may be granted (e.g., if 
biomarker data would be linked to safety issues).  The aggregate results of any research 
conducted using RCR or any other biomarker 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 or any other biomarker will become and remain the exclusive and 
unburdened property of Roche, except where agreed otherwise. 


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Appendix 1 
 
Liver Biopsy Scores 
Various liver biopsy classification systems may be used for entry into this study.  Some 
examples are included below.   
Scores considered as advanced fibrosis will be Metavir fibrosis 3, Knodell fibrosis score 
3, Modified Ishak fibrosis score 4, Batts & Ludwig score 3, or Scheuer score 3.  Subjects 
with these scores will be assigned to Group C. 
Scores considered as cirrhosis will be Metavir fibrosis 4, Knodell fibrosis score 4, 
Modified Ishak fibrosis score 5 and 6, Batts & Ludwig score 4, or Scheuer score 4.  
Subjects 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 
0. 
no fibrosis 
1. 
fibrous portal expansion 
3. 
bridging fibrosis (portal-portal or portal-central linkage) 
4. 
cirrhosis 
 
MODIFIED ISHAK FIBROSIS SCORE 
0. 
no fibrosis 
1. 
fibrous expansion of some portal areas, with or without short fibrous septa 
2. 
fibrous expansion of most portal areas, with or without short fibrous septa 
3. 
fibrous expansion of most portal areas, with occasional portal to portal 
(P-P) bridging 
4. 
fibrous expansion of portal areas, with marked bridging (P-P) as well as portal-
central (P-C) 
5. 
marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis) 
6. 
cirrhosis, probable or definite 
 


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Appendix 1 
 
Liver Biopsy Scores (cont.) 
 
BATTS & LUDWIG 
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 fibrotic portal tracts 
2. Periportal or portal -portal septa but intact architecture 
3. Fibrosis with architecture distortion but no cirrhosis 
4. Probable or definite cirrhosis 


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Appendix 2 
 
Child-Pugh Classification of Severity of Liver Disease 
 
Points Scored for Increasing Abnormality 
Clinical and Biochemical Measurements 
1 
2 
3 
Encephalopathy (grade) a 
None 
1 or 2 
3 or 4 
Ascites b 
Absent 
Slight 
Moderate 
Bilirubin (µmol/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, Burns, and Saunders (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 
 
 


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Appendix 3 
 
ICH Guidelines for Clinical Safety Data Management, Definitions 
and Standards for Expedited Reporting, Topic E2 
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect, or precaution.  It is any AE that at any dose fulfills at least 
one of the following criteria: 
– 
Is fatal (results in death) (Note:  Death is an outcome, not an event.) 
– 
Is life-threatening (Note: the term “life-threatening” refers to an event in which 
the subject was at immediate risk of death at the time of the event; it does not 
refer to an event which could hypothetically have caused a death had it been 
more severe.) 
– 
Requires in-patient hospitalization or prolongation of existing hospitalization 
– 
Results in persistent or significant disability/incapacity 
– 
Is a congenital anomaly/birth defect 
– 
Is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the Sponsor is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the subject or may require intervention to prevent one of the 
outcomes listed in the definitions above.  These situations should also usually be 
considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
An unexpected AE is one in which the nature or severity is not consistent with the 
applicable product information. 
Causality is initially assessed by the investigator.  For serious adverse events, possible 
causes of the event are indicated by selecting one or more options.  (Check all that 
apply.)  
• 
Pre-existing/underlying disease – specify  
• 
Study treatment – specify the drug(s) related to the event 
• 
Other treatment (concomitant or previous) – specify 
• 
Protocol-related procedure 
• 
Other (e.g., accident, new or intercurrent illness) – specify 
 


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Appendix 3 
 
ICH Guidelines for Clinical Safety Data Management, Definitions 
and Standards for Expedited Reporting, Topic E2 (cont.) 
 
The term severe is a measure of intensity, thus a severe AE is not necessarily serious.  
For example, nausea of several hours' duration may be rated as severe, but may not be 
clinically serious. 
A serious adverse event occurring during the study or that comes to the attention of the 
investigator within 15 days after stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, whether considered treatment-related or not, must be 
reported.  In addition, a serious adverse event that occurs after this time, if considered 
related to test “drug,” should be reported. 
Such preliminary reports will be followed by detailed descriptions later which will include 
copies of hospital case reports, autopsy reports and other documents when requested 
and applicable. 
For serious adverse events, the following must be assessed and recorded on the AEs 
eform of the eCRF: intensity, relationship to test substance, action taken, and outcome 
to date. 
The investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations. 
ROCHE LOCAL COUNTRY CONTACT for SAEs:  Local Monitor:  
See provided forms for details of study administrative and contact information, including 
the Local Monitor.  
Note:  The Study Monitor should be contacted for any routine and administrative queries such as 
patient eligibility queries. 
ROCHE HEADQUARTERS CONTACT for Medical Emergencies:   
Medical Monitor Contact Information 
Primary Contact 
Medical Monitor: 
, MD 
Telephone No.: 
Mobile Telephone No.: 
 


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Appendix 3 
 
ICH Guidelines for Clinical Safety Data Management, Definitions 
and Standards for Expedited Reporting, Topic E2 (cont.) 
 
Secondary Contact 
Medical Monitor: 
, MBChB Dip Pharm. Med 
Telephone No.: 
Mobile Telephone No.: 
 
 

SAP_001.pdf: 
 
Official Title: 
A Phase IIIb Parallel Group, Open Label Study of Pegylated 
Interferon alfa-2a Monotherapy (PEG-IFN, Ro 25-8310) Compared to 
Untreated Control in Children with HBeAg Positive Chronic Hepatitis 
B in the Immune Active Phase 
NCT Number: 
NCT01519960 
Document Date: 
SAP Version 1: 19-Feb-2016 
 
 


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Name
Reason for Signing
Date and Time
(UTC)
19-Feb-2016 06:51:55
STATISTICAL ANALYSIS PLAN APPROVAL 
 
 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE IIIB PARALLEL GROUP, OPEN LABEL STUDY OF 
PEGYLATED INTEFERON ALFA-2A MONOTHERAPY (PEG-
IFN, RO 25-8310) COMPARED TO UNTREATED CONTROL 
IN CHILDREN WITH HBeAg POSITIVE CHRONIC HEPATITIS 
B IN THE IMMUNE ACTIVE PHASE 
PROTOCOL NUMBER: 
YV25718 
STUDY DRUG: 
Pegylated Interferon alfa-2a 
VERSION NUMBER: 
1 
IND NUMBER: 
10144 
EUDRACT NUMBER: 
2011-002732-70 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
 
DATE FINAL: 
See electronic date stamp below. 
 
 


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TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 7 
2. 
STUDY DESIGN ........................................................................................... 7 
2.1 
Protocol Synopsis .................................................................... 9 
2.2 
Study Outcome Measures ....................................................... 9 
2.3 
Determination of Sample Size ................................................. 9 
2.4 
Analysis Timing ....................................................................... 9 
3. 
STUDY CONDUCT ..................................................................................... 10 
3.1 
Randomization Issues ........................................................... 10 
3.2 
Data Monitoring ..................................................................... 10 
4. 
STATISTICAL METHODS .......................................................................... 10 
4.1 
Analysis Populations ............................................................. 10 
4.1.1 
Intent-to-treat (ITT) Population .............................................. 11 
4.1.2 
Per Protocol (PP) Population ................................................. 11 
4.1.3 
Safety Population .................................................................. 12 
4.1.4 
Pharmacokinetic (PK) Population .......................................... 12 
4.2 
Analysis of Study Conduct ..................................................... 12 
4.3 
Baseline Characteristics ........................................................ 12 
4.3.1 
Demographics and Baseline Characteristics ......................... 12 
4.3.2 
Previous and Concomitant Diseases ..................................... 13 
4.3.3 
Previous and Concomitant Medications................................. 13 
4.4 
Efficacy Analysis .................................................................... 13 
4.4.1 
Primary Efficacy Endpoint ...................................................... 13 
4.4.1.1 
Definition of Primary Efficacy Endpoint ...................... 13 
4.4.1.2 
Hypothesis Testing and Analysis Methods ................. 14 
4.4.1.3 
Sensitivity Analysis for Primary Endpoints ................. 14 
4.4.2 
Secondary Efficacy Endpoints ............................................... 15 
4.4.3 
Subgroup Analyses ............................................................... 16 
4.4.4 
Exploratory Analysis .............................................................. 16 
4.4.5 
Liver Elasticity Sub-study....................................................... 17 
4.5 
Pharmacokinetic Analyses ..................................................... 17 


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4.6 
Safety Analyses ..................................................................... 17 
4.6.1 
Exposure of Study Medication ............................................... 17 
4.6.2 
Adverse Events ..................................................................... 18 
4.6.3 
Laboratory Data ..................................................................... 18 
4.6.4 
Vital Signs .............................................................................. 20 
4.6.5 
Growth ................................................................................... 20 
4.6.5.1 
Definitions .................................................................. 20 
4.6.5.2 
Summary of Growth Measurements........................... 20 
4.6.6 
Child Depression Inventory (CDI) .......................................... 21 
4.7 
Analyses of Group C ............................................................. 21 
4.8 
Analyses of Switch Arm ......................................................... 22 
4.9 
Interim Analyses .................................................................... 22 
5. 
REFERENCES ........................................................................................... 23 
 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments and ProceduresGroup A (PEG-
IFN) and Group C (Advanced Fibrotic PEG-IFN) ........................ 32 
Table 2 
Schedule of Assessments and ProceduresGroup B 
(Untreated Control) ..................................................................... 36 
Table 3 
Schedule of Assessments and ProceduresSwitch (PEG-
IFN) ............................................................................................. 40 
 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design ........................................................... 8 
Figure 2 
Potentially Clinically Relevant Laboratory Abnormalities for 
Neutrophil, Lymphocyte, Platelet Counts, Hemoglobin, 
Triglyceride Concentration and ALT ............................................ 19 
 
 
LIST OF APPENDICES 
Appendix 1 
 Protocol Synopsis ...................................................................... 24 
Appendix 2 
 Schedule of Assessments .......................................................... 31 
 
 


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GLOSSARY OF ABBREVIATIONS 
ACTG  
AIDS Clinical Trials Group 
AE  
Adverse event 
ALP  
Alkaline Phosphatase 
ALT  
Alanine aminotransferase 
anti-HBe  
Hepatitis B envelope antibody 
anti-HBs  
Hepatitis B surface antibody 
AST  
Aspartate aminotransferase 
AUC  
Area under the curve 
BMI  
Body mass index 
BSA  
Body surface area 
CHB  
Chronic hepatitis B 
CL/F  
Clearance 
Cmax  
Maximum concentration 
CSR  
Clinical Study Report 
DAIDS  
Division of AIDS 
DAP  
Data analysis plan 
DBP  
Diastolic blood pressure 
DNA  
Deoxyribonucleic acid 
DSMB  
Data Safety Monitoring Board 
FPE  
First patient enrollment 
FT3  
Free triiodothyronine 
FT4  
Free thyroxin 


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GGT  
Gamma glutamyl transpeptidase 
HBeAg  
Hepatitis B envelope antigen 
HBsAg  
hepatitis B surface antigen 
HBV  
hepatitis B virus 
HBV-DNA  
Hepatitis B DNA 
ITT  
Intent-to-treat 
IxRS  
Interactive voice or web response system 
LLN  
Lower limit of normal 
LOCF  
Last observation carried forward 
LSM  
Liver Stiffness Measure 
LTFU  
Long term follow-up 
MedDRA  
Medical Dictionary for Regulatory Activities 
PCR  
Polymerase chain reaction 
PD  
Pharmacodynamic 
PEG-IFN  
Pegylated-interferon alfa-2a 
PK  
Pharmacokinetic 
PT  
Preferred Term 
RNA  
ribonucleic acid 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SBP  
Systolic blood pressure 
SD  
Standard deviation 
SI units  
International System of Units 


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SOC  
System Organ Class 
TBG  
Thyroxine-binding globulin 
TPO  
Thyroid peroxidase 
TSH  
Thyroid-stimulating hormone 
ULN  
Upper limit of normal 
V/F  
Volume of distribution/bioavailability 


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1. 
BACKGROUND 
This randomized, controlled, parallel-group, open-label, multicenter study in children with 
hepatitis B envelope antigen (HBeAg) positive chronic hepatitis B (CHB) in the immune 
active phase will compare efficacy and safety between a group treated with pegylated 
interferon alfa-2a (PEG-IFN) monotherapy and an untreated control group, and evaluate 
pharmacokinetics (PK) of PEG-IFN following administration of a new body surface area 
(BSA)-based dosing regimen. 
The rationale for conducting a randomized controlled study in pediatric patients with 
CHB is to establish the efficacy and safety of PEG-IFN treatment in this pediatric 
immunoactive population. 
This statistical analysis plan (SAP, which is also known as Data Analysis Plan [DAP] 
Module 1) describes the data handling rules and statistical analysis methods to be used 
for the analysis of the clinical data from the phase IIIb study YV25718. The layout of 
tables, listings and figures will be provided in DAP Module 2; the data specification will 
be addressed in DAP Module 3.  
2. 
STUDY DESIGN 
This is a 2:1 randomized, controlled, parallel-group, open-label, multicenter study of 
PEG-IFN treatment compared to an untreated control (Figure 1).  Patients without 
advanced fibrosis/cirrhosis will be randomized 2:1 to PEG-IFN treatment (Group A) or 
untreated control (Group B), respectively.  Patients with advanced fibrosis will be 
assigned to PEG-IFN treatment (Group C).  Patients in Groups A and C will receive 
PEG-IFN for 48 weeks.  The first 48 weeks from randomization will be referred to as the 
treatment period for Groups A and C and the principal observation period (this is also the 
untreated control observation period in Figure 1) for Group B.  The primary endpoint will 
be assessed 24 weeks after the end of treatment/principal observation period. 
Forty-eight weeks after randomization, PEG-IFN will be offered to patients in the 
Group B untreated control group who have not experienced HBeAg seroconversion.  
This offer will be available for up to 1 year following Week 48.  If eligible, these patients 
will enter the Switch arm, where they will receive PEG-IFN for 48 weeks.  
The screening period will be up to 35 days.  All patients will be followed up for 5 years 
after the end of treatment/principal observation period.  For Group A, Group B 
non-switch, and Group C patients the study length is approximately 6 years (1-year 
treatment/principal observation period and 5 years of follow-up).  For Group B switch 
patients the study length is up to approximately 8 years (1-year principal observation 
period, up to 1 year follow-up whilst deciding whether to switch, 1-year switch treatment 
period, and 5-year follow-up period). 


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Figure 1 Schematic of Study Design1 
 
                                            
1 The untreated control observation period is the same as the principal observation period. 


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2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2. 
2.2 
STUDY OUTCOME MEASURES 
This study will compare efficacy and safety between a group treated with PEG-IFN 
monotherapy and an untreated control group, and evaluate pharmacokinetics (PK) of 
PEG-IFN following administration of a new BSA-based dosing regimen. 
Details of the study objectives could be found in the Protocol Synopsis as in Appendix 1. 
2.3 
DETERMINATION OF SAMPLE SIZE 
Sample size is based on the 
 test statistic. Assuming a 32% HBeAg seroconversion 
rate for Group A (PEG-IFN) and 10% for Group B (untreated control), a total sample size 
of 145 patients provides at least 80% power at the 0.05 level of significance with a two-
sided 
 test2. The sample size shall be increased by 10% and rounded to 160 patients 
to allow for advanced fibrotics (Group C). 
2.4 
ANALYSIS TIMING 
The clinical data cut for the primary analysis is determined based on the comparison of 
primary efficacy endpoint between Group A and Group B, i.e. 24 weeks after the end of 
treatment/principal observation period.  
The primary CSR will present the study results of efficacy, safety and pharmacokinetics 
on data up to the initial 24 weeks follow up after the end of treatment/principle 
observation period from Group A and B. Results from Group C from enrollment to 24 
weeks after the end of treatment will be summarized separately in the primary CSR. 
Data from the Switch arm will not be mature for reporting and interpreting, thus only a 
summary of patient disposition, patient listings for deaths, SAEs and AEs leading to 
discontinuation of study treatment as of the  cutoff date when all patients in Group A and 
Group B had their visits at 24 weeks after the end of treatment/principal observation 
periodwill be provided in the primary CSR. 
The final analysis will be performed at the end of the extended long-term follow-up 
(LTFU) period of the study, i.e. 5 years after the end of treatment/principal observation 
period for all patients (including patients who switched to PEG-IFN treatment from Group 
B). Long term efficacy and safety data from Group A, B, C, along with all data from the 
Switch arm will be summarized in the final CSR. 
                                            
2 At least 130 patients must be evaluable for the primary endpoint, as required by Pediatric 
Investigational Plan. 


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3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
After signing informed consent/assent and meeting screening parameters, patients 
without advanced fibrosis or cirrhosis (assessed by liver biopsy performed within 2 years 
prior to baseline) will be randomized 2:1 into the PEG-IFN treatment (Group A) or 
untreated control (Group B) respectively. Stratification will be performed by genotype (A 
versus non-A) and ALT (<5xULN versus ≥5xULN). Patients with advanced fibrosis 
(assessed by liver biopsy performed within 9 months prior to baseline) will be assigned 
to PEG-IFN treatment (Group C). Patients in Group A and Group C will receive PEG-IFN 
for 48 weeks. Group and dose, if applicable, will be assigned by an interactive voice or 
web response system (IxRS).  
The randomization list for the study was created by the IxRS vendor using their internal 
validated process. The study statistician reviewed a dummy randomization list that was 
created using the same validated process. 
3.2 
DATA MONITORING 
Starting from 8-10 months after first patient enrollment (FPE) and then approximately 
every 6 months thereafter, an external Data Safety Monitoring Board (DSMB) will review 
individual and aggregate safety data on a routine basis (see DSMB charter). Enrollment 
will be suspended and/or the study will be halted if serious concerns about safety are 
raised pending further analysis and review. Enrollment and/or study re-start will resume 
only if the DSMB and the Sponsor are satisfied with the safety of treatment. 
4. 
STATISTICAL METHODS 
All analyses for comparing the PEG-IFN treatment (Group A) with untreated control 
(Group B) are presented in Section 4.3 to Section 4.6. Analyses for Group C and the 
Switch arm will be presented in Section 4.7 and Section 4.8 respectively.   
4.1 
ANALYSIS POPULATIONS 
All patient populations will be defined and determined prior to the database lock for the 
primary CSR. All analyses below are planned for the primary CSR unless otherwise 
specified. Analyses for data in LTFU period will be summarized in final CSR. 
Analysis populations described in Section 4.1.1 to Section 4.1.3 are defined for Group A 
and Group B. Analysis of all efficacy endpoints will be based primarily on the Intent-to-
treat (ITT) population. In addition Per Protocol (PP) population will be used for the 
primary endpoint. Safety analyses will be performed based on the Safety population.  
Patients who have advanced fibrosis (diagnosed on liver biopsy) will receive PEG-INF 
treatment in an advanced fibrotic arm (Group C). Efficacy analyses and safety analyses 
will be reported from all patients in Group C who receive at least one dose of study 


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medication. 
The Switch arm includes patients randomized to Group B who opt to switch to initiating 
treatment with PEG-IFN after Week 48. Efficacy and safety data will be reported from all 
patients entering the switch arm if at least one dose of study medication was taken. 
4.1.1 
Intent-to-treat (ITT) Population 
For Group A, the ITT population shall include all patients who receive at least one dose 
of study medication. For the untreated Group B, the ITT population shall include all 
randomized patients. Patients will be assigned to the group to which they were 
randomized. 
4.1.2 
Per Protocol (PP) Population 
The per protocol population will include all patients randomized in Group A and Group B, 
who received at least one dose of study medication if in Group A, and who had none of 
the major protocol violations or deviations listed below. Patients will be assigned to the 
treatment group as per actual treatment they received. 
The criteria for exclusion from the PP populations are defined as: 
1. those in Group A who meet any of the criteria below, including: 
• 
received less than 39 doses of PEG-IFN or took ൑ 80% of treatment duration of 
PEG-IFN (i.e., less than 39 weeks of PEG-IFN treatment) 
2. those in Group A and Group B who meet the criteria below: 
• 
HBeAg negative at screening 
3. those in Group A and Group B who meet the criteria below: 
• 
ALT ൑ 1xULN or ALT > 10xULN at both screening and baseline 
4. those in Group A and Group B who meet the criteria below: 
• 
Who have had any of the treatment within 6 months prior to baseline or during 
study (Group A: up to 24 weeks after the end of treatment; Group B up to 24 
weeks after the end of principle observation period or prior to switch if switch 
occurs) as: interferons, lamivudine, tenofovir,emtricitabine, adefovir, entecavir, 
telbivudine 
5. those in Group A and Group B who meet the criteria below: 
• 
Neutrophil count < 1.5 x 109 cells/L at screening 


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6. those in Group A and Group B who meet the criteria below: 
• 
Platelet count < 90 x 109 cells/L at screening 
7. those in Group A and Group B who meet the criteria below: 
• 
Hemoglobin < lower limit of normal (LLN) at screening 
4.1.3 
Safety Population 
For Group A, the Safety population included all patients who received at least one dose 
of study medication and had at least one post-baseline safety assessment; for Group B, 
the safety population included all patients who had at least one post-baseline safety 
assessment. Patients will be assigned to treatment groups as treated.  
4.1.4 
Pharmacokinetic (PK) Population 
The pharmacokinetic evaluable population consists of all patients who are consented to 
PK sub-study and received PEG-IFN treatment, who have adequate PK collection over 
the first 24 weeks. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Reasons for exclusion from study populations  will be summarized by groups. Patients 
excluded from study populations will be listed. 
All major protocol violations will be listed and summarized by group. 
Number and percentage of patients completed 12, 24, 36 and 48 weeks of 
treatment/principal observation period, and 12, 24 weeks of follow-up will be 
summarized for Group A and Group B. 
The number of patients randomized to Group A who withdraw from treatment period, 
and the number of patients randomized to Group A and Group B who withdraw from 
study, will be separately summarized and presented; further the reasons for withdrawal 
will be included. Listing of withdrawal from study medication and withdrawal from study 
for all patients in Group A and Group B will be produced.  
Time windows will be defined in DAP Module 2. 
4.3 
BASELINE CHARACTERISTICS 
4.3.1 
Demographics and Baseline Characteristics 
Summary statistics will be presented for ITT population for the following demographics, 
including categorical variables: 
Sex, Age group (<5, 5 ~ 12, ൒12), Race, Ethnicity, Body surface area group, Country 
and continuous variables:  


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age, weight at baseline, height at baseline, Body Mass Index (BMI), body surface area, 
weight for age percentile, height for age percentile, weight for age z-score, height for age 
z-score. 
Summary statistics will be presented by ITT population for the baseline characteristics, 
including categorical factors:  
• 
ALT at Baseline (<1xULN,  ൒1xULN ~ <2xULN, ൒2xULN ~ <5xULN, ൒5xULN ~ 
<10xULN, ൒10xULN) 
• 
HBV genotype 
• 
Family history of HBV 
• 
Mode of HBV acquisition 
• 
Histological diagnosis for fibrosis 
• 
Scale or method used for fibrosis score 
• 
Fibrosis score 
and continuous factors:  
• 
HBV-DNA at Baseline 
• 
HBeAg at Baseline 
• 
HBsAg at Baseline 
• 
ALT at Baseline. 
4.3.2 
Previous and Concomitant Diseases 
All previous diseases and concomitant diseases will be summarized for ITT population. 
4.3.3 
Previous and Concomitant Medications 
All previous medications and concomitant medications will be summarized for ITT 
population.  
4.4 
EFFICACY ANALYSIS 
Analysis of all efficacy endpoints will be based primarily on the ITT population. In 
addition, the PP population will be used for the primary endpoint. 
Unless otherwise stated, all statistical tests will be two-sided and performed at the 5% of 
significance level. 
4.4.1 
Primary Efficacy Endpoint 
4.4.1.1 
Definition of Primary Efficacy Endpoint 
The primary efficacy endpoint is HBeAg seroconversion at 24 weeks after the end of 
treatment/ principal observation period for Group A and Group B. HBeAg seroconversion 


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is defined as absence of HBeAg (that is, a negative result for HBeAg) and presence of 
anti-HBe (that is, a positive result for anti-HBe).  
The response rate of HBeAg seroconversion for a particular analysis population will be 
determined by: 
T୦ୣ ୬୳୫ୠୣ୰ ୭୤ ୮ୟ୲୧ୣ୬୲ୱ ୵୧୲୦ Nୣ୥ୟ୲୧୴ୣ H୆ୣ୅୥ ୟ୬ୢ P୭ୱ୧୲୧୴ୣ H୆ୣ୅ୠ ୟ୲ ୣୟୡ୦ ୴୧ୱ୧୲
T୦ୣ ୬୳୫ୠୣ୰ ୭୤ ୮ୟ୲୧ୣ୬୲ୱ ୧୬ ୣୟୡ୦ ୥୰୭୳୮ ୤୭୰ ୲୦ୟ୲ ୟ୬ୟ୪yୱ୧ୱ ୮୭୮୳୪ୟ୲୧୭୬
× ͳͲͲ%. 
Patients without either HBeAg or anti-HBe at 24 weeks after the end of 
treatment/principal observation period will be counted as non-responders. Patients in 
Group B who switched to receive PEG-IFN after Week 48 and prior to 24 weeks post-
observation period will also be counted as non-responders. 
4.4.1.2 
Hypothesis Testing and Analysis Methods 
The following hypotheses will be tested using the Cochran-Mantel-Haenszel (CMH) test3 
stratified by genotype (A vs. non-A) and ALT (< 5xULN and ൒ 5xULN) at screening: 
H0: odds ratio of {probability to achieve HBeAg seroconversion in group A} versus 
{probability to achieve HBeAg seroconversion in group B} = 1 
against the alternative 
Ha: odds ratio of {probability to achieve HBeAg seroconversion in group A} versus 
{probability to achieve HBeAg seroconversion in group B} ≠ 1. 
The Cochran-Mantel-Haenszel estimates of the common odds ratio, adjusted by 
stratification factors (genotype (A vs. non-A) and ALT (< 5xULN and ൒ 5xULN)) , will be 
reported, accompanied by the associated 95% confidence intervals. Breslow-Day test 
will be used to assess the homogeneity of the odds ratios across the strata. The CMH 
test stratified by genotype (A vs. non-A) and ALT (< 5xULN and ൒ 5xULN) at screening 
will also be performed based on the PP population. 
4.4.1.3 
Sensitivity Analysis for Primary Endpoints 
In addition to the stratified statistical tests, unstratified tests such as Pearson chi-square 
test and Fisher’s exact test will be performed.  
In the primary efficacy analysis, patients with missing values of primary endpoint will be 
considered as non-responders. In order to evaluate the robustness, sensitivity analysis 
will be carried out using CMH test, where missing values will be imputed with the 
approach of last observation carried forward (LOCF). 
                                            
3 which is a superiority test. 


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4.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy analyses will be performed in the ITT population. No hierarchical 
or sequential testing will be used for secondary efficacy endpoints. 
Several secondary parameters will be assessed at the end of treatment/principal 
observation period, 24 weeks after the end of treatment/principal observation period in 
primary CSR; in addition, during the extended LTFU period, i.e. at 1, 2, 3, 4 and 5 years 
after the end of treatment/principal observation period in final CSR. 
Secondary efficacy endpoints include two types of endpoints: 
 
Binary endpoints: 
o HBeAg seroconversion (except HBeAg seroconversion at the time point of 24 
weeks at the end of treatment/principal observation period) 
o Loss of HBeAg 
o HBsAg seroconversion 
o Loss of HBsAg 
o Normal ALT (defined as ALT ൑ ULN, where each ULN is given by each 
laboratory) 
o Suppression of HBV-DNA: 
 
<20,000 IU/mL 
 
<2,000 IU/mL 
 
Undetectable (defined as <29 IU/mL as per TAQMAN-HBV QUANT  
polymerase chain reaction (PCR) assay) 
o Combined endpoints:  
 
HBeAg seroconversion and HBV-DNA <20,000 IU/ml 
 
HBeAg seroconversion and HBV-DNA <2,000 IU/mL 
 
Continuous endpoints: 
o Quantitative serum ALT value, and its change from baseline 
o Quantitative HBV-DNA value, and its change from baseline 
o Quantitative HBeAg value, and its change from baseline 
o Quantitative HBsAg value, and its change from baseline 
For all binary endpoints, missing values would be considered as non-responders. For all 
continuous endpoints, no imputation approach will be implemented to missing values. 


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Descriptive statistics of the secondary efficacy binary endpoints will be summarized by 
treatment group. P-values of these binary endpoints will be presented using Fisher’s 
exact test. 
Continuous endpoints will be descriptively summarized over time by treatment group. 
Graphs of continuous secondary endpoints and their corresponding 95% confidence 
intervals over time will be displayed by treatment group. 
4.4.3 
Subgroup Analyses 
Subgroup analyses will be conducted for the primary endpoint, i.e. HBeAg 
seroconversion at 24 weeks after the end of treatment/principal observation period in ITT 
population.  The follow baseline factors will be included in the subgroup analyses: 
• 
Age groups (<12, ൒12) 
• 
Age groups (<5, ൒5) 
• 
Baseline BSA groups 
• 
Race (Asian, Caucasian, Other) 
• 
Sex 
• 
BMI (<18.5, 18.5 ~ 24.9, >25.0) 
• 
HBV genotype (A, B, C, D, Other) 
• 
Baseline ALT (<5xULN, ൒5xULN) 
• 
Baseline log10(HBV-DNA) (൑median,  >median) 
• 
Baseline log10(HBeAg) (൑median,  >median) 
• 
Baseline log10(HBsAg) (൑median,  >median). 
4.4.4 
Exploratory Analysis 
Exploratory logistic regression analyses will be performed to examine the demographics 
and baseline disease characteristics on the response rate of HBeAg seroconversion at 
24 weeks after the end of treatment/principal observation period. Baseline factors 
including age, sex, race, BSA, BMI, HBV genotype, treatment group and ALT will be 
examined. Stepwise, backward and multiple logistic regression models will be explored. 


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4.4.5 
Liver Elasticity Sub-study 
Liver elasticity analysis in this section will be performed on those patients enrolled in 
liver elasticity sub-study4. Liver elasticity analysis results will be separately displayed for 
those patients enrolled in liver elasticity sub-study. 
Liver stiffness measure (LSM) and its change from baseline over time will be 
summarized by treatment group. Graphs of change from baselines of LSM and their 
corresponding 95% confidence intervals over time will be displayed by treatment group. 
Baseline LSM will be summarized by baseline characteristics subgroups, including 
fibrosis stages, age groups (<12, ൒12) and BMI (<18.5, 18.5 ~ 24.9, >25.0). Box plots 
of baseline LSM will be displayed by various baseline characteristics subgroups above. 
Baseline liver elasticity will also be explored for association with the screening liver 
biopsy result in these sub-study patients using liver biopsy fibrosis score, using 
Spearman’s correlation coefficients. Confidence intervals of correlation coefficients will 
be provided as needed. 
4.5 
PHARMACOKINETIC ANALYSES 
PK parameters (e.g., clearance [CL/F], volume of distribution [V/F], area under the curve 
[AUC], maximum concentration [Cmax], etc.) of PEG-IFN will be estimated using a 
population PK modeling approach. 
All PK parameters will be presented descriptively including arithmetic means, standard 
deviations, geometric means, coefficients of variation, medians, and ranges. 
The relationship between clinical endpoints and PEG-IFN serum exposure may be 
explored. 
The relationship between PK and pharmacodynamics (PD) parameters (e.g., AUC vs. 
neutropenia) may be explored. 
Detailed PK and PK/PD results will be separately planned and presented in a separate 
population PK analysis report. 
4.6 
SAFETY ANALYSES 
Safety analyses will be performed based on the Safety population. 
4.6.1 
Exposure of Study Medication 
The duration of study drug administration, actual cumulative dose and percentage of 
actual cumulative dose in planned cumulative dose will be summarized for Group A. A 
patient listing of study drug administration by center/patient number for Safety 
Population of Group A will be provided.   
                                            
4 At least 50 consenting/assenting patients at specific sites will take part in the liver elasticity sub-
study. 


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4.6.2 
Adverse Events 
All adverse events (AEs) will be coded according to the latest Medical Dictionary for 
Regulatory Activities (MedDRA) version during the study and will be classified by 
Preferred Term (PT) and System Organ Class (SOC). In primary CSR, AEs from study 
beginning to 24 weeks after the end of treatment/principal observation period will be 
reported.  
AE summaries will be generated as what follows: 
• 
All AEs by SOC and PT; 
• 
All AEs by intensity5; 
• 
AEs by relation to treatment; 
• 
Most frequent AEs with an incidence rate of at least 5% in decreasing order; 
• 
Serious adverse events (SAEs); 
• 
Non-serious AEs of special interests, including: ALT or AST > 3 x baseline value in 
combination with total bilirubin > 2 x ULN;  ALT or AST > 3 x baseline value in 
combination with clinical jaundice; Suspected transmission of an infectious agent by 
the study drug 
• 
AEs and lab abnormalities leading to dose modification (Group A);  
• 
AEs and lab abnormalities leading to withdrawal from the study treatment. 
Listings of all reported AEs, SAEs, non-serious AEs of special interests, death, AEs and 
lab abnormalities leading to dose modification, and AEs and lab abnormalities leading to 
withdrawal from the study treatment, will be provided. 
All AEs by SOC and PT will be summarized for age subgroups (<12, ൒12), and age 
subgroups (<5, ൒5), 
4.6.3 
Laboratory Data 
If more than one visit occurred during a single visit window, then the laboratory data 
closest to the scheduled visit day will be used. If the two laboratory assessments were 
equidistant from the scheduled visit day then the later assessment will be used; if there 
was more than one ‘later assessment’, that is recorded on the same date and time, then 
the ‘worst’ case will be used. The exception is the data within the Baseline visit; in this 
case, if two or more samples were collected on the day that was closest to the Baseline 
                                            
5 The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events should be used to assist in the assessment of intensity 


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target day, then the earliest sample was selected; if the sample collection time was the 
same then the worst value was selected. 
Laboratory data not reported in International System of Units (SI units) will be converted 
to SI units before further processing. The reference ranges of each investigator/local 
laboratory will be used for all parameters.  
Listings of laboratory parameters at each visit will be provided by treatment group for 
Safety population. Summary tables of mean change from baseline of laboratory 
parameters will be provided (some laboratory parameters will be summarised as 
multiples of ULN instead of raw values: ALT, AST, alkaline phosphatase (ALP), total 
bilirubin, gamma glutamyl transpeptidase (GGT)).  
Lowest and/or highest values of laboratory data post-baseline will be summarized by 
treatment group using the DAIDS grading system (except for those laboratory 
parameters with project-specific grandings provided in Figure 2). Shift table of the lowest 
and/or highest post-baseline DAIDS grade for laboratory parameters will be provided 
(except for those laboratory parameters with project-specific grandings provided). 
Patients with one or more thyroid function values outside the normal range and with 
change from baseline meeting pre-specified cutoffs (for free triiodothyronine [FT3] and 
free thyroxin [FT4], it is increase >=20% or decrease >=20%; for thyroid-stimulating 
hormone [TSH], it is increase >=30%) will be summarized and listed by treatment group 
in Safety Population. 
Figure 2 Potentially Clinically Relevant Laboratory Abnormalities for 
Neutrophil, Lymphocyte, Platelet Counts, Hemoglobin, 
Triglyceride Concentration and ALT 
 


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Patients with ALT flares (including ALT elevations over 10xULN, ALT elevations larger 
than 5xULN and less than 10xULN) will be summarized by treatment group based on 
Safety population. 
ALT and neutropenia will be summarized respectively by age subgroups (<12, ൒12), and 
age subgroups (<5, ൒5). 
AEs under infections and infestations for patients with ACTG grade 3-4 lymphopenia or 
neutropenia will be listed. 
4.6.4 
Vital Signs 
A summary table and a patient listing of the following vital signs parameters will be 
provided for Safety Population: 
 
Systolic blood pressure (SBP) 
 
Diastolic blood pressure (DBP) 
 
Heart rate 
 
Temperature. 
A summary table of vital sign abnormalities will be provided by treatment group in Safety 
Population. 
4.6.5 
Growth 
The continuous growth will be analyzed through the analyses of weight and height for 
patients in Safety Population. Growth (height) velocity will be explored. In primary CSR, 
growths from study beginning to 24 weeks after the end of treatment/principal 
observation period will be reported. 
4.6.5.1 
Definitions 
The primary endpoints for assessing treatment effects on growth are actual values at 
visit and their changes from baseline in (1) height (weight, BMI) for age percentile; (2) 
height (weight, BMI) for age z-score. 
For the current analysis, the gender-specific Centers for Disease Control and Prevention 
(CDC) Growth Charts for 2000 (Kuczmarski et al. 2000) will be used as reference to 
calculate the height (weight, BMI) for age percentile and height (weight, BMI) for age z-
score.  
4.6.5.2 
Summary of Growth Measurements 
All growth variables will be listed by treatment group and center/patient number in Safety 
Population, including raw height (weight, BMI) measurements at each visit, height 
(weight, BMI) for age z-scores and height (weight, BMI) for age percentiles (actual value 
and change from baseline). 
Descriptive summaries of the z-scores and percentiles for height, weight and BMI for 
age (actual value and change from baseline) for patients in Safety Population will be 
presented by visit. 


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Patients with height (weight, BMI) for age percentile drop (൒15%) from baseline will be 
summarized and listed by treatment group in Safety Population. 
Plots of the mean (and 95% CI) of z-score and percentile for height, weight and BMI for 
age by treatment group in Safety Population will be depicted from the study baseline to 
24 weeks after the end of treatment/principal observation period. 
Plots of the mean change from the baseline (and 95% CI) of z-score and percentile for 
height, weight and BMI for age by treatment group in Safety Population will be depicted 
from the study baseline to 24 weeks after the end of treatment/principal observation 
period. 
Individual change from baseline plots of z-score and percentile for height, weight and 
BMI for age by group will be depicted. 
4.6.6 
Child Depression Inventory (CDI) 
Child Depression Inventory (CDI) is a questionnaire that has been validated for children 
ages 7-17 years old to assess a range of depressive symptoms (Kovacs 1992). In 
primary CSR, CDI scores from study beginning to 24 weeks after the end of 
treatment/principal observation period will be reported. 
A list of patients, with a CDI raw score >19 (with or without an AE of depression) will be 
provided for Safety Population. 
The total T-scores are standardized scores with a mean of 50 and a standard deviation 
of 10 derived from a normative samples of 1226 Florida public school students (see CDI 
manual in [Kovacs 1992] for more details). 
The total T-score at each visit, and its change from baseline to week 12, 24, 36, 48 
during treatment/principal observation period and at week 4 of initial follow-up, will be 
summarized for Safety Population.  
4.7 
ANALYSES OF GROUP C 
Efficacy analyses and safety analyses from enrollment to 24 weeks after the end of 
treatment will be reported from all patients in Group C who receive at least one dose of 
study medication.  
The patient major PVs, patient disposition, and patient discontinuation for Group C will 
be summarized. 
Demographics and baseline characteristics, previous and concurrent disease, previous 
and concomitant Hepatitis B treatment for Group C will be summarized. 
The primary efficacy endpoint and all secondary efficacy endpoints will be descriptively 
summarized for Group C. Continuous secondary efficacy endpoints will be summarized 
over time. Graphs of continuous secondary endpoints and their corresponding 95% 
confidence intervals over time will be displayed.  


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All the safety analyses for Group C will be conducted similarly as the safety analyses 
performed as described in Section 4.6.  
4.8 
ANALYSES OF SWITCH ARM 
By the clinical cutoff for the primary CSR (24 weeks after the end of treatment period 
(Group A) or principal observation period (Group B)), very few patients in Switch arm 
would have completed their 24 week follow-up period after completion of treatment. 
Hence, only listings of deaths, SAEs, and AEs leading to discontinuation of study 
treatment will be presented in the primary CSR. All the other efficacy and safety data for 
Switch arm will be summarized and reported in the final CSR.  
4.9 
INTERIM ANALYSES 
No interim efficacy analyses are planned. 
 


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5. 
REFERENCES 
Kovacs M. Children’s Depression Inventory Manual. North Tonawanda NY: Multi-Health 
Systems; 1992. 
Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United 
States. Advance data from vital and health statistics; No. 314. Hyattsville, Maryland: 
National Center for Health Statistics; 2000. 


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Appendix 1  
Protocol Synopsis 
SYNOPSIS OF PROTOCOL YV25718, VERSION E 
 
TITLE 
A Phase IIIb Parallel Group, Open Label Study of Pegylated 
Interferon alfa-2a Monotherapy (PEG-IFN, Ro 25-8310) 
Compared to Untreated Control in Children with HBeAg Positive 
Chronic Hepatitis B in the Immune Active Phase 
SPONSOR 
Hoffmann-La Roche  
CLINICAL PHASE 
IIIb 
INDICATION 
Treatment of HBeAg positive chronic hepatitis B (CHB) in children. 
OBJECTIVES  
 
To compare efficacy and safety between a group treated with 
Pegylated-Interferon Alfa-2a (PEG-IFN) monotherapy and an 
untreated control group in HBeAg positive children with CHB 
virus infection in the immune active phase.  
 
To evaluate the pharmacokinetics of PEG-IFN following 
administration of a new BSA-based dosing regimen in HBeAg 
positive PEG-IFN treated children with CHB virus infection. 
 
TRIAL DESIGN 
 
A 2:1 randomized, controlled, parallel group, open label, 
multicenter study of PEG-IFN treatment (Group A) compared 
to an untreated control (Group B).  
 
Subjects without advanced fibrosis and without cirrhosis 
(assessed by liver biopsy) will be randomized 2:1 to PEG-IFN 
treatment (Group A) or untreated control (Group B) 
respectively.  That is for every 2 subjects randomized to 
PEG-IFN only 1 will be randomized to the untreated control.  
Subjects in Group A will receive PEG-IFN for 48 weeks.   
 
Subjects with advanced fibrosis (assessed by liver biopsy) 
will be assigned to PEG-IFN treatment (Group C: Advanced 
Fibrotic arm).  Subjects in Group C will receive PEG-IFN for 
48 weeks.   
 
The first 48 weeks from randomization will be referred to as 
the treatment period for Group A and Group C and the 
principal observation period for Group B. 
 
Forty-eight weeks after randomization, PEG-IFN will be 
offered to subjects in the Group B untreated control group 
who have not experienced HBeAg seroconversion.  This offer 
will be available for up to one year following Week 48.  If 
eligible, these subjects will enter the Switch arm and receive 
PEG-IFN for 48 weeks.  
 
All subjects will be followed up for 5 years after the end of 
treatment/principal observation period.  
 
Liver elastography will be performed in at least 50 subjects as 
a site specific sub-study. 
 
NUMBER OF SUBJECTS 
N = 160 


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TARGET POPULATION 
 
Children aged 3 to  18 years of age with CHB, HBeAgve, 
HBsAgve, detectable HBV DNA ( 10,000 copies/mL 
[ 2,000 IU/mL]) by PCR and ALT >ULN but   10  ULN 
(using the reference range of the testing laboratory). 
 
Liver biopsy needs to have been performed within 2 years 
prior to baseline, or within 9 months prior to baseline for 
subjects with advanced fibrosis.  Subjects with advanced 
fibrosis will be assigned to PEG-IFN treatment (Group C), and 
those without advanced fibrosis or cirrhosis will be 
randomized.  Cirrhotic subjects will be excluded from 
the study.   
 
Subjects co-infected with HCV, HDV, HIV or who have 
received therapy for hepatitis B in the prior 6 months or who 
have de-compensated liver disease will be excluded. 
 
LOCATION (Regions)  
Americas, Europe, Asia-Pacific. 
LENGTH OF STUDY  
 
For Group A, Group B non-switch and Group C subjects the 
study length is 6 years (1 year treatment/principal observation 
period, 5 years follow-up). 
 
For Group B switch subjects the study length is up to 8 years 
(1 year principal observation period, up to 1 year follow-up 
whilst deciding whether to switch, 1 year treatment period, 5-
year follow-up period). 
 
END OF STUDY 
 
Primary endpoint is assessed 24 weeks after the end of 
treatment/principal observation period, with a further 
4.5 years of follow- up. 
 
End of study is last subject last visit.  
 
INVESTIGATIONAL MEDICAL 
PRODUCT(S) 
DOSE/ ROUTE/ REGIMEN 
PEG-IFN for 48 weeks subcutaneously once weekly with dosing 
based on the following 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 
 
NON-INVESTIGATIONAL MEDICAL 
PRODUCT(S) 
N/A 
COMPARATOR “DRUG” (or 
STANDARD OF CARE) 
DOSE/ ROUTE/ REGIMEN 
N/A (Untreated control) 
ASSESSMENTS OF: 
 
- 
EFFICACY 
Primary:  
HBeAg seroconversion (loss of HBeAg and presence of anti-HBe) 
at 24 weeks post-end of treatment/principal observation period. 
Secondary:  
 
Loss of HBeAg, HBsAg seroconversion (loss of HBsAg and 
presence of anti-HBs), loss of HBsAg, quantitative serum 
ALT, proportion of normal ALT, quantitative HBV DNA, 
suppression of HBV DNA  100,000 copies/mL 
( 20,000 IU/mL), 10,000 copies/mL ( 2,000 IU/mL), 
undetectable and change from baseline, combined endpoint 
of HBeAg seroconversion and HBV 
DNA  100,000 copies/mL (  20,000 IU/mL), and combined 
endpoint of HBeAg seroconversion and HBV 
DNA   10,000 copies/mL (  2,000 IU/mL) at the end of 
treatment/principal observation period, at 24 weeks after end 
of treatment/principal observation period, and at 1, 2, 3, 4 and 
5 years after end of treatment/principal observation period. 


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Statistical Analysis Plan YV25718 
26 
 
Persistence of HBeAg seroconversion (loss of HBeAg and 
presence of anti-HBe) at the end of treatment/principal 
observation period, and at 1, 2, 3, 4 and 5 years after end of 
treatment/principal observation period. 
 
Descriptive change from baseline in liver elasticity (in liver 
elasticity site specific sub-study subjects) at end of 
treatment/principle observation period, and at 24 weeks and 
2 years after end of treatment/principal observation period. 
 
- 
SAFETY 
Safety during the treatment/principal observation period and initial 
24 weeks of follow-up: 
 
Serious and non-serious AEs (including neurological and 
psychiatric events, and non-serious AEs of special 
interest, and monitoring with neuro-psychiatric questionnaire 
for PEG-IFN treated subjects). 
 
Laboratory test results (including thyroid function). 
 
Vital signs. 
 
Growth: weight and height. 
 
Safety during the 4.5 year extended, long-term follow up period: 
 
All persisting AEs initially reported prior to follow-up Week 24 
(including neuro-psychiatric events). 
 
New-onset serious AEs (including neuro-psychiatric events) 
and non-serious AEs of special interest related to 
PEG-IFN. 
 
Deaths 
 
Thyroid function. 
 
Growth: weight and height. 
 
- 
PHARMACOKINETICS/
 
PHARMACODYNAMICS  
 
Site-specific sub-study 
 
Blood samples will be collected in PEG-IFN treated subjects 
to evaluate the pharmacokinetics of PEG-IFN following 
administration of a new BSA-based dosing regimen.  
 
 
Samples should be collected during weeks 1 and 24 at pre-
dose (0 hour) and 24-48, 72-96, and 168 hours post-dose.  
Additional pre-dose samples should be collected at weeks 4, 
8 and 12 within 6 hours prior to administration. 
 
- 
EXPLORATORY  
 
BIOMARKERS 
Optional Roche Clinical Repository (RCR) samples, including 
plasma and whole blood RNA and whole blood DNA (baseline 
only), will be taken from consenting/assenting subjects at 
Baseline, Weeks 12, 24 and 48, 24 weeks after end of 
treatment/principal observation period, and at 1, 2, 3, 4 and 5 
years after end of treatment/principal observation period.  These 
specimens will be used for research purposes, for example to help 
to better understand the pharmacogenetics, pathogenesis, course 
and outcome of CHB and related diseases, and identify dynamic 
biomarkers that are predictive of response to PEG-IFN treatment 
(in terms of dose, safety and tolerability).  These specimen(s) may 
be stored for up to 15 years after the end of Study YV25718. 
INTERIM ANALYSES AND 
STOPPING RULES  
 
Individual subject treatment with PEG-IFN must be discontinued in 
the event of any of the following: 
 
Severe hypersensitivity reactions (e.g., anaphylaxis, 
angioedema, bronchoconstriction) 
 
 
 
Severe depression  
 
Absolute neutrophil count <0.25  109 cells/L or febrile 
neutropenia 
 
Platelets   25  109 cells/L  
 
 


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27 
 
Discontinuation of individual patient treatment with Pegasys  
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 
 
  
A DSMB will review safety data on a routine basis (as per DSMB 
charter).  Enrollment will be suspended and/or the study will be 
halted if serious concerns about safety are raised pending further 
analysis and review.  Enrollment and/or study re-start will resume 
only if the DSMB and the sponsor are satisfied with the safety of 
treatment. 
 
PROCEDURES (Summary):   
After signing informed consent/assent and meeting screening parameters, subjects 
without advanced fibrosis and without cirrhosis (assessed by liver biopsy performed 
within 2 years prior to baseline) will be randomized 2:1 into the PEG-IFN treatment 
(Group A) or untreated control (Group B) respectively.  Stratification will be performed by 
genotype (A versus non-A) and ALT (< and 5   ULN).  Subjects with advanced fibrosis 
(assessed by liver biopsy performed within 9 months prior to baseline) will be assigned 
to PEG-IFN treatment (Group C).  Subjects in Group A and Group C will receive 
PEG-IFN for 48 weeks. 
Subjects treated with PEG-IFN (Group A and Group C) will be seen for evaluation at 
Weeks 1, 2, 4, 8, 12 and then every 6 weeks during the treatment period, and during the 
initial 24 weeks of follow-up at follow-up Weeks 4, 12, and 24.  
Subjects in the untreated arm (Group B) will be seen for evaluation at 12 weekly 
intervals during the principal 48-week observation period and during the initial 24 weeks 
of the follow-up period.   
For consenting/assenting subjects in the site specific liver elasticity sub-study, liver 
elastography will be performed at baseline, end of treatment/principal observation period, 
follow-up Week 24, and follow-up Year 2.   


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28 
Forty-eight weeks after randomization, PEG-IFN will be offered to subjects in the 
Group B untreated control group who have not experienced HBeAg seroconversion.  
This offer will be available for up to 1 year following 48 weeks from randomization.  If 
eligible, these subjects will enter the Switch arm, where they will start the Switch 
schedule of assessments and receive PEG-IFN for 48 weeks. 
For consenting/assenting subjects in the site specific PK sub-study, additional visits will 
also be required for PK blood sampling.  When adequate PK data have been collected 
over the first 24 weeks for at least 15 PEG-IFN-treated subjects, ideally with 
representation from all BSA categories, exposure will be analyzed and if necessary an 
adjustment will be made to the dosing regimen.  Once PK data up to Week 24/switch 
Week 24 are available for at least 5 to 10 subjects in each BSA category, subject PK 
sampling will be stopped.  However, the sub-study may be stopped even if data from a 
minimum of 5 subjects in each BSA category are not obtained in the case of excessively 
long recruitment times. 
Those subjects that do not complete the treatment period should still return for all follow-
up visits.  As well as evaluation during the initial 24 weeks post-end of 
treatment/principal observation period, all subjects will be followed up annually for 5 
years after the end of treatment/principal observation period.  Safety assessments at 
these extended long-term follow-up visits will include evaluation of persisting AEs which 
were initially reported prior to follow-up Week 24, assessment of new-onset SAEs 
(including neuro-psychiatric events) and non-serious AEs of special interest related to 
PEG-IFN, deaths, thyroid function, and growth (weight and height). 
Standard measures will be taken in this study to minimize the pediatric subjects’ possible 
pain and distress. 
STATISTICAL ANALYSES 
Sample Size 
Sample size is based on the 2 test statistic.  Assuming a 32% HBeAg seroconversion 
rate for Group A (PEG-IFN) and 10% for Group B (untreated control), a total sample size 
of 145 subjects provides at least 80% power at the 0.05 level of significance with a 
two-sided 2 test.  The sample size shall be increased by 10% and rounded to 
160 subjects to allow for advanced fibrotics (Group C) and withdrawals.   
Populations 
ITT population:  For Group A, the ITT population shall include all subjects who receive at 
least one dose of study drug.  For the untreated Group B the ITT population shall include 
all subjects with at least the baseline efficacy or safety data.  For the ITT population 
subjects will be analyzed according to the groups to which they were randomized.  


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Protocol YV25718     Report Number 1068022
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Statistical Analysis Plan YV25718 
29 
Subjects in Group B who switched to receive PEG-IFN after Week 48 and prior to 
24 weeks post-observation period will be counted as non-responders. 
Switch Population:  The switch population shall be those subjects randomized to 
Group B who opt to switch to initiating treatment with PEG-IFN after Week 48.   
Group C: Subjects who have advanced fibrosis (diagnosed on liver biopsy) will receive 
PEG-IFN in an advanced fibrotic arm (Group C).  
Efficacy 
 
The primary efficacy analysis will compare efficacy in Group A with Group B.  
Subjects with missing values will be considered as non-responders.  The efficacy 
data of Group A and Group B will be qualitatively evaluated alongside subjects in 
Group C and the Switch arm. 
 
The primary analysis of the response rate variables will be with the Cochran-Mantel-
Haenszel test (2) stratified by genotype (A versus non-A) and ALT (< and 
5    ULN).  Fisher’s exact test will be used as a secondary analysis.  The response 
rates for HBeAg seroconversion will be analyzed at the end of the initial 24-week 
follow-up period.  
 
Several secondary analyses are planned, including descriptive statistics of 
secondary endpoints, and exploratory p-values between Group A and Group B. 
 
Safety 
 
The primary safety analysis will compare safety in Group A with Group B.  
The safety data of Group A and Group B will be qualitatively evaluated alongside 
subjects in Group C and the Switch arm. 
 
Adverse events: AEs will be assigned preferred terms and categorized into body 
systems according to the Medical Dictionary for Regulatory Activities (MedDRA) 
classification of the World Health Organization (WHO) terminology.  Descriptive 
statistics will be used to summarize safety parameters by group.  Neurological and 
psychiatric AEs will be assessed in further detail, including persistence and duration, 
as well as new onset of SAEs and non-serious AEs of special interest related to 
PEG-IFN reported during the extended long-term follow-up period of this study. 
 
Laboratory Safety Data: The laboratory data will be analyzed according to Roche’s 
“International Guideline for the Handling and Reporting of Laboratory Data”. 
 
Growth (weight and height): The continuous growth will be analyzed with residual 
maximum likelihood, or analysis of covariance.  The assumptions of the analysis 
such as normally distributed residuals will be assessed.  If necessary rectifying 
transformations shall be applied.  Growth (height) velocity will be explored. 
 
Pharmacokinetic 


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Protocol YV25718     Report Number 1068022
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Statistical Analysis Plan YV25718 
30 
 
PK parameters (e.g., CL/F V/F, AUC, Cmax, etc,) of PEG-IFN will be estimated using 
non-compartmental analysis and/or a population PK modeling approach.  All PK 
parameters will be presented descriptively including arithmetic means, standard 
deviations, geometric means, coefficient of variation, medians, and ranges. 
 
The relationship between clinical endpoints and PEG-IFN serum exposure may be 
explored.  
The relationship between pharmacokinetic and pharmacodynamic parameters may be 
explored.


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Protocol YV25718     Report Number 1068022
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Statistical Analysis Plan YV25718 
31 
Appendix 2  
Schedule of Assessments 
 
 


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Protocol YV25718     Report Number 1068022
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Statistical Analysis Plan YV25718 
32 
Table 1 
Schedule of Assessments and ProceduresGroup A (PEG-IFN) and Group C (Advanced Fibrotic 
PEG-IFN) 
Assessment/Procedure 
Screen 
(days) 
BL 
(days) 
Treatment Period  
(weeks) 
Initial 24 Weeks of 
Follow-Up  
(Weeks Post-End of 
Treatment) 
Extended Long-Term  
Follow-Up Period 
(Years Post-End of  
Treatment Period) 
35 to 1 
1 
1 
2 
4 
8 
12 18 24 30 36 42 48 a 
4 a 
12 a 
24 a 
1 a 
1.5 a, b 
2 a 
3 a 
4 a 
5 a 
Informed Consent/Assent c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete medical history, including family 
history of HBV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
Symptom-directed physical examination 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
Vital signs  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Weight d 
x 
x f 
x 
x 
x 
x 
x f 
x 
xf 
x 
x f 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
Height d, e 
x 
x f 
 
 
 
 
x f 
 
xf 
 
x f 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
Parental height g  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ultrasound h, j 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology exam i, j 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
a 
Or upon and following study treatment withdrawal. 
b 
By telephone. 
c 
Informed Consent obtained from legal guardian, and assent obtained from child if appropriate.  
d 
Measurements must be taken using the same instruments in the same individual. 
e 
Using stadiometer and taking the mean of three readings. 
f 
Weight and height to be provided to IXRS. 
g 
From consenting biological parents. 
h 
To rule out hepatocellular carcinoma.  Further liver imaging assessment may be performed if necessary.  
i 
By ophthalmologist and including fundoscopic examination, visual acuity assessment, visual field testing, and color visual testing.  Any subject who 
develops ocular symptoms should receive a prompt eye examination by an ophthalmologist and additional examinations as necessary. 
j 
Within 6 months prior to baseline; repeat only if any change in the subject’s medical condition.  
 
 


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Protocol YV25718     Report Number 1068022
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Statistical Analysis Plan YV25718 
33 
Table 1 
Schedule of Assessments and ProceduresGroup A (PEG-IFN) and Group C (Advanced Fibrotic 
PEG-IFN) (cont.) 
Assessment/Procedure 
Screen 
(days) 
BL 
(days) 
Treatment Period  
(weeks) 
Initial 24 Weeks 
of Follow-Up  
(Week Post-End 
of Treatment) 
Extended Long-Term  
Follow-Up Period 
(Year Post-End of  
Treatment Period) 
35 to 1 
1 
1 2 
4 
8 12 18 24 30 36 42 48 a 4 a 
12 a 
24 a 
1 a 1.5 a, b 2 a 3 a 
4 a 
5 a 
Urine or serum HCG pregnancy 
test (selected subjects) c, d 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
 
Alfa-fetoprotein e,h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-HAV IgM, anti-HCV, 
anti-HIV, anti-HDV h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV genotypeh 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ceruloplasmin, A1AT, AMA, 
ASMA, ALKM1 h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-nuclear antibody (ANA) h 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Hematology  f, i  
x 
x 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
 
Chemistry f, i 
x 
x 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
 
Urinalysis d, f, g 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
 
a 
Or upon and following study treatment withdrawal. 
b 
By telephone. 
c 
For females of childbearing potential, a pregnancy test will be performed within 24 hours prior to baseline, and at any time secondary amenorrhea of more than 
1 week occurs.  Result of baseline pregnancy test must be available prior to randomization and commencement of treatment. 
d 
To be performed by local laboratory. 
e 
Subjects need to have serum alfa-fetoprotein assessed during the screening period to rule out hepatocellular carcinoma. 
f 
If there are clinically significant laboratory abnormalities, repeat no less frequently than every 2 weeks or as clinically indicated, with appropriate toxicity 
management, until they return to normal or baseline values.   
g 
Urinalysis to be performed via dipstick, with subsequent microscopic evaluation if positive for blood at the discretion of the investigator. 
h 
Parameter does not need to be repeated at re-screening if performed within 6 months prior to baseline, unless dictated by a change in the 
subject’s medical condition or the parameter accounted for the original screen failure. 
i 
To be performed by a local laboratory in countries activated prior to April 2013, and by a central laboratory in countries activated after April 
2013. 


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Protocol YV25718     Report Number 1068022
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Pegylated Interferon alfa-2a—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan YV25718 
34 
Table 1 
Schedule of Assessments and ProceduresGroup A (PEG-IFN) and Group C (Advanced Fibrotic 
PEG-IFN) (cont.) 
Assessment/Procedure 
Screen 
(days) 
BL 
(days) 
Treatment Period  
(weeks) 
Initial 24 Weeks of 
Follow-Up  
(Week Post-End 
of Treatment) 
Extended Long-Term  
Follow-Up Period 
Year Post-End of  
Treatment Period) 
35 to 1 
1 
1 
2 4 8 12 18 24 30 36 42 48 a 4 a 
12 a 
24 a 
1 a 1.5 a,b 2 a 
3 a 
4 a 
5 a 
FΤ3, FΤ4, TSH c 
xl 
 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
TBG 
xl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TPO antibodies 
xl 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Population PK d 
 
x 
x 
 
x x 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBeAg, anti-HBe e 
xl 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
HBV DNA e  
xl 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
HBsAg, anti-HBs e 
xl 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
Quantitative HBsAg and HBeAg e 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
 
x 
 
 
 
 
 
 
Serum bank f 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
RCR plasma & RNA specimen 
 
x 
 
 
 
 
x 
 
x 
 
 
 
x 
 
 
x 
x 
 
x 
x 
x 
x 
RCR DNA specimen 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
x 
x 
x 
x x 
x x x 
x x 
x 
x 
x 
x 
x 
x g 
x g 
x g 
x g 
x g 
x g 
Concomitant medications 
(including for CHB h) 
x 
x 
x 
x 
x x 
x x x 
x x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Concomitant medications for 
CHB only h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Subject study drug diary 
 
 
x 
x 
x x 
x x x 
x x 
x 
x 
 
 
 
 
 
 
 
 
 
Dispense study drug 
 
x 
 
 
x x 
x x x 
x x 
x 
 
 
 
 
 
 
 
 
 
 
Compliance 
 
 
x 
x 
x x 
x x x 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Neuro-Psychiatric Questionnaire i 
x 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
x 
 
 
 
 
 
 
 
 
Liver biopsy 
x j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver elastography k 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
a 
Or upon and following study treatment withdrawal. 
b 
By telephone. 
c 
If there are clinically significant laboratory abnormalities, repeat no less frequently than every 2 weeks or as clinically indicated, with appropriate toxicity 
management, until they return to normal or baseline values. 


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Protocol YV25718     Report Number 1068022
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Statistical Analysis Plan YV25718 
35 
Table 1 
Schedule of Assessments and ProceduresGroup A (PEG-IFN) and Group C (Advanced Fibrotic 
PEG-IFN) (cont.) 
d 
Specific sites.  Blood samples should be collected for PK analysis during Weeks 1 and 24 at pre-dose (0 hour) and 2448, 7296, and 168 hours post-dose.  
Additional pre-dose samples should be collected at Weeks 4, 8, and 12 within 6 hours prior to PEG-IFN administration.  The time of PEG-IFN administration on 
PK sampling days must be recorded on the eCRF. 
e 
Frozen for central processing.   
f 
Sample to be retained frozen at site in the event that any tests need to be repeated.  From RCR-consenting subjects, they also may be used for exploratory HBV 
biomarker analyses (DNA and/or non-DNA).  Sample to be retained frozen at site in the event that any tests need to be repeated. 
g 
During the 5-year follow-up period, only persistent AEs initially reported prior to follow-up Week 24, new-onset SAEs, non-serious AEs of special interest 
related to PEG-IFN, and deaths will be collected. 
h 
Concomitant medications for CHB include licensed or investigational immunomodulatory or antiviral therapy, and herbal, botanical and other agents 
(e.g., ursodeoxycholic acid) that are traditionally used for chronic HBV disease.  
i 
Not required for children  7 years of age. 
j 
Within 2 years prior to baseline or within 9 months prior to baseline for subjects with advanced fibrosis. 
k 
Subjects in site-specific liver elasticity sub-study only.  
l 
Parameter does not need to be repeated at re-screening if performed within 6 months prior to baseline, unless dictated by a  change in the 
subject’s medical condition or the parameter accounted for the original screen failure.  


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Protocol YV25718     Report Number 1068022
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Statistical Analysis Plan YV25718 
36 
Table 2 
Schedule of Assessments and ProceduresGroup B (Untreated Control) 
Assessment/Procedure 
Screen 
(days) 
BL 
(days) 
Principal 
Observation Period  
(weeks) 
Initial 24 Weeks of  
Follow-up (Week 
Post-End of Principal 
Observation Period) 
Extended Long-Term Follow-Up Period 
(Year Post-End of Principal  
Observation Period) 
35 to 
1 
1 
12 
24 
36 48 a 
12a 
24 a 
1 a 
1.5 b 
2 
3 
4 
5 
Informed Consent/Assent c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete medical history, including family 
history of HBV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
Symptom-directed physical examination 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
Vital signs  
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Weight d 
x 
x f 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
Height d, e 
x 
x f 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
Parental height g 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Ultrasound h,i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology exam i, j 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
Eligible subjects may switch at any time between Week 48 and 1 year following Week 48 at which time subjects will continue on the Switch Schedule of 
Assessments and Procedures. 
b 
By telephone. 
c 
Informed Consent obtained from legal guardian, and assent obtained from child if appropriate.  
d 
Measurements must be taken using the same instruments in the same individual.  
e 
Using stadiometer and taking the mean of three readings. 
f 
Weight and height to be provided to IXRS. 
g 
From consenting biological parents. 
h 
To rule out hepatocellular carcinoma.  Further liver imaging assessment may be performed if necessary. 
i 
Within 6 months prior to baseline; repeat only if any change in medical condition.  
j 
By ophthalmologist and including fundoscopic examination, visual acuity assessment, visual field testing, and color visual testing.  Any subject who 
develops ocular symptoms should receive a prompt eye examination by an ophthalmologist and additional examinations as necessary. 


Clinical Study Report: peginterferon alfa-2a - F. Hoffmann-La Roche Ltd
Protocol YV25718     Report Number 1068022
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Pegylated Interferon alfa-2a—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan YV25718 
37 
Table 2 
Schedule of Assessments and ProceduresGroup B (Untreated Control) (cont.)  
Assessment/Procedure 
Screen 
(days) 
BL 
(days) 
Principal 
Observation 
Period  
(weeks) 
Initial 24 Weeks of  
Follow-up  
(Week Post-End of 
Principal Observation 
Period) 
Extended Long-Term Follow-Up Period 
(Year Post-End of Principal  
Observation Period) 
35 to 
1 
1 
12 
24 
36 48 a 
12a 
24 a 
1 a 
1.5 b 
2 
3 
4 
5 
Urine or serum HCG pregnancy test 
(selected subjects) c, d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alfa-fetoprotein e, h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-HAV IgM, anti-HCV, anti-HIV, and 
anti-HDV h  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV genotype h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ceruloplasmin, A1AT, AMA, ANA, ASMA, 
ALKM1 h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology f,i  
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
 
Chemistry f,i 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
 
Urinalysis d, f, g 
x 
x 
 
 
 
x 
 
x 
 
 
 
 
 
 
FΤ3, FΤ4, TSH f, h 
x 
 
 
 
 
x 
 
x 
x 
 
x 
x 
x 
x 
TPO antibodies, TBG h 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
Eligible subjects may switch at any time between Week 48 and 1 year following Week 48 at which time subjects will continue on the Switch Schedule of 
Assessments and Procedures. 
b 
By telephone. 
c 
For females of childbearing potential, a pregnancy test will be performed within 24 hours prior to baseline, and at any time secondary amenorrhea of more than 1 
week occurs. Result of baseline pregnancy test must be available prior to randomization and commencement of treatment. 
d 
To be performed by local laboratory. 
e 
Subjects need to have serum alfa-fetoprotein assessed during the screening period to rule out hepatocellular carcinoma. 
f 
If there are clinically significant laboratory abnormalities, repeat no less frequently than every 2 weeks or as clinically indicated, with appropriate toxicity 
management, until they return to normal or baseline values.   
g 
Urinalysis to be performed via dipstick, with subsequent microscopic evaluation if positive for blood at the discretion of the investigator. 
h 
Parameter does not need to be repeated at re-screening if performed within 6 months prior to baseline, unless dictated by a change in the 
subject’s medical condition or the parameter accounted for the original screen failure.  
i 
To be performed by a local laboratory in countries activated prior to April 2013, and by a central laboratory in countries ac tivated after April 
2013. 


Clinical Study Report: peginterferon alfa-2a - F. Hoffmann-La Roche Ltd
Protocol YV25718     Report Number 1068022
3555
Pegylated Interferon alfa-2a—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan YV25718 
38 
Table 2 
Schedule of Assessments and ProceduresGroup B (Untreated Control) (cont.)  
Assessment/Procedure 
Screen 
(days) 
BL 
(days) 
Principal 
Observation Period  
(weeks) 
Initial 24 Weeks of  
Follow-Up  
(Week Post-End of 
Principal 
Observation 
Period) 
Extended Long-Term Follow-Up Period 
(Year Post-End of Principal  
Observation Period) 
35 to 1 
1 
12 
24 
36 48 a 
12 a 
24 a 
1 a 
1.5 b 
2 
3 
4 
5 
HBeAg, anti-HBe c 
x j 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
HBV-DNA c 
x j 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
HBsAg, anti-HBs c 
x j 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
Quantitative HBsAg and HBeAg c, j 
 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
 
Serum bank d 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
RCR plasma and RNA specimen 
 
x 
x 
x 
 
x 
 
x 
x 
 
x 
x 
x 
x 
RCR-DNA specimen 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x e 
x e 
x e 
x e 
x e 
x e 
Concomitant medications (including for  
CHB f) 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Concomitant medications for CHB only f 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Compliance 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Neuro-Psychiatric Questionnaire g 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Liver biopsy  
x h 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver elastography i 
 
x 
 
 
 
x 
 
x 
 
 
x 
 
 
 
a 
Eligible subjects may switch at any time between Week 48 and 1 year following Week 48 at which time subjects will continue on the Switch Schedule of 
Assessments and Procedures. 
b 
By telephone. 
c 
Frozen for central processing.   
d 
Sample to be retained frozen at site in the event that any tests need to be repeated.  From RCR-consenting subjects, they also may be used for exploratory HBV 
biomarker analyses (DNA and/or non-DNA). 
e 
During the 5-year follow-up period, only persistent AEs initially reported prior to follow-up Week 24 and deaths. 
f 
Concomitant medications for CHB include licensed or investigational immunomodulatory or antiviral therapy, and herbal, botanical and other agents 
(e.g., ursodeoxycholic acid) that are traditionally used for chronic HBV disease.  


Clinical Study Report: peginterferon alfa-2a - F. Hoffmann-La Roche Ltd
Protocol YV25718     Report Number 1068022
3556
Pegylated Interferon alfa-2a—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan YV25718 
39 
Table 2 
Schedule of Assessments and ProceduresGroup B (Untreated Control) (cont.)  
g 
Not required for children   7 years of age. 
h 
Within 2 years prior to baseline or within 9 months prior to baseline for subjects with advanced fibrosis. 
i 
Subjects in site-specific liver elasticity sub-study only.   
j 
Parameter does not need to be repeated at re-screening if performed within 6 months prior to baseline, unless dictated by a change in the 
subject’s medical condition or the parameter accounted for the original screen failure.  


Clinical Study Report: peginterferon alfa-2a - F. Hoffmann-La Roche Ltd
Protocol YV25718     Report Number 1068022
3557
Pegylated Interferon alfa-2a—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan YV25718 
40 
Table 3 
Schedule of Assessments and ProceduresSwitch (PEG-IFN) 
Assessment/Procedure 
Switch 
BL a 
Treatment Period  
(weeks) 
Initial 24 Weeks of  
Follow-Up  
(Week Post-End of 
Treatment Period) 
Extended Long-Term Follow-Up 
Period (Year Post-End of  
Treatment Period) 
 
SW 
1 
SW 
2 
SW 
4 
SW 
8 SW 
12 
SW 
18 
SW 
24 
SW 
30 
SW 
36 
SW 
42 
SW 
48 b 
SW  
4 b 
SW  
12 b 
SW  
24 b 
SW 
1 b 
SW 
1.5 b, c SW 
2 b 
SW 
3 b 
SW 
4 b 
SW 
5 b 
Physical examination 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
Vital signs  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Weight d 
x f 
x 
x 
x 
x x f x x f x x f x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
Height d, e 
x f 
 
 
 
 
x f 
 
x f 
 
x f 
 
x 
 
x 
x 
x 
 
x 
x 
x 
x 
Ophthalmology exam g 
xj 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
Urine or serum HCG pregnancy test 
(selected subjects) h, i 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Anti-HAV IgM, anti-HCV, anti-HIV, 
and anti-HDV j  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANA 
xj 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
a 
Switch baseline will take place at the time of the final visit of the pre-switch schedule.  Results from all switch baseline assessments must be available and 
subjects must meet all switch criteria prior to commencing PEG-IFN. 
b 
Or upon and following study treatment withdrawal. 
c 
By telephone. 
d 
Measurements must be taken using the same instruments in the same individual. 
e 
Using stadiometer and taking the mean of three readings. 
f 
Weight and height to be provided to IXRS. 
g 
By ophthalmologist and including fundoscopic examination, visual acuity assessment, visual field testing, and color visual testing.  Any subject who 
develops ocular symptoms should receive a prompt eye examination by an ophthalmologist and additional examinations as necessary. 
h 
For females of childbearing potential, a pregnancy test will be performed within 24 hours prior to switch baseline, and at any time secondary amenorrhea of 
more than 1 week occurs. Result of baseline pregnancy test must be available prior to randomization and commencement of treatment. 
i 
To be performed by local laboratory. 
j 
Parameter does not need to be repeated at switch baseline if performed within 6 months prior to switch baseline, unless dicta ted by a change 
in the subject’s medical condition. 


Clinical Study Report: peginterferon alfa-2a - F. Hoffmann-La Roche Ltd
Protocol YV25718     Report Number 1068022
3558
Pegylated Interferon alfa-2a—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan YV25718 
41 
Table 3 
Schedule of Assessments and ProceduresSwitch (PEG-IFN) (cont.)  
Assessment/Procedure 
Switch 
BL a 
Treatment Period  
(weeks) 
Initial 24 Weeks of  
Follow-Up  
(Week Post-End of 
Treatment Period) 
Extended Long-Term Follow-up 
Period (Year Post-End of  
Treatment Period) 
SW 
1 
SW 
2 
SW 
4 
SW 
8 SW 
12 
SW 
18 
SW 
24 
SW 
30 
SW 
36 
SW 
42 
SW 
48 b 
SW  
4 b 
SW 
12 b 
SW 
24b 
SW 
1 b 
SW 
1.5 b,c SW 
2 b 
SW 
3 b 
SW 
4 b 
SW 
5 b 
Hematology d,j  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Chemistry d,j 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Urinalysis d, e, f 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
FΤ3, FΤ4, TSH d 
xi 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
 
x 
x 
x 
TPO antibodies 
xi 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
TBG 
xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Population PK g 
x 
x 
 
x 
x 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBeAg, anti-HBe h 
xi 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
 
x 
x 
x 
HBV-DNA h  
xi 
 
 
 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
HBsAg, anti-HBs h 
xi 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
 
x 
x 
x 
a 
Switch baseline will take place at the time of the final visit of the pre-switch schedule.  Results from all switch baseline assessments must be available and 
subjects must meet all switch criteria prior to commencing PEG-IFN. 
b 
Or upon and following study treatment withdrawal. 
c 
By telephone. 
d 
If there are clinically significant laboratory abnormalities, repeat no less frequently than every 2 weeks or as clinically indicated, with appropriate toxicity 
management, until they return to normal or baseline values.   
e 
Urinalysis to be performed via dipstick, with subsequent microscopic evaluation if positive for blood at the discretion of the investigator. 
f 
To be performed by local laboratory. 
g 
Specific sites.  Blood samples should be collected for PK analysis during switch Weeks 1 and 24 at pre-dose (0 hour) and 2448, 7296, and 168 hours post-
dose.  Additional pre-dose samples should be collected at switch Weeks 4, 8 and 12 within 6 hours prior to PEG-IFN administration.  The time of PEG-IFN 
administration on PK sampling days must be recorded on the eCRF. 
h 
Frozen for central processing.   
i 
Parameter does not need to be repeated at switch baseline if performed within 6 months prior to switch baseline, unless dicta ted by a change 
in the subject’s medical condition. 
j 
To be performed by a local laboratory in countries activated prior to April 2013, and by a central laboratory in countries activate d after April 
2013. 


Clinical Study Report: peginterferon alfa-2a - F. Hoffmann-La Roche Ltd
Protocol YV25718     Report Number 1068022
3559
Pegylated Interferon alfa-2a—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan YV25718 
42 
Table 3 
Schedule of Assessments and ProceduresSwitch (PEG-IFN) (cont.)  
Assessment/Procedure 
Switch 
BLa 
Treatment Period  
(weeks) 
Initial 24 Weeks of 
Follow-Up 
(Weeks Post-End 
of Treatment 
Period) 
Extended Long-Term Follow-up 
Period 
(Year Post-End of Treatment Period) 
 
SW 
1 
SW 
2 
SW 
4 
SW 
8 SW 
12 
SW 
18 
SW 
24 
SW 
30 
SW 
36 
SW 
42 
SW 
48 b 
SW  
4 b 
SW  
12 b 
SW  
24 b 
SW  
1 b 
SW 
1.5 b,c SW 
2 b 
SW 
3 b 
SW 
4 b 
SW 
5 b 
Quantitative HBsAg and HBeAg d 
xk 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
 
x 
 
 
 
 
 
 
Serum bank e 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
 
x 
x 
x 
x 
RCR plasma and RNA specimen 
x 
 
 
 
 
x 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xf 
xf 
xf 
xf 
xf 
xf 
Concomitant medications (including for 
CHB g) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Concomitant medications for CHB only 
g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
Subject study drug diary 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Dispense study drug 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
Compliance 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Neuro-Psychiatric Questionnaire h 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
x 
 
 
 
 
 
 
 
 
Liver biopsy i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ultrasound i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver elastography j 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
a 
Switch baseline will take place at the time of the final visit of the pre-switch schedule.  Results from all switch baseline assessments must be available and 
subjects must meet all switch criteria prior to commencing PEG-IFN. 
b 
Or upon and following study treatment withdrawal. 
c 
By telephone. 
d 
Frozen for central processing.   
e 
Sample to be retained frozen at site in the event that any tests need to be repeated.  From RCR-consenting subjects, they also may be used for exploratory HBV 
biomarker analyses (DNA and/or non-DNA). 
f 
During the 5-year follow-up period, only persistent AEs initially reported prior to follow-up Week 24, new-onset SAEs, non-serious AEs of special interest 
related to PEG-IFN, and deaths will be collected. 


Clinical Study Report: peginterferon alfa-2a - F. Hoffmann-La Roche Ltd
Protocol YV25718     Report Number 1068022
3560
Pegylated Interferon alfa-2a—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan YV25718 
43 
Table 3 
Schedule of Assessments and ProceduresSwitch (PEG-IFN) (cont.)  
g 
Concomitant medications for CHB include licensed or investigational immunomodulatory or antiviral therapy, ursodeoxycholic acid, and herbal, botanical and 
other agents (e.g., ursodeoxycholic acid) that are traditionally used for chronic HBV disease. 
h 
Not required for children  7 years of age. 
i 
Either a liver biopsy performed within 2 years prior to switch baseline to exclude c irrhosis, OR clinical, laboratory, and ultrasound data within 6 
months prior to switch baseline which together exclude cirrhosis. 
j 
Subjects in site-specific liver elasticity sub-study only. 
k 
Parameter does not need to be repeated at switch baseline if performed within 6 months prior to switch baseline, unless dictated by a change 
in the subject’s medical condition.